WO2019045006A1 - Morphinan derivative - Google Patents

Abstract

A morphinan derivative represented by general formula (I) (in the formula, R1 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, or the like, R2 and R3 are the same or different and represent a hydrogen atom, a hydroxy group, or the like, R4 represents a hydrogen atom, a halogen atom, a hydroxy group, or the like, R5 represents a hydrogen atom, hydroxy group, or the like, R6 represents a hydrogen atom, a C1-6 alkyl group, or the like, R7 and R8 are the same or different and represent a hydrogen atom, a C1-6 alkyl group, or the like, R9 represents a hydrogen atom, a C1-6 alkyl group, an optionally substituted C6-10 aryl group, or the like, X represents a nitrogen atom or the like, Y represents an oxygen atom or the like, and n represents an integer of 0-3), a tautomer, a stereoisomer, a deuterium substitution product, or a pharmaceutically acceptable salt of the compound or a solvate of these, and a medicine, an analgesic, and an antipruritic having these as an active ingredient.

Description

Morphinan derivatives

The present invention relates to morphinan derivatives having an opioid kappa receptor agonist activity.

Three types of opioid receptors are known: μ, δ, κ. Morphine, which has a strong affinity for the mu receptor, has long been used as an analgesic. However, opioid mu receptor agonists are known to cause adverse events such as dependence formation, respiratory depression and the like through mu receptors.
On the other hand, κ receptor agonists also exhibit analgesia but are known not to be involved in the adverse events observed with morphine.
On the other hand, κ receptor agonists are generally known to exhibit sedative or drug aversion effects. The only κ receptor agonist that isolates drug aversion is Nalfurafine (Patent Document 1), but because nalfurafine exhibits sedation at analgesic doses, it has been approved as an anti-diarrhea, but as an analgesic Approval has not been received. That is, there is still no opioid kappa receptor selective agonist approved as an analgesic.
Therefore, κ receptor selective agonists that do not exhibit sedative or drug aversive effects are expected to be excellent therapeutics or amelioration or prevention of diseases and conditions related to opioid κ receptors including analgesics.
Patent Document 2 includes the following formula (A),

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

The compound represented by is reported. It is described that this compound has opioid κ receptor selective binding and analgesic activity. However, their analgesic activity was not satisfactory.
Furthermore, these derivatives do not disclose the effects desired as drugs, such as the effect when actually administered and the stability in vivo. If the compound is unstable in vivo, the development as a pharmaceutical product becomes difficult due to the lack of expected medicinal effects and the influence on the living body of degradation products, etc. It becomes an important requirement.
Also, Non-Patent Document 1 includes the following formula (C),

There is disclosed a very high activity morphinan derivative represented by However, there is a problem that this compound is not enough in metabolic stability.
Therefore, among the marketed analgesics, there is still no drug having high opioid kappa receptor agonist activity.
Therefore, in aiming at an analgesic, a compound that exhibits high activity and selectivity for the opioid kappa receptor, is isolated from sedation, and is excellent in metabolic stability is desired.

International Publication No. 1993/5081 Pamphlet JP, 2008-179554, A Patent No. 2525552

An object of the present invention is to provide a medicine effective for treating or ameliorating or preventing various diseases and symptoms related to the opioid 受 容 receptor, in which the sedative action and the drug aversion effect are suppressed.

Under these circumstances, the present inventors conducted extensive studies and found that certain morphinan derivatives have high opioid kappa receptor selectivity and potent agonist activity for opioid kappa receptors and are highly stable in vivo. It has been found that it has a property, and the present invention has been completed.
(1) That is, the present invention relates to the following general formula (I):

(Wherein, R ¹ represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _3-6 cycloalkyl C _1-6 alkyl group which may have a substituent, a substituent Represents an acyl group which may have an amino protecting group,
Whether R ² and R ³ are the same or different and hydrogen atom, hydroxy group, C _1-6 alkoxy group which may have a substituent, halogen atom or R ² and R ³ together represent a carbonyl group R ² and R ³ combine to represent a cyclic ketal,
R ⁴ is a hydrogen atom, a halogen atom, a hydroxy group, a C _1-6 alkoxy group which may have a substituent, an amino group, a C _1-6 alkylamino group, a di C _1-6 alkylamino group, a cyano group , A carbamoyl group, a C _1-6 alkyl carbamoyl group, a di C _1-6 alkyl carbamoyl group,
R ⁵ represents a hydrogen atom, a hydroxy group, or a C _1-6 alkoxy group which may have a substituent,
R ⁶ represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a hydroxy group, a C _1-6 alkoxy group which may have a substituent,
R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or R ⁷ and R ⁸ on the same carbon are bonded to have a substituent good C _3-6 saturated hydrocarbon ring optionally either show a good saturated heterocyclic ring optionally having a substituent, substituents bonded to R ⁷ each other on different carbons when n is 2 or 3 And a C _3-6 saturated hydrocarbon ring which may have one or more substituents, and a saturated heterocyclic ring which may have one or more substituents,
R ⁹ 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, a C _2-4 alkenyl group, C _2-4 An alkynyl group, a C _1-6 alkoxy group which may have a substituent, a hydroxy group, a C _6-10 aryl group which may have a substituent (provided that R ¹ is cyclopropylmethyl, R ² and When R ³ is a hydrogen atom, R ⁴ and R ⁵ are a hydroxy group, R ⁶ is a hydrogen atom, C _1-6 alkyl group, R ⁷ and R ⁸ are a hydrogen atom, R ⁹ is a phenyl group, and n is 0 to 2 A heteroaryl group which may have a substituent, a cyclic amino group which may have a substituent, or a saturated complex which R ⁶ and R ⁹ may be bonded to have a substituent Indicates an unsaturated heterocyclic ring which may have a ring or a substituent,
X represents a nitrogen atom or N-oxide,
Y represents an oxygen atom or a sulfur atom,
n represents an integer of 0 to 3. )
And a tautomer, stereoisomer, deuterium substitution product or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(2) The present invention also relates to the morphinan derivative according to the above (1), wherein R ⁴ and R ⁵ are a hydroxy group and / or a C _1-6 alkoxy group, a tautomer, stereoisomer or deuterium of the compound The present invention relates to a substitution product or a pharmaceutically acceptable salt thereof or a solvate thereof.
(3) The present invention also relates to the morphinan derivative according to the above (1) or (2), wherein R ⁴ and R ⁵ are a hydroxy group, a tautomer, stereoisomer, deuterium substitution product of the compound or a pharmaceutical thereof And salts thereof.
(4) In the present invention, the morphinan derivative according to any one of the above (1) to (3), wherein R ² and R ³ are hydrogen atoms, a tautomer, stereoisomer, deuterium substitution product of the compound or a pharmaceutical thereof And salts thereof.
(5) In the present invention, the morphinan derivative according to any one of the above (1) to (4), wherein R ⁶ is a C _1-6 alkyl group which may have a substituent, a tautomer of the compound, or a steric The present invention relates to an isomer, deuterium substitution product or a pharmaceutically acceptable salt thereof or a solvate thereof.
(6) In the present invention, the morphinan derivative according to any one of the above (1) to (5), wherein n is 1, a tautomer, stereoisomer, deuterium substitution product or pharmaceutically acceptable form of the compound It relates to a salt or a solvate thereof.
(7) Further, the present invention provides the morphinan derivative according to any one of the above (1) to (6), wherein R ⁷ and R ⁸ are hydrogen atoms, a tautomer, stereoisomer, deuterium substitution product of the compound or a pharmaceutical thereof And salts thereof.
(8) In the present invention, the R ⁹ is a C _6-10 aryl group which may have a substituent or a heteroaryl group which may have a substituent. And a tautomer, stereoisomer, deuterium substitution product or a pharmaceutically acceptable salt of the compound, or a solvate thereof.
(9) Further, the present invention provides the morphinan derivative according to any one of the above (1) to (8), wherein the optionally substituted C _6-10 aryl group according to the above (8) is a phenyl group, The present invention relates to tautomers, stereoisomers, deuterium substitution products or pharmaceutically acceptable salts thereof or solvates thereof.
(10) In the present invention, the heteroaryl group which may have a substituent according to (8) is a pyridyl group, a pyrimidyl group, a pyridadyl group, a pyrazyl group or an oxodihydropyridyl group. (8) The morphinan derivative according to (8), a tautomer, stereoisomer, deuterium substitution product or pharmaceutically acceptable salt of the compound, or a solvate thereof.
(11) The present invention also relates to the morphinan derivative according to any one of the above (1) to (10), wherein Y is an oxygen atom, a tautomer, stereoisomer, deuterium substitution product or pharmaceutically acceptable thereof. Salts or solvates thereof.
(12) In the present invention, R ¹ is a C _1-6 alkyl group which may have a substituent or a C _3-6 cycloalkyl C _1-6 alkyl group which may have a substituent The present invention relates to a morphinan derivative according to the above (1) to (11), a tautomer, stereoisomer, deuterium substitution product or a pharmaceutically acceptable salt of the compound or a solvate thereof.
(13) The present invention also relates to the morphinan derivative according to any one of the above (1) to (12), wherein X is a nitrogen atom, a tautomer, stereoisomer, deuterium substitution product or pharmaceutically acceptable thereof. Salts or solvates thereof.
(14) Further, according to the present invention, the morphinan derivative according to any one of the above (1) to (13), a tautomer, stereoisomer, deuterium substitution product or pharmaceutically acceptable salt thereof of the compound or the same The present invention relates to a pharmaceutical composition comprising as an active ingredient a solvate of
(15) The present invention also relates to the medicament according to the above (14), which is an agent for treating, ameliorating or preventing a disease associated with an opioid κ receptor.
(16) The present invention also relates to the medicament according to the above (14) or (15), which is an analgesic.
(17) The present invention also relates to the medicament according to the above (14) or (15), which is an antipruritic.

The invention will now be described in more detail.
Among the morphinan derivatives represented by the above general formula (I), tautomers, stereoisomers, deuterium substitution products or pharmaceutically acceptable salts thereof of the compounds, or solvates thereof, preferably The ones of
Examples of the C _1-6 alkyl group in the C _1-6 alkyl group which may have a substituent represented by R ¹ , R ⁶ , R ⁷ , R ⁸ and R ⁹ include a methyl group, an ethyl group and a propyl group And isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group and hexyl group, preferably methyl group, ethyl group and propyl group, and more preferably methyl group.

The _{C 3-6} cycloalkyl represented by _{C 3-6} cycloalkyl and ^{R 9} in which may have a substituent _{C 3-6} cycloalkyl _{C 1-6} alkyl group represented by R ^1, a cyclopropyl And cyclobutyl, cyclopentyl and cyclohexyl, preferably cyclopropyl and cyclobutyl, more preferably cyclopropyl.
As the C _1-6 alkyl group in an optionally substituted C _3-6 be cycloalkyl C _1-6 alkyl group represented by R ¹ are the same as those described above, preferably a methyl group And an ethyl group and a propyl group are mentioned, More preferably, it is a methyl group.

The acyl group which may have a substituent represented by R ¹ is, for example, C _1-6 alkylcarbonyl group such as formyl group, acetyl group, propionyl group, etc., C such as cyclopropyl carbonyl group, cyclobutyl carbonyl group _{And 3-6} cycloalkylcarbonyl groups and benzoyl and the like arylcarbonyl groups.

Examples of the C _2-4 alkenyl group represented by R ⁹ include vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group and the like.

Examples of the C _2-4 alkynyl group represented by R ⁹ include ethynyl group and propargyl group.

Examples of the amino protecting group represented by R ¹ include alkyl protecting groups (allyl group, dimethoxymethyl group, diethoxymethyl group, tert-butyl group, triphenylmethyl group, benzyl group, 4-methoxybenzyl group, etc.), aryl Protecting group (2-pyridyl group, 4-pyridyl group, 2-pyrazyl group, 2-pyrimidyl group, 2-triazyl group, etc.), and protecting group of catechate group (methoxycarbonyl group, ethoxycarbonyl group, tert- Butoxycarbonyl group, tert-amyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group P-phenylazobenzyloxycarbonyl group p-methoxy Cyphenylazobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, p-biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, 2- (trimethylsilyl) Ethoxycarbonyl group, 9-fluorenylmethyloxycarbonyl group etc.) Other protective groups such as alkylsulfonyl group such as methanesulfonyl group, arylsulfonyl group such as p-toluenesulfonyl group, alkylacyl group such as acetyl group And arylacyl groups such as benzoyl group can be used.

_{C 1-6} alkylamino group represented by R ^4, _{di-C 1-6} alkylamino _group, a _{C 1-6} alkyl group in the _{C 1-6} alkylcarbamoyl group and a _{di-C 1-6} alkylcarbamoyl group, the a The same thing is mentioned.

A C _1-6 alkyl group which may have a substituent represented by R ¹ , a C _3-6 cycloalkyl C _1-6 alkyl group which may have a substituent and a substituent As a substituent in the good acyl group, a C _1-6 alkyl group such as methyl group, ethyl group or propyl group (as a substituent, a halogen atom such as hydroxy group, carbamoyl group, C _1-6 alkoxy group or fluorine atom) And halogen atoms such as fluorine atom and chlorine atom, hydroxy group, carboxy group, amino group, cyano group and the like.
In addition, a substituent in the C _3-6 cycloalkyl C _1-6 alkyl group may be present in either or both of C _3-6 cycloalkyl and C _1-6 alkyl.
Such C _3-6 hydroxyalkyl group as a substituent on the cycloalkyl, carboxy group, more preferably a carboxy group. The substituent on C _1-6 alkyl is preferably a hydroxy group or a fluorine atom.

As a C _1-6 alkoxy group in the C _1-6 alkoxy group which may have a substituent represented by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁹ , a methoxy group, an ethoxy group And a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group and the like, and preferably a methoxy group.

As a substituent in the C _1-6 alkoxy group which may have a substituent represented by R ⁴ and R ⁵ , a halogen atom such as a fluorine atom or a chlorine atom can be mentioned, with preference given to a fluorine atom. Specifically, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and the like can be mentioned.

The halogen atom represented by R ^2, R ³ and R ^4, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably fluorine atom, chlorine atom, or more preferably fluorine atom.

Examples of the _optionally substituted C _3-6 saturated hydrocarbon ring formed by combining R ⁷ and R ⁸ include cyclopropane, cyclobutane, cyclopentane and cyclohexane.

As a substituent in the C _3-6 saturated hydrocarbon ring which may have a substituent formed by bonding of R ⁷ and R ⁸ , C _1-6 alkyl such as methyl group, ethyl group, propyl group and the like C _1-6 alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group and butoxy group, halogen atom such as fluorine atom and chlorine atom, hydroxy group, carboxy group, nitro group, cyano group, amino group , C _1-6 alkylamino group, di C _1-6 alkylamino group, formyl group and the like.

Examples of the optionally substituted saturated heterocycle formed by combining R ⁷ and R ⁸ include a 3- to 8-membered saturated heterocycle, preferably a 4- to 6-membered saturated heterocycle. There is a ring. Examples of these heterocyclic rings include cyclic amino groups such as aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine, and cyclic ether groups such as epoxide, oxetane, tetrahydrofuran, tetrahydropyran and dioxane.

As a substituent in the saturated heterocyclic ring which may have a substituent formed by bonding of R ⁷ and R ^8, a C _1-6 alkyl group such as methyl group, ethyl group, propyl group and the like, fluoromethyl group , Halogenated methyl group such as difluoromethyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, etc. C _1-6 alkoxy group, fluorine atom, halogen atom such as chlorine atom, Examples thereof include a hydroxy group, a carboxy group, a nitro group, a cyano group, an amino group, a C _1-6 alkylamino group, a di C _1-6 alkylamino group, and a formyl group.
When a nitrogen atom is contained as a constituent atom of a saturated heterocyclic ring, it has a C _1-6 alkyl group such as a methyl group and an ethyl group, and a substituent such as the aforementioned acyl group or amino protecting group on the nitrogen atom. May be

As a C _3-6 saturated hydrocarbon ring which may have a substituent formed by combining R ⁷ on different carbons, a saturated heterocyclic ring which may have a substituent and the substituent thereof , The same as those described in paragraph [0029].

The aryl group in the aryl group which may be substituted represented by R ⁹ includes a phenyl group and a naphthyl group.

The heteroaryl group in the heteroaryl group which may have a substituent represented by R ⁹ includes monocyclic or monocyclic groups containing 1 to 4 heteroatoms selected from N, O and S as ring members. Examples thereof include bicyclic heteroaryl groups, for example, 5-membered ring heteroaryl groups such as furanyl group, imidazolyl group, pyrazolyl group and thienyl group, 6-membered ring heteroaryl groups such as pyridyl group, pyrimidyl group, pyridadyl group and pyrazyl group Groups, benzimidazolyl groups, benzofuranyl groups, benzothienyl groups, benzoxazolyl groups, and bicyclic heteroaryl groups such as benzothiazolyl groups, and the like, with preference given to pyridyl, pyrimidyl, pyridazyl and pyrazyl groups. .
Also, depending on the substituents on these heteroaryl groups, tautomers may exist, for example, when a hydroxy group is substituted on a pyridyl group, 6-hydroxypyridin-2-yl group and its tautomers And 6-oxo-1,6-dihydropyridin-2-yl group, and 4-hydroxypyridin-2-yl group, and 4-oxo-1,4-dihydropyridin-2-yl group as a tautomer thereof Be

The optionally substituted aryl group and heteroaryl group represented by R ⁹ may have 1 to 3 substituents on the ring, and the substituents include a methyl group, an ethyl group, C _1-6 alkyl groups such as propyl group, fluoromethyl group, difluoromethyl group, a halogenated methyl group such as a trifluoromethyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or butoxy group C _{1- 6} Alkoxy groups, halogen atoms such as fluorine atoms and chlorine atoms, hydroxy groups, nitro groups, cyano groups, amino groups, C _1-6 alkylamino groups, di C _1-6 alkylamino groups, formyl groups and the like.

The cyclic amino group in the cyclic amino group which may have a substituent represented by R ⁹ includes 4- to 6-membered rings such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl Can be mentioned.

The substituent for the cyclic amino group which may have a substituent represented by R ⁹ is a fluorine atom, a halogen atom such as chlorine atom, a C _1-6 alkyl group such as a methyl group or an ethyl group, a methoxy group, And C _1-6 alkoxy groups such as ethoxy group and propoxy group, and hydroxy groups.

Examples of the saturated heterocyclic ring which may have a substituent formed by combining R ⁶ and R ⁹ include azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine, etc. The same substituents as those for the amino group can be mentioned.

The substituent in the saturated heterocyclic ring which may have a substituent formed by combining R ⁶ and R ⁹ is a C _1-6 alkyl group such as a methyl group, an ethyl group or a propyl group, a methoxy group, C _1-6 alkoxy group such as ethoxy group, propoxy group, isopropoxy group and butoxy group, halogen atom such as fluorine atom and chlorine atom, hydroxy group, carboxy group, nitro group, cyano group, amino group, C _1-6 Examples include alkylamino group, diC _1-6 alkylamino group, formyl group and the like.

The unsaturated heterocyclic ring which may be substituted and formed by combining R ⁶ and R ⁹ includes monocyclic or bicyclic ones, and examples thereof include pyrrole, imidazole, pyrazole, indole and isoindole And tetrahydroquinoline, tetrahydrohydroquinoline and the like, and examples of the substituent include the same as described above.

As a substituent in the unsaturated heterocyclic ring which may have a substituent formed by bonding of R ⁶ and R ^9, a C _1-6 alkyl group such as a methyl group, an ethyl group or a propyl group, fluoromethyl group, difluoromethyl group, a halogenated methyl group such as a trifluoromethyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, C _1-6 alkoxy group or a butoxy group, a fluorine atom, a halogen atom such as a chlorine atom And a hydroxy group, a carboxy group, a nitro group, a cyano group, an amino group, a C _1-6 alkylamino group, a di C _1-6 alkylamino group, a formyl group and the like.

X is a nitrogen atom or N-oxide, preferably a nitrogen atom.

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

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

In the morphinan derivative represented by the above general formula (I), a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt is preferably an acid addition. Examples of the acid addition salt include (i) salts with mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; And salts with organic carboxylic acids such as acids, and (iii) salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like.

In the morphinan derivative represented by the above general formula (I), a tautomer, stereoisomer of the compound or a pharmaceutically acceptable salt thereof or a solvate thereof, the stereoisomer may be cis, trans An isomer, a racemate, an optically active substance, etc. are mentioned.

In a morphinan derivative represented by the above general formula (I), a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof as a hydrate or a solvate thereof Can also exist. Thus, the compounds of the invention are intended to include all crystalline forms and hydrates or solvates thereof.
Further, compounds represented by the above general formula (I), tautomers, stereoisomers of the compounds, or pharmaceutically acceptable salts thereof, or solvates thereof are stable isotopes such as deuterium. It may be replaced by

Next, a process for producing morphinan derivatives represented by the above general formulas (h) and (i), tautomers, stereoisomers of the compounds, or pharmaceutically acceptable salts thereof or solvates thereof Is shown below.

(Method A) Production method when X is a nitrogen atom Invention compounds (h), (h ′) and (i) can be obtained by the following (first step) to (seventh step).

(Wherein, R ¹ to R ⁹ , Y and n are as defined above)

(First step)
Raw material (a) and 1 to 10 equivalents of 2-chloroacrylonitrile as aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; Alcohols such as methanol and ethanol; Aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; Bases such as sodium hydrogen carbonate, lithium carbonate, sodium carbonate and potassium carbonate in aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide After reacting at 80 to 190 ° C. for 3 to 24 hours in the presence or absence, or in a sealed tube, microwave irradiation is carried out using a microwave synthesis apparatus, and then compound (b) is hydrolyzed by hydrolysis. It can be synthesized. The hydrolysis reaction can be carried out using an acid or a base according to a generally known method, but a base is preferred. For example, ethers such as tetrahydrofuran and dioxane; 1 to 10 mol in an alcohol solvent such as methanol and ethanol The reaction can be carried out by adding 1 to 6 equivalents of an inorganic basic aqueous solution such as an aqueous solution of lithium hydroxide, sodium hydroxide, potassium hydroxide or the like at 1 / L, and reacting for 1 to 24 hours under room temperature to heating under reflux.
Starting materials (a) can be synthesized by generally known methods. For example, J. Chem. Soc. C, 1966, 617 or J.I. Chem. Soc. C, 1969, 2569, J. Chem. Soc. Perkin Trans. It can synthesize | combine by the method of I, 1994,911 description.

(Second step)
Compound (b) is diethyl ether, tetrahydrofuran, dioxane, monoglyme, ether such as diglyme in the presence of hydrogen formate or potassium formate (1 to 5 equivalents), etc .; alcohols such as methanol, ethanol, 2-propanol; water, Metal catalysts, for example, nickel catalysts such as Raney nickel, palladium-activated carbon (Pd / C) and palladium catalysts such as Pearlman's Catalyst (Pearl's Catalyst: Pd (OH) ₂ ) in a solvent such as acetic acid or a mixed solvent thereof Alternatively, compound (c) can be synthesized by reacting in the presence of a platinum catalyst such as Adams catalyst (PtO ₂ ) for 1 to 24 hours under heating to reflux at room temperature.

(Third step)
Compound (c) to an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme in an inert gas atmosphere; potassium bis (trimethylsilyl) in a solvent such as halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride ) Bases such as amide (KHMDS), lithium diisopropylamide (LDA), etc .; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, Organic bases such as diethylamine, cyclohexylamine, procaine, etc .; trifluoromethanesulfonic anhydride or N-phenyl-bis (trifluoromethanesulfonimide) in the presence of an inorganic base such as potassium carbonate, lithium carbonate etc. Equal to (1-5 equivalents) can be synthesized compound (d) by reaction for 30 minutes to 5 hours at -78 ° C. ~ room temperature.

(Fourth step)
Compound (d) is an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like in an inert gas atmosphere; a solvent such as aromatic hydrocarbons such as benzene, toluene, and xylene, tetrakistriphenylphosphine palladium, etc. Zero-valent palladium catalyst or divalent palladium catalyst such as palladium acetate, palladium acetate (dichlorobis (tri-o-tolylphosphine)), phosphine ligands such as Xantphos, DPEPhos, (±) -BINAP, and trimethylamine, triethylamine, triol Organic bases such as butylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, etc. Inorganic bases such as potassium carbonate, lithium carbonate Presence, a 2,4,6-trichlorophenyl formate (1-2 equivalents) was reacted for 1 to 24 hours under 0 ° C. ~ heated to reflux, can be synthesized compound (e).

(Step 5)
Compound (e) is a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; a mineral acid such as hydrochloric acid, sulfuric acid or hydrobromic acid; or an organic acid such as p-toluenesulfonic acid In the presence of water, alcohols such as methanol, ethanol and propanol, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, solvents such as acetic acid, or a mixture of these, room temperature to 120 ° C., 1 to Compound (f) can be synthesized by hydrolysis for 24 hours.

(Sixth process)
Compound (f): aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; methanol Alcohols such as ethanol, etc .; Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; N, N-dimethylaminopyridine in aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, Trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, etc. Organic base: 1 to 2 equivalents of an amine (g) in the presence of an inorganic base such as potassium carbonate or lithium carbonate, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetra Methyluronium hexafluorophosphate (HATU), O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), N, N'-dicyclo Hexyl carbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4 Invention Compound (h) is synthesized by reacting using a condensing agent such as -methylmorpholinium chloride n-hydrate (DMT-MM) at 0 ° C to heating under reflux for 1 to 12 hours. It can be. Invention compounds (h) are aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride A sulfurizing agent such as diphosphorus pentasulfide, Lawesson's reagent, Davy's reagent, Japanese's reagent, Bereau's reagent, etc. in aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin etc. Invention compound (h ') can be synthesized by reacting for 12 hours.

Compound (h) can also be synthesized directly from compound (e) as follows.

(Wherein, R ¹ to R ⁹ and n are as defined above)

Compound (e): aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; pentane Aliphatic hydrocarbons such as hexane, heptane and ligroin; N, N-dimethylaminopyridine, trimethylamine, triethylamine and N, N- in aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide Organic bases such as diisopropylethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, etc .: potassium carbonate, lithium carbonate etc. The presence of an inorganic base, by reacting 1 to 12 hours amine (g) under 0 ° C. ~ heated to reflux, can be synthesized Compound (h).

(The seventh step)
When R ⁴ is a C _1-6 alkoxy group, compound (h) or (h ′) may be a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride; or an organic solvent such as acetic acid or ethyl acetate or no solvent Or sodium tribromide, trimethylsilyl iodide, hydrogen bromide, pyridinium hydrochloride etc. (1 to 3 equivalents) at -30 to 180 ° C for 30 minutes to 5 hours, or N, N-dimethylformamide, dimethylacetamide In 1-propanethiol, 1-dodecanethiol, etc. in the presence of an organic base such as potassium tert-butoxide, sodium tert-butoxide, etc. in an aprotic polar solvent such as N-methylpyrrolidone, dimethylsulfoxide at 100 ° C to 180 ° C. Invention compound (i) can be obtained by reacting for 30 minutes to 24 hours. In the case of siloxy groups such as R ⁴ = tert-butyldimethylsilyl and tert-butyldiphenylsilyl, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; in solvents such as acetonitrile and acetic acid or with these and water Inventive compound (i) is obtained by reacting tetrabutylammonium fluoride, potassium fluoride, hydrofluoric acid, hydrogen fluoride-pyridine complex etc. in a mixed solvent of from 30 minutes to 24 hours at 0 to 50 ° C. be able to.

(Method B) A production method where R ⁴ is a hydrogen atom.
The compound (c-5) is synthesized from the compound (c-2) according to (the first step) to (the third step) as follows, and then the compound of the present invention (h-1) is synthesized in the same manner as method A It can also be done.

(Wherein, R ⁴ represents a C _1-6 alkoxy group, and R ¹ to R ³ , R ⁵ to R ⁹ , Y and n are as defined above)

(First step)
Whether the compound (c-2) is reacted with 1 to 5 equivalents of boron tribromide at -30 to 50 ° C. for 30 minutes to 5 hours in a solvent such as methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, etc. Or 1-propanethiol in the presence of 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, dimethylsulfoxide or the like The compound (c-3) can be synthesized by reacting dodecanethiol or the like at 100 ° C. to 180 ° C. for 30 minutes to 24 hours.

(Second step)
Compound (c-3) and 5-chloro-1-phenyl-1H-tetrazole 1 to 1.5 equivalents of an aromatic hydrocarbon such as benzene, toluene or xylene; diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme etc Alcohols such as methanol and ethanol; Aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; Sodium carbonate and potassium carbonate in aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide Compound (c-4) can be synthesized by reacting for 3 to 24 hours at room temperature to 50 ° C. in the presence of an inorganic base such as

(Third step)
Compound (c-4) is an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme or the like in a hydrogen atmosphere or in the presence of potassium formate (1 to 5 equivalents) or the like; alcohols such as methanol, ethanol, 2-propanol; Metal catalysts such as nickel catalysts such as Raney nickel, palladium-activated carbon (Pd / C), Pearlman's Catalyst (Pearlman's Catalyst: Pd (OH) in an organic solvent such as acetic acid or ethyl acetate or a mixed solvent of these with water Compound (c-5) can be synthesized by reacting in the presence of a palladium catalyst such as 2) or the like or a platinum catalyst such as Adams catalyst (PtO ₂ ) at room temperature to heating under reflux for 1 to 24 hours.
The synthesis of the compound (h-1) of the present invention from the compound (C-5) can be carried out in the same manner as in the third to seventh steps described above in (Method A).

(Method C) R ¹ has a C _1-6 alkyl group which may have a substituent, a C _3-6 cycloalkyl C _1-6 alkyl group which may have a substituent, a substituent In the case of an optionally C _2-8 acyl group or an amino protecting group, the compound (c-8) synthesized from the compound (c-6) by the (first step) to (sixth step) as follows is used Invention compounds (h-2) and (i-1) can also be synthesized in the same manner as in method A.

(Wherein, R ^1a represents a C _1-6 alkyl group which may have a substituent, a C _3-6 cycloalkyl C _1-6 alkyl group which may have a substituent, and R ¹⁰ represents hydrogen An atom, a C _1-5 alkyl group which may have a substituent, a C _1-6 alkoxy group, a C _3-6 cycloalkyl group or a C _3-6 cycloalkyl C _1-5 alkyl group, R ¹¹ is substituted have a group indicates also a C _1-6 alkyl group or C _3-6 cycloalkyl C _1-6 alkyl group, X represents a chlorine atom, a halogen atom such as a bromine atom, Z is a leaving group And R ² to R ⁹ , Y and n are as defined above)

(First step)
Raw material (c-6) and 2,2 equivalents of 2,2,2-trichloroethyl chloroformate (TrocCl), aromatic hydrocarbons such as benzene, toluene, xylene and the like; methylene chloride, chloroform, 1,2-dichloroethane, tetrachloride 30 in the presence or absence of a base such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate or the like in a solvent such as carbon, halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane and the like, and at 30 ° C. to 150 ° C. The compound (c-7) can be synthesized by reacting for a minute to 24 hours, or by irradiating and reacting in a sealed tube with a microwave synthesis apparatus using a microwave synthesis apparatus.

(Second step)
Compound (c-7) and 1 to 2 equivalents of ethylene glycol in the presence of an organic acid such as p-toluenesulfonic acid or (±) -camphorsulfonic acid in a solvent such as aromatic hydrocarbons such as benzene, toluene and xylene The reaction can be carried out at 80 ° C. to 160 ° C. for 30 minutes to 24 hours to synthesize compound (j).

(Third step)
Compound (j) and metallic zinc powder in an amount of 1 to 3 equivalents of ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; alcohols such as methanol, ethanol and the like; solvents such as acetic acid; Compound (j-2) can be synthesized by reacting at 100 ° C. for 30 minutes to 24 hours.

(Fourth step)
Compound (j-2) to aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme: halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride Alcohols such as methanol and ethanol; Aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; A, N, N-dimethylamino in an aprotic polar solvent such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide Pyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, Organic bases like: potassium carbonate, the presence of an inorganic base lithium ^carbonate, represented by R 10 a carboxylic acid represented by ^COOH, acid halide represented by R 10 COX, or ^(R 10 _{CO) 2} O O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), O- (1-1.5 equivalents of anhydride) (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (WSC), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium Chlora Compound (j-3) is synthesized by reacting in the presence or absence of 1 to 2 equivalents of condensing agent such as id n-hydrate (DMT-MM) at 0 ° C. to heating under reflux for 1 to 12 hours. can do.

(Step 5)
Compound (j-3) and 1 to 1.5 equivalents of a reducing agent such as lithium aluminum hydride or borane-tetrahydrofuran complex, in a solvent such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc., at room temperature to 100 ° C. for 30 minutes Compound (j-4) can be synthesized by reacting for ̃24 hours.

(Sixth process)
Compound (j-4), Ethers such as tetrahydrofuran; Alcohols such as methanol, ethanol etc .; Solvents such as acetone, water etc. or in the absence of solvents, mineral acids such as hydrochloric acid, sulfuric acid etc., organics such as p-toluenesulfonic acid The compound (c-8) can be synthesized by reacting with an acid.
The compounds of the present invention (h-2) and (i-2) from the compound (c-8) can be synthesized in the same manner as in the third to seventh steps described in (Method A).

(The seventh step)
Compound (j-4) can be obtained by subjecting compound (j-2) to a generally known alkylation reaction, and examples thereof include dialkyls such as (j-2) and dimethyl sulfate, diethyl sulfate, dipropyl sulfate and the like. Alkyl iodides such as sulfuric acid, methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide, etc., alkyl bromides such as methyl bromide, ethyl bromide, propyl bromide, isopropyl bromide, butyl bromide, methanesulfonyl, Sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide and the like as an alkylating agent such as alcohol activated with a sulfonyl group such as p-toluenesulfonyl or the like. Inorganic base or pyridine, picoline, N Aromatic hydrocarbons such as benzene and toluene in the presence of an organic base such as N-dimethylaniline, N-methylmorpholine, dimethylamine, triethylamine, 1,8-diazabicyclo [5.4.0] undecene (DBU), Obtained by reaction at room temperature to 100 ° C. for 10 minutes to 24 hours in an aprotic polar solvent such as diethyl ether, tetrahydrofuran, ethers such as dioxane, or acetonitrile, N-methylpyrrolidone, N, N-dimethylformamide, etc. Can.

Inventive compound (h-4), (In the same manner as in the first step, the third step, the fourth step and the seventh step of (Method C), using the inventive compound (h-3) as follows. h-5) and (h-6) can also be sequentially synthesized.

(Wherein, R ^1a represents a C _1-6 alkyl group which may have a substituent, a C _3-6 cycloalkyl C _1-6 alkyl group which may have a substituent, and R ¹² is a substituent) R ¹ to R ⁹ , Y and n represent an optionally protected C _1-6 alkyl group, a C _3-6 cycloalkyl C _1-6 alkyl group, a C _2-8 acyl group or an amino protecting group Is the same as above.)

The (first step) to (third step) can be carried out in the same manner as the method described in (method C).

(Method D) Manufacturing method when X is N-oxide

(Wherein, R ¹ to R ⁹ , Y and n are as defined above)

Invention compound (h) is an oxidizing agent such as an aqueous solution of hydrogen peroxide (H ₂ O ₂ ) or m-chloroperbenzoic acid (mCPBA) in a halogenated hydrocarbon solvent such as methylene chloride, chloroform or carbon tetrachloride Invention compound (h-7) can be synthesized by reacting equivalent amounts at 0 ° C. to room temperature for 30 minutes to 24 hours.

The compound obtained by the above method can be purified, for example, by silica gel column chromatography, if necessary. Furthermore, if necessary, an acid addition salt can be formed by a conventional method. For example, the compound (h) or (i) of the present invention can be used as an organic solvent such as ethyl acetate; alcohols such as methanol and ethanol; Mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid in polar solvents; organic carboxylic acids such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid; methanesulfonic acid, benzenesulfonic acid, p- The reaction can be carried out by appropriately heating at 0 ° C. to room temperature or in the presence of an organic sulfonic acid such as toluene sulfonic acid, mesitylene sulfonic acid, naphthalene sulfonic acid and the like.

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

Solid preparations for oral administration include capsules, tablets, pills, powders and granules. In preparing this solid preparation, excipients, disintegrants, binders, lubricants, dyes and the like can be used. Here, as an excipient, lactose, D-mannitol, crystalline cellulose, glucose and the like, as a disintegrant, starch, calcium carboxymethylcellulose (CMC-Ca) and the like, magnesium lubricant, as a lubricant, As a binder, talc and the like include hydroxypropyl cellulose (HPC), gelatin, polyvinyl pyrrolidone (PVP) and the like. Buffers may additionally be used in the case of capsules, tablets and pills. Tablets and pills may be provided with an enteric coating.

The form of the composition of the present invention for injection includes 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 may be reduced, for example, by filtration through bacteria retention filters, or by incorporation of the sterilization agent in the form of a sterile solid composition which can be dissolved in the sterilization agent or some other sterile injectable medium immediately before use. It can be germinated.

Formulations for eye drop administration may preferably contain, in addition to the compound of the present invention, solubilizers, preservatives, tonicity agents, thickeners and the like.

Liquid formulations for oral administration include inert diluents commonly used among those skilled in the art, such as pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing water. In addition to such inert diluents, the compositions may also contain 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 the compound of the present invention, excipients such as cocoa butter or a suppository wax.

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

Diseases and conditions associated with the opioid kappa receptor include, for example, cardiovascular diseases, digestive diseases, blood diseases, respiratory diseases, liver diseases, nervous diseases, urinary disorders, pain, cough, pruritus, etc. It includes ischemic brain disease, drug dependence and the like. The compounds of the present invention have high opioid kappa receptor selectivity and potent agonist activity for opioid kappa receptors, and thus are effective for the treatment, amelioration and prevention of these diseases and conditions.

Next, the present invention will be described in more detail by way of 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-ethan-4,12- Synthesis of methanobenzofuro [3,2-e] isoquinolin-14-one (1)

(4R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-2,3,4,7a-tetrahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinoline (J. Synthesized by the method described in Chem. Soc. C, 1966, 617, J. Chem. Soc. C, 1969, 2569 and J. Chem. Soc. Perkin Trans. 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. The microwaves were respectively irradiated in a micro-bead synthesizer and reacted for 30 minutes under 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 2-chloroacrylonitrile adduct was dissolved in ethanol (144 mL), 1 M aqueous sodium hydroxide solution (36 mL) was added, and the mixture was heated to reflux for 3 hours. After cooling, 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 1 (2.5 g, 44%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08 to 0.20 (m, 2 H), 0.45 to 0.60 (m, 2 H), 0.77 to 0.91 (m) , 1H), 1.87 (dd, J = 3, 13 Hz, 1 H), 2.07 (ddd, J = 5, 13, 13 Hz, 1 H), 2.17 (d, J = 19 Hz, 1 H), 2 .32-2.55 (m, 4 H), 2.77 (dd, J = 5, 12 Hz, 1 H), 3.17 (d, J = 18 Hz, 1 H), 3.32 (d, J = 19 Hz, 1H), 3.63 (s, 3H), 3.65 (d, J = 7 Hz, 1 H), 3.83 (s, 3 H), 4.68 (d, J = 1 Hz, 1 H), 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, 4aS, 7S, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12- Synthesis of methanobenzofuro [3,2-e] isoquinolin-6 (5H) -one (2)

Compound 1 (2.43 g, 6.18 mmol) was dissolved in ethanol (100 mL) and 5% palladium on activated carbon (2.01 g) was added. The mixture was stirred at 60 ° C. for 12 hours under a hydrogen atmosphere, allowed to cool, and filtered through celite. The filtrate was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the residue, and the mixture was extracted twice with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol, filtered and purified by recrystallization to give the title compound 2 (2.25 g, 92%) as colorless plate crystals (melting point: 164-165 ° C.)
Got as.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06 to 0.16 (m, 2 H), 0.43 to 0.56 (m, 2 H), 0.73 to 0.86 (m) , 1H), 1.01 (dddd, J = 3, 3, 13, 13 Hz, 1 H), 1.26 (ddd, J = 6, 13, 13 Hz, 1 H), 1.49-1.61 (m, 1) 1H), 1.68 (dd, J = 4, 13 Hz, 1 H), 1.76 (ddd, J = 6, 13, 13 Hz, 1 H), 2.01 (ddd, J = 6, 13, 13 Hz, 1 H) ), 2.22 (d, J = 20 Hz, 1 H), 2.29-2. 42 (m, 4 H), 2. 70 (dd, J = 6, 12 Hz, 1 H), 3.07 (d, J = 18 Hz, 1 H), 3. 13 (d, J = 6 Hz, 1 H), 3.46-3. 55 (m, 1 H), 3.53 (s, 3 H), .89 (s, 3H), 4.60 (s, 1H), 6.63 (d, J = 8Hz, 1H), 6.76 (d, J = 8Hz, 1H).

(Reference Example 3)
(4R, 4aS, 7S, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12- Synthesis of methanobenzofuro [3,2-e] isoquinolin-6-yl trifluoromethanesulfonate (3)

Under an argon atmosphere, 11% KHMDS toluene solution (5.5 mL, 2.75 mmol) was added to anhydrous tetrahydrofuran (4 mL) and cooled to -78.degree. A solution of compound 2 (885 mg, 2.24 mmol) in anhydrous tetrahydrofuran (4 mL) and a solution of N-phenyl-bis (trifluoromethanesulfonimide) (1.1 g, 3.36 mmol) in anhydrous tetrahydrofuran (2 mL) were added sequentially, and 1 hour It stirred. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added, and the temperature was raised to room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (15-25% diethyl ether / hexane) to give the title compound 3 (1.17 g, 99%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.20 (m, 2 H), 0.46-0.61 (m, 2 H), 0.76 (ddd, J = 3 , 10, 13 Hz, 1 H), 0.80 to 0.92 (m, 1 H), 1.03 (ddd, J = 6, 12, 12 Hz, 1 H), 1.43 (dddd, J = 2, 2, 12, 12 Hz, 1 H), 1. 65 (dd, J = 2, 13 Hz, 1 H), 1.79 (ddd, J = 6, 10, 12 Hz, 1 H), 1.91 (ddd, J = 6, 13 , 13 Hz, 1 H), 2.26-2.45 (m, 4 H), 2.62 (dd, J = 6, 12 Hz, 1 H), 3.09 (d, J = 18 Hz, 1 H), 3.42 (D, J = 6 Hz, 1 H), 3.58 (s, 3 H), 3. 90 (s, 3 H), 4.62 (d, J = 2 Hz, 1 ), 6.54 (s, 1H), 6.61 (d, J = 8Hz, 1H), 6.76 (d, J = 8Hz, 1H).

(Reference Example 4)
2,4,6-Trichlorophenyl (4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a, Synthesis of 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxylate (4)

Compound 3 (1.07 g, 2.03 mmol) is dissolved in toluene (15 mL) and formic acid 2,4,6-trichlorophenyl (564 mg, 2.50 mmol), palladium acetate (46 mg, 0.21 mmol) and 4, 5-Bis (diphenylphosphino) -9,9-dimethylxanthene (234 mg, 0.40 mmol) was added. Triethylamine (0.34 mL, 2.44 mmol) was slowly added dropwise under an argon atmosphere, and the mixture was stirred at room temperature for 10 hours. Saturated aqueous sodium hydrogen carbonate solution (15 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to give the title compound 4 (1.1 g, 90%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.21 (m, 2 H), 0.47 to 0.62 (m, 2 H), 0.74 to 0.84 (m) , 1 H), 0.85 to 0.96 (m, 1 H), 0.98 (ddd, J = 6, 13, 13 Hz, 1 H), 1.43-1. 54 (m, 1 H), 1.66 -1.76 (m, 2 H), 1.81 (ddd, J = 6, 13, 13 Hz, 1 H), 2.28-2.51 (m, 4 H), 2.63 (dd, J = 5, 12 Hz, 1 H), 3.12 (d, J = 18 Hz, 1 H), 3.51 (d, J = 7 Hz, 1 H), 3.56 (s, 3 H), 3. 90 (s, 3 H), 4 .65 (d, J = 1 Hz, 1 H), 6.63 (d, J = 8 Hz, 1 H), 6.77 (d, J = 8 Hz, 1 H), 7.40 (s, 2 H), 8.0 (S, 1H).

(Reference Example 5)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12- Synthesis of methanobenzofuro [3,2-e] isoquinoline-6-carboxylic acid hydrochloride (5)

Compound 4 (54.9 mg, 0.091 mmol) was dissolved in tetrahydrofuran (2 mL), 1 M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at 60 ° C. After 7 hours, 6 M sodium hydroxide (1 mL) was added and stirred at 60 ° C. for 3 hours. After cooling, a saturated aqueous ammonium chloride solution (10 mL) was added, and the mixture was extracted three times with 2-propanol / chloroform (1: 4). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was dissolved in methanol (3 mL), and 1 M hydrogen chloride-ethyl acetate solution (0.3 mL, 0.30 mmol) was added and stirred. Diethyl ether (50 mL) was added little by little, and the mixture was placed under ice-cooling for 30 minutes, and the precipitated white precipitate was collected by filtration to give the title compound 5 (25 mg, 60%) as a white solid (melting point: 137-138 ° C.) I got

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.47 to 0.64 (m, 2 H), 0.75 to 0.94 (m, 3 H), 1.11-1.30 ( m, 2H), 1.34-1. 46 (m, 1 H), 1.61-1. 73 (m, 1 H), 1.93-2.17 (m, 2 H), 3.03 (dd, J = 7, 20 Hz, 1 H), 3.08-3.24 (m, 2 H), 3.29-3. 53 (m, 3 H), 3.56 (s, 3 H), 3.89 (s, 3) 3H), 4.50 (d, J = 7 Hz, 1 H), 4.67 (d, J = 1 Hz, 1 H), 6.81 (d, J = 8 Hz, 1 H), 6.95 (d, J = 8 Hz, 1 H), 7.71 (s, 1 H).

Example 1
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (4-fluorobenzyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a Of 1-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (6)

Compound 4 (50.4 mg, 0.084 mmol) is dissolved in tetrahydrofuran (2 mL), 4-fluoro-N-methylbenzylamine (44.0 μL, 0.33 mmoL), triethylamine (23.0 μL, 0.17 mmol) and N, N-dimethyl-4-aminopyridine (5.0 mg, 0.041 mmol) was added and stirred at 50 ° C. for 6.5. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (65-86% ethyl acetate / hexane) to give the title compound 6 (41.8 mg, 92%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.15 (m, 2 H), 0.49-0.56 (m, 2 H), 0.69-1.04 (m , 3H), 1.29-1.37 (m, 1 H), 1.66 (dd, J = 2, 13 Hz, 1 H), 1.85-1.99 (m, 2 H), 2.26-2 .43 (m, 4 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 2.90 (s, 1.2 H), 2.94 (s, 1.8 H), 3.02-3 .11 (m, 1 H), 3.31 (d, J = 6 Hz, 0.4 H), 3.42 (d, J = 6 Hz, 0.6 H), 3.53 (s, 1.8 H), 3 .59 (s, 1.2 H), 3.89-3. 90 (m, 3 H), 4.49-4. 70 (m, 3 H), 6.57-6.76 (m, 3 H), 7 .00-7.06 (m, 2 ), 7.28-7.34 (m, 2H).

(Example 2)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (4-fluorobenzyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (7)

Compound 6 (41.8 mg, 0.077 mmol) was dissolved in dichloromethane (4 mL), and 1 M boron tribromide solution in dichloromethane (0.40 mL, 0.40 mmol) was added under ice-cooling. After stirring at room temperature for 7.5 hours, 28% aqueous ammonia solution (1.5 mL) was added under ice-cooling and stirred for a while. Saturated aqueous sodium hydrogen carbonate solution (3 mL) was added, and the mixture was extracted three times with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (92-100% ethyl acetate / hexane) to give the title compound 7 (29.5 mg, 74%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2 H), 0.43-0.55 (m, 2 H), 0.68-1.00 (m) , 3H), 1.25-1.35 (m, 1H), 1.56-1.84 (m, 3H), 2.24-2.47 (m, 4H), 2.51-2.64 (M, 1 H), 2.95-3. 09 (m, 4 H), 3.31-3. 43 (m, 1 H), 4.53 (s, 1 H), 4.59-4. 83 (m , 3H), 5.80 (br s, 1 H), 6.55-6.57 (m, 1 H), 6.76 (d, J = 8 Hz, 1 H), 6.83-6.85 (m, 1) 1 H), 7.0 3-7. 10 (m, 2 H), 7.2 3-7. 32 (m, 2 H).

(Example 3)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (3-fluorobenzyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (8)

The title compound 8 was obtained from compound 4 and 3-fluoro-N-methylbenzylamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.15 (m, 2 H), 0.45-0.56 (m, 2 H), 0.69-0.90 (m) , 2H), 1.02 (ddd, J = 5, 12, 12 Hz, 1H), 1.31-1.37 (m, 1H), 1.65-1.67 (m, 1H), 1.85 -2.00 (m, 2 H), 2.25-2. 43 (m, 4 H), 2.59 (dd, J = 6, 12 Hz, 1 H), 2.93 (s, 1.2 H), 2 .96 (s, 1.8 H), 3.03-3. 11 (m, 1 H), 3.32 (d, J = 6 Hz, 0.4 H), 3.43 (d, J = 6 Hz, 0. 6). 6H), 3.58 (s, 1.8 H), 3.59 (s, 1.2 H), 3.89 (s, 1.2 H), 3.91 (s, 1.8 H), 4.52 -4.80 (m, 3H) 6.57-6.76 (m, 3H), 6.94-7.00 (m, 1H), 7.06-7.11 (m, 2H), 7.28-7.34 (m, 1H) ).

(Example 4)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (3-fluorobenzyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (9)

The title compound 9 was obtained from compound 8 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05 to 0.15 (m, 2 H), 0.37 to 0.60 (m, 2 H), 0.65 to 1.03 (m , 3H), 1.25-1.37 (m, 1H), 1.56-1.88 (m, 3H), 2.23-2.65 (m, 5H), 2.99-3.11. (M, 4H), 3.28-3. 43 (m, 1H), 4.54 (s, 1H), 4.60-4.82 (m, 3H), 5.95 (br s, 1H) , 6.52-6.60 (m, 1 H), 6.75 (d, J = 8 Hz, 1 H), 6.82-6. 87 (m, 1 H), 6.98-7.12 (m, 1) 3H), 7.30-7.40 (m, 1H).

(Example 5)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (2-fluorobenzyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (10)

The title compound 10 was obtained from compound 4 and 2-fluoro-N-methylbenzylamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.16 (m, 2 H), 0.44 to 0.56 (m, 2 H), 0.67 to 0.90 (m) , 2H), 1.00 (ddd, J = 6, 12, 12 Hz, 1 H), 1.32-1.38 (m, 1 H), 1.62-1. 67 (m, 1 H), 1.82 -1.99 (m, 2 H), 2.24-2. 43 (m, 4 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 2.98 (s, 1.2 H), 3 .00 (s, 1.8 H), 3.02-3.11 (m, 1 H), 3.29 (d, J = 6 Hz, 0.4 H), 3.42 (d, J = 6 Hz, 0. 2). 6H), 3.52 (s, 1.8 H), 3.59 (s, 1.2 H), 3.88 (s, 1.2 H), 3. 90 (s, 1.8 H), 4.60 -4.85 (m, 3H) 6.56-6.76 (m, 3H), 7.00-7.14 (m, 2H), 7.23-7.28 (m, 1H), 7.36-7.50 (m, 1H) ).

(Example 6)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (2-fluorobenzyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a Of 1-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (11)

The title compound 11 was obtained from compound 10 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05 to 0.15 (m, 2 H), 0.37 to 0.60 (m, 2 H), 0.63 to 1.02 (m) , 3H), 1.25-1.37 (m, 1H), 1.55-1.88 (m, 3H), 2.20-2.48 (m, 4H), 2.49-2.64 (M, 1H), 3.01-3.16 (m, 4H), 3.30-3.44 (m, 1H), 4.51 (s, 1H), 4.66-4.94 (m , 3H), 5.65 (br s, 1 H), 6.52-6.60 (m, 1 H), 6.75 (d, J = 8 Hz, 1 H), 6.81-6.88 (m, 1 H), 7.06-7. 10 (m, 1 H), 7.13-7. 43 (m, 3 H).

(Example 7)
(4R, 4aS, 7R, 7aR, 12bS) -N- (4-chlorobenzyl) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (12)

The title compound 12 was obtained from compound 4 and 4-chloro-N-methylbenzylamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.16 (m, 2 H), 0.49-0.56 (m, 2 H), 0.69-1.04 (m , 3H), 1.30-1.36 (m, 1 H), 1.66 (dd, J = 2, 13 Hz, 1 H), 1.84-1.99 (m, 2 H), 2.25-2 .43 (m, 4 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 2.91 (s, 1.2 H), 2.93 (s, 1.8 H), 3.02-3 .11 (m, 1 H), 3.30 (d, J = 6 Hz, 0.4 H), 3.42 (d, J = 6 Hz, 0.6 H), 3.54 (s, 1.8 H), 3 .58 (s, 1.2 H), 3.89-3. 90 (m, 3 H), 4.49-4.89 (m, 3 H), 6.57-6.76 (m, 3 H), 7 .24-7.34 (m, 4 ).

(Example 8)
(4R, 4aS, 7R, 7aR, 12bS) -N- (4-chlorobenzyl) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (13)

The title compound 13 was obtained from compound 12 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.15 (m, 2 H), 0.42-0.57 (m, 2 H), 0.65-1.02 (m , 3H), 1.25-1.36 (m, 1H), 1.52-1.88 (m, 3H), 2.22-2.47 (m, 4H), 2.48-2.65 (M, 1 H), 2.97-3. 09 (m, 4 H), 3. 29-3. 43 (m, 1 H), 4.53 (s, 1 H), 4.55-4. 82 (m , 3H), 5.80 (br s, 1 H), 6.55-6.56 (m, 1 H), 6.75 (d, J = 8 Hz, 1 H), 6.86-6.86 (m, 1H), 7.22-7.38 (m, 4H).

(Example 9)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (4-iodobenzyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (14)

The title compound 14 was obtained from the compound 4 and 4-iodo-N-methylbenzylamine (synthesized by the method described in WO2013117120) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.16 (m, 2 H), 0.47 to 0.56 (m, 2 H), 0.68 to 1.04 (m , 3H), 1.30-1.36 (m, 1 H), 1.66 (dd, J = 2, 13 Hz, 1 H), 1.83-1. 98 (m, 2 H), 2.25-2 .43 (m, 4 H), 2.58 (dd, J = 5, 12 Hz, 1 H), 2.92 (s, 1.2 H), 2.93 (s, 1.8 H), 3.02-3 .11 (m, 1 H), 3.30 (d, J = 6 Hz, 0.4 H), 3.42 (d, J = 6 Hz, 0.6 H), 3.54 (s, 1.8 H), 3 .58 (s, 1.2 H), 3.89-3. 90 (m, 3 H), 4.46-4. 80 (m, 3 H), 6.57-6.76 (m, 3 H), 7 .05-7.12 (m, 2 ), 7.65-7.69 (m, 2H).

(Example 10)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N- (4-iodobenzyl) -N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (15)

The title compound 15 was obtained from compound 14 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04 to 0.15 (m, 2 H), 0.42 to 0.57 (m, 2 H), 0.62 to 1.01 (m) , 3H), 1.25-1.35 (m, 1H), 1.57-1.85 (m, 3H), 2.22-2.46 (m, 4H), 2.48-2.66 (M, 1 H), 2.98-3. 10 (m, 4 H), 3. 27-3. 43 (m, 1 H), 4. 48-4. 71 (m, 4 H), 5. 28 (br s, 1 H), 6.55-6. 57 (m, 1 H), 6. 75 (d, J = 8 Hz, 1 H), 6.79-6. 86 (m, 1 H), 7.00-7. 10 (m, 2H), 7.68-7.74 (m, 2H).

(Example 11)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N- (4-methoxybenzyl) -N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (16)

The title compound 16 was obtained from compound 4 and 4-methoxy-N-methylbenzylamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08 to 0.18 (m, 2 H), 0.42 to 0.58 (m, 2 H), 0.66 to 1.08 (m , 3H), 1.20-1.45 (m, 1 H), 1.55-1.70 (m, 1 H), 1.77-2.05 (m, 2 H), 2.23-2.45 (M, 4H), 2.46-2.61 (m, 1 H), 2.89 (s, 1.2 H), 2.92 (s, 1.8 H), 3.02-3.12 (m , 1 H), 3.23 (d, J = 6 Hz, 0.4 H), 3.43 (d, J = 6 Hz, 0.6 H), 3.53 (s, 1.8 H), 3.60 (s) , 1.2H), 3.80 (s, 3H), 3.89 (s, 1.2H), 3.90 (s, 1.8H), 4.40 to 4.80 (m, 3H), 6.56-6.61 (m, 1H), 6. 9 (s, 1H), 6.70-6.79 (m, 1H), 6.83-6.92 (m, 2H), 7.17-7.29 (m, 2H).

(Example 12)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N- (4-hydroxybenzyl) -N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (17)

The title compound 17 was obtained from compound 16 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.18 (m, 2 H), 0.38-0.58 (m, 2 H), 0.60-1.00 (m) , 3H), 1.19-1.38 (m, 1 H), 1.50-1.65 (m, 1 H), 1.62-1.90 (m, 2 H), 2.18-2.47. (M, 4 H), 2.48-2.63 (m, 1 H), 2.86 (s, 1.5 H), 3.01 (s, 1.5 H), 3.02-3. 10 (m , 1H), 3.31-3.50 (m, 1H), 4.43 (d, J = 14 Hz, 0.5 H), 4.48-4.60 (m, 0.5 H), 4.55 (S, 1 H), 4.65 (d, J = 14 Hz, 0.5 H), 4. 74 (d, J = 15 Hz, 0.5 H), 5.10-5.55 (m, 1 H), 6 .47-6.55 (m, 1 H , 6.74 (d, J = 8Hz, 1H), 6.78-6.88 (m, 3H), 7.01-7.15 (m, 2H).

(Example 13)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N- (3-dimethoxybenzyl) -N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (18)

The title compound 18 was obtained from compound 4 and 3-methoxy-N-methylbenzylamine (synthesized by the method described in Organometallics 2002, 21, 4505) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.15 (m, 2 H), 0.45-0.56 (m, 2 H), 0.68-0.93 (m) , 2H), 1.00 (ddd, J = 6, 12, 12 Hz, 1 H), 1.32-1. 39 (m, 1 H), 1.65 (dd, J = 2, 13 Hz, 1 H), 1 .80-1.99 (m, 2 H), 2.25-2. 43 (m, 4 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 2.92-2.95 (m, 2) 3H), 3.03-3.11 (m, 1H), 3.32 (d, J = 6 Hz, 0.4 H), 3.42 (d, J = 6 Hz, 0.6 H), 3.55 (d s, 1.8 H), 3.60 (s, 1.2 H), 3.80-3.81 (m, 3 H), 3.89 (s, 1.2 H), 3. 90 (s, 1. S). 8H), 4.40 4.71 (m, 3 H), 6.57-6. 61 (m, 1 H), 6.69 (s, 1 H), 6.72-6. 94 (m, 4 H), 7.24-7. 29 (m, 1 H).

(Example 14)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N- (3-hydroxybenzyl) -N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (19)

The title compound 19 was obtained from compound 18 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.17 (m, 2 H), 0.47 to 0.58 (m, 2 H), 0.66 to 1.03 (m , 3H), 1.24-1.36 (m, 1H), 1.65-1.93 (m, 3H), 2.26-2.45 (m, 4H), 2.56- 2.64 (M, 1 H), 2.92 (s, 1.8 H), 3.04-3. 10 (m, 2.2 H), 3.39-3. 45 (m, 1 H), 4. 20 (d , J = 15 Hz, 0.4 H), 4.41 (d, J = 15 Hz, 0.6 H), 4.60-4.62 (m, 1 H), 5.00-5.23 (m, 2 H) , 6.55 (d, J = 8 Hz, 1 H), 6.75-6.98 (m, 5 H), 7.15-7.21 (m, 1 H), 8.00 (br s, 1 H).

(Example 15)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (2-hydroxybenzyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (20)

The title compound 20 was obtained from compound 4 and 2-hydroxy-N-methylbenzylamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.17 (m, 2 H), 0.43 to 0.58 (m, 2 H), 0.68 to 0.79 (m , 1 H), 0.80 to 0.90 (m, 1 H), 0.91 to 11. 11 (m, 1 H), 1.28 to 1.38 (m, 1 H), 1.61 to 1.69 (M, 1 H), 1.77-1. 93 (m, 2 H), 2.2 1-2. 43 (m, 4 H), 2.56 (dd, J = 5, 18 Hz, 1 H), 3.07 (D, J = 18 Hz, 1 H), 3.08 (s, 3 H), 3.41-3. 44 (m, 1 H), 3.43 (s, 3 H), 3. 87 (s, 3 H), 4.42 (d, J = 14 Hz, 1 H), 4.63 (d, J = 14 Hz, 1 H), 4.65 (s, 1 H), 6.60 (d, J = 8 Hz, 1 H), 6. 74 (d, J = Hz, 1 H), 6.77 (s, 1 H), 6.82 (dt, J = 1, 8 Hz, 1 H), 6.97 (dd, J = 1, 8 Hz, 1 H), 7.14 (dd, J = 2, 7 Hz, 1 H), 7.24 (dt, J = 2, 7 Hz, 1 H), 9.60 (br s, 1 H).

(Example 16)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N- (2-hydroxybenzyl) -N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (21)

The title compound 21 was obtained from compound 20 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08 to 0.18 (m, 2 H), 0.41 to 0.58 (m, 2 H), 0.62 to 0.73 (m) , 1H), 0.78-0.98 (m, 2H), 1.18-1.34 (m, 1H), 1.53-1.95 (m, 3H), 2.20-2.45 (M, 4 H), 2.48-2.65 (m, 1 H), 3.05 (d, J = 18 Hz, 1 H), 3.20 (s, 3 H), 3.42 (d, J = 6 Hz , 1H), 4.50 (d, J = 14 Hz, 1 H), 4.57 (d, J = 14 Hz, 1 H), 4.60-4.90 (m, 1 H), 6.53 (d, J = 8 Hz, 1 H), 6.74 (d, J = 8 Hz, 1 H), 6.84 (t, J = 8 Hz, 1 H), 6.89 (s, 1 H), 6.98 (d, J = 8 Hz , 1H), .15 (d, J = 8Hz, 1H), 7.21-7.28 (m, 1H), 9.62 (br s, 1H).

(Example 17)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (furan-2-ylmethyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (22)

The title compound 22 was obtained from compound 4 and N-methylfurfurylamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.14 (m, 2 H), 0.47 to 0.55 (m, 2 H), 0.72 to 0.89 (m) , 2H), 0.98 (ddd, J = 6, 13, 13 Hz, 1 H), 1.33-1.39 (m, 1 H), 1.63-1.66 (m, 1 H), 1.77 -1.98 (m, 2H), 2.26-2.42 (m, 4H), 2.56-2.60 (m, 1H), 2.99 (s, 1.2 H), 3.03 (S, 1.8 H), 3.08 (d, J = 18 Hz, 1 H), 3. 36 (d, J = 6 Hz, 0.4 H), 3.41 (d, J = 6 Hz, 0.6 H) , 3.47 (s, 1.8 H), 3.55 (s, 1.2 H), 3.89 (s, 3 H), 4.52-4. 68 (m, 3 H), 6.31-6 .35 (m, 2H), 6 59 (d, J = 8Hz, 1H), 6.68-6.75 (m, 2H), 7.37 (s, 1H).

(Example 18)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (furan-2-ylmethyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (23)

The title compound 23 was obtained from compound 22 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.17 (m, 2 H), 0.47 to 0.56 (m, 2 H), 0.70 to 0.89 (m) , 2H), 0.95 (ddd, J = 6, 13, 13 Hz, 1 H), 1.26 to 1.34 (m, 1 H), 1.66 to 1.85 (m, 3 H), 2.28 -2.46 (m, 4H), 2.59 (d, J = 5, 12 Hz, 1 H), 3.02-3.40 (m, 5 H), 4.51 (s, 1 H), 4.60 −4.76 (m, 3 H), 5.48 (br s, 1 H), 6.36 (br s, 2 H), 6.56 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 7.86-7. 10 (m, 1 H), 7.42 (br s, 1 H).

(Example 19)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (thiophen-2-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (24)

The title compound 24 was obtained from compound 4 and N-methyl-2-thiophenemethylamine (synthesized by the method described in Journal lf Medicinal Chemistry 2017, 60, 972) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.16 (m, 2 H), 0.47 to 0.55 (m, 2 H), 0.72 to 0.89 (m) , 2H), 0.98 (ddd, J = 5, 12, 12 Hz, 1 H), 1.33-1.39 (m, 1 H), 1.64-1. 66 (m, 1 H), 1.79. -1.98 (m, 2H), 2.26-2.43 (m, 4H), 2.58 (dd, J = 5, 12 Hz, 1 H), 2.96 (s, 1.2 H), 3 .01 (s, 1.8 H), 3.05-3. 10 (m, 1 H), 3. 35 (d, J = 6 Hz, 0.4 H), 3.41 (d, J = 6 Hz, 0. 6). 6H), 3.49 (s, 1.8 H), 3.58 (s, 1.2 H), 3.89 (s, 3 H), 4.69-4.88 (m, 3 H), 6.59 (D, J = 8 Hz, 1 ), 6.68-6.78 (m, 2H), 6.95-7.04 (m, 2H), 7.24-7.28 (m, 1H).

Example 20
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (thiophen-2-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (25)

The title compound 25 was obtained from compound 24 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08 to 0.17 (m, 2 H), 0.44 to 0.57 (m, 2 H), 0.70 to 0.88 (m) , 2H), 0.94 (ddd, J = 6, 13, 13 Hz, 1H), 1.27-1.34 (m, 1H), 1.66-1.84 (m, 3H), 2.27 -2.40 (m, 4 H), 2.55-2.63 (m, 1 H), 3.00-3.21 (m, 4 H), 3.34-3.44 (m, 1 H), 4 .51 (s, 1 H), 4.60-4.95 (m, 3 H), 5. 40 (br s, 1 H), 6.56 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 6.87-7.05 (m, 3 H), 7. 27-7. 29 (m, 1 H).

(Example 21)
(4R, 4aS, 7R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((1-methyl-1H-pyrazol-3-yl) methyl) -1 Synthesis of 2,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (26)

Titles of compound 4 and N-methyl-1- (1-methyl-1H pyrazol-3-yl) methanamine (synthesized by the method described in Journal af Medicinal Chemistry 2017, 60, 972) according to the method described in Example 1 Compound 26 was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.15 (m, 2 H), 0.47 to 0.57 (m, 2 H), 0.70 to 0.89 (m) , 2H), 0.98 (ddd, J = 6, 13, 13 Hz, 1 H), 1.33-1.39 (m, 1 H), 1.60-1.68 (m, 1 H), 1.79. -1.98 (m, 2H), 2.26-2.43 (m, 4H), 2.58 (dd, J = 5, 12 Hz, 1 H), 2.95 (s, 1.5 H), 3 .00 (s, 1.5 H), 3.06-3. 10 (m, 1 H), 3. 35-3. 42 (m, 1 H), 3.51 (s, 1.5 H), 3.57 (Br s, 1.5 H), 3.87-3. 89 (m, 6 H), 4.50-4. 82 (m, 3 H), 6. 28-6. 29 (m, 1 H), 6. 57-6.60 (m, 1 ), 6.66 (s, 0.5H), 6.71 (s, 0.5H), 6.73-6.75 (m, 1H), 7.30-7.31 (m, 1H).

(Example 22)
(4R, 4aS, 7R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N-((1-methyl-1H-pyrazol-3-yl) methyl) -1 Synthesis of 2,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (27)

The title compound 27 was obtained from compound 26 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.17 (m, 2 H), 0.45 to 0.57 (m, 2 H), 0.68 to 1.00 (m) , 3H), 1.28-1.34 (m, 1 H), 1.64-1.89 (m, 3 H), 2.27-2.45 (m, 4 H), 2.55-2.62 (M, 1 H), 2.98-3. 16 (m, 4 H), 3. 36-3. 44 (m, 1 H), 3. 88 (s, 3 H), 4.5 1-4. 76 (m , 3H), 4.93 (s, 0.4 H), 5.29 (s, 0.6 H), 5.87 (br s, 1 H), 6.26 (s, 1 H), 6. 55 (d) , J = 8 Hz, 1 H), 6.75 (d, J = 8 Hz, 1 H), 6.86-6. 91 (m, 1 H), 7.32 (s, 1 H).

(Example 23)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (pyridin-4-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (28)

The title compound 28 was obtained from compound 4 and N-methyl-1- (pyridin-4-yl) methanamine (synthesized by the method described in WO2009057827) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.17 (m, 2 H), 0.45 to 0.57 (m, 2 H), 0.68 to 0.87 (m , 2H), 1.02 (ddd, J = 6, 12, 12 Hz, 1 H), 1.31-1.36 (m, 1 H), 1.65-1. 68 (m, 1 H), 1.84 -1.99 (m, 2H), 2.24-2.44 (m, 4H), 2.59 (dd, J = 5, 12 Hz, 1 H), 2.97 (s, 0.9 H), 2 .99 (s, 2.1 H), 3.02-3.12 (m, 1 H), 3. 29 (d, J = 6 Hz, 0.3 H), 3.44 (d, J = 6 Hz, 0. 2). 7H), 3.58 to 3.60 (m, 3H), 3.88 (s, 0.9 H), 3.91 (s, 2.1 H), 4.54 to 4.80 (m, 3 H) , 6.57-6.77 m, 3H), 7.23-7.28 (m, 2H), 8.57-8.60 (m, 2H).

(Example 24)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (pyridin-4-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (29)

The title compound 29 was obtained from compound 28 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04 to 0.20 (m, 2 H), 0.38 to 0.59 (m, 2 H), 0.62 to 1.05 (m) , 3H), 1.28-1 to 39 (m, 1H), 1.60-1.89 (m, 3H), 2.21-2.66 (m, 5H), 2.99-3.18. (M, 4 H), 3.26-3. 45 (m, 1 H), 4. 46-4. 82 (m, 4 H), 6. 18 (br s, 1 H), 6.57-6. m, 3H), 7.23-7.26 (m, 2H), 8.65 (br s, 2H).

(Example 25)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (pyridin-3-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (30)

The title compound 30 was obtained from compound 4 and N-methyl-1- (pyridin-3-yl) methanamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11-0.15 (m, 2 H), 0.50-0.56 (m, 2 H), 0.70-0.88 (m) , 2H), 1.01 (ddd, J = 6, 13, 13 Hz, 1 H), 1.30-1.36 (m, 1 H), 1.61-1.67 (m, 1 H), 1.87 -1.98 (m, 2H), 2.27-2.44 (m, 4H), 2.59 (dd, J = 5, 12 Hz, 1 H), 2.92 (s, 0.9 H), 2 .97 (s, 2.1 H), 3.04-3. 11 (m, 1 H), 3.34-3. 44 (m, 1 H), 3.54 (s, 2.1 H), 3.59 (S, 0.9 H), 3.89-3. 90 (m, 3 H), 4.53-4. 80 (m, 3 H), 6.57-6.61 (m, 1 H), 6.70 -6.76 (m, 2H) 7.27-7.30 (m, 1H), 7.74-7.76 (m, 1H), 8.54-8.58 (m, 2H).

(Example 26)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (pyridin-3-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (31)

The title compound 31 was obtained from compound 30 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.16 (m, 2 H), 041-0.57 (m, 2 H), 0.67-1.02 (m, 3 H) ), 1.29-1.35 (m, 1 H), 1.60-1.85 (m, 3 H), 2.23-2.56 (m, 5 H), 2.95-3. 47 (m) , 5H), 4.24-5.32 (m, 4H), 6.55 (d, J = 8 Hz, 1H), 6.72-6. 83 (m, 2H), 7.31-7. 37 (M, 1 H), 7.64-7. 73 (m, 1 H), 8. 16 (br s, 1 H), 8.56-9.0 4 (m, 2 H).

(Example 27)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (pyridin-2-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (32)

The title compound 32 was obtained from the compound 4 and N-methyl-1- (pyridin-2-yl) methanamine (synthesized by the method described in WO2016100850) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.16 (m, 2 H), 0.43 to 0.56 (m, 2 H), 0.65 to 0.88 (m) , 2H), 1.01 (ddd, J = 6, 12, 12 Hz, 1 H), 1.33-1.39 (m, 1 H), 1.65-1. 67 (m, 1 H), 1.80 -2.00 (m, 2 H), 2.23-2.61 (m, 5 H), 3.01-3.11 (m, 4 H), 3.27 (d, J = 6 Hz, 0.3 H) , 3.42 (d, J = 6 Hz, 0.7 H), 3.55 (s, 3 H), 3.87 (s, 0.9 H), 3. 90 (s, 2.1 H), 4.63 -4.86 (m, 3 H), 6.55-6. 76 (m, 3 H), 7. 18-7.2 1 (m, 1 H), 7. 39 (d, J = 8 Hz, 0.3 H) , 7.47 (d, J = 8 z, 0.7H), 7.66-7.73 (m, 1H), 8.55 (d, J = 4Hz, 1H).

(Example 28)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (pyridin-2-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (33)

The title compound 33 was obtained from compound 32 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06 to 0.17 (m, 2 H), 042 to 0.55 (m, 2 H), 0.66 to 1.04 (m, 3 H) ), 1.21-1.33 (m, 1 H), 1.63-1.89 (m, 3 H), 2.23-2.46 (m, 4 H), 2.53-2.64 (m) , 1H), 2.96-3.59 (m, 5H), 4.51-6.08 (m, 5H), 6.51-6.59 (m, 1H), 6.65-6.92 (M, 2H), 7.19-7.48 (m, 2H), 7.66-7.78 (m, 1H), 8.55-6.81 (m, 1H).

(Reference Example 6)
Synthesis of tert-butyl ((5-methylpyridin-2-yl) methylcarbamate (34)

After dissolving 2-cyano-5-methylpyridine (1.00 g, 8.46 mmol) in tetrahydrofuran (30 mL) and adding lithium aluminum hydride (641 mg, 16.9 mmol) with ice cooling, Stir for 5 hours. Under ice-cooling, water (1 mL), 15% aqueous sodium hydroxide solution (1 mL), water (3 mL), and magnesium sulfate were sequentially added, and the mixture was stirred at room temperature for a while. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained crude product (769 mg) is dissolved in dichloromethane (20 mL), triethylamine (1.74 mL, 12.6 mmol), di-tert-butyl dicarbonate (1.59 mL, 6.92 mmol) are added and the mixture is stirred at room temperature. Stir for 25 hours. Saturated aqueous sodium hydrogen carbonate solution (20 mL) was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (30-51% ethyl acetate / hexane) to give the title compound 34 (834 mg, 44%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.46 (s, 9 H), 2. 32 (s, 3 H), 4. 40 (d, J = 5 Hz, 2 H), 5.51 ( Br s, 1 H), 7.17 (d, J = 8 Hz, 1 H), 7.46 (dd, J = 2, 8 Hz, 1 H), 8.36 (s, 1 H).

(Reference Example 7)
Synthesis of N-methyl-1- (5-methylpyridin-2-yl) methanamine (35)

Compound 34 (834 mg, 3.75 mmol) obtained in Reference Example 6 is dissolved in tetrahydrofuran (19 mL), lithium aluminum hydride (427 mg, 11.3 mmol) is added under ice cooling, and then heating under reflux 3 Stir for .5 hours. Under ice-cooling, water (1 mL), 15% aqueous sodium hydroxide solution (1 mL), water (3 mL), and magnesium sulfate were sequentially added, and the mixture was stirred at room temperature for a while. 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 (51-70% methanol / chloroform) to give the title compound 35 (70.5 mg, 14%) as a brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.32 (s, 3 H), 2.47 (s, 3 H), 3.83 (s, 2 H), 7.19 (d, J = 8 Hz, 1 H), 7. 45 (dd, J = 2, 8 Hz, 1 H), 8.39 (s, 1 H).

(Example 29)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((5-methylpyridin-2-yl) methyl) -1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (36)

The title compound 36 was obtained from compound 4 and compound 35 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.16 (m, 2 H), 0.44-0.56 (m, 2 H), 0.65-1. 05 (m , 3H), 1.32-1.39 (m, 1H), 1.64-1.67 (m, 1H), 1.79-2.00 (m, 2H), 2.24-2.43 (M, 7 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 3.01-3.11 (m, 4 H), 3.27 (d, J = 6 Hz, 0.4 H), 3 .42 (d, J = 6 Hz, 0.6 H), 3.54-3. 55 (m, 3 H), 3.88 (s, 1.2 H), 3. 90 (s, 1.8 H), 4 .62-4.90 (m, 3H), 6.55-6.76 (m, 3H), 7.28-7.38 (m, 1H), 7.48-7.52 (m, 1H) , 8.36 (s, 1 H).

(Example 30)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N-((5-methylpyridin-2-yl) methyl) -1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (37)

The title compound 37 was obtained from compound 36 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.17 (m, 2 H), 042 to 0.55 (m, 2 H), 0.65 to 1.01 (m, 3 H) ), 1.22-1.35 (m, 1 H), 1.62-1. 90 (m, 3 H), 2.25-2.45 (m, 7 H), 2.53-2.64 (m) , 1 H), 2.94-3. 21 (m, 4 H), 3.33 (d, J = 6 Hz, 0.6 H), 3.43 (d, J = 6 Hz, 0.4 H), 4.51 (S, 1 H), 4.61-6. 25 (m, 4 H), 6.53-6.57 (m, 1 H), 6.73-6.90 (m, 2 H), 7.19-7 30 (m, 1 H), 7.50-7.56 (m, 1 H), 8.39-8.43 (m, 1 H).

(Reference Example 8)
Synthesis of tert-butyl ((6-methylpyridin-2-yl) methyl) carbamate (38)

The title compound 38 was obtained from 2-cyano-6-methylpyridine according to the method described in Reference Example 6.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.47 (s, 9 H), 2.54 (s, 3 H), 4.40 (d, J = 5 Hz, 2 H), 5.54 (5.5 MHz) Br s, 1 H), 7.03 (d, J = 8 Hz, 1 H), 7.06 (d, J = 8 Hz, 1 H), 7.54 (dd, J = 8, 8 Hz, 1 H).

(Reference Example 9)
Synthesis of N-methyl-1- (6-methylpyridin-2-yl) methanamine (39)

The title compound 39 was obtained from compound 38 according to the method described in Reference Example 7.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.49 (s, 3 H), 2.54 (s, 3 H), 3.82 (s, 2 H), 7.02 (d, J = 8 Hz, 1 H), 7.10 (d, J = 8 Hz, 1 H), 7.53 (dd, J = 8, 8 Hz, 1 H).

(Example 31)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((6-methylpyridin-2-yl) methyl) -1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (40)

The title compound 40 was obtained from compound 4 and compound 39 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.16 (m, 2 H), 0.44 to 0.57 (m, 2 H), 0.65 to 1.06 (m) , 3H), 1.33-1.39 (m, 1 H), 1.64-1. 67 (m, 1 H), 1.78-2.00 (m, 2 H), 2.23-2.43 (M, 4H), 2.46-2.61 (m, 4H), 3.01-3.11 (m, 4H), 3.26 (d, J = 6 Hz, 0.4H), 3.42 (D, J = 6 Hz, 0.6 H), 3.54 (s, 1.2 H), 3.56 (s, 1.8 H), 3.87 (s, 1.2 H), 3. 90 (s , 1.8 H), 4.63-4.90 (m, 3 H), 6.55-6. 76 (m, 3 H), 7.04 (d, J = 8 Hz, 1 H), 7.17-7 .26 (m, 1 H), 7.52-7 61 (m, 1H).

(Example 32)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N-((6-methylpyridin-2-yl) methyl) -1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (41)

The title compound 41 was obtained from compound 40 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.17 (m, 2 H), 0.42 to 0.55 (m, 2 H), 0.66 to 1.02 (m , 3H), 1.23-1.33 (m, 1H), 1.62-1. 76 (m, 2H), 1.85 (ddd, J = 6, 13, 13 Hz, 1H), 2.25 -2.45 (m, 4H), 2.51-2.62 (m, 4H), 2.96-3. 21 (m, 4H), 3.33 (d, J = 6 Hz, 0.7 H) , 3.44 (d, J = 6 Hz, 0.3 H), 4.53 (s, 1 H), 4.64-4. 89 (m, 2 H), 6.01 (s, 1 H), 6.52 -6.57 (m, 1 H), 6.73-6.92 (m, 2 H), 7.06-7.17 (m, 2 H), 7.56-7.65 (m, 1 H).

(Example 33)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-((6-methoxypyridin-2-yl) methyl) -N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (42)

The title compound 42 was obtained from compound 4 and 1- (6-methoxypyridin-2-yl) -N-methylmethanamine (synthesized by the method described in WO2015050798) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06 to 0.15 (m, 2 H), 0.43 to 0.56 (m, 2 H), 0.66 to 0.90 (m) , 2H), 1.01 (ddd, J = 6, 12, 12 Hz, 1 H), 1.34-1.40 (m, 1 H), 1.61-1.67 (m, 1 H), 1.79 -2.00 (m, 2 H), 2.23-2.42 (m, 4 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 3.01-3.07 (m, 2. 5H), 3.11 (s, 1.5 H), 3.26 (d, J = 6 Hz, 0.5 H), 3.42 (d, J = 6 Hz, 0.5 H), 3.53 (s, 1.5 H), 3.55 (br s, 1.5 H), 3.88-3. 93 (m, 6 H), 4.57-4. 76 (m, 3 H), 6.56-6. 76 (M, 4H), 6. 6 (d, J = 8Hz, 0.5H), 6.98 (d, J = 8Hz, 0.5H), 7.53-7.58 (m, 1H).

(Example 34)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-((6-methoxypyridin-2-yl) methyl) -N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (43)

The title compound 43 was obtained from compound 42 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.17 (m, 2 H), 0.39-0.58 (m, 2 H), 0.65-1. 02 (m , 3H), 1.23-1.35 (m, 1H), 1.62-1.87 (m, 3H), 2.23-2.62 (m, 5H), 3.01-3.11 (M, 3H), 3.27-3.44 (m, 2H), 3.94 (s, 3H), 4.51-4.94 (m, 4H), 5.94 (br s, 1H) , 6.53-7.03 (m, 5H), 7.54-7.61 (m, 1 H).

(Example 35)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((6-oxo-1,6-dihydropyridin-2-yl) methyl) Synthesis of -1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (44)

The title compound 44 was obtained from compound 4 and 6-((methylamino) methyl) pyridin-2 (1H) -one (synthesized by the method described in WO2015050798) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11 to 0.16 (m, 2 H), 0.48 to 0.56 (m, 2 H), 0.75 to 11 1 (m) , 3H), 1.27-1.33 (m, 1H), 1.66-1.68 (m, 1H), 1.88-2.09 (m, 2H), 2.27-2.46 (M, 4H), 2.59 (dd, J = 5, 12 Hz, 1H), 2.90 (s, 1.2 H), 3.03-3.11 (m, 2.8 H), 3.36 (Br s, 0.4 H), 3.44 (d, J = 7 Hz, 0.6 H), 3.65 (s, 1.8 H), 3.81 (s, 1.2 H), 3.90 3.91 (m, 3 H), 4.40 to 4. 81 (m, 3 H), 6.05 to 6. 10 (m, 1 H), 6.46 to 6.49 (m, 1 H), 6. 60 (d, J = 8 Hz, 1 H), .74-6.77 (m, 2H), 7.31-7.35 (m, 1H).

(Example 36)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N-((6-oxo-1,6-dihydropyridin-2-yl) methyl) Synthesis of -1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (45)

The title compound 45 was obtained from compound 44 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.17 (m, 2 H), 0.45-0.57 (m, 2 H), 0.68-0.90 (m , 2H), 0.96 (ddd, J = 5, 13, 13 Hz, 1 H), 1.32-1. 42 (m, 1 H), 1.65-1. 89 (m, 3 H), 2. 25 -2.62 (m, 5 H), 2.91-3. 15 (m, 4 H), 3.40-3. 46 (m, 1 H), 4.33-4. 68 (m, 3 H), 6 .16 (d, J = 6 Hz, 0.5 H), 6.26 (d, J = 6 Hz, 0.5 H), 6.51-6.88 (m, 4 H), 7.35-7.47 ( m, 1 H).

(Example 37)
((4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of -Methanobenzofuro [3,2-e] isoquinolin-6-yl) (isoindolin-2-yl) methanone (46)

The title compound 46 was obtained from compound 4 and isoindoline according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08 to 0.19 (m, 2 H), 0.41 to 0.58 (m, 2 H), 0.71 to 0.95 (m) , 2H), 1.00-1.10 (m, 1 H), 1.22-1. 30 (m, 1 H), 1.38-1.48 (m, 1 H), 1.68-1.74 (M, 1 H), 1.80 to 1.91 (m, 1 H), 1.95 to 2.55 (m, 1 H), 2.25 to 2.42 (m, 3 H), 2.61 (dd , J = 5, 12 Hz, 1 H), 3.09 (d, J = 18 Hz, 1 H), 3.44 (d, J = 6 Hz, 1 H), 3.53 (s, 3 H), 3. 90 (s) , 3H), 4.74 (d, J = 2 Hz, 1 H), 4.82-5.00 (m, 4 H), 6.62 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), .84 (s, 1H), 7.25-7.35 (m, 4H).

(Example 38)
((4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of -Methanobenzofuro [3,2-e] isoquinolin-6-yl) (isoindolin-2-yl) methanone (47)

The title compound 47 was obtained from compound 46 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.18 (m, 2 H), 0.46 to 0.60 (m, 2 H), 0.72 to 0.92 (m) , 2H), 0.95-1.05 (m, 1H), 1.20-1.38 (m, 2H), 1.65-1.82 (m, 2H), 1.83-1.92. (M, 1 H), 2.28-2.46 (m, 4 H), 2.62 (dd, J = 5, 12 Hz, 1 H), 3.08 (d, J = 18 Hz, 1 H), 3.45 (D, J = 7 Hz, 1 H), 4.56 (s, 1 H), 4.84-5.05 (m, 4 H), 5. 37 (br s, 1 H), 6.56 (d, J = 8 Hz, 1 H), 6.77 (d, J = 8 Hz, 1 H), 7.12 (s, 1 H), 7.10-7.33 (m, 4 H).

(Example 39)
((4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of -Methanobenzofuro [3,2-e] isoquinolin-6-yl) (3,4-dihydroquinolin-1 (2H) -yl) methanone (48)

Compound 5 (49.6 mg, 0.108 mmol) is dissolved in N, N-dimethylformamide (2 mL), 1,2,3,4-tetrahydroquinoline (41.0 μL, 0.33 mmoL), N, N-diisopropyl Ethylamine (94.0 μL, 0.55 mmol) and HATU (62.0 mg, 0.163 mmol) were added and stirred at room temperature for 19.5 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (44-65% ethyl acetate / hexane) to give the title compound 48 (9.0 mg, 16%) as white crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08 to 0.15 (m, 2 H), 0.47 to 0.55 (m, 2 H), 0.58 to 0.94 (m) , 3H), 1.50-2.13 (m, 7H), 2.24-2.40 (m, 4H), 2.53-2.60 (m, 1H), 2.74-2.82 (M, 2 H), 3.04 (d, J = 18 Hz, 1 H), 3.32-3.52 (m, 4 H), 3.75-4. 79 (m, 5 H), 6.56 (d , J = 8 Hz, 1 H), 6.66-6.78 (m, 2 H), 7.01-7. 17 (m, 4 H).

(Example 40)
((4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of -Methanobenzofuro [3,2-e] isoquinolin-6-yl) (3,4-dihydroquinolin-1 (2H) -yl) methanone (49)

The title compound 49 was obtained from compound 48 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02 to 0.09 (m, 2 H), 0.39 to 0.49 (m, 2 H), 0.62 to 0.90 (m) , 3H), 1.13-1.38 (m, 2H), 1.58-1.79 (m, 3H), 1.93-2.03 (m, 1H), 2.10-2.32 (M, 5 H), 2.49 (dd, J = 5, 12 Hz, 1 H), 2.81-2. 84 (m, 2 H), 3.00 (d, J = 18 Hz, 1 H), 3.15 (D, J = 6 Hz, 1 H), 3.66 to 3.74 (m, 1 H), 4.06 to 4.12 (m, 1 H), 4.51 (s, 1 H), 4.82 (br) s, 1 H), 6.40 (br s, 1 H), 6.53 (d, J = 8 Hz, 1 H), 6.73 (d, J = 8 Hz, 1 H), 7.06-7.23 (m , 4H).

(Example 41)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (3-phenylpropyl) -1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (50)

The title compound 50 was obtained from compound 4 and N-methyl-3-phenylpropan-1-amine (Bioorganic & Medicinal Chemistry 2008, 16, 9729) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.15 (m, 2 H), 0.46 to 0.55 (m, 2 H), 0.60 to 1.03 (m) , 3H), 1.32-2.00 (m, 7H), 2.26-2.42 (m, 4H), 2.54-2.71 (m, 3H), 3.00-3.10 (M, 4 H), 3.24-3.52 (m, 5 H), 3.89 (s, 3 H), 4.69 (br s, 1 H), 6.58-6.63 (m, 2 H) , 6.73-6.75 (m, 1 H), 7.13-7. 31 (m, 5 H).

(Example 42)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (3-phenylpropyl) -1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (51)

The title compound 51 was obtained from compound 50 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.12 to 0.17 (m, 2 H), 0.48 to 0.56 (m, 2 H), 0.60 to 0.99 (m) , 3H), 1.10-1.33 (m, 1 H), 1.60-1.83 (m, 3 H), 1.93-2.05 (m, 2 H), 2.26-2.46 (M, 4 H), 2.56-2.71 (m, 3 H), 3.01-3. 16 (m, 4 H), 3.32 (d, J = 6 Hz, 0.5 H), 3.41 (D, J = 6 Hz, 0.5 H), 3.49-3.55 (m, 2 H), 4.46-4. 48 (m, 1 H), 4.56 (s, 0.5 H), 4 .85 (s, 0.5 H), 5.61 (br s, 1 H), 6.55 (d, J = 8 Hz, 1 H), 6.75-6. 79 (m, 2 H), 7.14 7.31 (m, 5H).

(Example 43)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N- (2-morpholinoethyl) -1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (52)

The title compound 52 was obtained from compound 4 and 2-morpholineethane-1-amine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.15 (m, 2 H), 0.47 to 0.57 (m, 2 H), 0.68 to 0.75 (m) , 1 H), 0.85 to 0.95 (m, 2 H), 1.23-1.30 (m, 2 H), 1.58 (dd, J = 2, 13 Hz, 1 H), 1.76-1 .86 (m, 2 H), 2.27-2. 40 (m, 4 H), 2.50-2. 60 (m, 6 H), 3.08 (d, J = 18 Hz, 1 H), 3.43 -3.50 (m, 3H), 3.61 (s, 3H), 3.72-3.74 (m, 4H), 3.90 (s, 3H), 4.47 (d, J = 2 Hz) , 1H), 6.61 (d, J = 8 Hz, 1 H), 6.75 (d, J = 8 Hz, 1 H), 7.79 (s, 1 H), 8.15 (t, J = 5 Hz, 1 H) ).

(Example 44)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (2-morpholinoethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (53)

Compound 52 (44.6 mg, 0.0833 mmol) is dissolved in N, N-dimethylformamide (2 mL), sodium hydride (55%, 18.4 mg, 0.42 mmol) is added under ice cooling, and the mixture is stirred for 10 minutes. did. After adding methyl iodide (21 μL, 0.34 mmol) and stirring at room temperature for 8 hours, water (10 mL) was added to the reaction mixture and extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (2-9% methanol / chloroform) to give the title compound 53 (34.1 mg, 74%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.15 (m, 2 H), 0.47 to 0.55 (m, 2 H), 0.72 to 0.88 (m) , 2H), 0.98 (ddd, J = 6, 13, 13 Hz, 1 H), 1.33-1.39 (m, 1 H), 1.62-1. 66 (m, 1 H), 1.79. -1. 97 (m, 2 H), 2.27-2. 61 (m, 11 H), 3.04-3. 11 (m, 4 H), 3. 35-3. 73 (m, 10 H), 3 .89 (s, 3H), 4.68 (br s, 1H), 6.60 (d, J = 8 Hz, 1 H), 6.65 (s, 1 H), 6.75 (d, J = 8 Hz, 1H).

(Example 45)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (2-morpholinoethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (54)

The title compound 54 was obtained from compound 53 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.12 to 0.18 (m, 2 H), 0.49 to 0.57 (m, 2 H), 0.72 to 0.99 (m) , 3H), 1.25-1.31 (m, 1H), 1.63-1.86 (m, 3H), 2.28-2.62 (m, 11H), 3.05-3.21 (M, 4 H), 3.38-3. 42 (m, 1 H), 3.52-3. 74 (m, 6 H), 4.48 (s, 1 H), 6.56 (d, J = 8 Hz , 1 H), 6.75 (d, J = 8 Hz, 1 H), 6.85-6.88 (m, 1 H).

(Example 46)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((1-methyl-1H-indol-3-yl) methyl) -1 Synthesis of 2,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (55)

The title compound 55 was obtained from compound 4 and N-methyl-1- (1-methyl-1H-indol-3-yl) methanamine (Journal оf Medicinal Chemistry 2003, 46, 1627) according to the method described in Example 1 .

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.15 (m, 2 H), 0.46 to 0.54 (m, 2 H), 0.69 to 1.01 (m , 3H), 1.30-1.40 (m, 1 H), 1.59-1.65 (m, 1 H), 1.79-2.00 (m, 2 H), 2.25-2.40 (M, 4H), 2.55-2.60 (m, 1H), 2.95 (s, 3H), 3.05-3.09 (m, 1H), 3.35-3.49 (m , 3H), 3.63 (br s, 1 H), 3.78 (s, 3 H), 3.89 (s, 3 H), 4.75 to 4.92 (m, 3 H), 6.57-6 77 (m, 3 H), 7.08-7. 18 (m, 2 H), 7.23-7. 34 (m, 2 H), 7.63-7. 79 (m, 1 H).

(Example 47)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N- (2-phenylpropan-2-yl) -1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (56)

The title compound 56 was obtained from compound 4 and 1-methyl-1-phenylethylamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.10 (m, 2 H), 0.43 to 0.51 (m, 2 H), 0.71 (ddd, J = 3) , 10, 13 Hz, 1 H), 0.80 to 0.95 (m, 2 H), 1.24-1. 31 (m, 1 H), 1.56-1.60 (m, 1 H), 1.76 -1.89 (m, 8 H), 2.26-2.37 (m, 4 H), 2.55 (d, J = 5, 12 Hz, 1 H), 3.06 (d, J = 18 Hz, 1 H) , 3.41 (d, J = 7 Hz, 1 H), 3.63 (s, 3 H), 3. 90 (s, 3 H), 4.51 (d, J = 2 Hz, 1 H), 6.60 (d , J = 8 Hz, 1 H), 6.75 (d, J = 8 Hz, 1 H), 7.22 (tt, J = 1, 8 Hz, 1 H), 7.34 (t, J = 8 Hz, 2 H), 7 .4 (Dd, J = 1,8Hz, 2H), 7.78 (s, 1H), 8.34 (br s, 1H).

(Example 48)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (2-phenylpropan-2-yl) -1,2,3,4 Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (57)

The title compound 57 was obtained from compound 56, according to the method described in Example 44.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11-0.15 (m, 2 H), 0.48-0.57 (m, 2 H), 0.68-0.90 (m , 2H), 0.96 (ddd, J = 6, 12, 12 Hz, 1 H), 1.28-1.38 (m, 1 H), 1.55-1.60 (m, 1 H), 1.75 -1.84 (m, 7 H), 1.91 (ddd, J = 6, 13, 13 Hz, 1 H), 2.27-2.41 (m, 4 H), 2.55 (d, J = 5, 12 Hz, 1 H), 3.05-3.09 (m, 4 H), 3.39-3. 46 (m, 1 H), 3.54 (s, 3 H), 3.89 (s, 3 H), 4 .67 (br s, 1 H), 6.55 (s, 1 H), 6.58 (d, J = 8 Hz, 1 H), 6.74 (d, J = 8 Hz, 1 H), 7.19 (t, J = 8H , 1H), 7.31 (t, J = 8Hz, 2H), 7.43 (dd, J = 1,8Hz, 2H).

(Example 49)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a, 7-ethano- Synthesis of 4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (58)

The title compound 58 was obtained from compound 57 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.12 to 0.18 (m, 2 H), 0.50 to 0.58 (m, 2 H), 0.65 to 0.71 (m) , 1 H), 0.82-0.92 (m, 2 H), 1.23-31 (m, 1 H), 1.61-1. 80 (m, 3 H), 2.26-2.47 (M, 4H), 2.58 (dd, J = 5, 12 Hz, 1 H), 2.92 (d, J = 5 Hz, 3 H), 3.07 (d, J = 18 Hz, 1 H), 3.46 (D, J = 6 Hz, 1 H), 4.39 (s, 1 H), 5.81 (br s, 1 H), 6.56 (d, J = 8 Hz, 1 H), 6.75 (d, J = 8 Hz, 1 H), 6. 90 (br s, 1 H), 7.42 (s, 1 H).

(Reference Example 10)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a, Synthesis of 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (59)

The title compound 59 was obtained from compound 4 and N-methyl-1-phenylmethanamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06 to 0.19 (m, 2 H), 0.44 to 0.60 (m, 2 H), 0.65 to 0.94 (m) , 2.4 H), 1.00 (ddd, J = 6, 12, 12 Hz, 0.6 H), 1.30 to 1.43 (m, 0.4 H), 1.55 to 1.76 (m, 2H), 1.81-2.03 (m, 1.6 H), 2.23-2.46 (m, 4 H), 2.47-2.66 (m, 1 H), 2.92 (s, 1.2 H), 2.95 (s, 1.8 H), 3.05 (d, J = 18 Hz, 0.4 H), 3.09 (d, J = 18 Hz, 0.6 H), 3.31 (d d, J = 6 Hz, 0.4 H), 3.43 (d, J = 6 Hz, 0.6 H), 3.54 (s, 1.8 H), 3.59 (s, 1.2 H), 3. 89 (s, 1.2 H), 3 90 (s, 1.8 H), 4.48-4.91 (m, 3 H), 6.58 (d, J = 8 Hz, 0.4 H), 6.60 (d, J = 8 Hz, 0.6 H) ), 6.66-6.72 (m, 1 H), 6.73 (d, J = 8 Hz, 0.4 H), 6. 75 (d, J = 8 Hz, 0.6 H), 7.24-7 .41 (m, 5H).

(Reference Example 11)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a, Synthesis of 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (60)

The title compound 60 was obtained from compound 59 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.01-0.20 (m, 2 H), 0.37-0.59 (m, 2 H), 0.65-1. 05 (m , 3H), 1.23-1.39 (m, 1H), 1.58-1.96 (m, 3H), 2.20-2.48 (m, 4H), 2.49-2.67 (M, 1 H), 2.91-3. 17 (m, 4 H), 3. 29 (d, J = 5 Hz, 0.6 H), 3.43 (d, J = 5 Hz, 0.4 H), 4 .57 (s, 1 H), 4.6 1-4.99 (m, 3 H), 6. 5-6. 60 (m, 1 H), 6.7 2-6. 80 (d, J = 8 Hz, 1 H) , 6.84 (s, 1 H), 7.25-7.43 (m, 5 H).

(Example 50)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3- (cyclopropylmethyl) -9-hydroxy-7-methoxy-N-methyl-1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (61)

Compound 59 (40.9 mg, 0.078 mmol) is dissolved in N, N-dimethylformamide (3 mL), 1-dodecanethiol (93 μL, 0.39 mmol) and potassium tert-butoxide (44.8 mg, 0.40 mmol) Was added and stirred at 140 ° C. for 5.5 hours. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-6% methanol / chloroform) to give the title compound 61 (35.6 mg, 89%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.15 (m, 2 H), 0.47 to 0.56 (m, 2 H), 0.66 to 1.03 (m , 3H), 1.25-1.44 (m, 1 H), 1.58-1.68 (m, 1 H), 1.75-1. 82 (m, 1 H), 1.91-1.99 (M, 1 H), 2.23-2.62 (m, 5 H), 2.93 (s, 1.2 H), 2.96 (s, 1.8 H), 3.01-3. 09 (m , 1H), 3.30 (d, J = 7 Hz, 0.4 H), 3.42 (d, J = 7 Hz, 0.6 H), 3.49 (s, 1.8 H), 3.56 (s) , 1.2H), 4.56-4.78 (m, 3H), 6.52-6.56 (m, 1H), 6.60-6. 76 (m, 2H), 7.28-7 .38 (m, 5H).

(Example 51)
(4R, 4aS, 7R, 7aR, 12bS) -N- (3-carbamoylbenzyl) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (62)

The title compound 62 was obtained from compound 4 and 3-((methylamino) methyl) benzamide (synthesized by the method described in WO2007124898) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.17 (m, 2 H), 0.47 to 0.56 (m, 2 H), 0.65 to 0.92 (m) , 2.4 H), 0.97-1. 05 (m, 0.6 H), 1.25-1.39 (m, 1 H), 1.56-2.05 (m, 3 H), 2.22 -2.65 (m, 5 H), 2.93 (s, 1.2 H), 2.97 (s, 1.8 H), 3.02-3.14 (m, 1 H), 3.30-3 .43 (m, 1 H), 3.55-3.75 (m, 3 H), 3.89 (s, 1.2 H), 3. 90 (s, 1.8 H), 4.25-5. 10 (M, 3 H), 5.54 (br s, 1 H), 6.42 (br s, 1 H), 6.56-6.63 (m, 1 H), 6.75-6.78 (m, 2 H) ), 7.40-7.55 (m, 2H) , 7.75-7.90 (m, 2H).

(Example 52)
(4R, 4aS, 7R, 7aR, 12bS) -N- (3-carbamoylbenzyl) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (63)

The title compound 63 was obtained from compound 62 according to the method described in Example 2.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.04-0.24 (m, 2 H), 0.40-1.05 (m, 5 H), 1.17-1. 38 ( m, 1 H), 1.45-1.80 (m, 2.4 H), 1.86-2.00 (m, 0.6 H), 2.20-2.68 (m, 5 H), 96-3.14 (m, 4H), 3.36 (d, J = 5 Hz, 0.4 H), 3.50 (d, J = 5 Hz, 0.6 H), 4.34 (s, 0.4 H) ), 4.43 (s, 0.6 H), 4.68-4.85 (m, 2 H), 6.45-6. 55 (m, 1 H), 6.60-6.73 (m, 2 H) ), 7.42-7.60 (m, 2H), 7.73-7.91 (m, 2H).

(Reference Example 12)
Synthesis of N-methyl-1- (3- (trifluoromethoxy) phenyl) methanamine (64)

3- (Trifluoromethoxy) benzaldehyde (500 mg, 2.63 mmol) was dissolved in methanol (5 mL), 2 M methylamine-ethanol solution (7.9 mL, 15.8 mmol) was added, and stirred at room temperature for 6 hours. Sodium borohydride (497.4 mg, 13.1 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound 64 (505 mg, 93%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.46 (s, 3 H), 3.77 (s, 2 H), 7.08 to 7.12 (m, 1 H), 7.20 ( s, 1 H), 7.23-7. 27 (m, 1 H), 7. 35 (t, J = 8 Hz, 1 H).

(Example 53)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (3- (trifluoromethoxy) benzyl) -1,2,3,4 Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (65)

The title compound 65 was obtained from compound 4 and compound 64 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.19 (m, 2 H), 0.45-0.58 (m, 2 H), 0.68-0.88 (m , 3H), 1.25-1.41 (m, 1 H), 1.56-1.70 (m, 1 H), 1.83-2.20 (m, 1.6 H), 2.25-2 .67 (m, 5.4 H), 2.93 (s, 1.2 H), 2.97 (s, 1.8 H), 3.03-3.14 (m, 1 H), 3.32 (d , J = 6 Hz, 0.4 H), 3.43 (d, J = 6 Hz, 0.6 H), 3.57 (s, 1.8 H), 3.59 (s, 1.2 H), 3.89 (S, 1.2H), 3.90 (s, 1.8H), 4.53-4.86 (m, 3H), 6.55-6.62 (m, 1H), 6.67-6 .78 (m, 2H), 7.12-7.17 m, 1H), 7.20-7.30 (m, 2H), 7.34-7.41 (m, 1H).

(Example 54)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (3- (trifluoromethoxy) benzyl) -1,2,3,4 Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (66)

The title compound 66 was obtained from compound 65 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.01-0.20 (m, 2 H), 0.37-0.59 (m, 2 H), 0.62-1.06 (m , 3H), 1.20-1.40 (m, 1 H), 1.58-1.91 (m, 3 H), 2.20-2.66 (m, 5 H), 2.96-3.15 (M, 4H), 3.30 (d, J = 5 Hz, 0.4 H), 3.44 (d, J = 5 Hz, 0.6 H), 4.56-4. 85 (m, 3 H), 4 .93 (br s, 1 H), 6.52-6.59 (m, 1 H), 6.72-6. 89 (m, 2 H), 7.10-7.20 (m, 2 H), 7. 23-7. 31 (m, 1 H), 7.35-7. 46 (m, 1 H).

(Reference Example 13)
Synthesis of 3- (methylsulfonyl) benzaldehyde (67)

Dissolve (3- (methylsulfonyl) phenyl) methanol (synthesized by the method described in WO2005044817) (866 m, 4.65 mmol) in ethyl acetate (25 mL) and add manganese dioxide (2.02 g, 23.2 mmol) The mixture was heated to reflux for 1 hour. After allowing to cool, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound 67 (776 mg, 91%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.11 (s, 3 H), 7.79 (dd, J = 8, 8 Hz, 1 H), 8.18-8.24 (m, 2 H) ), 8.46 (dd, J = 2, 2 Hz, 1 H), 10.1 (s, 1 H).

(Reference Example 14)
Synthesis of N-methyl-1- (3- (methylsulfonyl) phenyl) methanamine (68)

The title compound 68 was obtained from compound 67 according to the method described in Reference Example 12.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.47 (s, 3 H), 3.06 (s, 3 H), 3.85 (s, 2 H), 7.54 (dd, J = 8, 8 Hz, 1 H), 7.64 (d, J = 8 Hz, 1 H), 7. 84 (d, J = 8 Hz, 1 H), 7.92 (s, 1 H).

(Example 55)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (3- (methylsulfonyl) benzyl) -1,2,3,4, Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (69)

The title compound 69 was obtained from compound 4 and compound 68 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11 to 0.16 (m, 2 H), 0.49 to 0.56 (m, 2 H), 0.69 to 1.05 (m , 3H), 1.26 to 1.36 (m, 1H), 1.65 to 1.99 (m, 2H), 2.26 to 2.43 (m, 4H), 2.57 to 2.61 (M, 1 H), 2.94-3.12 (m, 8 H), 3.35-3. 43 (m, 1 H), 3.58-3. 61 (m, 3 H), 3.88-3 .90 (m, 3H), 4.69-4.81 (m, 3H), 6.57-6.61 (m, 1H), 6.75-6.76 (m, 2H), 7.54 -7.59 (m, 1 H), 7.65-7.71 (m, 1 H), 7.87-7.90 (m, 2 H).

(Example 56)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (3- (methylsulfonyl) benzyl) -1,2,3,4, Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (70)

The title compound 70 was obtained from compound 69 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.15 (m, 2 H), 0.46-0.55 (m, 2 H), 0.70-0.99 (m) , 3H), 1.12-1.36 (m, 2H), 1.66-1.83 (m, 2H), 2.22-2.62 (m, 5H), 3.02-3.16 (M, 7 H), 3.33-3. 46 (m, 1 H), 4.50-4.99 (m, 4 H), 6.57 (d, J = 8 Hz, 1 H), 6.75 (d , J = 8 Hz, 1 H), 6.83-6.90 (m, 1 H), 7.57-7.68 (m, 2 H), 7.85-7.88 (m, 2 H).

(Reference Example 15)
Synthesis of 1- (2-Fluoro-3-methoxyphenyl) -N-methylmethanamine (71)

The title compound 71 was obtained from 2-fluoro-3-methoxybenzaldehyde according to the method described in Reference Example 12.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.44 (s, 3 H), 3.81 (s, 2 H), 3.89 (s, 3 H), 6.86 to 6.91 ( m, 2H), 7.03 (ddd, J = 1, 8, 8 Hz, 1H).

(Example 57)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (2-fluoro-3-methoxybenzyl) -7,9-dimethoxy-N-methyl-1,2,3,4 Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (72)

The title compound 72 was obtained from compound 4 and compound 71 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.15 (m, 2 H), 0.44 to 0.55 (m, 2 H), 0.68 to 1.03 (m , 3H), 1.25-1.38 (m, 1H), 1.58-1.99 (m, 3H), 2.25-2.61 (m, 5H), 2.97-3.14 (M, 4H), 3.30 (d, J = 6 Hz, 0.6 H), 3.42 (d, J = 6 Hz, 0.4 H), 3.52 (s, 1.8 H), 3.56 (S, 1.2 H), 3.88-3. 90 (m, 6 H), 4.67-4. 78 (m, 3 H), 6.56-6.76 (m, 3 H), 6.86 -7.10 (m, 3H).

(Example 58)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (2-fluoro-3-hydroxybenzyl) -7,9-dihydroxy-N-methyl-1,2,3,4 Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (73)

The title compound 73 was obtained from compound 72 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.13 (m, 2 H), 0.44 to 0.58 (m, 2 H), 0.50 to 0.95 (m) , 3H), 1.23-1.83 (m, 4H), 2.27-2.58 (m, 5H), 2.95-3.12 (m, 4H), 3.36-3.47. (M, 1 H), 4.53 (s, 1 H), 4. 68-4. 90 (m, 2 H), 6.55 (d, J = 8 Hz, 1 H), 6.75-7.02 (m , 5H).

(Reference Example 16)
Synthesis of 1- (2-Fluoro-5-methoxyphenyl) -N-methylmethanamine (74)

The title compound 74 was obtained from 2-fluoro-5-methoxybenzaldehyde according to the method described in Reference Example 12.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.45 (s, 3 H), 3.77 (br s, 2 H), 3.79 (s, 3 H), 6.72-6. 76 (M, 1 H), 6.85-6. 87 (m, 1 H), 6. 95 (dd, J = 9, 9 Hz, 1 H).

(Example 59)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (2-fluoro-5-methoxybenzyl) -7,9-dimethoxy-N-methyl-1,2,3,4 Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (75)

The title compound 75 was obtained from compound 4 and compound 74 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08 to 0.15 (m, 2 H), 0.45 to 0.55 (m, 2 H), 0.68 to 1.04 (m , 3H), 1.26 to 1.38 (m, 1H), 1.61 to 1.99 (m, 3H), 2.25 to 2.61 (m, 5H), 2.97 (s, 1) .2 H), 2.99 (s, 1.8 H), 3.03-3. 11 (m, 1 H), 3.31 (d, J = 6 Hz, 0.4 H), 3.41 (d, J = 6 Hz, 0.6 H), 3.54 (s, 1.8 H), 3.58 (s, 1.2 H), 3.77 (s, 3 H), 3.88 (s, 1.2 H), 3.90 (s, 1.8 H), 4.56-4. 79 (m, 3 H), 6.56-6.77 (m, 4 H), 6.92-7.01 (m, 2 H).

(Example 60)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (2-fluoro-5-hydroxybenzyl) -7,9-dihydroxy-N-methyl-1,2,3,4 Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (76)

The title compound 76 was obtained from compound 75 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11 to 0.17 (m, 2 H), 0.52 to 0.55 (m, 2 H), 0.66 to 0.98 (m , 3H), 1.18-1.37 (m, 1H), 1.64-1.86 (m, 3H), 2.29-2.42 (m, 4H), 2.59-2.64 (M, 1 H), 2.97-3. 11 (m, 4 H), 3.41-3. 49 (m, 1 H), 4.43-5. 12 (m, 4 H), 6.56 (d , J = 8 Hz, 1 H), 6.70-7.00 (m, 5 H).

(Reference Example 17)
Synthesis of 1- (2,6-difluorophenyl) -N-methylmethanamine (77)

The title compound 77 was obtained from 2,6-difluorobenzaldehyde according to the method described in Reference Example 12.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.42 (s, 3 H), 3.86 (s, 2 H), 6.84-6.92 (m, 2 H), 7.18 7.25 (m, 1 H).

(Example 61)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (2,6-difluorobenzyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7 Synthesis of 7, 7a-hexahydro-4a, 7-ethano-4, 12-methanobenzofuro [3, 2-e] isoquinoline-6-carboxamide (78)

The title compound 78 was obtained from compound 4 and compound 77 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.14 (m, 2 H), 0.47 to 0.55 (m, 2 H), 0.71 to 1.05 (m) , 3H), 1.30 to 1.41 (m, 1 H), 1.62 to 1.97 (m, 3 H), 2.26 to 2.42 (m, 4 H), 2.55 to 2.59 (M, 1 H), 2.87 (s, 1.2 H), 2.97 (s, 1.8 H), 3.05-3.11 (m, 1 H), 3.40-3.56 (m , 4H), 3.89 (s, 1.8 H), 3.90 (s, 1.2 H), 4.54-4.88 (m, 3 H), 6.58-6.94 (m, 5 H) ), 7.23-7.30 (m, 1 H).

(Example 62)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (2,6-difluorobenzyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7 Synthesis of 7, 7a-hexahydro-4a, 7-ethano-4, 12-methanobenzofuro [3, 2-e] isoquinoline-6-carboxamide (79)

The title compound 79 was obtained from compound 78 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.18 (m, 2 H), 0.48 to 0.56 (m, 2 H), 0.72 to 0.97 (m) , 3H), 1.26 to 1.38 (m, 1H), 1.66 to 1.86 (m, 3H), 2.28 to 2.44 (m, 4H), 2.57 to 2.61 (M, 1 H), 2.90-3. 10 (m, 4 H), 3.41-3. 43 (m, 1 H), 4.5 6-4. 96 (m, 4 H), 5. 85 (br s, 1 H), 6.55 (d, J = 8 Hz, 1 H), 6.75-7.00 (m, 4 H), 7. 26-7. 34 (m, 1 H).

(Example 63)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N- (1-phenylcyclopropyl) -1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (80)

The title compound 80 was obtained from Compound 4 and 1-phenylcyclopropan-1-amine (synthesized by the method described in Journal of Organic Chemistry 2003, 68, 7133) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.12 (m, 2 H), 0.45 to 0.53 (m, 2 H), 0.68 to 0.74 (m) , 1H), 0.85-1.09 (m, 6H), 1.22-1. 33 (m, 1H), 1.57-1.86 (m, 3H), 2.27-2.39 (M, 4H), 2.57 (dd, J = 5, 12 Hz, 1 H), 3.07 (d, J = 18 Hz, 1 H), 3.43 (d, J = 6 Hz, 1 H), 3.55 (S, 3 H), 3. 90 (s, 3 H), 4. 48 (d, J = 2 Hz, 1 H), 6.61 (d, J = 8 Hz, 1 H), 6.75 (d, J = 8 Hz , 1 H), 7.16-7.34 (m, 5 H), 7.82 (s, 1 H), 8.33 (br s, 1 H).

(Example 64)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (1-phenylcyclopropyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (81)

The title compound 81 was obtained from compound 80 according to the method described in Example 44.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): -0.04-0.15 (m, 2 H), 0.36-1.03 (m, 5 H), 1.26-1. 66 ( m, 7H), 1.81-1.99 (m, 1H), 2.13-2.60 (m, 5H), 2.89-3.19 (m, 5H), 3.44-3. 58 (m, 3 H), 3.88-3. 90 (m, 3 H), 4. 70 (br s, 1 H), 6.52 (d, J = 8 Hz, 0.4 H), 6.59-6 .63 (m, 1.6 H), 6.70 (d, J = 8 Hz, 0.4 H), 6.75 (d, J = 8 Hz, 0.6 H), 7.02-7.34 (m, 5H).

(Example 65)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -9-hydroxy-7-methoxy-N-methyl-N- (1-phenylcyclopropyl) -1,2,3,4, Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (82)

The title compound 82 was obtained from compound 81 according to the method described in Example 50.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): -0.03-0.13 (m, 2 H), 0.35-1.01 (m, 5 H), 1.25-1.41 ( m, 6H), 1.64-1.82 (m, 2H), 1.91-2.61 (m, 5H), 2.88-3. 19 (m, 4H), 3.44-3. 55 (m, 4 H), 4. 70 (br s, 1 H), 5.0 5 (br s, 1 H), 6.22-6. 75 (m, 3 H), 7.02-7.32 (m, 5H).

(Example 66)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (1-phenylcyclopropyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (83)

The title compound 83 was obtained from compound 81 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): -0.16-0.15 (m, 2H), 0.26-0.98 (m, 5H), 1.23-1.83 ( m, 8H), 2.00-2.61 (m, 5H), 2.90-3. 11 (m, 2H), 3.20 (s, 3H), 4.50-4.98 (m, 5H) 2H), 6.50-6.81 (m, 3H), 7.03-7. 37 (m, 5H).

(Example 67)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((1R, 2S) -2-phenylcyclopropyl) -1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (84)

The title compound 84 was obtained from the compound 4 and (1R, 2S) -N-methyl-2-phenylcyclopropan-1-amine hydrochloride (synthesized by the method described in WO2001036421) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.18 (m, 2 H), 0.36 to 1.10 (m, 5 H), 1.20 to 1.96 (m) , 6H), 2.07-2.43 (m, 5H), 2.53-2.61 (m, 1H), 2.84-3.45 (m, 6H), 3.51-3.57 (M, 3 H), 3.85-3. 92 (m, 3 H), 4. 67 (s, 1 H), 6.51-6.77 (m, 3 H), 6.96-7.30 (m , 5H).

(Example 68)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N-((1R, 2S) -2-phenylcyclopropyl) -1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (85)

The title compound 85 was obtained from compound 84 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11 to 0.19 (m, 2 H), 0.50 to 0.59 (m, 2 H), 0.65 to 0.91 (m) , 3H), 1.20-1.80 (m, 6H), 2.20-2.42 (m, 5H), 2.60 (dd, J = 5, 11 Hz, 1H), 3.04-3 .32 (m, 6 H), 4.44 (d, J = 2 Hz, 1 H), 4.79 (s, 1 H), 5.21 (br s, 1 H), 6.55 (d, J = 8 Hz, 1 H), 6.75 (d, J = 8 Hz, 1 H), 6.95-7.32 (m, 6 H).

(Reference Example 18)
Synthesis of tert-butyl methyl ((1S, 2R) -2-phenylcyclopropyl) carbamate (86)

The title compound 86 was obtained from tert-butyl ((1S, 2R) -2-phenylcyclopropyl) carbamate (synthesized by the method described in Journal of American Chemical Society 2010, 132, 6827) according to the method described in Example 44. Obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.19 (ddd, J = 7, 7, 7 Hz, 1 H), 1. 28 (ddd, J = 5, 7, 10 Hz, 1 H), 1 .43 (s, 9H), 2.10 (ddd, J = 3, 6, 10 Hz, 1 H), 2.71 (ddd, J = 4, 5, 7 Hz, 1 H), 2.90 (s, 3 H) , 7.10-7.28 (m, 5H).

(Reference Example 19)
Synthesis of (1S, 2R) -N-Methyl-2-phenylcyclopropan-1-amine hydrochloride (87)

To compound 86 (184 mg, 0.74 mmol) was added 2 M hydrogen chloride-methanol solution (2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and lyophilized to give the title compound 87 (139 mg, quantitative) as a colorless powder.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 1.36 (q, J = 7 Hz, 1 H), 1.47-1. 52 (m, 1 H), 2.45-2.51 ( m, 1 H), 2.83 (s, 3 H), 2.95- 3.00 (m, 1 H), 7. 16-7. 32 (m, 5 H).

(Example 69)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((1S, 2R) -2-phenylcyclopropyl) -1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (88)

The title compound 88 was obtained from compound 4 and compound 87 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.17 (m, 2 H), 0.48-1.02 (m, 5 H), 1.11-1. 98 (m) , 6 H), 2.20-2.44 (m, 5 H), 2.53-2.61 (m, 1 H), 2.85-3. 45 (m, 6 H), 3.48-3. 58 (M, 3 H), 3.86-3. 92 (m, 3 H), 4.67-4. 73 (m, 1 H), 6.53-6.77 (m, 3 H), 6.95-7 .32 (m, 5H).

(Example 70)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N-((1S, 2R) -2-phenylcyclopropyl) -1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (89)

The title compound 89 was obtained from the compound 88 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.41 (m, 3 H), 0.48 to 0.55 (m, 2 H), 0.69 to 0.92 (m) , 2H), 1.03-1.80 (m, 6H), 2.01-2.53 (m, 6H), 2.82-3.56 (m, 6H), 4.40 (s, 1H) ), 4.97-5.05 (m, 1 H), 5. 26 (br s, 1 H), 6.45-6. 51 (m, 1 H), 6.71 (d, J = 8 Hz, 1 H) , 6.93-7.28 (m, 6H).

(Example 71)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N- (2,2,2-trifluoroethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (90)

The title compound 90 was obtained from compound 4 and 2,2,2-trifluoroethan-1-amine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11 to 0.16 (m, 2 H), 0.47 to 0.55 (m, 2 H), 0.70 to 0.77 (m) , 1H), 0.86-0.96 (m, 2H), 1.22-1.30 (m, 1H), 1.59-1.91 (m, 3H), 2.28-2.41 (M, 4 H), 2.58 (dd, J = 5, 12 Hz, 1 H), 3.08 (d, J = 18 Hz, 1 H), 3. 45 (d, J = 7 Hz, 1 H), 3.62 (S, 3 H), 3. 90 (s, 3 H), 3. 94-4. 12 (m, 2 H), 4. 48 (d, J = 2 Hz, 1 H), 6.62 (d, J = 8 Hz) , 1H), 6.76 (d, J = 8 Hz, 1 H), 7.91 (s, 1 H), 8.27 (t, J = 6 Hz, 1 H).

(Example 72)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (2,2,2-trifluoroethyl) -1,2,3, Synthesis of 4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (91)

The title compound 91 was obtained from compound 90, according to the method described in Example 44.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.16 (m, 2 H), 0.47 to 0.56 (m, 2 H), 0.74 to 0.90 (m) , 2H), 0.99 (ddd, J = 6, 13, 13 Hz, 1 H), 1.32-1.38 (m, 1 H), 1.62-1. 67 (m, 1 H), 1.82 -1.95 (m, 2 H), 2.27-2.44 (m, 4 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 3.07-3. 16 (m, 4 H) , 3.37-3.44 (m, 1H), 3.55 (s, 3H), 3.90 (s, 3H), 4.02-4.21 (m, 2H), 4.67 (s) , 1 H), 6.60 (d, J = 8 Hz, 1 H), 6.74-6. 78 (m, 2 H).

(Example 73)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (2,2,2-trifluoroethyl) -1,2,3, Synthesis of 4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (92)

The title compound 92 was obtained from compound 91 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.13 to 0.17 (m, 2 H), 0.50 to 0.57 (m, 2 H), 0.73 to 1.02 (m) , 3H), 1.25-1.33 (m, 1H), 1.67-1.83 (m, 3H), 2.30-2.45 (m, 4H), 2.62 (d, J) = 5, 12 Hz, 1 H), 3.06 to 3.44 (m, 5 H), 4.04 to 4.51 (m, 4 H), 6.57 (d, J = 8 Hz, 1 H), 6.76 (D, J = 8 Hz, 1 H), 6.93 (s, 1 H).

(Example 74)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (prop-2-yn-1-yl) -1,2,3, Synthesis of 4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (93)

The title compound 93 was obtained from compound 4 and N-methylprop-2-yn-1-amine according to the methods described in Examples 1 and 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.20 (m, 2 H), 0.45-0.60 (m, 2 H), 0.81-0.89 (m , 1H), 0.91-1.04 (m, 1H), 1.20-1.35 (m, 1H), 1.61-1.89 (m, 3H), 2.25-2.49 (M, 5 H), 2.53-2.65 (m, 1 H), 3.05-3. 33 (m, 4 H), 3.43 (d, J = 6 Hz, 1 H), 4.12 (d , J = 18 Hz, 0.5 H), 4.20-4. 45 (m, 1.5 H), 4.53 (s, 1 H), 4.86 (br s, 1 H), 6.56 (d, 5) J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 6.90 (br s, 0.5 H), 7.15 (br s, 0.5 H).

(Example 75)
(4R, 4aS, 7R, 7aR, 12bS) -N- (Cyclobutylmethyl) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a, Synthesis of 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (94)

The title compound 94 was obtained from compound 4 and cyclobutylmethanamine (synthesized by the method described in Journal of Medicinal Chemistry 2007, 50, 2597) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.14 (m, 2 H), 0.47 to 0.54 (m, 2 H), 0.68 to 0.74 (m) , 1 H), 0.86-0.95 (m, 2 H), 1.23-1. 31 (m, 1 H), 1.57 (dd, J = 2, 13 Hz, 1 H), 1.70-1 .96 (m, 6 H), 2.05-2.13 (m, 2 H), 2.27-2.40 (m, 4 H), 2.5 1-2. 60 (m, 2 H), 3.07 (D, J = 18 Hz, 1 H), 3.32-3. 45 (m, 3 H), 3.57 (s, 3 H), 3. 90 (s, 3 H), 4. 45 (d, J = 2 Hz) , 1H), 6.60 (d, J = 8 Hz, 1 H), 6.75 (d, J = 8 Hz, 1 H), 7.74 (t, J = 5 Hz, 1 H), 7.78 (s, 1 H) ).

(Example 76)
(4R, 4aS, 7R, 7aR, 12bS) -N- (cyclobutylmethyl) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a- Synthesis of hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (95)

The title compound 95 was obtained from compound 94 according to the method described in Example 44.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.12 to 0.15 (m, 2 H), 0.49 to 0.53 (m, 2 H), 0.71 to 0.88 (m) , 2H), 0.98 (ddd, J = 6, 13, 13 Hz, 1 H), 1.25-1.38 (m, 1 H), 1.61-2.09 (m, 9 H), 2.26 -2.43 (m, 4H), 2.56-2.69 (m, 2H), 2.95 (s, 1.5 H), 2.98 (s, 1.5 H), 3.08 (d , J = 18 Hz, 1 H), 3.35-3.51 (m, 6 H), 3.89 (s, 3 H), 4.68 (br s, 1 H), 6.58-6.62 (m, 6) 2H), 6.73-6. 76 (m, 1 H).

(Example 77)
(4R, 4aS, 7R, 7aR, 12bS) -N- (cyclobutylmethyl) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a- Synthesis of hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (96)

The title compound 96 was obtained from compound 95 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11 to 0.17 (m, 2 H), 0.49 to 0.57 (m, 2 H), 0.72 to 0.99 (m) , 3H), 1.23-1.32 (m, 1 H), 1.66-1.98 (m, 7 H), 2.05-2.12 (m, 2 H), 2.28-2.40 (M, 4H), 2.58-2.68 (m, 2H), 2.98-3.14 (m, 4H), 3.41-3.69 (m, 3H), 4.51 (br s, 1 H), 4.72-4. 89 (m, 1 H), 6.55 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 6.78 (s, 1H).

(Example 78)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N-((3,3-difluorocyclobutyl) methyl) -7,9-dimethoxy-1,2,3,4,7 Synthesis of 7, 7a-hexahydro-4a, 7-ethano-4, 12-methanobenzofuro [3, 2-e] isoquinoline-6-carboxamide (97)

The title compound 97 was obtained from the compound 4 and (3,3-difluorocyclobutyl) methanamine (synthesized by the method described in WO2015115673) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.16 (m, 2 H), 0.49 to 0.53 (m, 2 H), 0.69 to 0.75 (m) , 1H), 0.86-0.95 (m, 2H), 1.21-1.27 (m, 1H), 1.57-1.89 (m, 3H), 2.26-2.46 (M, 7 H), 2.56-2.73 (m, 3 H), 3.07 (d, J = 18 Hz, 1 H), 3.41-3. 55 (m, 3 H), 3.60 (s , 3H), 3.90 (s, 3H), 4.46 (d, J = 2 Hz, 1 H), 6.61 (d, J = 8 Hz, 1 H), 6.75 (d, J = 8 Hz, 1 H) ), 7.82 (s, 1 H), 7.95 (t, J = 6 Hz, 1 H).

(Example 79)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N-((3,3-difluorocyclobutyl) methyl) -7,9-dimethoxy-N-methyl-1,2,3 Synthesis of 2,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (98)

The title compound 98 was obtained from compound 97, according to the method described in Example 44.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.16 (m, 2 H), 0.47 to 0.55 (m, 2 H), 0.73 to 0.89 (m) , 2H), 0.99 (ddd, J = 5, 12, 12 Hz, 1H), 1.29-1.35 (m, 1H), 1.64-1.67 (m, 1H), 1.82. -1.97 (m, 2 H), 2.26-2. 70 (m, 10 H), 2.98 (s, 1 H), 3.03 (s, 2 H), 3.08 (d, J = 18 Hz , 1H), 3.36-3.60 (m, 6H), 3.90 (s, 3H), 4.67 (s, 1H), 6.59-6.64 (m, 2H), 6. 75 (d, J = 8 Hz, 1 H).

(Example 80)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N-((3,3-dibromocyclobutyl) methyl) -7,9-dihydroxy-N-methyl-1,2,3 Synthesis of 4,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (99)

The title compound 99 was obtained from compound 98 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.14 to 0.17 (m, 2 H), 0.50 to 0.58 (m, 2 H), 0.73 to 0.90 (m) , 2H), 0.96 (ddd, J = 6, 12, 12 Hz, 1 H), 1.25-1.29 (m, 1 H), 1.66-1.78 (m, 3 H), 2.29 −2.45 (m, 4 H), 2.60 (dd, J = 4, 12 Hz, 1 H), 2.94-3.67 (m, 12 H), 4.50 (s, 1 H), 4.69 (Br s, 1 H), 5. 90 (br s, 1 H), 6.56 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 6.81 (s, 1 H) ).

(Example 81)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N- (2-methoxyethyl) -N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (100)

The title compound 100 was obtained from compound 4 and N- (2-methoxyethyl) methylamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.15 (m, 2 H), 0.46-0.56 (m, 2 H), 0.69-1.03 (m , 3H), 1.15-1.99 (m, 4H), 2.25-2.44 (m, 4H), 2.55-2.62 (m, 1H), 3.04-3.12 (M, 4H), 3.32-3.66 (m, 11H), 3.89 (s, 3H), 4.67-4.70 (m, 1H), 6.59 (d, J = 8 Hz) , 1 H), 6.6 4-6. 66 (m, 1 H), 6. 74 (d, J = 8 Hz, 1 H).

(Example 82)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N- (2-hydroxyethyl) -N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (101)

The title compound 101 was obtained from compound 100 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.19 (m, 2 H), 0.46-0.59 (m, 2 H), 0.67-1.01 (m) , 3H), 1.18-1.91 (m, 4H), 2.26-2.46 (m, 4H), 2.56-2.64 (m, 1H), 2.80-2.91. (M, 1 H), 3.01-3.12 (m, 2 H), 3.23-3. 31 (m, 2 H), 3.37-3. 46 (m, 1 H), 3.60-3 .95 (m, 4 H), 4.44-4. 58 (m, 1 H), 4.81-5. 07 (m, 1 H), 6.56 (d, J = 8 Hz, 1 H), 6.70 -6.95 (m, 2H).

(Example 83)
((4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of -Methanobenzofuro [3,2-e] isoquinolin-6-yl) (pyrrolidin-1-yl) methanone (102)

The title compound 102 was obtained from compound 4 and pyrrolidine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.18 (m, 2 H), 0.45 to 0.58 (m, 2 H), 0.68 to 0.77 (m) , 1 H), 0.78-0.90 (m, 1 H), 0.98 (ddd, J = 5, 13, 13 Hz, 1 H), 1.34-1. 45 (m, 1 H), 1.62 -1.67 (m, 1 H), 1.74-1.82 (m, 1 H), 1.88-1.99 (m, 6 H), 2.25-2.43 (m, 4 H), 2 .58 (dd, J = 5, 12 Hz, 1 H), 3.08 (d, J = 18 Hz, 1 H), 3.41 (d, J = 6 Hz, 1 H), 3.44-3. 58 (m, 3H), 3.52 (s, 3H), 3.89 (s, 3H), 4.67 (d, J = 2 Hz, 1 H), 6.59 (d, J = 8 Hz, 1 H), 6.73 (D, J 8Hz, 1H), 6.76 (s, 1H).

(Example 84)
((4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of -Methanobenzofuro [3,2-e] isoquinolin-6-yl) (pyrrolidin-1-yl) methanone (103)

The title compound 103 was obtained from compound 102 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.20 (m, 2 H), 0.47 to 0.58 (m, 2 H), 0.68 to 0.79 (m) , 1 H), 0.82-0.99 (m, 2 H), 1.21-1. 35 (m, 1 H), 1.62-2.03 (m, 7 H), 2.28-2.45 (M, 4 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 3.06 (d, J = 18 Hz, 1 H), 3.41 (d, J = 6 Hz, 1 H), 3.52 -3.70 (m, 4H), 4.51 (d, J = 2 Hz, 1 H), 5.59 (br s, 1 H), 6.55 (d, J = 8 Hz, 1 H), 6.75 ( d, J = 8 Hz, 1 H), 6.98 (s, 1 H).

(Example 85)
((4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of -Methanobenzofuro [3,2-e] isoquinolin-6-yl) (piperidin-1-yl) methanone (104)

The title compound 104 was obtained from compound 4 and piperidine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.18 (m, 2 H), 0.44 to 0.56 (m, 2 H), 0.62 to 1.08 (m) , 3H), 1.42-2.08 (m, 10H), 2.21-2.65 (m, 5H), 3.08 (d, J = 18 Hz, 1 H), 3.32-3.80 (M, 8 H), 3.89 (s, 3 H), 4.52-4. 82 (m, 1 H), 6.59 (d, J = 8 Hz, 1 H), 6.63 (br s, 1 H) , 6.74 (d, J = 8 Hz, 1 H).

(Example 86)
((4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of -Methanobenzofuro [3,2-e] isoquinolin-6-yl) (piperidin-1-yl) methanone (105)

The title compound 105 was obtained from compound 104 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.18 (m, 2 H), 0.45 to 0.58 (m, 2 H), 0.70 to 1.01 (m) , 3H), 1.20-1.35 (m, 2H), 1.55-1.88 (m, 8H), 2.27-2.45 (m, 4H), 2.58 (dd, J) = 5, 12 Hz, 1 H), 3.06 (d, J = 18 Hz, 1 H), 3.41 (d, J = 6 Hz, 1 H), 3.54-3. 73 (m, 4 H), 4.58 (D, J = 2 Hz, 1 H), 4.90 (br s, 1 H), 6.55 (d, J = 8 Hz, 1 H), 6.72 (s, 1 H), 6.75 (d, J = 8 Hz, 1 H).

(Example 87)
((4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of -Methanobenzofuro [3,2-e] isoquinolin-6-yl) (morpholino) methanone hydrochloride (106)

According to the methods described in Examples 1 and 2, the free form of the title compound 106 was obtained from Compound 4 and morpholine. The obtained free form (16.5 mg, 0.036 mmol) was dissolved in ethyl acetate (1 mL), 1 M hydrochloric acid-diethyl ether solution (1 mL) was added dropwise under ice-cooling, and the mixture was stirred for 30 minutes. The precipitated solid was filtered and then dried in a lyophilizer to give the title compound 106 (13.7 mg, 77%) as a colorless powder.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.44 to 0.56 (m, 2 H), 0.73 to 0.90 (m, 3 H), 1.10-1.26 ( m, 2H), 1.27-1.36 (m, 1H), 1.64-1. 73 (m, 1H), 1.92-2.02 (m, 1H), 2.05-2. 18 (m, 1 H), 2.93-3. 02 (m, 1 H), 3.06-3. 20 (m, 2 H), 3. 30-3. 44 (m, 4 H), 3.51- 3.58 (m, 1 H), 3.66-3.75 (m, 6 H), 4.34-4. 42 (m, 1 H), 4.50 (s, 1 H), 6.65 (s, 1 h) 1 H), 6.67 (d, J = 8 Hz, 1 H), 6.77 (d, J = 8 Hz, 1 H).

(Reference Example 20)
Synthesis of 6- (trifluoromethyl) picolinaldehyde (107)

The title compound 107 was obtained from (6- (trifluoromethyl) pyridin-2-yl) methanol (synthesized by the method described in WO2010059393) according to the method described in Reference Example 13.

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, 1 H), 10.1 (s, 1 H).

(Reference Example 21)
Synthesis of N-methyl-1- (6- (trifluoromethyl) pyridin-2-yl) methanamine (108)

The title compound 108 was obtained from compound 107, according to the method described in Reference Example 12.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.45 (s, 3 H), 3.95 (s, 2 H), 7.53 to 5.57 (m, 2 H), 7.83 ( dd, J = 8, 8 Hz, 1 H).

(Example 88)
(4R, 4aS, 7R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((6- (trifluoromethyl) pyridin-2-yl) methyl)- Synthesis of 1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (109)

The title compound 109 was obtained from compound 4 and compound 108 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.15 (m, 2 H), 0.47-0.56 (m, 2 H), 0.66-0.90 (m , 2H), 1.02 (ddd, J = 5, 12, 12 Hz, 1H), 1.31-1.38 (m, 1H), 1.61-1.99 (m, 3H), 2.24 −2.61 (m, 5 H), 3.02−3. 11 (m, 4 H), 3.28 (d, J = 6 Hz, 0.6 H), 3.43 (d, J = 6 Hz, 0. 4H), 3.54 (s, 3 H), 3.87 (s, 1.2 H), 3. 90 (s, 1.8 H), 4.61-4. 93 (m, 3 H), 6.56 -6.76 (m, 3 H), 7.58-7.69 (m, 2 H), 7.83-7. 93 (m, 1 H).

(Example 89)
(4R, 4aS, 7R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N-((6- (trifluoromethyl) pyridin-2-yl) methyl)- Synthesis of 1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (110)

The title compound 110 was obtained from compound 109 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04 to 0.15 (m, 2 H), 0.42 to 0.57 (m, 2 H), 0.69 to 1.02 (m , 3H), 1.11-1.36 (m, 1H), 1.61-1.87 (m, 3H), 2.20-2.63 (m, 5H), 3.01-3.46 (M, 5 H), 4.53 (s, 0.4 H), 4.55 (s, 0.6 H), 4.72-5.09 (m, 3 H), 6.53-6.58 (m , 1 H), 6.73-6.77 (m, 1 H), 6.83 (s, 0.4 H), 6.94 (s, 0.6 H), 7.56-7.63 (m, 2 H) ), 7.85-7.97 (m, 1 H).

(Reference Example 22)
Synthesis of 2-((methylamino) methyl) pyridin-3-ol (111)

The title compound 111 was obtained from 3-hydroxypicolinaldehyde (synthesized by the method described in WO2002022600) according to the method described in Reference Example 12.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.52 (s, 3 H), 4.18 (s, 2 H), 5.10-6.00 (m, 2 H), 7.09- 7.10 (m, 2H), 8.00-8.01 (m, 1H).

(Example 90)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N-((3-hydroxypyridin-2-yl) methyl) -7,9-dimethoxy-N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (112)

The title compound 112 was obtained from the compound 4 and the compound 111 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.15 (m, 2 H), 0.47 to 0.55 (m, 2 H), 0.72 to 0.89 (m) , 2H), 0.97 (ddd, J = 6, 12, 12 Hz, 1 H), 1.29-1.36 (m, 1 H), 1.64-1.68 (m, 1 H), 1.79 -1.91 (m, 2H), 2.23-2.45 (m, 4H), 2.57 (dd, J = 5, 12 Hz, 1 H), 3.07 (d, J = 18 Hz, 1 H) , 3.21 (s, 3 H), 3.43 (s, 3 H), 3. 44 (d, J = 7 Hz, 1 H), 3.89 (s, 3 H), 4.61 (d, J = 14 Hz) , 1H), 4.65 (d, J = 2 Hz, 1 H), 4.81 (d, J = 14 Hz, 1 H), 6.60 (d, J = 8 Hz, 1 H), 6.75 (d, J = Hz, 1 H), 6.77 (s, 1 H), 7.19 (dd, J = 4, 8 Hz, 1 H), 7.26-7. 29 (m, 1 H), 8.07 (dd, J = 1, 4 Hz, 1 H), 10.0 (br s, 1 H).

(Example 91)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -9-hydroxy-N-((3-hydroxypyridin-2-yl) methyl) -7-methoxy-N-methyl-1, 2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (113) and (4R, 4aS, 7R, 7aR, 12bS) -3- (Cyclopropylmethyl) -7,9-dihydroxy-N-((3-hydroxypyridin-2-yl) methyl) -N-methyl-1,2,3,4,7,7a-hexahydro-4a Synthesis of 7,7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (114)

The title compounds 113 and 114 were obtained from compound 112 according to the method described in Example 2.

(Compound 113)
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.14 (m, 2 H), 0.47 to 0.56 (m, 2 H), 0.71 to 0.90 (m) , 2H), 0.95 (ddd, J = 6, 13, 13 Hz, 1 H), 1.35-1. 42 (m, 1 H), 1.65-1. 77 (m, 2 H), 1.86 (Ddd, J = 6, 13, 13 Hz, 1 H), 2.24-2.45 (m, 4 H), 2.58 (dd, J = 5, 12 Hz, 1 H), 3.07 (d, J = 18 Hz, 1 H), 3.22 (s, 3 H), 3. 36 (s, 3 H), 3. 44 (d, J = 6 Hz, 1 H), 4.59 (d, J = 14 Hz, 1 H), 4 .65 (d, J = 2 Hz, 1 H), 4. 84 (d, J = 14 Hz, 1 H), 5.11 (br s, 1 H), 6.56 (d, J = 8 Hz, 1 H , 6.74 (d, J = 8 Hz, 1 H), 6.80 (s, 1 H), 7.19 (dd, J = 4, 8 Hz, 1 H), 7.28 (d, J = 1, 8 Hz, 1 H), 8.08 (dd, J = 1, 4 Hz, 1 H), 10.0 (s, 1 H).

(Compound 114)
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11-0.16 (m, 2 H), 0.49-0.57 (m, 2 H), 0.71-0.90 (m , 2H), 0.95 (ddd, J = 5, 13, 13 Hz, 1H), 1.28 to 1.31 (m, 1 H), 1.68 to 1.82 (m, 3 H), 2.28 -2.46 (m, 4H), 2.60 (dd, J = 4, 12 Hz, 1 H), 3.08 (d, J = 18 Hz, 1 H), 3.36 (s, 3 H), 3.45 (D, J = 7 Hz, 1 H), 4.36 (br s, 1 H), 4. 45 (d, J = 2 Hz, 1 H), 4.64 (d, J = 14 Hz, 1 H), 4.81 ( d, J = 14 Hz, 1 H), 6.56 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 6.99 (s, 1 H), 7.22 (d , J = 4,8Hz, 1H), 7.28 (dd, J = 1,8Hz, 1H), 8.10 (dd, J = 1,4Hz, 1H), 9.92 (br s, 1H).

(Example 92)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N-((3-hydroxypyridin-2-yl) methyl) -7,9-dimethoxy-1,2,3,4, Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (115)

The title compound 115 was obtained from compound 4 and 2- (aminomethyl) pyridin-3-ol according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11-0.15 (m, 2 H), 0.49-0.56 (m, 2 H), 0.72 (ddd, J = J = 3, 10, 13 Hz, 1 H), 0.85 to 0.92 (m, 2 H), 1.13-1. 21 (m, 1 H), 1.56-1.76 (m, 2 H), 1 .91 (ddd, J = 5, 10, 12 Hz, 1 H), 2.26-2.42 (m, 4 H), 2.56 (dd, J = 5, 11 Hz, 1 H), 3.07 (d, J = 18 Hz, 1 H), 3.45 (d, J = 6 Hz, 1 H), 3.60 (s, 3 H), 3.89 (s, 3 H), 4.46 (d, J = 2 Hz, 1 H) , 4.55-4.65 (m, 2H), 6.60 (d, J = 8 Hz, 1 H), 6.75 (d, J = 8 Hz, 1 H), 7.16 (dd, J = 5, Hz, 1 H), 7. 26-7. 28 (m, 1 H), 7. 95 (s, 1 H), 8.06 (dd, J = 2, 5 Hz, 1 H), 9.01 (t, J = 6 Hz, 1 H), 10.6 (s, 1 H).

(Example 93)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-((3-hydroxypyridin-2-yl) methyl) -1,2,3,4, Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (116)

The title compound 116 was obtained from compound 115 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11-0.15 (m, 2 H), 0.49-0.57 (m, 2 H), 0.67-0.72 (m) , 1 H), 0.81-0.94 (m, 2 H), 1.23-1.29 (m, 1 H), 1.58-1. 78 (m, 3 H), 2.26-2.43 (M, 4 H), 2.58 (dd, J = 4, 12 Hz, 1 H), 3.07 (d, J = 18 Hz, 1 H), 3.46 (d, J = 6 Hz, 1 H), 4.43 (S, 1 H), 4.5 7-4. 72 (m, 2 H), 5. 65 (br s, 1 H), 6.57 (d, J = 8 Hz, 1 H), 6.81 (d, J = 8 Hz, 1 H), 7.22-7.26 (m, 1 H), 7. 35 (d, J = 8 Hz, 1 H), 7.89 (s, 1 H), 8.10 (d, J = 4 Hz, 1H), 9. 6 (br s, 1H), 11.5 (br s, 1H).

(Reference Example 23)
Synthesis of 1- (4-Methoxypyridin-2-yl) -N-methylmethanamine (117)

The title compound 117 was obtained from 4-methoxypicolinaldehyde (synthesized by the method described in Bulletin of the Chemical Society of Japan 2015, 88, 784) according to the method described in Reference Example 12.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.48 (s, 3 H), 3.82 (s, 2 H), 3.85 (s, 3 H), 6.70 (dd, J = 3,6 Hz, 1 H), 6.86 (d, J = 3 Hz, 1 H), 8.37 (d, J = 6 Hz, 1 H).

(Example 94)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-((4-methoxypyridin-2-yl) methyl) -N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (118)

The title compound 118 was obtained from the compound 4 and the compound 117 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.14 (m, 2 H), 0.46-0.55 (m, 2 H), 0.65-1. 05 (m , 3H), 1.32-1.38 (m, 1H), 1.64-1.99 (m, 3H), 2.24-2.60 (m, 5H), 3.02-3.11 (M, 4H), 3.29 (d, J = 6 Hz, 0.4 H), 3.41 (d, J = 6 Hz, 0.6 H), 3.56 (s, 3 H), 3.84-3 .90 (m, 6 H), 4.40-5.05 (m, 3 H), 6.56-6.76 (m, 4 H), 6.97 (d, J = 2 Hz, 0.4 H), 7 .01 (d, J = 2 Hz, 0.6 H), 8.32 (d, J = 6 Hz, 0.4 H), 8. 35 (d, J = 6 Hz, 0.6 H).

(Example 95)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-((4-methoxypyridin-2-yl) methyl) -N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (119)

The title compound 119 was obtained from compound 118 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.15 (m, 2 H), 0.43 to 0.57 (m, 2 H), 0.65 to 1.02 (m , 3H), 1.20-1.35 (m, 1 H), 1.62-1. 90 (m, 3 H), 2.25-2.44 (m, 4 H), 2.54-2.61. (M, 1 H), 2.95 (s, 2.1 H), 3.03-3. 11 (m, 1 H), 3.23 (s, 0.9 H), 3.34 (d, J = 6 Hz) , 0.7 H), 3.43 (d, J = 6 Hz, 0.3 H), 3.84 (s, 0.9 H), 3.88 (s, 2.1 H), 4.52-4.90 (M, 3 H), 5.20-6. 35 (m, 1 H), 6.53-6. 57 (m, 1 H), 6.72-6. 93 (m, 4 H), 8. 37 (d , J = 6 Hz, 0.3 H), 8.42 d, J = 6Hz, 0.7H).

(Reference Example 24)
Synthesis of N- (6-((methylamino) methyl) pyridin-2-yl) acetamide (120)

The title compound 120 was obtained from N- (6-formylpyridin-2-yl) acetamide (synthesized by the method described in WO2014069434) according to the method described in Reference Example 12.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.20 (s, 3 H), 2.47 (s, 3 H), 3.76 (s, 2 H), 7.01 (d, J = 8 Hz, 1 H), 7.65 (dd, J = 8, 8 Hz, 1 H), 7.95 (br s, 1 H), 8.05 (d, J = 8 Hz, 1 H).

(Example 96)
(4R, 4aS, 7R, 7aR, 12bS) -N-((6-acetamidopyridin-2-yl) methyl) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (121)

The title compound 121 was obtained from the compound 4 and the compound 120 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.17 (m, 2 H), 0.43 to 0.56 (m, 2 H), 0.66 to 1.05 (m , 3H), 1.32-1.39 (m, 1 H), 1.56-1.96 (m, 3 H), 2.21-2. 61 (m, 8 H), 3.00-3.12 (M, 4H), 3.27 (d, J = 6 Hz, 0.4 H), 3.42 (d, J = 6 Hz, 0.6 H), 3.55 (s, 1.8 H), 3.58 (S, 1.2 H), 3.88 (s, 1.2 H), 3. 90 (s, 1.8 H), 4.59 to 4.80 (m, 3 H), 6.56 to 6.76 (M, 3 H), 7.02 (d, J = 8 Hz, 0.4 H), 7. 15 (d, J = 8 Hz, 0.6 H), 7.66-7.71 (m, 1 H), 8 .00-8.13 (m, 2H).

(Example 97)
(4R, 4aS, 7R, 7aR, 12bS) -N-((6-acetamidopyridin-2-yl) methyl) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (122)

The title compound 122 was obtained from compound 121 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11-0.14 (m, 2 H), 0.46-0.52 (m, 2 H), 0.66-1.01 (m , 3H), 1.26 to 1.33 (m, 1H), 1.56 to 1.88 (m, 3H), 2.21 to 2.63 (m, 8H), 2.89 to 3.17 (M, 4H), 3.36 (d, J = 6 Hz, 0.8 H), 3.44 (d, J = 6 Hz, 0.2 H), 4.51-4.87 (m, 3 H), 6 .53-6.57 (m, 1 H), 6.75 (d, J = 8 Hz, 1 H), 6.89 (s, 1 H), 6.92 (d, J = 8 Hz, 0.8 H), 7 .04 (d, J = 8 Hz, 0.2 H), 7.67 (dd, J = 8, 8 Hz, 1 H), 8.11 (d, J = 8 Hz, 1 H), 8.38 (br s, 0 .2H), 9.10 ( r s, 0.8H).

(Reference Example 25)
Synthesis of tert-butyl (2-((methylamino) methyl) pyridin-3-yl) carbamate (123)

The title compound 123 was obtained from tert-butyl (2-formylpyridin-3-yl) carbamate in accordance with the method described in Reference Example 12.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.54 (s, 9 H), 2.45 (s, 3 H), 4.04 (s, 2 H), 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 98)
tert-Butyl (2-(((4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a- Synthesis of hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamido) methyl) pyridin-3-yl) carbamate (124)

The title compound 124 was obtained from the compound 4 and the compound 123 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08 to 0.15 (m, 2 H), 0.46 to 0.55 (m, 2 H), 0.72 to 0.90 (m) , 2H), 0.97 (ddd, J = 6, 13, 13 Hz, 1 H), 1.28-1.34 (m, 1 H), 1.51-1.69 (m, 10 H), 1.78 -1.85 (m, 2 H), 1.91 (ddd, J = 6, 13, 13 Hz, 1 H), 2.24-2. 50 (m, 4 H), 2.57 (dd, J = 5) 11 Hz, 1 H), 3.07 (d, J = 18 Hz, 1 H), 3.12 (s, 3 H), 3.41-3. 44 (m, 4 H), 3.89 (s, 3 H), 4 .66-4.70 (m, 2 H), 4.78 (d, J = 14 Hz, 1 H), 6.59 (d, J = 8 Hz, 1 H), 6.68 (s, 1 H), 6.7 (D, J = 8 Hz, 1 H), 7.23 (dd, J = 5, 8 Hz, 1 H), 8. 20 (dd, J = 2, 5 Hz, 1 H), 8.41 (dd, J = 2) 8 Hz, 1 H), 9.19 (br s, 1 H).

(Example 99)
(4R, 4aS, 7R, 7aR, 12bS) -N-((3-aminopyridin-2-yl) methyl) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (125)

The title compound 125 was obtained from compound 124 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11 to 0.16 (m, 2 H), 0.48 to 0.57 (m, 2 H), 0.71 to 0.90 (m , 2H), 0.95 (ddd, J = 6, 12, 12 Hz, 1 H), 1.26 to 2.32 (m, 1 H), 1.66 to 1.85 (m, 3 H), 2.27 −2.46 (m, 4 H), 2.59 (dd, J = 4, 11 Hz, 1 H), 3.08 (d, J = 18 Hz, 1 H), 3.23 (s, 3 H), 3.43 (D, J = 6 Hz, 1 H), 4.47 (s, 1 H), 4.60-5.04 (m, 4 H), 6.56 (d, J = 8 Hz, 1 H), 6.75 (d , J = 8 Hz, 1 H), 6.88 (s, 1 H), 6.97 (d, J = 8 Hz, 1 H), 7.07 (dd, J = 4, 8 Hz, 1 H), 7.94 (d , J 4Hz, 1H).

(Example 100)
(4R, 4aS, 7R, 7aR, 12bS) -N-((3-acetamidopyridin-2-yl) methyl) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (126)

Compound 124 (20.7 mg, 0.032 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.50 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with chloroform. It 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 (17.0 mg) was dissolved in dichloromethane (1.5 mL) and triethylamine (43.0 μL, 0.31 mmol) was added. Under ice-cooling, acetyl chloride (22.0 μL, 0.31 mmol) was added and stirred at room temperature for 26.5 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted three times with chloroform. The organic layer was washed with 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 126 (14.9 mg, 79%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.15 (m, 2 H), 0.48 to 0.56 (m, 2 H), 0.74 to 1.03 (m) , 4H), 1.25-1.92 (m, 3H), 2.26-2.45 (m, 7H), 2.58 (dd, J = 6, 12 Hz, 1H), 3.08 (d , J = 18 Hz, 1 H), 3.09 (s, 3 H), 3. 39 (s, 3 H), 3.43 (d, J = 6 Hz, 1 H), 3.89 (s, 3 H), 4. 63 (s, 1 H), 4.67-4. 91 (m, 2 H), 6. 60 (d, J = 8 Hz, 1 H), 6. 70 (s, 1 H), 6. 75 (d, J = 8 Hz, 1 H), 7. 28 (dd, J = 4, 8 Hz, 1 H), 8.2 4 (d, J = 4 Hz, 1 H), 8. 72 (d, J = 8 Hz, 1 H), 9.99 ( s, 1H)

(Example 101)
(4R, 4aS, 7R, 7aR, 12bS) -N-((3-acetamidopyridin-2-yl) methyl) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (127)

The title compound 127 was obtained from compound 126 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.12 to 0.16 (m, 2 H), 0.49 to 0.58 (m, 2 H), 0.72 to 0.90 (m) , 2H), 0.96 (ddd, J = 6, 13, 13 Hz, 1 H), 1.26 to 1.31 (m, 1 H), 1.63-1.82 (m, 3 H), 2.26 −2.46 (m, 7 H), 2.61 (dd, J = 4, 12 Hz, 1 H), 3.09 (d, J = 18 Hz, 1 H), 3.32 (s, 3 H), 3.45 (D, J = 6 Hz, 1 H), 4.46 (s, 1 H), 4.69 (d, J = 14 Hz, 1 H), 4.88 (d, J = 14 Hz, 1 H), 5.48 (br s, 1 H), 6.57 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 6.98 (s, 1 H), 7.31 (dd, J = 4, Hz, 1H), 8.27 (d, J = 4Hz, 1H), 8.69 (d, J = 8Hz, 1H), 10.1 (s, 1H).

(Reference Example 26)
Synthesis of 1- (furan-3-yl) -N-methylmethanamine (128)

The title compound 128 was obtained from furan-3-carbaldehyde according to the method described in Reference Example 12.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.46 (s, 3 H), 3.61 (s, 2 H), 6.39 (s, 1 H), 7.36 to 7.39 ( m, 2H).

(Example 102)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (furan-3-ylmethyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (129)

The title compound 129 was obtained from compound 4 and compound 128 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.15 (m, 2 H), 0.47 to 0.55 (m, 2 H), 0.73 to 0.90 (m) , 2H), 0.99 (ddd, J = 6, 12, 12 Hz, 1 H), 1.31-1.37 (m, 1 H), 1.63-1.98 (m, 3 H), 2.26 -2.43 (m, 4 H), 2.58 (dd, J = 5, 12 Hz, 1 H), 2.93 (s, 1.2 H), 2.96 (s, 1.8 H), 3.08 (D, J = 18 Hz, 1 H), 3. 35 (d, J = 6 Hz, 0.4 H), 3.41 (d, J = 6 Hz, 0.6 H), 3.51 (s, 1.8 H) , 3.58 (s, 1.2 H), 3.90 (s, 3 H), 4.34-4.69 (m, 3 H), 6.44-6. 48 (m, 1 H), 6.59 (D, J = 8 Hz 1H), 6.66-6.68 (m, 1H), 6.74 (d, J = 8Hz, 1H), 7.39-7.43 (m, 2H).

(Example 103)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (furan-3-ylmethyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (130)

The title compound 130 was obtained from compound 129 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.16 (m, 2 H), 0.47 to 0.56 (m, 2 H), 0.72 to 0.99 (m) , 3H), 1.30-1.33 (m, 1 H), 1.62-1. 85 (m, 3 H), 2.28-2.40 (m, 4 H), 2.58-2.60 (M, 1 H), 3.00-3. 11 (m, 4 H), 3.37-3. 42 (m, 1 H), 4.43-4. 88 (m, 4 H), 6. 45 (s , 1 H), 6.55 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 6.84-6.89 (m, 1 H), 7.42-7.46 (M, 2H).

(Example 104)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (isoxazol-3-ylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (131)

The title compound 131 was obtained from compound 4 and isoxazol-3-ylmethanamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.15 (m, 2 H), 0.48-0.55 (m, 2 H), 0.73 (ddd, J = 3 , 10, 13 Hz, 1 H), 0.86-0.95 (m, 2 H), 1.20-1. 24 (m, 1 H), 1.58 (dd, J = 2, 13 Hz, 1 H), 1 .75-1.91 (m, 2H), 2.27-2.41 (m, 4H), 2.58 (dd, J = 5, 12 Hz, 1 H), 3.08 (d, J = 18 Hz, 1H), 3.45 (d, J = 6 Hz, 1 H), 3.59 (s, 3 H), 3.90 (s, 3 H), 4.47 (d, J = 2 Hz, 1 H), 4.63 (Dd, J = 6, 16 Hz, 1 H), 4.68 (dd, J = 6, 16 Hz, 1 H), 6.42 (d, J = 1 Hz, 1 H), 6.61 (d, J = Hz, 1 H), 6. 75 (d, J = 8 Hz, 1 H), 7. 84 (s, 1 H), 8. 36 (d, J = 1 Hz, 1 H), 8.41 (dd, J = 6) 6 Hz, 1 H).

(Example 105)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N- (isoxazol-3-ylmethyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (132)

The title compound 132 was obtained from compound 131, according to the method described in Example 44.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.15 (m, 2 H), 0.48 to 0.56 (m, 2 H), 0.72 to 0.90 (m) , 2H), 0.99 (ddd, J = 5, 12, 12 Hz, 1H), 1.29-1.35 (m, 1H), 1.62-1.97 (m, 3H), 2.27 -2.43 (m, 4 H), 2.59 (dd, J = 5, 11 Hz, 1 H), 2.96 (s, 0.9 H), 3.01 (s, 2.1 H), 3.08 (D, J = 18 Hz, 1 H), 3.36-3. 43 (m, 1 H), 3.50 (s, 2.1 H), 3.58 (s, 0.9 H), 3. 90 (s) , 3H), 4.67-4.83 (m, 3H), 6.47-6.61 (m, 2H), 6.69 (s, 0.7 H), 6.71 (s, 0.3 H) ), 6.75 (d, J) 8Hz, 1H), 8.37-8.40 (m, 1H).

(Example 106)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N- (isoxazol-3-ylmethyl) -N-methyl-1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (133)

The title compound 133 was obtained from compound 132 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.18 (m, 2 H), 0.46 to 0.58 (m, 2 H), 0.72 to 0.99 (m) , 3H), 1.28 to 1.32 (m, 1 H), 1.66 to 1.82 (m, 3 H), 2.28 to 2.45 (m, 4 H), 2.55 to 2.63. (M, 1 H), 3.02-3.19 (m, 4 H), 3.36-3. 45 (m, 1 H), 4.50 (s, 1 H), 4. 66 (d, J = 15 Hz) , 0.6 H), 4.82-4.92 (m, 1.4 H), 6.47-6.51 (m, 1 H), 6.56 (d, J = 8 Hz, 1 H), 6.76 (D, J = 8 Hz, 1 H), 6.91 (s, 1 H), 8.39-8.43 (m, 1 H).

(Reference Example 27)
Synthesis of N-methyl-1- (1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-2-yl) methanamine (134)

From 1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole-2-carbaldehyde (synthesized by the method described in Journal of Organic Chemistry 2006, 71, 8807) according to the method described in Reference Example 12 Compound 134 was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): −0.01 (s, 9 H), 0.90 (t, J = 8 Hz, 2 H), 2.44 (s, 3 H), 3.50 (T, J = 8 Hz, 2 H), 3.86 (s, 2 H), 5.33 (s, 2 H), 6.96 (s, 2 H).

(Embodiment 107)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((1-((2- (trimethylsilyl) ethoxy) methyl) -1H- Imidazol-2-yl) methyl) -1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (135) Synthesis

The title compound 135 was obtained from compound 4 and compound 134 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): -0.05-0.05 (m, 9 H), 0.10-0.15 (m, 2 H), 0.45-0.55 ( m, 2H), 0.70-1.02 (m, 5H), 1.25-1.35 (m, 1H), 1.50-1.70 (m, 2H), 1.80-1. 95 (m, 2 H), 2.25-2.45 (m, 4 H), 2.54-2.61 (m, 1 H), 3.06 (s, 3 H), 3. 40 (d, J = 6 Hz, 1 H), 3.46 (s, 3 H), 3.50-3.58 (m, 2 H), 3.89 (s, 3 H), 4. 65 (s, 1 H), 4.73 (d , J = 15 Hz, 1 H), 4.86 (d, J = 15 Hz, 1 H), 5.42 (d, J = 11 Hz, 1 H), 5.50 (d, J = 11 Hz, 1 H), 6.58 (D, J = 8 H , 1 H), 6.65 (s, 1 H), 6.73 (d, J = 8 Hz, 1 H), 7.00 (d, J = 1 Hz, 1 H), 7.03 (d, J = 1 Hz, 1 H) ).

(Example 108)
(4R, 4aS, 7R, 7aR, 12bS) -N-((1H-imidazol-2-yl) methyl) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-1,2,3 Synthesis of 2,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide dihydrochloride (136)

According to the method described in Example 2, free form of the title compound 136 was obtained from compound 135 (21.0 mg, 0.032 mmol). The obtained free form was dissolved in methanol (1 mL), 2 M hydrochloric acid-methanol solution (100 μL) was added dropwise under ice-cooling, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was dried in a lyophilizer to give the title compound 136 (11.2 mg, 60%) as a colorless powder.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.45-0.62 (m, 2 H), 0.75-0.95 (m, 3 H), 1.18-1.45 ( m, 3H), 1.65-1.75 (m, 1H), 1.95-2.00 (m, 1H), 2.10-2.20 (m, 1H), 2.92-3. 02 (m, 1 H), 3.08-3.18 (m, 2 H), 3.29 (s, 3 H), 3.25-3. 48 (m, 5 H), 4.42 (d, J = 7 Hz, 1H), 4.49 (s, 1 H), 6.68 (d, J = 8 Hz, 1 H), 6.78 (d, J = 8 Hz, 1 H), 6.92 (s, 1 H), 7 .50 (s, 2H).

(Example 109)
(4R, 4aS, 7R, 7aR, 12bS) -N-((1H-imidazol-2-yl) methyl) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7 Synthesis of 7, 7a-hexahydro-4a, 7-ethano-4, 12-methanobenzofuro [3, 2-e] isoquinoline-6-carboxamide (137)

The title compound 137 was obtained from compound 4 and (1H-imidazol-2-yl) methanamine dihydrochloride according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.19 (m, 2 H), 0.48 to 0.58 (m, 2 H), 0.69 to 0.78 (m) , 1 H), 0.85 to 0.96 (m, 1 H), 1.12-1. 35 (m, 1 H), 1.50-1. 95 (m, 4 H), 2. 25-2.45 (M, 4 H), 2.58 (dd, J = 5, 12 Hz, 1 H), 3.08 (d, J = 18 Hz, 1 H), 3.45-3. 50 (m, 1 H), 3.57 (S, 3 H), 3.89 (s, 3 H), 4. 45 (s, 1 H), 4.52 (d, J = 5 Hz, 2 H), 6.60 (d, J = 8 Hz, 1 H), 6.75 (d, J = 8 Hz, 1 H), 6.96 (s, 2 H), 7.88 (s, 1 H), 8.58-8. 65 (m, 1 H), 1 0.25 (br s , 1 H).

(Example 110)
(4R, 4aS, 7R, 7aR, 12bS) -N-((1H-imidazol-2-yl) methyl) -3- (cyclopropylmethyl) -7,9-dihydroxy-1,2,3,4,7 , 7a-Hexahydro-4a, 7-Ethano-4,12-Methanobenzofuro [3,2-e] isoquinoline-6-carboxamide Dihydrochloride (138)

The title compound 138 was obtained from compound 137, according to the method described in Example 108.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.48 to 0.60 (m, 2 H), 0.78 to 0.92 (m, 3 H), 1.15-1. 39 ( m, 3H), 1.65-1.75 (m, 1H), 1. 9-22. 08 (m, 2H), 2.99 (dd, J = 7, 20 Hz, 1 H), 3.08- 3.20 (m, 2 H), 3.25-3. 50 (m, 5 H), 4.40-4. 48 (m, 2 H), 6.69 (d, J = 8 Hz, 1 H), 6 80 (d, J = 8 Hz, 1 H), 7.48 (s, 2 H), 7.73 (s, 1 H).

(Example 111)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((1-methyl-1H-imidazol-2-yl) methyl) -1 Synthesis of 2,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (139)

The title compound 139 was obtained from compound 4 and N-methyl-1- (1-methyl-1H-imidazol-2-yl) methanamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.15 (m, 2 H), 0.45-0.55 (m, 2 H), 0.70-0.90 (m , 2H), 0.98 (dt, J = 6, 13 Hz, 1 H), 1. 20-1. 35 (m, 1 H), 1.5 0-1. 75 (m, 1 H), 1.8 5 -1. .95 (m, 2 H), 2.25-2. 45 (m, 4 H), 2.58 (dd, J = 5, 11 Hz, 1 H), 3.00 (s, 3 H), 3.07 (d , J = 19 Hz, 1 H), 3.41 (d, J = 6 Hz, 1 H), 3.48 (s, 3 H), 3.71 (s, 3 H), 3.89 (s, 3 H), 4. 62-4.75 (m, 2 H), 4.85-4. 95 (m, 1 H), 6.59 (d, J = 8 Hz, 1 H), 6.64 (s, 1 H), 6.74 ( d, J = 8 Hz 1H), 6.87 (d, J = 1Hz, 1H), 6.96 (d, J = 1Hz, 1H).

(Example 112)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N-((1-methyl-1H-imidazol-2-yl) methyl) -1 Synthesis of 1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide dihydrochloride (140)

The title compound 140 was obtained from compound 139, according to the method described in Example 108.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.48 to 0.58 (m, 2 H), 0.75 to 0.92 (m, 3 H), 1.15-1. 42 ( m, 3H), 1.60-1. 78 (m, 1 H), 1.95-2.03 (m, 1 H), 2.10-2.20 (m, 1 H), 2.90-3. 22 (m, 6 H), 3.25-3. 50 (m, 5 H), 3.78 (s, 0.3 H), 3.89 (s, 2.7 H), 4.40 (s, 0. 6). 2H), 4.51 (s, 1.8 H), 6.65-6. 72 (m, 1 H), 6.73-6. 83 (m, 2 H), 7.05-7.20 (m, 2) 0.2 H), 7.22-7.45 (m, 1.8 H).

(Reference Example 28)
1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carbaldehyde (141) and 1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-3-carbaldehyde (142) Synthesis of

Dissolve 1H-pyrazole-3-carbaldehyde (200 mg, 2.08 mmol) in N, N-dimethylformamide (21 mL) and add sodium hydride (55% oil dispersion) (100 mg, 2.29 mmol), It stirred under nitrogen atmosphere. After 1 hour, under an ice bath, 2- (chloromethoxy) ethyltrimethoxysilane (406 μL, 2.29 mmol) was added and stirred at room temperature for 1 hour. Under an ice bath, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-30% ethyl acetate / heptane) to give a mixture of the title compounds 141 and 142 (235 mg, 50%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): -0.02-0.00 (m, 9 H), 0.82-0.92 (m, 2 H), 3.55-3.62 ( m, 2H), 5.51 (s, 1.2 H), 5.82 (s, 0.8 H), 6.87 (d, J = 3 Hz, 0.6 H), 6.97 (d, J = 3 Hz, 0.4 H), 7.60-7.62 (m, 1 H), 9.95 (s, 0.4 H), 10.00 (s, 0.6 H).

(Reference Example 29)
N-Methyl-1- (1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-yl) methanamine (143) and N-methyl-1- (1-((2- (trimethylsilyl)) Synthesis of (ethoxy) methyl) -1H-pyrazol-3-yl) methanamine (144)

In accordance with the method described in Reference Example 12, a mixture of the title compounds 143 and 144 was obtained from the mixture of the compounds 141 and 142.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): -0.15 to 0.05 (m, 9 H), 0.82 to 0.95 (m, 2 H), 2.44 (s, 1 H) , 2.46 (s, 2H), 3.45-3.58 (m, 2H), 3.77 (s, 1.33 H), 3.84 (s, 0.67 H), 5.37 (s) , 1.33 H), 5.50 (s, 0.67 H), 6.23 (s, 0.33 H), 6.27 (s, 0.67 H) 7.43 (s, 0.33 H), 7 .49 (s, 0.67 H).

(Example 113)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((1-((2- (trimethylsilyl) ethoxy) methyl) -1H- Pyrazol-5-yl) methyl) -1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (145) and (4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N-((1-((2- (trimethylsilyl) ethoxy) methyl) -1H- Pyrazol-3-yl) methyl) -1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12-methanobenzofuro [3,2-e] isoquinoline-6- Synthesis of Rubokisamido (146)

According to the method described in Example 1, a mixture of the title compounds 145 and 146 was obtained from the mixture of the compound 4 and the compounds 143 and 144.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): -0.05-0.02 (m, 9 H), 0.10-0.16 (m, 2 H), 0.45-0.55 ( m, 2H), 0.70-1.02 (m, 5H), 1.22-1.40 (m, 1H), 1.40-1.70 (m, 1H), 1.78-2. 00 (m, 2 H), 2.25-2.42 (m, 4 H), 2.55-2.62 (m, 1 H), 2.93 (s, 1 H), 2.98 (s, 1 H) , 3.05 (s, 0.5 H), 3.10 (s, 0.5 H), 3.30-3.62 (m, 6 H), 3.89 (s, 3 H), 4.55-4 .85 (m, 3H), 5.37 (s, 0.67 H), 5.38 (s, 1.33 H), 6.38 (d, J = 2 Hz, 1 H), 6.57-6.62 (M, 1 H), 6.66 (s, 1 ), 6.70-6.75 (m, 1H), 7.50-7.52 (m, 1H).

(Example 114)
(4R, 4aS, 7R, 7aR, 12bS) -N-((1H-pyrazol-5-yl) methyl) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-1,2,3 Synthesis of 1,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide dihydrochloride (147)

The title compound 147 was obtained from the mixture of compounds 145 and 146 according to the method described in Example 108.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.45-0.58 (m, 2 H), 0.75-0.95 (m, 3 H), 1.15-1. 45 ( m, 4H), 1.65-1.75 (m, 1 H), 1.90-2.02 (m, 1 H), 2.10-2.22 (m, 1 H), 2.90-3. 02 (m, 1.2 H), 2.95 (s, 1.2 H), 3.08-3.18 (m, 1.8 H), 3.15 (s, 1.8 H), 3.25 3.48 (m, 4 H), 4.35-4. 45 (m, 1 H), 4.50 (s, 0.4 H), 4.51 (s, 0.6 H), 6.48 (s, 0.65) 0.4 H), 6.60-6.82 (m, 3.6 H), 7.74 (s, 0.4 H), 7.96 (s, 0.6 H).

(Example 115)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N-((3-fluoropyridin-2-yl) methyl) -7,9-dimethoxy-N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (148)

The title compound 148 was obtained from compound 4 and 1- (3-fluoropyridin-2-yl) -N-methylmethanamine (synthesized by the method described in WO2012054510) according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05 to 0.16 (m, 2 H), 0.41 to 0.56 (m, 2 H), 0.65 to 1.03 (m , 3H), 1.35-1.43 (m, 1 H), 1.53-1.65 (m, 1 H), 1.72-1. 86 (m, 1.4 H), 1.9 1-2. .02 (m, 0.6 H), 2.20-2.43 (m, 4.4 H), 2.58 (dd, J = 5, 12 Hz, 0.6 H), 2.99-3. m, 1 H), 3.06 (s, 1.2 H), 3. 13 (s, 1.8 H), 3. 25 (d, J = 6 Hz, 0.4 H), 3.42 (d, J = 6 Hz, 0.6 H), 3.50 (s, 1.8 H), 3.54 (s, 1.2 H), 3.89 (s, 3 H), 4.71 (s, 1 H), 4.86 (D, J = 14 Hz, 1 H), 4. 1 (d, J = 14 Hz, 1 H), 6.54-6.61 (m, 1 H), 6.66 (s, 0.4 H), 6.71-6.79 (m, 1.6 H), 7.21-7.28 (m, 1 H), 7.34-7.42 (m, 1 H), 8.37-8.45 (m, 1 H).

(Example 116)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -N-((3-fluoropyridin-2-yl) methyl) -9-hydroxy-7-methoxy-N-methyl-1, 2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (149) and (4R, 4aS, 7R, 7aR, 12bS) -3- (Cyclopropylmethyl) -N-((3-fluoropyridin-2-yl) methyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a Synthesis of 1,7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (150)

The title compounds 149 and 150 were obtained from compound 148 according to the method described in Example 2.

(Compound 149)
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06 to 0.15 (m, 2 H), 0.41 to 0.55 (m, 2 H), 0.62 to 0.79 (m) , 1H), 0.83-1.03 (m, 2H), 1.28-1.76 (m, 3.4 H), 1.93 (ddd, J = 6, 13, 13 Hz, 0.6 H) , 2.21-2.55 (m, 4.4 H), 2.59 (dd, J = 5, 12 Hz, 0.6 H), 2.98-3. 13 (m, 1 H), 3.07 (m. s, 1.2 H), 3.16 (s, 1.8 H), 3.26 (d, J = 4 Hz, 0.4 H), 3.41 (d, J = 6 Hz, 0.6 H), 3. 46 (s, 1.8 H), 3.51 (s, 1.2 H), 4. 70 (s, 1 H), 4.82-4. 95 (m, 2 H), 4.95 (br s, 1 H) ), 6.52-6.58 m, 1 H), 6.68-6. 78 (m, 2 H), 7.20-7. 30 (m, 1 H), 7. 35-7.4 1 (m, 1 H), 8. 38 (d, 1 h) J = 5 Hz, 0.6 H), 8.43 (d, J = 5 Hz, 0.4 H).

(Compound 150)
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04 to 0.18 (m, 2 H), 0.40 to 0.58 (m, 2 H), 0.65 to 1.02 (m , 2H), 1.20-1.38 (m, 1H), 1.56-1.79 (m, 2H), 1.85 (ddd, J = 6, 13, 13 Hz, 1H), 2.24 -2.46 (m, 5H), 2.51-2.64 (m, 1H), 2.97 (s, 2.1 H), 3.01-3.12 (m, 1 H), 3.26 (S, 0.9 H), 3. 35 (d, J = 6 Hz, 0.7 H), 3.43 (d, J = 6 Hz, 0.3 H), 4.53 (s, 1 H), 4.84 -4.95 (m, 2 H), 5.13 (br s, 1 H), 5.81 (br s, 1 H), 6.53 (d, J = 8 Hz, 1 H), 6.74 (d, J = 8 Hz, 1 H), 6 .87 (s, 0.7 H), 6.91 (s, 0.3 H), 7. 29-7. 38 (m, 1 H), 7. 39 7. 50 (m, 1 H), 8. 39 -8.48 (m, 1 H).

(Reference Example 30)
Synthesis of N-methyl-1- (pyridazin-3-yl) methanamine (151)

The title compound 151 was obtained from pyridazine-3-carbaldehyde according to the method described in Reference Example 12.

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

(Example 117)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (pyridazin-3-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (152)

The title compound 152 was obtained from the compound 4 and the compound 151 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.12 to 0.15 (m, 2 H), 0.48 to 0.56 (m, 2 H), 0.69 to 0.90 (m) , 2H), 1.01 (ddd, J = 5, 13, 13 Hz, 1H), 1.28-1.35 (m, 1H), 1.64-1.97 (m, 3H), 2.25 -2.43 (m, 4 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 2.99-3.11 (m, 4 H), 3.33-3. 56 (m, 4 H) , 3.88-3.90 (m, 3 H), 4.68 (s, 1 H), 4.85-5. 35 (m, 2 H), 6.57-6. 76 (m, 3 H), 7 42-7.76 (m, 2H), 9.12-9.22 (m, 1 H).

(Example 118)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (pyridazin-3-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (153)

The title compound 153 was obtained from compound 152 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.15 (m, 2 H), 0.46-0.57 (m, 2 H), 0.74-1.01 (m) , 3H), 1.13-1.33 (m, 1H), 1.66-1.86 (m, 3H), 2.28-2.46 (m, 4H), 2.54-2.62. (M, 1 H), 3.03-3. 27 (m, 4 H), 3.34 (d, J = 6 Hz, 0.2 H), 3. 45 (d, J = 6 Hz, 0.8 H), 4 53 (s, 1 H), 4.78 (br s, 1 H), 4.89 (d, J = 14 Hz, 0.8 H), 5.03 (d, J = 14 Hz, 0.2 H), 5. 10 (d, J = 14 Hz, 0.8 H), 5. 26 (d, J = 14 Hz, 0.2 H), 6.57 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz , 1H), 6 86-6.92 (m, 1H), 7.49-7.73 (m, 2H), 9.15 (d, J = 5Hz, 1H).

(Reference Example 31)
Synthesis of tert-butyl methyl (pyrazin-2-ylmethyl) carbamate (154)

tert-Butyl (pyrazin-2-ylmethyl) carbamate (synthesized by the method described in WO2012122422) (797 mg, 3.81 mmol) is dissolved in N, N-dimethylformamide (19 mL), and sodium hydride (55 % Oil dispersion) (218 mg, 5.00 mmol) was added and stirred for 10 minutes. Subsequently, methyl iodide (1.2 mL, 19.0 mmol) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted five times with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-4% methanol / chloroform) to give the title compound 154 (639 mg, 75%) as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.44-1.50 (m, 9 H), 2.94-3.00 (m, 3 H), 4.54-4. 60 (m , 2H), 8.49-8.57 (m, 3H).

(Example 32)
Synthesis of N-methyl-1- (pyrazin-2-yl) methanamine dihydrochloride (155)

Compound 154 (639 mg, 2.86 mmol) was dissolved in methanol (10 mL), 3 M hydrogen chloride in 1,4-dioxane solution (10 mL) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and then lyophilized to give the title compound 155 (525 mg, 94%) as brown crystals.

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

(Example 119)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (pyrazin-2-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (156)

The title compound 156 was obtained from compound 4 and compound 155 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.17 (m, 2 H), 0.49 to 0.58 (m, 2 H), 0.70 to 0.93 (m) , 2H), 1.01 (ddd, J = 6, 13, 13 Hz, 1 H), 1.32-1.36 (m, 1 H), 1.60-1.99 (m, 3 H), 2.27 -2.45 (m, 4H), 2.59 (dd, J = 5, 12 Hz, 1 H), 3.05-3.12 (m, 4 H), 3.45-3.62 (m, 4 H) , 3.88 (s, 0.9 H), 3. 90 (s, 2.1 H), 4.51 to 4. 90 (m, 3 H), 6.57 to 6.89 (m, 3 H), 8 50-50.57 (m, 2H), 8.66 (s, 0.3 H), 8.75 (s, 0.7 H).

(Example 120)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (pyrazin-2-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (157)

The title compound 157 was obtained from compound 156 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04 to 0.15 (m, 2 H), 0.42 to 0.57 (m, 2 H), 0.70 to 0.88 (m) , 2H), 0.99 (ddd, J = 6, 13, 13 Hz, 1 H), 1.31-1.37 (m, 1 H), 1.51-1.87 (m, 3 H), 2.18 -2.48 (m, 5 H), 3.03-3. 49 (m, 5 H), 4. 14 (d, J = 14 Hz, 0.8 H), 4.51 (s, 0.2 H), 4 .63 (s, 0.8 H), 4.83 (d, J = 14 Hz, 0.2 H), 4.95 (d, J = 14 Hz, 0.2 H), 5.09 (s, 0.2 H) , 5.32 (d, J = 14 Hz, 0.8 H), 5.68 (s, 0.8 H), 6.55 (d, J = 8 Hz, 1 H), 6.60 (s, 1 H), 6 .78 (d, J 8Hz, 1H), 8.53-8.65 (m, 2H), 9.15 (br s, 1H), 9.34 (s, 1H).

(Example 121)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N- (pyrazin-2-ylmethyl) -1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (158)

The title compound 158 was obtained from compound 4 and pyrazin-2-ylmethanamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.14 (m, 2 H), 0.47-0.55 (m, 2 H), 0.73 (ddd, J = 3 , 10, 13 Hz, 1 H), 0.85-0.97 (m, 2 H), 1.24-1. 31 (m, 1 H), 1.5 8-1.61 (m, 1 H), 1.76 -1.92 (m, 2H), 2.28-2.41 (m, 4H), 2.59 (dd, J = 5, 12 Hz, 1 H), 3.08 (d, J = 18 Hz, 1 H) , 3.45 (d, J = 6 Hz, 1 H), 3.62 (s, 3 H), 3. 90 (s, 3 H), 4.51 (s, 1 H), 4.68-4.80 (m , 2H), 6.61 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 7.88 (s, 1 H), 8.49 (d, J = 2 Hz, 1 H) ), 8 54 (dd, J = 1,2Hz, 1H), 8.66 (d, J = 1Hz, 1H), 8.75 (t, J = 6Hz, 1H).

(Example 122)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N, N-dimethyl-1,2,3,4,7,7a-hexahydro-4a, 7- Synthesis of ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (159)

The title compound 159 was obtained from compound 158, according to the method described in Example 44.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.15 (m, 2 H), 0.47 to 0.55 (m, 2 H), 0.71 to 0.89 (m) , 2H), 0.98 (ddd, J = 6, 13, 13 Hz, 1H), 1.25-1.66 (m, 2H), 1.79-1 .98 (m, 2H), 2.28 -2.41 (m, 4 H), 2.58 (dd, J = 5, 12 Hz, 1 H), 3.03 (s, 3 H), 3.04 (s, 3 H), 3.08 (d, J = 19 Hz, 1 H), 3. 40 (d, J = 6 Hz, 1 H), 3.52 (s, 3 H), 3. 90 (s, 3 H), 4.69 (s, 1 H), 6.59 ( d, J = 8 Hz, 1 H), 6.65 (s, 1 H), 6. 74 (d, J = 8 Hz, 1 H).

(Example 123)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N, N-dimethyl-1,2,3,4,7,7a-hexahydro-4a, 7- Synthesis of ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (160)

The title compound 160 was obtained from compound 159 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.12 to 0.17 (m, 2 H), 0.48 to 0.58 (m, 2 H), 0.71 to 0.89 (m) , 2H), 0.96 (ddd, J = 6, 13, 13 Hz, 1 H), 1.25-1.33 (m, 1 H), 1.63-1. 84 (m, 3 H), 2.28 -2.44 (m, 4 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 3.05-3. 10 (m, 4 H), 3.21 (s, 3 H), 4.41 (D, J = 6 Hz, 1 H), 4.50 (d, J = 2 Hz, 1 H), 4.94 (s, 1 H), 5.58 (br s, 1 H), 6.56 (d, J = 8 Hz, 1 H), 6.75 (d, J = 8 H, 1 H), 6.85 (s, 1 H).

(Reference Example 33)
Synthesis of tert-butyl methyl (pyrimidin-2-ylmethyl) carbamate (161)

The title compound 161 was obtained from tert-butyl (pyrimidin-2-ylmethyl) carbamate (synthesized by the method described in WO2013013238) according to the method described in Reference Example 31.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.33-1.50 (m, 9 H), 2.99-3.04 (m, 3 H), 4.60-4. 70 (m) , 2H), 7.17-7.18 (m, 1 H), 8.70-8.71 (m, 2 H).

(Reference Example 34)
Synthesis of N-methyl-1- (pyrimidin-2-yl) methanamine dihydrochloride (162)

The title compound 162 was obtained from compound 161 according to the method described in Reference Example 32.

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

(Example 124)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (pyrimidin-2-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (163)

The title compound 163 was obtained from the compound 4 and the compound 162 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05 to 0.16 (m, 2 H), 0.40 to 0.56 (m, 2 H), 0.62 to 1.04 (m) , 3H), 1.30-2.00 (m, 4H), 2.21-2.62 (m, 5H), 3.01 (d, J = 18 Hz, 0.5 H), 3.09 (d , J = 18 Hz, 0.5 H), 3.17-3.56 (m, 7 H), 3.88 (s, 1.5 H), 3. 90 (s, 1.5 H), 4.69-4 .87 (m, 2.5 H), 4.99 (d, J = 16 Hz, 0.5 H), 6.55 (s, 0.5 H), 6.56 (d, J = 8 Hz, 0.5 H) , 6.59 (d, J = 8 Hz, 0.5 H), 6.71 (d, J = 8 Hz, 0.5 H), 6.75 (d, J = 8 Hz, 0.5 H), 6.81 (d s, 0.5 H), 7.1 -7.20 (m, 1H), 8.71-8.73 (m, 2H).

(Example 125)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (pyrimidin-2-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (164)

The title compound 164 was obtained from compound 163 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06 to 0.16 (m, 2 H), 0.40 to 0.53 (m, 2 H), 0.64 to 1.00 (m) , 3H), 1.17-1.37 (m, 1H), 1.59-1.88 (m, 3H), 2.23-2.44 (m, 4H), 2.50-2.62. (M, 1 H), 3.00 to 3.43 (m, 5 H), 4.47 (s, 0.7 H), 4.51 (s, 0.3 H), 4.88 (d, J = 16 Hz) , 1H), 4.97 (d, J = 16 Hz, 1 H), 6.51 to 6.76 (m, 2 H), 6.84 (s, 0.7 H), 6.97 (s, 0.3 H) , 7.21-7.31 (m, 1 H), 8.75 (d, J = 5 Hz, 0.6 H), 8.78 (d, J = 5 Hz, 1.4 H).

(Example 126)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N- (pyrimidin-2-ylmethyl) -1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (165)

The title compound 165 was obtained from compound 4 and pyrimidin-2-ylmethanamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09 to 0.16 (m, 2 H), 0.48 to 0.55 (m, 2 H), 0.69 to 0.78 (m) , 1H), 0.86-0.99 (m, 2H), 1.29-1.39 (m, 1H), 1.59-1.64 (m, 1H), 1.79-1.90 (M, 2H), 2.26-2.40 (m, 4H), 2.59 (dd, J = 5, 12 Hz, 1 H), 3.08 (d, J = 18 Hz, 1 H), 3.45 (D, J = 6 Hz, 1 H), 3.68 (s, 3 H), 3.9 1 (s, 3 H), 4.56 (d, J = 2 Hz, 1 H), 4.79-4.91 (m , 2H), 6.61 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 7.21 (t, J = 5 Hz, 1 H), 7.87 (s, 1 H) ), 8.74 d, J = 5Hz, 2H), 9.04 (t, J = 4Hz, 1H).

(Example 127)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N- (pyrimidin-2-ylmethyl) -1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (166)

The title compound 166 was obtained from compound 165 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08 to 0.18 (m, 2 H), 0.43 to 0.55 (m, 2 H), 0.58 to 0.66 (m) , 1H), 0.75 to 0.92 (m, 2H), 1.21 to 1.31 (m, 1H), 1.48 to 1.55 (m, 1H), 1.59 to 1.78 (M, 2H), 2.20-2.41 (m, 4H), 2.52 (dd, J = 5, 11 Hz, 1 H), 3.02 (d, J = 18 Hz, 1 H), 3.41 (D, J = 6 Hz, 1 H), 4.40 (s, 1 H), 4.77-4. 88 (m, 2 H), 6.48 (d, J = 8 Hz, 1 H), 6.72 (d , J = 8 Hz, 1 H), 7.20 (t, J = 4 Hz, 1 H), 7.63 (s, 1 H), 8.61 (br s, 1 H), 8.71 (d, J = 4 Hz, 2H).

(Example 128)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (pyrimidin-4-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (167)

The title compound 167 was obtained from compound 4 and N-methyl-1- (pyrimidin-4-yl) methanamine dihydrochloride according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.19 (m, 2 H), 0.43-0.60 (m, 2 H), 0.63-0.93 (m) , 2H), 0.98-1.10 (m, 1H), 1.20-1.41 (m, 1H), 1.56-1.88 (m, 2H), 1.89-1.99 (M, 1 H), 2.21-2. 47 (m, 4 H), 2.5 5-2. 64 (m, 1 H), 3.0 5-3. 14 (m, 4 H), 3. 28 (d , J = 5 Hz, 0.3 H), 3.44 (d, J = 5 Hz, 0.7 H), 3.52 (s, 0.9 H), 3.58 (s, 2.1 H), 3.87 (S, 0.9 H), 3.91 (s, 2.1 H), 4.50-4. 93 (m, 3 H), 6.57 (d, J = 8 Hz, 0.3 H), 6.61 (D, J = 8 Hz, 0.7 H), 6 64 (s, 0.3 H), 6. 73 (d, J = 8 Hz, 0.7 H), 6. 75 (s, 0.7 H), 6. 76 (d, J = 8 Hz, 0.3 H), 7.42 (d, J = 5 Hz, 0.3 H), 7. 50 (d, J = 5 Hz, 0.7 H), 8. 70 (d, J = 5 Hz, 0.7 H), 8.75 (d , J = 5 Hz, 0.3 H), 9.16 (s, 1 H).

(Example 129)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (pyrimidin-4-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (168)

The title compound 168 was obtained from compound 167 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.01-0.09 (m, 0.8 H), 0.09-0.18 (m, 1.2 H), 0.38-0 .58 (m, 2H), 0.61-1.00 (m, 3H), 1.11-1. 37 (m, 1H), 1.52-1. 86 (m, 3H), 2.17 -2.63 (m, 5 H), 2.96-3. 10 (m, 1 H), 3.04 (s, 1.2 H), 3. 25 (s, 1.8 H), 3. 20-3 .29 (m, 0.4 H), 3.42 (d, J = 6 Hz, 0.6 H), 4.42 (s, 0.4 H), 4.49 (s, 0.6 H), 4.68 (D, J = 16 Hz, 0.6 H), 4.71-4. 92 (m, 1.4 H), 6.51 (d, J = 8 Hz, 0.4 H), 6.53 (d, J = 8 Hz, 0.6 H), 6.72 (d, J 8 Hz, 0.4 H), 6.73 (s, 0.4 H), 6.76 (d, J = 8 Hz, 0.6 H), 6.91 (s, 0.6 H), 7.36-7. 45 (m, 1 H), 8. 73 (d, J = 4 Hz, 0.6 H), 8. 80 (d, J = 4 Hz, 0.4 H), 9. 18 (s, 0.6 H), 9. 22 (s, 0.4 H).

(Example 130)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (pyrimidin-5-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (169)

The title compound 169 was obtained from compound 4 and N-methyl-1- (pyrimidin-5-yl) methanamine dihydrochloride according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.18 (m, 2 H), 0.44 to 0.59 (m, 2 H), 0.70 to 0.91 (m) , 2H), 1.01 (ddd, J = 5, 13, 13 Hz, 1H), 1.24-1.36 (m, 1H), 1.60-1. 79 (m, 1H), 1.88 -1.98 (m, 2H), 2.26-2.37 (m, 3H), 2.41 (dd, J = 6, 13 Hz, 1 H), 2.59 (dd, J = 5, 12 Hz, 1H), 3.02 (s, 3 H), 3.09 (d, J = 18 Hz, 1 H), 3.43 (d, J = 6 Hz, 1 H), 3.54 (s, 3 H), 3.90 (S, 3 H), 4.43-4. 89 (m, 3 H), 6. 60 (d, J = 8 Hz, 1 H), 6.72 (s, 1 H), 6. 75 (d, J = 8 Hz) , 1 ), 8.73 (s, 0.4H), 8.76 (s, 1.6H), 9.17 (s, 0.8H), 9.18 (s, 0.2H).

(Example 131)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (pyrimidin-5-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (170)

The title compound 170 was obtained from compound 169 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.01 to 0.16 (m, 2 H), 0.41 to 0.58 (m, 2 H), 0.73 to 0.86 (m) , 2H), 0.97 (ddd, J = 5, 12, 12 Hz, 1 H), 1.23-1.37 (m, 1 H), 1.48-1.57 (m, 1 H), 1.71 (Ddd, J = 6, 13, 13 Hz, 1 H), 1.76-1.87 (m, 1 H), 2.20 (dd, J = 13, 7 Hz, 1 H), 2.23-2.36 ( m, 2H), 2.39-2.49 (m, 1H), 2.45 (dd, J = 6, 12 Hz, 1 H), 3.05 (d, J = 18 Hz, 1 H), 3.29 ( s, 3H), 3.47 (d, J = 6 Hz, 1 H), 3.96 (d, J = 14 Hz, 1 H), 4.62 (s, 1 H), 5.25 (d, J = 1 Hz, 1 H), 6.55 (d, J = 8 Hz, 1 H), 6.61 (s, 1 H) 6.78 (d, J = 8 Hz, 1 H), 9. 13 (s, 2 H), 9. 24 (s, 1 H).

(Example 132)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N- (pyrimidin-4-ylmethyl) -1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (171)

The title compound 171 was obtained from compound 4 and pyrimidin-4-ylmethanamine dihydrochloride according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10-0.18 (m, 2 H), 0.46-0.56 (m, 2 H), 0.75 (ddd, J = 2 , 10, 12 Hz, 1 H), 0.85-0.98 (m, 2 H), 1.20-1. 34 (m, 2 H), 1. 80 (ddd, J = 6, 13, 13 Hz, 1 H) , 1.92 (ddd, J = 5, 10, 12 Hz, 1 H), 2.28-2.45 (m, 4 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 3.09 (m. d, J = 18 H, 1 H), 3.46 (d, J = 6 Hz, 1 H), 3.67 (s, 3 H), 3.9 1 (s, 3 H), 4.53 (d, J = 2 Hz, 1H), 4.64 (dd, J = 5, 17 Hz, 1 H), 4.71 (dd, J = 6, 17 Hz, 1 H), 6.62 (d, J = 8 Hz, 1 ), 6.76 (d, J = 8 Hz, 1 H), 7. 35 (dd, J = 1, 5 Hz, 1 H), 7.89 (s, 1 H), 8.68 (d, J = 5 Hz, 1 H) ), 8.83 (dd, J = 5, 6 Hz, 1 H), 9.18 (d, J = 1 Hz, 1 H).

(Example 133)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N- (pyrimidin-4-ylmethyl) -1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (172)

The title compound 172 was obtained from compound 171 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.18 (m, 2 H), 0.45 to 0.60 (m, 2 H), 0.62 to 0.72 (m) , 1H), 0.82 to 0.93 (m, 2H), 1.20 to 1.34 (m, 1H), 1.56 to 1.80 (m, 3H), 2.25 to 2.36 (M, 3 H), 2.40 (dd, J = 6, 13 Hz, 1 H), 2.58 (dd, J = 4, 11 Hz, 1 H), 3.07 (d, J = 18 Hz, 1 H), 3 .45 (d, J = 7 Hz, 1 H), 4.41 (s, 1 H), 4.64 (d, J = 17 Hz, 1 H), 4.72 (d, J = 17 Hz, 1 H), 6.55 (D, J = 8 Hz, 1 H), 6.74 (d, J = 8 Hz, 1 H), 7.40 (d, J = 5 Hz, 1 H), 7.66 (s, 1 H), 8.43 (br , 1H), 8.71 (d, J = 5Hz, 1H), 9.19 (s, 1H).

(Example 134)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N- (pyrimidin-5-ylmethyl) -1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (173)

The title compound 173 was obtained from compound 4 and pyrimidin-5-ylmethanamine dihydrochloride according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.15 (m, 2 H), 0.46-0.57 (m, 2 H), 0.69-0.78 (m , 1H), 0.82 to 0.97 (m, 2H), 1.17 to 1.28 (m, 2H), 1.78 (ddd, J = 6, 13, 13 Hz, 1H), 1.91 (Ddd, J = 6, 10, 12 Hz, 1 H), 2.26-2.37 (m, 3 H), 2. 38 (dd, J = 6, 13 Hz, 1 H), 2.59 (dd, J = 5, 12 Hz, 1 H), 3.08 (d, J = 18 Hz, 1 H), 3. 45 (d, J = 6 Hz, 1 H), 3. 60 (s, 3 H), 3.89 (s, 3 H) , 4.47 (d, J = 3 Hz, 1 H) 4.52 (dd, J = 6, 15 Hz, 1 H), 4.61 (dd, J = 6, 15 Hz, 1 H), 6. 1 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 7.88 (s, 1 H), 8.36 (dd, J = 6, 6 Hz, 1 H), 8. 75 (s, 2 H), 9. 14 (s, 1 H).

(Example 135)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N- (pyrimidin-5-ylmethyl) -1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (174)

The title compound 174 was obtained from compound 173 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.15 (m, 2 H), 0.43 to 0.58 (m, 2 H), 0.61 to 0.71 (m) , 1H), 0.78 to 0.92 (m, 2H), 1.19 to 1.28 (m, 1H), 1.52-1.67 (m, 2H), 1.73 (ddd, J) = 6, 13, 13 Hz, 1 H), 2.22-2.38 (m, 3 H), 2.41 (dd, J = 6, 13 Hz, 1 H), 2.55 (dd, J = 5, 12 Hz, 1H), 3.05 (d, J = 18 Hz, 1 H), 3.45 (d, J = 6 Hz, 1 H), 4. 35 (s, 1 H), 4.52 (d, J = 15 Hz, 1 H) , 4.61 (d, J = 15 Hz, 1 H), 6, 53 (d, J = 8 Hz, 1 H), 6.74 (d, J = 8 Hz, 1 H), 7.63 (s, 1 H) 8.28 (br s, 1H), 8.85 (s, 2H), 9.14 (s, 1H).

(Example 136)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-((3-methoxypyridin-2-yl) methyl) -N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (175)

Compound 112 (12.9 mg, 0.024 mmol) is dissolved in anhydrous N, N-dimethylformamide (1 mL), potassium carbonate (65.9 mg, 0.48 mmol) and methyl iodide (30.0 μL, 0.48 mmol) Was added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 97: 3) to give the title compound 175 (11.7 mg, 89%) as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.15 (m, 2 H), 0.44 to 0.53 (m, 2 H), 0.64 to 1.03 (m) , 3H), 1.28-2.01 (m, 4H), 2.24-2.61 (m, 5H), 3.00-3.11 (m, 4H), 3.26-3.89 (M, 10 H), 4.56-5.00 (m, 3 H), 6.56-6.75 (m, 3 H), 7.1 1-7. 20 (m, 2 H), 8. 15 (dd , J = 2,5 Hz, 0.4 H), 8.19 (dd, J = 2,5 Hz, 0.6 H).

(Example 137)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-((3-methoxypyridin-2-yl) methyl) -N-methyl-1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (176)

The title compound 176 was obtained from compound 175 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.14 (m, 2 H), 0.44 to 0.52 (m, 2 H), 0.65 to 0.95 (m) , 3H), 1.23-1.29 (m, 1H), 1.62-1. 76 (m, 2H), 1.88 (ddd, J = 5, 13, 13 Hz, 1H), 2.25 -2.38 (m, 4H), 2.53-2.64 (m, 1 H), 2.88 (s, 2.4 H), 3.03-3.10 (m, 1 H), 3.20 (S, 0.6 H), 3. 35 (d, J = 6 Hz, 0.8 H), 3.41 (d, J = 6 Hz, 0.2 H), 3.88 (s, 3 H), 4.51 -4.53 (m, 1 H), 4.83 (d, J = 16 Hz, 1 H), 4.89 (d, J = 16 Hz, 1 H), 6.53 (d, J = 8 Hz, 1 H), 6 .73 (d, J 8 Hz, 1 H), 6.82 (s, 0.8 H), 6. 91 (s, 0.2 H), 7. 18-7. 28 (m, 2 H), 8. 19 (d, J = 4 Hz, 1H).

(Example 138)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-N-methyl-N- (thiazol-2-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (177)

The title compound 177 is obtained from the compound 4 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 1. The

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.12 to 0.15 (m, 2 H), 0.45 to 0.56 (m, 2 H), 0.70 to 1.03 (m) , 3H), 1.27-1.38 (m, 1H), 1.61-1.97 (m, 3H), 2.27-2.43 (m, 4H), 2.53-2.61 (M, 1 H), 3.04-3. 10 (m, 4 H), 3.32 (d, J = 6 Hz, 0.3 H), 3.42 (d, J = 6 Hz, 0.7 H), 3 .50 (s, 2.1 H), 3.56 (s, 0.9 H), 3.89 (s, 3 H), 4.69 (s, 1 H), 4.95-5.03 (m, 2 H) ), 6.57-6.61 (m, 1 H), 6.72-6. 77 (m, 2 H), 7.34-7. 35 (m, 1 H), 7.72-7. , 1 H).

(Example 139)
(4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dihydroxy-N-methyl-N- (thiazol-2-ylmethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (178)

The title compound 178 was obtained from compound 177 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07 to 0.17 (m, 2 H), 0.44 to 0.57 (m, 2 H), 0.68 to 0.99 (m) , 3H), 1.26 to 1.32 (m, 1H), 1.58 to 1.84 (m, 3H), 2.26 to 2.44 (m, 4H), 2.52 to 2.64 (M, 1 H), 3.08-3. 42 (m, 5 H), 4. 49 (s, 1 H), 4.72-6. 10 (m, 3 H), 6.56 (d, J = 8 Hz , 1 H), 6.75 (d, J = 8 Hz, 1 H), 6.94-6.97 (m, 1 H), 7.35-7.36 (m, 1 H), 7.75-7.80 (M, 1 H).

(Example 140)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3- (cyclopropylmethyl) -7-methoxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a, 7- Synthesis of ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide

(1) (4R, 4aS, 7S, 7aR, 12bS) -3- (cyclopropylmethyl) -7, 9-dihydroxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4 Synthesis of 1,12-Methanobenzofuro [3,2-e] isoquinolin-6 (5H) -one (179)

The title compound 179 was obtained from compound 2 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.13 (m, 2 H), 0.47 to 0.54 (m, 2 H), 0.75 to 0.85 (m) , 1H), 0.94-1.01 (m, 1H), 1.20-1.34 (m, 2H), 1.67 (dd, J = 2, 13 Hz, 1H), 1.87-2 .03 (m, 2H), 2.29-2.41 (m, 5H), 2.71 (dd, J = 6, 12 Hz, 1 H), 3.07 (d, J = 18 Hz, 1 H), 3 .16 (d, J = 6 Hz, 1 H), 3.61 (dd, J = 4, 20 Hz, 1 H), 3.81 (br s, 1 H), 4.30 (d, J = 1 Hz, 1 H), 5.33 (br s, 1 H), 6.59 (d, J = 8 Hz, 1 H), 6.77 (d, J = 8 Hz, 1 H).

(2) (4R, 4aS, 7S, 7aR, 12bS) -3- (cyclopropylmethyl) -7-hydroxy-9-((1-phenyl-1H-tetrazol-5-yl) oxy) -1,2, Synthesis of 3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinolin-6 (5H) -one (180)

Compound 179 (236 mg, 0.64 mmol) is dissolved in anhydrous N, N-dimethylformamide (6 mL), potassium carbonate (220 mg, 1.59 mmol) and 5-chloro-1-phenyl-1H-tetrazole (130 mg, 0. 1). 72 mmol) was added and stirred at room temperature for 8 hours. Water was added to the reaction mixture and extracted three times with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (35-56% ethyl acetate / hexane) to give the title compound 180 (272 mg, 83%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.11 to 0.16 (m, 2 H), 0.49 to 0.56 (m, 2 H), 0.77 to 0.86 (m , 1 H), 1.00-1.09 (m, 1 H), 1.26-1. 36 (m, 2 H), 1.74 (dd, J = 3, 13 Hz, 1 H), 1.97-2 .10 (m, 2 H), 2. 30-2. 47 (m, 5 H), 2. 76 (dd, J = 5, 12 Hz, 1 H), 3. 15 (d, J = 19 Hz, 1 H), 3 .20 (d, J = 6 Hz, 1 H), 3.62 (s, 1 H), 3.63 (dd, J = 4, 20 Hz, 1 H), 4.34 (d, J = 1 Hz, 1 H), 6 .76 (d, J = 8 Hz, 1 H), 7.16 (d, J = 8 Hz, 1 H), 7.47-7.52 (m, 1 H), 7.55-7.59 (m, 2 H) , 7 84-7.87 (m, 2H).

(3) (4R, 4aS, 7S, 7aR, 12bS) -3- (cyclopropylmethyl) -7-hydroxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of 4-Methanobenzofuro [3,2-e] isoquinolin-6 (5H) -one (181)

Compound 180 (272 mg, 0.53 mmol) was dissolved in acetic acid (5 mL), 5% palladium on activated carbon (340 mg) was added, and the reaction mixture was stirred at 100 ° C. for 23 hours under a hydrogen atmosphere. After allowing to cool, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To the residue was added 3 M aqueous sodium hydroxide solution, and the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (16-37% ethyl acetate / hexane) to give the title compound 181 (97.0 mg, 52%) as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.10 to 0.14 (m, 2 H), 0.48 to 0.55 (m, 2 H), 0.76 to 0.86 (m) , 1H), 0.91-1.00 (m, 1H), 1.20-1.32 (m, 2H), 1.66 (dd, J = 3, 13 Hz, 1H), 1.82-1 .91 (m, 1 H), 1.99 (ddd, J = 6, 13, 13 Hz, 1 H), 2.29-2.43 (m, 5 H), 2.72 (dd, J = 6, 12 Hz, 1H), 3.13 (d, J = 19 Hz, 1 H), 3.17 (d, J = 6 Hz, 1 H), 3.62 (dd, J = 4, 20 Hz, 1 H), 3.65 (s, 1H), 4.23 (d, J = 2 Hz, 1 H), 6.68 (d, J = 8 Hz, 1 H), 6.70 (d, J = 8 Hz, 1 H), 7.13 (dd, = 8,8Hz, 1H).

(4) (4R, 4aS, 7S, 7aR, 12bS) -3- (cyclopropylmethyl) -7-methoxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of 4-Methanobenzofuro [3,2-e] isoquinolin-6 (5H) -one (182)

The title compound 182 was obtained from compound 181 according to the method described in Example 44.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.15 (m, 2 H), 0.46-0.54 (m, 2 H), 0.75-0.85 (m) , 1 H), 0.92-1.01 (m, 1 H), 1.26 (ddd, J = 6, 13, 13 Hz, 1 H), 1.56-1. 72 (m, 3 H), 2.02 (Ddd, J = 6, 13, 13 Hz, 1 H), 2.23 (d, J = 20 Hz, 1 H), 2.32-2.42 (m, 4 H), 2.72 (dd, J = 6, 12 Hz, 1 H), 3.13 (d, J = 19 Hz, 1 H), 3.15 (d, J = 6 Hz, 1 H), 3.52 (s, 3 H), 3.53 (dd, J = 4, 20 Hz, 1 H), 4.53 (d, J = 2 Hz, 1 H), 6.68-6. 70 (m, 2 H), 7.12 (dd, J = 8, 8 Hz, 1 H).

(5) (4R, 4aS, 7S, 7aR, 12bS) -3- (cyclopropylmethyl) -7-methoxy-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12 Synthesis of 2-Methanobenzofuro [3,2-e] isoquinolin-6-yl trifluoromethanesulfonate (183)

The title compound 183 was obtained from compound 182 according to the method described in Reference Example 3.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.12 to 0.16 (m, 2 H), 0.50 to 0.58 (m, 2 H), 0.67 (ddd, J = 3 , 10, 13 Hz, 1 H), 0.82-0.92 (m, 1 H), 1.01 (ddd, J = 6, 12, 12 Hz, 1 H), 1.39-1.47 (m, 1 H) , 1.64 (dd, J = 2, 13 Hz, 1 H
), 1.72 (ddd, J = 6, 10, 12 Hz, 1 H), 1.92 (ddd, J = 6, 13, 13 Hz, 1 H), 2.31-2. 43 (m, 4 H), 2 .64 (dd, J = 5, 12 Hz, 1 H), 3. 14 (d, J = 19 Hz, 1 H), 3.41 (d, J = 6 Hz, 1 H), 3.56 (s, 3 H), 4 .57 (d, J = 2 Hz, 1 H), 6.56 (s, 1 H), 6.63 (d, J = 8 Hz, 1 H), 6.66 (d, J = 8 Hz, 1 H), 7.12 (Dd, J = 8, 8 Hz, 1 H).

(6) 2,4,6-Trichlorophenyl (4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -7-methoxy-1,2,3,4,7,7a-hexahydro-4a Synthesis of 7,7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxylate (184)

The title compound 184 was obtained from compound 183, according to the method described in Reference Example 4.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.13-0.20 (m, 2 H), 0.50-0.59 (m, 2 H), 0.74 (ddd, J = 3) , 10, 13 Hz, 1 H), 0.87-1. 02 (m, 2 H), 1. 49-1.27 (m, 3 H), 1.81 (ddd, J = 6, 13, 13 Hz, 1 H) , 2.32-2.49 (m, 4H), 2.65 (dd, J = 5, 12 Hz, 1 H), 3.17 (d, J = 19 Hz, 1 H), 3.52 (d, J = 6 Hz, 1 H), 3.54 (s, 3 H), 4.59 (d, J = 2 Hz, 1 H), 6.67-6.69 (m, 2 H), 7.13 (dd, J = 8, 8 Hz, 1 H), 7.41 (s, 2 H), 8.11 (s, 1 H).

(7) (4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3- (cyclopropylmethyl) -7-methoxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a Synthesis of 1,7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (185)

The title compound 185 was obtained from compound 184 and N-methyl-1-phenylmethanamine according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.07-0.17 (m, 2 H), 0.46-0.56 (m, 2 H), 0.62-1.03 (m , 3H), 1.28-1.41 (m, 1H), 1.61-2.00 (m, 3H), 2.28-2.63 (m, 5H), 2.92 (s, 1) .2 H), 2.96 (s, 1.8 H), 3.09 (d, J = 18 Hz, 0.4 H), 3. 13 (d, J = 18 Hz, 0.6 H), 3.32 (d , J = 6 Hz, 0.4 H), 3.44 (d, J = 6 Hz, 0.6 H), 3.50 (s, 1.8 H), 3.56 (s, 1.2 H), 4.53 -4.77 (m, 3 H), 6.60-6.71 (m, 3 H), 7.07-7. 13 (m, 1 H), 7.28-7. 39 (m, 5 H).

(Example 141)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3- (cyclopropylmethyl) -7-hydroxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a, 7- Synthesis of ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (186)

The title compound 186 was obtained from compound 185 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.03-0.17 (m, 2 H), 0.40-1.00 (m, 5 H), 1.25-1.37 (m , 1H), 1.59-1.83 (m, 3H), 2.22-2.65 (m, 5H), 2.97-3.48 (m, 5H), 4.40-4.79 (M, 4H), 6.62-6.67 (m, 2H), 6.86 (br s, 1H), 7.08-7.12 (m, 1H), 7.29-7.38 ( m, 5H).

(Example 142)
2,2,2-Trichloroethyl (4R, 4aS, 7R, 7aR, 12bS) -6- (benzyl (methyl) carbamoyl) -7,9-dimethoxy-1,2,7,7a-tetrahydro-4a, 7- Synthesis of ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-3 (4H) -carboxylate (187)

A mixture of compound 59 (110 mg, 0.21 mmol), trichloroethyl chloroformate (680 μL, 2.09 mmol), and potassium carbonate (288 mg, 2.09 mmol) in 1,2-dichloroethane (6 mL) was mixed with a microwave device to 180 Stir for 30 minutes at ° C. The reaction mixture was filtered through celite and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (33-50% ethyl acetate / hexane) to give the title compound 187 (101 mg, 75%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.69 to 0.84 (m, 1 H), 1.00-1. 19 (m, 1 H), 1.30 to 1.43 (m) , 1H), 1.64-1.84 (m, 2H), 1.88-2.03 (m, 2H), 2.88 (s, 1.8 H), 2.90 (s, 1.2 H) 2.92-3.25 (m, 3 H), 3.55 (s, 1.8 H), 3. 60 (s, 1.2 H), 3. 90 (s, 1.2 H), 3. 91 (s, 1.8 H), 4.00-4.12 (m, 1 H), 4. 36-4. 93 (m, 5 H), 6. 38-6. 46 (m, 1 H), 6. 61-6.69 (m, 1 H), 6.77-6. 83 (m, 1 H), 7.23-7. 39 (m, 5 H).

(Example 143)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dihydroxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12- Synthesis of methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (188)

Compound 187 (24.6 mg, 0.038 mmol) was dissolved in dichloromethane (1 mL), and 1 M boron tribromide-dichloromethane solution (0.19 mL, 0.19 mmol) was added under ice-cooling. After stirring at room temperature for 1 hour, a 28% aqueous ammonia solution was added under ice-cooling and the mixture was stirred for a while. The mixture was extracted three times with chloroform, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was dissolved in acetic acid (1.5 mL), zinc powder (173 mg, 2.65 mmol) was added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 91: 9) to give the title compound 188 (13.1 mg, 76%) as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.65-0.80 (m, 1 H), 0.85-1. 05 (m, 1 H), 1.20-1. 38 (m , 2H), 1.59-1.89 (m, 3H), 2.75-3.08 (m, 3H), 2.95 (s, 1.8 H), 3. 11 (s, 1.2 H) ), 3.40 to 3.70 (m, 2H), 4.41 to 4. 50 (m, 1H), 4.64 to 4.84 (m, 2H), 6.53 to 6.61 (m) , 1 H), 6.73-6.81 (m, 1 H), 6.89-7.11 (m, 1 H), 7.20-7.41 (m, 5 H).

(Example 144)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dimethoxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a, 7-ethan-4,12- Synthesis of methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (189)

Compound 187 (75.6 mg, 0.12 mmol) was dissolved in acetic acid (2 mL), zinc powder (76.2 mg, 1.17 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite 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 189 (31.1 mg, 56%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.70-0.88 (m, 1 H), 0.90-1. 13 (m, 1 H), 1.32-1. 48 (m , 1H), 1.64-1.80 (m, 1H), 1.85-1.95 (m, 1H), 2.00-2.09 (m, 1H), 2.91 (s, 1) .2H), 2.94-3.13 (m, 3H), 2.95 (s, 1.8 H), 3.19-3. 30 (m, 1 H), 3.54 (s, 1.8 H) ), 3.59 (s, 1.2 H), 3.68 (d, J = 6 Hz, 0.4 H), 3.75 (d, J = 7 Hz, 0.6 H), 3.89 (s, 1) .2H), 3.91 (s, 1.8 H), 4.42-4.80 (m, 3 H), 6.61-6.69 (m, 1 H), 6.76-6.82 (m) , 1 H), 6.87 (s, 1 H), 7. 4-7.40 (m, 5H).

(Example 145)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3- (cyclopropanecarbonyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a, Synthesis of 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (190)

Compound 189 (19.3 mg, 0.041 mmol) is dissolved in anhydrous N, N-dimethylformamide (1.5 mL), cyclopropanecarboxylic acid (20 μL, 0.25 mmol), N, N-diisopropylethylamine (36 μL, 0) .21 mmol) and HATU (24.0 mg, 0.063 mmol) were sequentially added, and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and extracted three times with ethyl acetate. The organic layer was washed with 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 190 (10.5 mg, 48%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.71 to 0.88 (m, 3 H), 0.97 to 1.16 (m, 3 H), 1.28 to 1.44 (m) , 1H), 1.72-2.06 (m, 3H), 2.81-3.45 (m, 7H), 3.54-3.60 (m, 3H), 3.91-4.04 (M, 4 H), 4.31-5. 28 (m, 4 H), 6. 29-6. 41 (m, 1 H), 6. 63 (d, J = 8 Hz, 0.4 H), 6. 65 (D, J = 8 Hz, 0.6 H), 6.79 (d, J = 8 Hz, 0.4 H), 6.80 (d, J = 8 Hz, 0.6 H), 7.26-7.36 ( m, 5H).

(Example 146)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3- (cyclopropanecarbonyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a, Synthesis of 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (191)

The title compound 191 was obtained from compound 190 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.72-1.16 (m, 6 H), 1.23-1. 39 (m, 1 H), 1.70-1. 90 (m) , 3H), 2.79-3.49 (m, 6H), 3.98-5.27 (m, 6H), 6.14-6.63 (m, 3H), 6.81 (d, J) = 8 Hz, 1 H), 7.21-7.41 (m, 5 H).

(Example 147)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dihydroxy-N, 3-dimethyl-1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4, Synthesis of 12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (192)

Compound 189 (17.1 mg, 0.036 mmol), methyl iodide (3.4 μL, 0.054 mmol), potassium carbonate (10 mg, 0.072 mmol) in N, N-dimethylformamide (1 mL) at room temperature for 21 hours It stirred. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted three times with chloroform, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane (6 mL), and 1 M boron tribromide-dichloromethane solution (0.17 mL, 0.17 mmol) was added under ice-cooling. After stirring at room temperature for 3 hours, a 28% aqueous ammonia solution was added under ice-cooling and the mixture was stirred for a while. The mixture was extracted three times with chloroform, 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 192 (9.8 mg, 59%) as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.68 to 0.83 (m, 1 H), 0.88-103 (m, 1 H), 1.20 to 1.36 (m) , 2H), 1.60-1.90 (m, 3H), 2.22-2.46 (m, 6H), 2.92 (s, 1.2 H), 2.98-3. 24 (m) , 2H), 3.07 (s, 1.8 H), 4.50-4.96 (m, 3 H), 6.53-6.61 (m, 1 H), 6.74-6. 78 (m) , 1 H), 6.81-6.85 (m, 1 H), 7.21-7.41 (m, 5 H).

(Example 148)
2,2,2-Trichloroethyl (4R, 4aS, 7R, 7aR, 12bS) -6- (benzyl (methyl) carbamoyl) -7,9-dihydroxy-1,2,7,7a-tetrahydro-4a, 7- Synthesis of ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-3 (4H) -carboxylate (193)

The title compound 193 was obtained from compound 187 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.70-1.89 (m, 6 H), 2.85-3. 26 (m, 6 H), 4.00-4. 11 (m , 1H), 4.53-5.09 (m, 7H), 5.87-6.83 (m, 4H), 7.21-7.38 (m, 5H).

(Example 149)
2,2,2-Trichloroethyl (4R, 4aS, 7R, 7aR, 12bS) -6- (benzyl (methyl) carbamoyl) -9-((tert-butyldiphenylsilyl) oxy) -7-hydroxy-1,2 Synthesis of 7,7a-Tetrahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-3 (4H) -carboxylate (194)

Compound 193 (299 mg, 0.46 mmol) is dissolved in anhydrous N, N-dimethylformamide (4.5 mL) and tert-butyldiphenylchlorosilane (236 μL, 0.92 mmol) and imidazole (126 mg, 1.85 mmol) are added, Stir at room temperature for 17 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (19-40% ethyl acetate / hexane) to give the title compound 194 (293 mg, 74%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.55-0.68 (m, 1 H), 0.87-1.30 (m, 11 H), 1.59-1.78 (m , 3H), 2.81-3.15 (m, 6H), 3.59-3.71 (m, 1 H), 3.93-4. 05 (m, 1 H), 4.32 (br s, 1H), 4.51-5.03 (m, 5H), 6.32-6.52 (m, 3H), 7.20-7.45 (m, 11H), 7.72-7. m, 4H).

(Example 150)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-9-((tert-butyldiphenylsilyl) oxy) -7-hydroxy-N-methyl-1,2,3,4,7,7a-hexahydro -4a, 7-Ethano-4,12-Methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (195) Synthesis

The title compound 195 was obtained from compound 194, according to the method described in Example 144.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.53 to 0.65 (m, 1 H), 0.80 to 0.94 (m, 1 H), 1.14-1. 30 (m , 10H), 1.50-1.98 (m, 3H), 2.63-3.87 (m, 9H), 4.30-4.33 (m, 1H), 4.63-4.78 (M, 2 H), 6. 28-6. 48 (m, 2 H), 6.7 2-6. 77 (m, 1 H), 7.2 4-7. 44 (m, 11 H), 7.7 3-7 .80 (m, 4H).

(Example 151)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dihydroxy-3-isobutyl-N-methyl-1,2,3,4,7,7a-hexahydro-4a, 7-ethano- Synthesis of 4,12-Methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (196)

Compound 195 (15.0 mg, 0.022 mmol), 1-bromo-2-methylpropane (14.2 μL, 0.13 mmol), sodium iodide (1.6 mg, 0.011 mmol), potassium carbonate (12.1 mg, A solution of 0.088 mmol) in acetonitrile (3 mL) was heated to reflux for 27.5 h. To the reaction mixture was added 1-bromo-2-methylpropane (30 μL, 0.28 mmol), and the mixture was heated to reflux for another 30 minutes. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with chloroform, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in tetrahydrofuran (1 mL), 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (0.20 mL, 0.20 mmol) was added, and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, extracted three times with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-4% methanol / chloroform) to give the title compound 196 (5.5 mg, 50%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.64 to 0.97 (m, 8 H), 1.22 to 1.36 (m, 2 H), 1.57 to 1.88 (m) , 4H), 1.98-2.51 (m, 5H), 2.90-3.18 (m, 5H), 3.83 (br s, 1H), 4.53 (d, J = 2 Hz, 1H), 4.66-4.85 (m, 2H), 6.50-6.60 (m, 1H), 6.73-6.78 (m, 1H), 6.83-6.99 (m. m, 1 H), 7.23-7. 40 (m, 5 H).

(Example 152)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dihydroxy-3-isopentyl-N-methyl-1,2,3,4,7,7a-hexahydro-4a, 7-ethano- Synthesis of 4,12-Methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (197)

Compound 189 (10.0 mg, 0.021 mmol), 1-bromo-3-methylbutane (16.0 μL, 0.13 mmol), sodium iodide (1.6 mg, 0.011 mmol), potassium carbonate (11.7 mg, 0) A solution of .085 mmol) in acetonitrile (2 mL) was heated to reflux for 18 h. To the reaction mixture was added 1-bromo-3-methylbutane (16.0 μL, 0.13 mmol), and the mixture was heated to reflux for another 30 minutes. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with chloroform, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane (1 mL), and 1 M boron tribromide-dichloromethane solution (0.10 mL, 0.10 mmol) was added under ice-cooling. After stirring for 30 minutes at room temperature, a 28% aqueous ammonia solution was added under ice-cooling and stirred for a while. The mixture was extracted three times with chloroform, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-6% methanol / chloroform) to give the title compound 197 (10.2 mg, 94%) as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.65 to 0.78 (m, 1 H), 0.81 to 0.99 (m, 8 H), 1.18 to 1.40 (m) , 2H), 1.50-1.86 (m, 4H), 2.20-2.54 (m, 5H), 2.97 (s, 1.8 H), 3.00-3.19 (m) , 2H), 3.07 (s, 1.2 H), 4.56 (d, J = 2 Hz, 1 H), 4.67-4.80 (m, 2 H), 6.51-6.60 (m) , 1H), 6.74-6.84 (m, 2H), 7.25-7.41 (m, 5H).

(Example 153)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3- (cyclobutylmethyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a-hexahydro-4a, Synthesis of 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (198)

Compound 189 (15.5 mg, 0.033 mmol), (bromomethyl) cyclobutane (29.3 μL, 0.20 mmol), sodium iodide (39.3 mg, 0.26 mmol), potassium carbonate (18.1 mg, 0.13 mmol) A solution of (3 mL) in acetonitrile was heated to reflux for 21 h. To the reaction mixture was added (bromomethyl) cyclobutane (50.0 μL, 0.34 mmol), and the mixture was heated to reflux for 8 hours. Sodium iodide (50.0 mg, 0.33 mmol) and potassium carbonate (50.0 mg, 0.36 mmol) were added to the reaction mixture, and the mixture was further heated to reflux for 16 hours. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with chloroform, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane (2 mL), and 1 M boron tribromide-dichloromethane solution (0.14 mL, 0.14 mmol) was added under ice-cooling. After stirring at room temperature for 2 hours, a 28% aqueous ammonia solution was added under ice-cooling and the mixture was stirred for a while. The mixture was extracted three times with chloroform, 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 198 (12.6 mg, 75%) as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.62 to 0.78 (m, 1 H), 0.80-0.99 (m, 1 H), 1.20-1. 35 (m , 2H), 1.50-2.12 (m, 9H), 2.22-2.56 (m, 6H), 2.91-3.18 (m, 5H), 4.57 (d, J) = 2 Hz, 1 H), 4.65-4. 75 (m, 2 H), 4.85-5.05 (m, 1 H), 6.50-6. 60 (m, 1 H), 6.70-6 81 (m, 2H), 7.23-7.40 (m, 5H).

(Reference Example 35)
Synthesis of cyclopropylmethyl-d ₂ methanesulfonate (199)

To a solution of cyclopropylmethane-d ₂ -ol (100 mg, 1.35 mmol) and triethylamine (245 μL, 1.75 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (136 μL, 1.75 mmol) under ice-cooling, and at room temperature Stir for 3 hours. The reaction mixture was added with water and extracted three times with chloroform, dried over sodium sulfate and concentrated under reduced pressure to give the title compound 199 (234 mg, quantitative) as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.38 to 0.42 (m, 2 H), 0.67 to 0.73 (m, 2 H), 1.20-1. 27 (m) , 1 H), 3.03 (s, 3 H).

(Example 154)
(4R, 4aS, 7R, 7aR , 12bS) -N- benzyl-3- (cyclopropylmethyl _-d 2)-7,9-dimethoxy -N- methyl -1,2,3,4,7,7a- hexahydro -4a, 7-Ethano-4,12-Methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (200)

Compound 189 (28.2 mg, 0.06 mmol), compound 199 (54.5 mg, 0.36 mmol), sodium iodide (4.5 mg, 0.03 mmol), potassium carbonate (33 mg, 0.24 mmol) in acetonitrile (3 mL) ) The solution was heated to reflux for 16 hours. The reaction mixture was allowed to cool, 2M hydrochloric acid was added, and the mixture was extracted with a hexane / ethyl acetate (1/1) solution. The organic layer was washed twice with 2 M hydrochloric acid. The aqueous layer was basified with potassium carbonate and extracted three times with chloroform. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 97: 3) to give the title compound 200 (5.9 mg, 19%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.19 (m, 2 H), 0.46-0.58 (m, 2 H), 0.68-1.07 (m , 3H), 1.18-1.40 (m, 0.4H), 1.55-1.68 (m, 2H), 1.80-2.00 (m, 1.6H), 2.21 -2.42 (m, 2H), 2.45-2.62 (m, 1 H), 2.92 (s, 1.2 H), 2.94 (s, 1.8 H), 3.01-3 .14 (m, 1 H), 3.30 (d, J = 6 Hz, 0.4 H), 3.42 (d, J = 6 Hz, 0.6 H), 3.54 (s, 1.8 H), 3 .60 (s, 1.2 H), 3.89 (s, 1.2 H), 3.90 (s, 1.8 H), 4.50-4. 83 (m, 3 H), 6.56-6 .63 (m, 1 H), 6.67-6.70 m, 1H), 6.71-6.77 (m, 1H), 7.24-7.40 (m, 5H).

(Example 155)
(4R, 4aS, 7R, 7aR , 12bS) -N- benzyl-3- (cyclopropylmethyl _-d 2)-7,9-dihydroxy -N- methyl -1,2,3,4,7,7a- hexahydro -4a, 7-Ethano-4,12-Methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (201)

The title compound 201 was obtained from compound 200 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.20 (m, 2 H), 0.35-0.59 (m, 2 H), 0.64-1.03 (m) , 3H), 1.19-1.37 (m, 1H), 1.57-1.93 (m, 3H), 2.22-2.42 (m, 2H), 2.49-2.64 (M, 1 H), 2.92-3. 14 (m, 4 H), 3. 28 (d, J = 5 Hz, 0.6 H), 3.42 (d, J = 5 Hz, 0.4 H), 4 .55 (s, 1 H), 4.56-4. 90 (m, 2 H), 6.51-6. 60 (m, 1 H), 6.73-6.80 (m, 1 H), 6.83 -6.90 (m, 1 H), 7.23-7. 44 (m, 5 H).

(Example 156)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dimethoxy-N-methyl-3- (2,2,2-trifluoroethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (202)

The title compound 202 was obtained from compound 189 and 2,2,2-trifluoroethyl trifluoromethanesulfonate according to the method described in Example 154.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.64 to 0.76 (m, 1 H), 0.86 to 1.05 (m, 1 H), 1.31 to 1.38 (m) , 1 H), 1.64-2. 07 (m, 3 H), 2.53-3. 22 (m, 10 H), 3.54 (s, 1.5 H), 3.59 (s, 1.5 H) ), 3.89 (s, 1.5 H), 3. 90 (s, 1.5 H), 4.49-4. 88 (m, 3 H), 6.59-6. 66 (m, 2 H), 6.75 (d, J = 8 Hz, 0.5 H), 6.77 (d, J = 8 Hz, 0.5 H), 7.28-7.38 (m, 5 H).

(Example 157)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dihydroxy-N-methyl-3- (2,2,2-trifluoroethyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (203)

The title compound 203 was obtained from compound 202 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.64 to 0.76 (m, 1 H), 0.88-1.01 (m, 1 H), 1.25-1.36 (m) , 1 H), 1.63-1.90 (m, 3 H), 2.53-3. 21 (m, 10 H), 4.56 (d, J = 2 Hz, 1 H), 4.60-4.90 (M, 3H), 5.98-6.58 (m, 2H), 6.78 (d, J = 8 Hz, 1H), 6.84 (s, 1H), 7.29-7.39 (m , 5H).

(Example 158)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dimethoxy-N-methyl-3- (3,3,3-trifluoropropyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (204)

The title compound 204 was obtained from the compound 189 and 3,3,3-trifluoropropyl 4-nitrobenzenesulfonate (synthesized by the method described in ChemMedChem 2016, 11, 2216) according to the method described in Example 154.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.67-1.03 (m, 2H), 1.32-1. 37 (m, 1 H), 1.65-1. 97 (m , 3H), 2.19-2.79 (m, 7H), 2.93 (s, 3H), 3.03-3.12 (m, 2H), 3.54 (s, 1.5H), 3.59 (s, 1.5 H), 3.89 (s, 1.5 H), 3. 90 (s, 1.5 H), 4.51 to 4. 80 (m, 3 H), 6.58- 6.63 (m, 2H), 6.74 (d, J = 8 Hz, 0.5 H), 6.76 (d, J = 8 Hz, 0.5 H), 7.26-7.38 (m, 5 H) ).

(Example 159)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dihydroxy-N-methyl-3- (3,3,3-trifluoropropyl) -1,2,3,4,7, Synthesis of 7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (205)

The title compound 205 was obtained from compound 204 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.66-1.00 (m, 2 H), 1.25-1.38 (m, 1 H), 1.64-1. 85 (m , 4H), 2.06-2.16 (m, 1 H), 2.30-2.82 (m, 5 H), 3.00-3.15 (m, 5 H), 4.52 (br s, 1H), 4.75 to 4.87 (m, 3H), 5.51 to 5.87 (m, 1H), 6.55 to 6.60 (m, 1H), 6.75 to 6.81 ( m, 2H), 7.24-7.40 (m, 5H).

(Reference Example 36)
Synthesis of (1- (difluoromethyl) cyclopropyl) methyl 4-methylbenzenesulfonate (206)

(1- (Difluoromethyl) cyclopropyl) methyl benzoate (synthesized by the method described in WO 2017050807) (381 mg, 1.68 mmol) is dissolved in methanol (6.5 mL), and 2 M aqueous solution of sodium hydroxide (1 mL) under ice-cooling ) Was added and stirred at room temperature for 6 hours. The reaction mixture was diluted with diethyl ether, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained crude product (594 mg) is dissolved in anhydrous dichloromethane (3 mL), triethylamine (0.34 mL, 2.5 mmol), trimethylamine hydrochloride (23.8 mg, 0.249 mmol) and p-toluene under ice-cooling The sulfonyl chloride (350 mg, 1.84 mmol) was sequentially added and stirred at room temperature for 80 minutes. Water was added to the reaction mixture and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (4-25% ethyl acetate / hexane) to give the title compound 206 (228 mg, 49%) as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.66-0.69 (m, 2 H), 0.93 to 0.96 (m, 2 H), 2.46 (s, 3 H), 4.04 (s, 2H), 5.76 (t, J = 60 Hz, 1 H), 7.36 (d, J = 8 Hz, 2 H), 7.79 (d, J = 8 Hz, 2 H).

(Example 160)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-9-((tert-butyldiphenylsilyl) oxy) -3-((1- (difluoromethyl) cyclopropyl) methyl) -7-hydroxy-N Of 1-Methyl-1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (207)

The title compound 207 was obtained from compound 195 and compound 206, according to the method described in Example 154.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.35-0.65 (m, 3 H), 0.78-0.92 (m, 3 H), 1.14-1.26 (m , 10H), 1.53-1.77 (m, 4H), 2.21-2.34 (m, 3H), 2.55-3.16 (m, 6H), 3.81 (br s, 0.6 H), 3.95 (br s, 0.4 H), 4.34 (br s, 1 H), 4.63-4.77 (m, 2 H), 5.56-6.09 (m, 1H), 6.24-6.26 (m, 1H), 6.43 (d, J = 8 Hz, 1H), 6.71 (s, 0.6 H), 6.75 (s, 0.4 H) , 7.24-7.44 (m, 11 H), 7.7-7.79 (m, 4 H).

(Example 161)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3-((1- (difluoromethyl) cyclopropyl) methyl) -7,9-dihydroxy-N-methyl-1,2,3,4, Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (208)

Compound 207 (18.1 mg, 0.0230 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (69 μL, 0.069 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 98: 2) to give the title compound 208 (11.2 mg, 89%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.33 to 0.52 (m, 2 H), 0.66 to 1.10 (m, 4 H), 1.26 to 1. 33 (m , 1H), 1.67-1.83 (m, 3H), 2.28-2.42 (m, 3H), 2.60-2.84 (m, 2H), 2.96-3.25 (M, 5 H), 4.53 (s, 1 H), 4.66-4. 88 (m, 3 H), 5.55-6. 08 (m, 2 H), 6.53-6.55 (m , 1H), 6.75-6.86 (m, 2H), 7.32-7.41 (m, 5H).

(Reference Example 37)
Synthesis of (1- (trifluoromethyl) cyclopropyl) methyl methanesulfonate (209)

The title compound 209 was obtained from (1- (trifluoromethyl) cyclopropyl) methanol according to the method described in Reference Example 35.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.93 to 0.98 (m, 2 H), 1.19 to 1.23 (m, 2 H), 3.06 (s, 3 H), 4.30 (s, 2H).

(Example 162)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dimethoxy-N-methyl-3-((1- (trifluoromethyl) cyclopropyl) methyl) -1,2,3,4 Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (210)

The title compound 210 was obtained from compounds 189 and 209 according to the method described in Example 154.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.55 to 0.79 (m, 3 H), 0.82 to 1.05 (m, 3 H), 1.25 to 1. 39 (m , 1 H), 1.50-1.68 (m, 1 H), 1.80-2.00 (m, 2 H), 2.30-2.45 (m, 2 H), 2.46-2.62 (M, 2 H), 2.74-2. 90 (m, 1 H), 2. 93 (s, 1.5 H), 2. 93 (s, 1.5 H), 2.99 (d, J = 14 Hz) , 0.5 H), 3.04 (d, J = 15 Hz, 0.5 H), 3. 12 (d, J = 6 Hz, 0.5 H), 3. 20 (d, J = 6 Hz, 0.5 H) , 3.54 (s, 1.5 H), 3.58 (s, 1.5 H), 3.89 (s, 1.5 H), 3.91 (s, 1.5 H), 4.50-4 .89 (m, 2H), 4.71 ( , 1 H), 6.57 (d, J = 8 Hz, 0.5 H), 6.59 (d, J = 8 Hz, 0.5 H), 6.64 (s, 0.5 H), 6.64 (s) , 0.5 H), 6.73 (d, J = 8 Hz, 0.5 H), 6.75 (d, J = 8 Hz, 0.5 H), 7.25-7.40 (m, 5 H).

(Example 163)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dihydroxy-N-methyl-3-((1- (trifluoromethyl) cyclopropyl) methyl) -1,2,3,4 Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (211)

The title compound 211 was obtained from compound 210 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.44 to 0.76 (m, 3 H), 0.80-1. 20 (m, 3 H), 1.21 to 1. 39 (m) , 2H), 1.56-1.90 (m, 2H), 2.30-2.49 (m, 3H), 2.53-2.72 (m, 1H), 2.75-3.28 (M, 3H), 2.97 (s, 1.8 H), 3.09 (s, 1.2 H), 4.55 (s, 1 H), 4.60 to 4.91 (m, 2.6 H) ), 5.09 (br s, 0.4 H), 6.50-6.58 (m, 1 H), 6.72-6. 80 (m, 1 H), 6.83 (s, 0.6 H) , 6.91 (s, 0.4 H), 7.22-7.43 (m, 5 H).

(Reference Example 38)
Synthesis of (2,2-difluorocyclopropyl) methyl 4-nitrobenzenesulfonate (212)

Dissolve (2,2-difluorocyclopropyl) methanol (200 mg, 1.85 mmol) in anhydrous dichloromethane (6 mL), triethylamine (0.51 mL, 3.66 mmol) and p-nitrobenzenesulfonyl chloride (451 mg, 2.04 mmol) Were sequentially added and stirred at room temperature for 15.5 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted three times with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (14-35% ethyl acetate / hexane) to give the title compound 212 (107 mg, 20%) as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.21-1.29 (m, 1 H), 1.56-1.65 (m, 1 H), 1.94-2.05 (m , 1H), 4.13-4.19 (m, 1H), 4.26-4.32 (m, 1H), 8.13 (d, J = 9 Hz, 2H), 8.43 (d, J) = 9 Hz, 2 H).

(Example 164)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-9-((tert-butyldiphenylsilyl) oxy) -3-((2,2-difluorocyclopropyl) methyl) -7-hydroxy-N- Methyl-1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (213, diastereomer A) and (4R , 4aS, 7R, 7aR, 12bS) -N-benzyl-9-((tert-butyldiphenylsilyl) oxy) -3-((2,2-difluorocyclopropyl) methyl) -7-hydroxy-N-methyl- 1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxyl The synthesis of bromide (214, diastereomer B)

The title compounds 213 and 214 were obtained from compound 195 and compound 212, respectively, according to the method described in Example 154.

Diastereomer A (213)
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.54-0.67 (m, 1 H), 0.76-1. 08 (m, 2 H), 1.14-1. 79 (m , 15H), 2.21-2.67 (m, 5H), 2.92-3. 10 (m, 5H), 3.83 (br s, 1 H), 4.34 (br s, 1 H), 4.59-4.82 (m, 2 H), 6.25-6. 29 (m, 1 H), 6.42-6. 46 (m, 1 H), 6.69-6. 72 (m, 1 H) ), 7.24-7.44 (m, 11 H), 7.73-7. 79 (m, 4 H).

Diastereomer B (214)
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.55-0.67 (m, 1 H), 0.79-1.05 (m, 2 H), 1.14-1. 80 (m , 15H), 2.21-2.67 (m, 5H), 2.89-3.15 (m, 5H), 3.79 (br s, 0.4 H), 3.86 (br s, 0) .6 H), 4.34 (s, 1 H), 4.60-4. 74 (m, 2 H), 6.25-6. 30 (m, 1 H), 6.42-6. 47 (m, 1 H) ], 6.67 (s, 0.6 H), 6.69 (s, 0.4 H), 7.24-7. 44 (m, 11 H), 7.73-7. 80 (m, 4 H).

(Example 165)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3-((2,2-difluorocyclopropyl) methyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7 Synthesis of 7, 7a-hexahydro-4a, 7-ethano-4, 12-methanobenzofuro [3, 2-e] isoquinoline-6-carboxamide (215)

The title compound 215 was obtained from compound 213, according to the method described in Example 161.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.68 to 0.79 (m, 1 H), 0.83-1.10 (m, 2 H), 1.24-1. 85 (m) , 6H), 2.33-2.73 (m, 5H), 2.99-3.20 (m, 5H), 4.57 (s, 1H), 4.64-4.86 (m, 3H) 6.00-6.56 (m, 2 H), 6.75-6. 77 (m, 2 H), 7. 29-7. 41 (m, 5 H).

(Example 166)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3-((2,2-difluorocyclopropyl) methyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7 Synthesis of 7, 7a-hexahydro-4a, 7-ethano-4, 12-methanobenzofuro [3, 2-e] isoquinoline-6-carboxamide (216)

The title compound 216 was obtained from compound 214 according to the method described in Example 161.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.68 to 0.81 (m, 1 H), 0.86-1 to 07 (m, 2 H), 1.28 to 1.87 (m , 6H), 2.30-2.74 (m, 5H), 2.94-3.24 (m, 5H), 4.56 (s, 1H), 4.61-4.86 (m, 3H) 6.09-6.59 (m, 2 H), 6.73-6. 82 (m, 2 H), 7. 28-7. 41 (m, 5 H).

(Reference Example 39)
Synthesis of (1-cyanocyclopropyl) methyl 4-methylbenzenesulfonate (217)

1- (Hydroxymethyl) cyclopropane-1-carbonitrile (132 mg, 1.36 mmol) is dissolved in anhydrous dichloromethane (2.5 mL), triethylamine (0.38 mL, 2.7 mmol) under ice-cooling, trimethylamine hydrochloride (13.0 mg, 0.136 mmol) and p-toluenesulfonyl chloride (390 mg, 2.05 mmol) were sequentially added and stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (27-48% ethyl acetate / hexane) to give the title compound 217 (316 mg, 93%) as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.06-1.09 (m, 2 H), 1.35-1. 39 (m, 2 H), 2.47 (s, 3 H), 4.00 (s, 2 H), 7. 38 (d, J = 8 Hz, 2 H), 7. 83 (d, J = 8 Hz, 2 H).

(Example 167)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3-((1-cyanocyclopropyl) methyl) -7,9-dimethoxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (218)

The title compound 218 was obtained from compound 189 and compound 217, according to the method described in Example 154.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.68-1.12 (m, 4 H), 1.25-1.40 (m, 3 H), 1.66-1.70 (m , 1H), 1.83-1.91 (m, 1H), 2.04 (ddd, J = 5, 13, 13 Hz, 1H), 2.38-2.69 (m, 5H), 2.90 -3.02 (m, 4 H), 3.28 (d, J = 6 Hz, 0.4 H), 3. 36 (d, J = 6 Hz, 0.6 H), 3.55 (s, 1.8 H) , 3.60 (s, 1.2 H), 3.89 (s, 1.2 H), 3.90 (s, 1.8 H), 4.53-4.87 (m, 3 H), 6.57 -6.61 (m, 1 H), 6.73-6.77 (m, 1 H), 6.83 (s, 1 H), 7.28-7.38 (m, 5 H).

(Example 168)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3-((1-cyanocyclopropyl) methyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (219)

The title compound 219 was obtained from compound 218 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.69-1.04 (m, 4 H), 1.26-1.39 (m, 3 H), 1.64-1. 98 (m , 3H), 2.38-2.68 (m, 5H), 2.93-3.13 (m, 4H), 3.29 (d, J = 6 Hz, 0.5 H), 3.38 (d , J = 6 Hz, 0.5 H), 4.57 (s, 1 H), 4.62-5.19 (m, 3 H), 5.99-6.78 (m, 3 H), 7.07 (s) , 0.5 H), 7.20 (s, 0.5 H), 7.28-7.40 (m, 5 H).

(Example 169)
(4R, 4aS, 7R, 7aR, 12bS) -3- (3-amino-3-oxopropyl) -N-benzyl-7,9-dimethoxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (220)

A solution of compound 189 (15.0 mg, 0.032 mmol) and acrylamide (22.6 mg, 0.32 mmol) in methanol (1 mL) was stirred in a sealed tube at 100 ° C. for 7 hours. The reaction mixture was allowed to cool 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 220 (17.4 mg, quantitative) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.72-1.04 (m, 2 H), 1.23-1. 37 (m, 1 H), 1.60-2.01 (m) , 3H), 2.32 to 2.62 (m, 5H), 2.64 to 2.76 (m, 1H), 2.79 to 2.89 (m, 1H), 2.91 (s, 1) .5 H), 2.94 (s, 1.5 H), 3.07-3.18 (m, 1.5 H), 3.22 (d, J = 7 Hz, 0.5 H), 3.55 (s) , 1.5 H), 3.59 (s, 1.5 H), 3.89 (s, 1.5 H), 3. 90 (s, 1.5 H), 4.46 (s, 0.5 H), 4.50 (s, 0.5 H), 4.54-4. 97 (m, 2 H), 5. 46 (br s, 1 H), 6.43 (s, 0.5 H), 6.47 (s , 0.5 H), 6.60 (d, J = 8 Hz, .5 H), 6.62 (d, J = 8 Hz, 0.5 H), 6.76 (d, J = 8 Hz, 0.5 H), 6.77 (d, J = 8 Hz, 0.5 H), 7 .22-7.40 (m, 5H).

(Example 170)
(4R, 4aS, 7R, 7aR, 12bS) -3- (3-amino-3-oxopropyl) -N-benzyl-7,9-dihydroxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (221)

The title compound 221 was obtained from compound 220 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.70-1.02 (m, 2 H), 1.21-1. 37 (m, 1 H), 1.62-2.10 (m , 3H), 2.27-2.58 (m, 5H), 2.61-2.92 (m, 2H), 2.96-3.26 (m, 2H), 2.98 (s, 1) .5 H), 3.03 (s, 1.5 H), 4.55 (s, 1 H), 4.62-4. 93 (m, 3 H), 5.23 (br s, 0.5 H), 5 .68 (br s, 0.5 H), 6.53-6. 62 (m, 1.5 H), 6.67 (s, 0.5 H), 6.77 (d, J = 8 Hz, 1 H), 7.09 (br s, 1 H), 7.22-7.47 (m, 5 H).

(Example 171)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-9-((tert-butyldiphenylsilyl) oxy) -3-((1-cyanocyclopropyl) methyl) -7-hydroxy-N-methyl- Synthesis of 1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (222)

The title compound 222 was obtained from compound 195 and compound 217, according to the method described in Example 154.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.56-0.66 (m, 1 H), 0.77-0.99 (m, 3 H), 1.14 (s, 9 H), 1.25-1.30 (m, 3H), 1.57-1.92 (m, 3H), 2.27-2.61 (m, 5H), 2.83-3.11 (m, 4H) ), 3.21 (d, J = 6 Hz, 0.5 H), 3. 30 (d, J = 6 Hz, 0.5 H), 3.98 (br s, 0.5 H), 4.36-4. 45 (m, 1.5 H), 4.62-4. 85 (m, 2 H), 6. 25 (d, J = 8 Hz, 1 H), 6.42 (d, J = 8 Hz, 1 H), 7. 00 (s, 0.5 H), 7.11 (s, 0.5 H), 7.30-7.44 (m, 11 H), 7.73-7.80 (m, 4 H).

(Example 172)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-9-((tert-butyldiphenylsilyl) oxy) -3-((1-carbamoylcyclopropyl) methyl) -7-hydroxy-N-methyl- Synthesis of 1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (223)

Compound 222 (9.5 mg, 0.012 mmol) is dissolved in ethanol (0.8 mL) and water (0.2 mL), triphenylphosphine (6.3 mg, 0.024 mmol), acetoaldoxime (15.0 μL, 15.0 μL, 0.25 mmol) and palladium acetate (2.8 mg, 0.012 mmol) were added and stirred at 95 ° C. for 5 hours. After allowing to cool, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: methanol = 98: 2) to give the title compound 223 (7.2 mg, 77%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.46-0.70 (m, 3 H), 0.83-0.95 (m, 1 H), 1. 14 (s, 9 H), 1.20-1.80 (m, 6H), 2.20-2.72 (m, 5H), 2.89-2 9.97 (m, 4H), 3.27 (d, J = 6 Hz, 0 .6 H), 3.39 (d, J = 6 Hz, 0.4 H), 3.55 (br s, 0.4 H), 3.82 (br s, 0.6 H), 4. 34 (d, J = 2 Hz, 1 H), 4.59-4.86 (m, 2.6 H), 5.47 (br s, 0.4 H), 6.26-6.31 (m, 1 H), 6.46- 6.52 (m, 2 H), 7.24-7. 49 (m, 11 H), 7.72-7. 79 (m, 4 H), 8.33 (br s, 0.6 H), 8.83 (Br s, 0.4 H).

(Example 173)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-3-((1-carbamoylcyclopropyl) methyl) -7,9-dihydroxy-N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (224)

The title compound 224 was obtained from compound 223 according to the method described in Example 161.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.50 to 0.65 (m, 2 H), 0.77 to 1.00 (m, 2 H), 1.23 to 1. 84 (m) , 6H), 2.28-2.78 (m, 5H), 2.98-3.08 (m, 4H), 3.34-3.47 (m, 1H), 4.49-5.48 (M, 5 H), 6.55-6. 63 (m, 2 H), 6.77 (d, J = 8 Hz, 1 H), 7.34-7.52 (m, 5 H), 8. 25 (br s, 0.6 H), 8. 80 (br s, 0.4 H).

(Reference Example 40)
Synthesis of 1-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropane-1-carbaldehyde (225)

(1-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropyl) methanol (synthesized by the method described in WO2016055496) (566 mg, 3.04 mmol) is dissolved in anhydrous dichloromethane (14 mL), Under ice-cooling, sodium hydrogen carbonate (510 mg, 6.07 mmol) and des-Martin periodinane (1.55 g, 3.65 mmol) were sequentially added, and stirred at room temperature for 1.5 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted three times with chloroform. The organic layer was washed with saturated aqueous saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (8-29% ethyl acetate / hexane) to give the title compound 225 (488 mg, 87%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.09-1.28 (m, 4 H), 1.49-1.62 (m, 4 H), 1.68-1.84 (m , 2H), 3.49-3.55 (m, 1 H), 3.76 (d, J = 10 Hz, 1 H), 3.84 (d, J = 10 Hz, 1 H), 3.84-3.90 (M, 1 H), 4.65-4. 67 (m, 1 H), 9.08 (s, 1 H).

(Reference Example 41)
Synthesis of 1-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropane-1-carboxylic acid (226)

Compound 225 (488 mg, 2.65 mmol) is dissolved in tert-butyl alcohol (9 mL) and water (3 mL), sodium dihydrogenphosphate (632 mg, 5.27 mmol), 2-methyl-2-butene (2.25 mL) (21.2 mmol) and sodium chlorite (481 mg, 5.32 mmol) were sequentially added, and stirred at room temperature for 45 minutes. Water was added to the reaction mixture and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (36-57% ethyl acetate / hexane) to give the title compound 226 (454 mg, 86%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.94-1.01 (m, 2 H), 1.31-1.39 (m, 2 H), 1.51-1. 64 (m , 4H), 1.70-1.87 (m, 2H), 3.49-3. 55 (m, 1H), 3.67 (d, J = 10 Hz, 1H), 3.76 (d, J) = 10 Hz, 1 H), 3.84-3.90 (m, 1 H), 4.66-4. 68 (m, 1 H).

(Reference Example 42)
Synthesis of methyl 1-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) cyclopropane-1-carboxylate (227)

According to the method described in Example 136, the title compound 227 was obtained from compound 226.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.89-0.97 (m, 2 H), 1.22-1. 32 (m, 2 H), 1.49-1. 62 (m , 4H), 1.67-1.74 (m, 1H), 1.78-1.85 (m, 1H), 3.48-3.53 (m, 1H), 3.68 (s, 3H) ), 3.70 (d, J = 10 Hz, 1 H), 3.75 (d, J = 10 Hz, 1 H), 3.83-3.90 (m, 1 H), 4.64-4.66 (m , 1 H).

(Reference Example 43)
Synthesis of methyl 1- (iodomethyl) cyclopropane-1-carboxylate (228)

Compound 227 (217 mg, 1.01 mmol) was dissolved in methanol (5 mL), p-toluenesulfonic acid monohydrate (38.6 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Dissolve 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (346 mg, 1.52 mmol) in anhydrous dichloromethane (7 mL), triphenylphosphine (396 mg, 1.51 mmol) under ice cooling, tetra A solution of butyl ammonium iodide (566 mg, 1.53 mmol) and the crude product obtained above (369 mg) in anhydrous dichloromethane (2 mL) was sequentially added, and stirred at 0 ° C. for 1.5 hours and at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (1-22% ethyl acetate / hexane) to give the title compound 228 (197 mg, 81%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.97-1.00 (m, 2 H), 1.63-1.66 (m, 2 H), 3.42 (s, 2 H), 3.73 (s, 3 H).

(Example 174)
Methyl 1-(((4R, 4aS, 7R, 7aR, 12bS) -6- (benzyl (methyl) carbamoyl) -9-((tert-butyldiphenylsilyl) oxy) -7-hydroxy-1,2,7, Synthesis of 7a-Tetrahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinolin-3 (4H) -yl) methyl) cyclopropane-1-carboxylate (229)

The title compound 229 was obtained from compound 195 and compound 228, according to the method described in Example 154.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.54 to 0.90 (m, 4 H), 1.14-1.29 (m, 12 H), 1.48 to 1. 73 (m , 3H), 2.24-2.53 (m, 4H), 2.85-3.14 (m, 6H), 3.59 (s, 1.5H), 3.63 (s, 1.5H) ), 3.71 (br s, 0.5 H), 3.94 (br s, 0.5 H), 4.32 (s, 1 H), 4.64-4. 71 (m, 2 H), 6. 27 (d, J = 8 Hz, 1 H), 6.44 (d, J = 8 Hz, 1 H), 6.66 (s, 1 H), 7.29-7.44 (m, 11 H), 7.72- 7.79 (m, 4H).

(Example 175)
Methyl 1-(((4R, 4aS, 7R, 7aR, 12bS) -6- (benzyl (methyl) carbamoyl) -7,9-dihydroxy-1,2,7,7a-tetrahydro-4a, 7-ethano-4 Synthesis of 1,12-Methanobenzofuro [3,2-e] isoquinolin-3 (4H) -yl) cyclopropane-1-carboxylate (230)

The title compound 230 was obtained from compound 229 according to the method described in Example 161.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.60 to 0.98 (m, 4 H), 1.12-1.18 (m, 1 H), 1.25-1.75 (m) , 5H), 2.34-2.57 (m, 4H), 2.97-3.22 (m, 6H), 3.58 (s, 1.5H), 3.64 (s, 1.5H) ), 4.50 (s, 1 H), 4.64-4. 83 (m, 3 H), 5. 36 (br s, 0.5 H), 5. 65 (br s, 0.5 H), 6. 56 (d, J = 8 Hz, 1 H), 6.75-6. 77 (m, 2 H), 7. 29-7. 39 (m, 5 H).

(Example 176)
1-(((4R, 4aS, 7R, 7aR, 12bS) -6- (benzyl (methyl) carbamoyl) -7,9-dihydroxy-1,2,7,7a-tetrahydro-4a, 7-ethano-4, Synthesis of 12-Methanobenzofuro [3,2-e] isoquinolin-3 (4H) -yl) methyl) cyclopropane-1-carboxylic acid (231)

Compound 230 (11.6 mg, 0.021 mmol) is dissolved in tetrahydrofuran (1 mL), methanol (1 mL) and water (0.5 mL), lithium hydroxide monohydrate (17.4 mg, 0.42 mmol) is added The mixture was stirred at 60 ° C. for 80 minutes. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with chloroform / isopropanol (4/1). The organic layer was washed with 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, 3 times) to give the title compound 231 (8.7 mg, 77%) as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.64 to 0.70 (m, 2 H), 0.78 to 0.87 (m, 1 H), 0.96 to 1.08 (m , 1H), 1.30-2.00 (m, 6 H), 2.46-2.64 (m, 3 H), 2.94-3. 13 (m, 6 H), 3.42 (d, J) = 6 Hz, 0.5 H), 3.46 (d, J = 6 Hz, 0.5 H), 4.51-4.86 (m, 3 H), 5.02-5. 90 (m, 1 H), 6 .57-6.61 (m, 1 H), 6.79-6. 82 (m, 1 H), 6.86 (s, 1 H), 7. 29-7. 42 (m, 5 H).

(Example 177)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-9-((tert-butyldiphenylsilyl) oxy) -7-hydroxy-N-methyl-3-((1-(((tetrahydro-2H- Pyran-2-yl) oxy) methyl) cyclopropyl) methyl) -1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline- Synthesis of 6-carboxamide (232)

The title compound 232 was obtained from compound 195 and 2-((1- (iodomethyl) cyclopropyl) methoxy) tetrahydro-2H-pyran (synthesized by the method described in WO2016055496) according to the method described in Example 154.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.26-0.31 (m, 2 H), 0.44-0.62 (m, 3 H), 0.79-0.94 (m) , 1H), 1.14-1.29 (m, 10H), 1.57-1.81 (m, 9H), 2.21-2.57 (m, 5H), 2.91-4.06 (M, 10 H), 4. 35 (s, 1 H), 4.58-4. 78 (m, 3 H), 6. 25 (d, J = 8 Hz, 1 H), 6.43 (d, J = 8 Hz) , 1 H), 6.82-6. 90 (m, 1 H), 7. 29-7. 42 (m, 11 H), 7.7 3-7. 80 (m, 4 H).

(Example 178)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-9-((tert-butyldiphenylsilyl) oxy) -7-hydroxy-3-((1- (hydroxymethyl) cyclopropyl) methyl) -N Of 1-Methyl-1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (233)

Compound 232 (14.9 mg, 0.018 mmol) is dissolved in methanol (1.5 mL), p-toluenesulfonic acid monohydrate (6.3 mg, 0.033 mmol) is added, and the mixture is added at 50.degree. Stir for hours. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-7% methanol / chloroform) to give the title compound 233 (11.2 mg, 83%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.25-0.44 (m, 3 H), 0.62-0.73 (m, 2 H), 0.83-0.98 (m) , 1H), 1.14 (s, 9H), 1.25-1.82 (m, 4H), 2.18-2.34 (m, 3H), 2.89-3.28 (m, 8H) ), 3.86 (d, J = 11 Hz, 0.5 H), 3.87 (s, 0.5 H), 3.99 (d, J = 11 Hz, 0.5 H), 4.17 (s, 0) .5 H), 4.31-4. 37 (m, 1 H), 4.58-4.87 (m, 2 H), 5. 35 (br s, 1 H), 6. 24 (d, J = 8 Hz, 0.5 H), 6.26 (d, J = 8 Hz, 0.5 H), 6.42 (d, J = 8 Hz, 0.5 H), 6.44 (d, J = 8 Hz, 0.5 H), 6.76 (s, 1 H), .28-7.44 (m, 11H), 7.73-7.79 (m, 4H).

(Example 179)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dihydroxy-3-((1- (hydroxymethyl) cyclopropyl) methyl) -N-methyl-1,2,3,4, Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (234)

The title compound 234 was obtained from compound 233, according to the method described in Example 161.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.29-0.35 (m, 2 H), 0.42-0.50 (m, 1 H), 0.67-0.81 (m) , 2H), 0.86-1.02 (m, 1H), 1.28-1.85 (m, 4H), 2.23-2.43 (m, 3H), 2.92-3.18 (M, 7 H), 3.26 (d, J = 6 Hz, 0.5 H), 3. 35 (d, J = 6 Hz, 0.5 H), 3.86 (d, J = 11 Hz, 0.5 H) , 4.01 (d, J = 11 Hz, 0.5 H), 4.48-5.60 (m, 5 H), 6.54 (d, J = 8 Hz, 0.5 H), 6.56 (d, J = 8 Hz, 0.5H), 6.74 to 6.80 (m, 1H), 6.84 (s, 0.5H), 6.85 (s, 0.5H), 7.29-7. 41 (m, 5 H).

(Example 180)
(4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dihydroxy-3-((1-hydroxycyclopropyl) methyl) -N-methyl-1,2,3,4,7,7a Of 2-Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide

(1) 2,2,2-trichloroethyl (4R, 4aS, 7S, 7aR, 12bS) -7, 9-Dimethoxy-6-oxo-1, 2, 5, 6, 7, 7a-hexahydro-4a, 7 Synthesis of 4-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-3 (4H) -carboxylate (235)

The title compound 235 was obtained from compound 2 according to the method described in Example 142.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.98-1.08 (m, 1 H), 1.33-1. 45 (m, 1 H), 1.55-1. 68 (m , 1H), 1.72-1.83 (m, 2H), 2.01 (ddd, J = 5, 13, 13 Hz, 1 H), 2. 39 (dd, J = 6, 19 Hz, 1 H), 2 .81-3.01 (m, 2 H), 3.04-3.28 (m, 2 H), 3.51 (s, 1.5 H), 3.51 (s, 1.5 H), 3.91 (S, 3 H), 4. 13 (d, J = 5 Hz, 0.5 H), 4. 17 (d, J = 5 Hz, 0.5 H), 4.5 1 (dd, J = 7, 17 Hz, 1 H) , 4.59 (d, J = 2 Hz, 0.5 H), 4.60 (d, J = 2 Hz, 0.5 H), 4.69 (d, J = 9 Hz, 0.5 H), 4.72 (d d, J = 9 z, 0.5H), 4.85 (d, J = 10 Hz, 0.5 H), 4.89 (d, J = 10 Hz, 0.5 H), 6.70 (d, J = 8 Hz, 1 H), 6.83 (d, J = 8 Hz, 1 H).

(2) 2,2,2-Trichloroethyl (4'R, 4a'S, 7'S, 7a'R, 12b'S) -7 ', 9'-Dimethoxy-1', 2 ', 7', 7a'-Tetrahydro-5'H-spiro [[1,3] dioxolane-2,6 '-[4a, 7] ethano [4,12] methanobenzofuro [3,2-e] isoquinoline] -3' (4 ' H) -Carboxylate (236) synthesis

A solution of compound 235 (915 mg, 1.77 mmol), p-toluenesulfonic acid monohydrate (168.4 mg, 0.89 mmol) and ethylene glycol (583.4 μL, 10.6 mmol) in toluene (20 mL) was prepared with Dean- The mixture was heated to reflux for 12 hours using a Stark apparatus. The reaction mixture was allowed to cool and then concentrated under reduced pressure. To the concentration residue was added saturated aqueous sodium hydrogen carbonate solution, extracted three times with chloroform, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (30-50% ethyl acetate / hexane) to give the title compound 236 (708 mg, 71%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.72 to 0.83 (m, 1 H), 1.18 to 1.32 (m, 1 H), 1.50 to 1.60 (m) , 1H), 1.61-1.72 (m, 2H), 1.89 (dd, J = 7, 14 Hz, 1 H), 2.27-2.44 (m, 2 H), 2.83 (d , J = 14 Hz, 0.4 H), 2.88 (d, J = 14 Hz, 0.6 H), 2.97 (d, J = 7 Hz, 0.6 H), 3.02 (d, J = 8 Hz, 0.4 H), 3.04-3.20 (m, 1 H), 3.53 (s, 1.2 H), 3.54 (s, 1.8 H), 3. 90 (s, 3 H), 3 .91-4.04 (m, 3H), 4.08-4.15 (m, 2H), 4.40-4.37 (m, 1H), 4.68 (d, J = 10 Hz, 0. 6). 4H), 4.71 ( , J = 10Hz, 0.6H), 4.85-4.92 (m, 2H), 6.61 (d, J = 8Hz, 1H), 6.76 (d, J = 8Hz, 1H).

(3) (4'R, 4a'S, 7'S, 7a'R, 12b'S) -7 ', 9'-Dimethoxy-1', 2 ', 3', 4 ', 7', 7a ' -Hexahydro-5'H-spiro [[1,3] dioxolane-2,6 '-[4a, 7] ethano [4,12] methanobenzofuro [3,2-e] isoquinoline] (237)

The title compound 237 was obtained from compound 236 according to the method described in Example 144.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.75 to 0.83 (m, 1 H), 1.21 to 1.33 (m, 1 H), 1.50 to 1.60 (m) , 1H), 1.67-1.75 (m, 1H), 1.77-1.85 (m, 1H), 2.01 (d, J = 14 Hz, 1H), 2.58 (ddd, J = 5, 14, 14 Hz, 1 H), 2.94-3. 05 (m, 2 H), 3. 13 (ddd, J = 4, 14, 14 Hz, 1 H), 3.41 (d, J = 19 Hz, 1H), 3.35-3. 43 (m, 1 H), 3.53 (s, 3 H), 3.72 (d, J = 7 Hz, 1 H), 3. 90 (s, 3 H), 3.94 -4.16 (m, 4H), 4.95 (d, J = 2 Hz, 1 H), 6.65 (d, J = 8 Hz, 1 H), 6.79 (d, J = 8 Hz, 1 H).

(4) ((4'R, 4a'S, 7'S, 7a'R, 12b'S) -7 ', 9'-Dimethoxy-1', 2 ', 7', 7a'-tetrahydro-5 ' H-spiro [[1,3] dioxolane-2,6 '-[4a, 7] ethano [4,12] methanobenzofuro [3,2-e] isoquinoline] -3' (4'H) -yl) (1 Of (-Hydroxycyclopropyl) methanone (238)

A solution of compound 237 (300 mg, 0.78 mmol) in N, N-dimethylformamide (5 mL), 1-hydroxycyclopropane-1-carboxylic acid (95.3 mg, 0.93 mmol), 4-dimethylaminopyridine (47. Add 5 mg (0.39 mmol), 1-hydroxybenzotriazole monohydrate (316 mg, 2.33 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (448 mg, 2.33 mmol), The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added with 2 M hydrochloric acid, extracted three times with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-10% methanol / chloroform and 86-100% ethyl acetate / hexane) to give the title compound 238 (401 mg, quantitative) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.74-0.84 (m, 1 H), 0.90-1.03 (m, 2 H), 1.05-1. 15 (m) , 2H), 1.22-1.32 (m, 1 H), 1.50-1.74 (m, 4 H), 1.90 (d, J = 14 Hz, 1 H), 2.22-2.48 (M, 2H), 2.81 (d, J = 18 Hz, 1 H), 3.01 (d, J = 18 Hz, 1 H), 3.53 (s, 3 H), 3. 90 (s, 3 H), 3.91-4.03 (m, 3 H), 4.09-4.13 (m, 1 H), 4.35-4. 44 (m, 1 H), 4.69 (d, J = 6 Hz, 1 H) ), 4.90 (d, J = 1 Hz, 1 H), 6.60 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H).

(5) ((4'R, 4a'S, 7'S, 7a'R, 12b'S) -7 ', 9'-Dimethoxy-1', 2 ', 7', 7a'-tetrahydro-5 ' H-spiro [[1,3] dioxolane-2,6 '-[4a, 7] ethano [4,12] methanobenzofuro [3,2-e] isoquinoline] -3' (4'H) -yl) (1 Of (Methoxycyclopropyl) methanone (239)

Sodium hydride (55% oil dispersion) (192 mg, 4.41 mmol) and methyl iodide (275 μL, 4.41 mmol) in a solution of compound 238 (414 mg, 0.88 mmol) in tetrahydrofuran (5 mL) under ice-cooling In addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was added with saturated aqueous ammonium chloride solution, extracted three times with chloroform, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (57-77% ethyl acetate / hexane) to give the title compound 239 (379 mg, 91%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.74 to 0.86 (m, 1 H), 0.87-1.18 (m, 4 H), 1.20-1. 35 (m , 1H), 1.49 to 1.75 (m, 4H), 1.85 to 1.94 (m, 1H), 2.20 to 2.43 (m, 2H), 2.69 to 3.10 (M, 2 H), 3.32 (s, 1.5 H), 3. 35 (s, 1.5 H), 3.53 (s, 3 H), 3. 90 (s, 3 H), 3.91- 4.06 (m, 3 H), 4.09-4. 16 (m, 1 H), 4. 35-4. 49 (m, 1 H), 4.62-4. 73 (m, 1 H), 4. 89 (s, 0.5 H), 4.91 (s, 0.5 H), 6.61 (d, J = 8 Hz, 1 H), 6.77 (d, J = 8 Hz, 1 H).

(6) (4R, 4aS, 7S, 7aR, 12bS) -7,9-dimethoxy-3-((1-methoxycyclopropyl) methyl) -1,2,3,4,7,7a-hexahydro-4a, Synthesis of 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinolin-6 (5H) -one (240)

To a solution of compound 239 (370 mg, 0.76 mmol) in tetrahydrofuran (5 mL) was added 0.9 M borane-tetrahydro complex-tetrahydrofuran solution (8.7 mL, 7.87 mmol) under ice-cooling, and the reaction mixture was stirred for 1.5 hours Heated to reflux. The reaction mixture was concentrated under reduced pressure, 2 M hydrochloric acid (7 mL) was added, and the mixture was heated to reflux for 13 hours. The reaction mixture was allowed to cool and then poured into a saturated aqueous sodium hydrogen carbonate solution to be basic. The mixture is extracted three times with chloroform, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-2% methanol / chloroform) to give the title compound 240 (280 mg, 89%) as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.43 to 0.49 (m, 2 H), 0.74 to 0.82 (m, 2 H), 0.96 to 1.09 (m) , 1H), 1.22-1.32 (m, 1H), 1.51-1.56 (m, 1H), 1.65-1.79 (m, 2H), 2.03 (ddd, J = 6, 13, 13 Hz, 1 H), 2.27 (d, J = 20 Hz, 1 H), 2.39-2.48 (m, 2 H), 2.57 (d, J = 13 Hz, 1 H), 2 .67 (d, J = 13 Hz, 1 H), 2.70-2. 75 (m, 1 H), 3.07 (d, J = 18 Hz, 1 H), 3. 17 (d, J = 7 Hz, 1 H) , 3.31 (s, 3 H), 3.50 (dd, J = 4, 20 Hz, 1 H), 3.53 (s, 3 H), 3.89 (s, 3 H), 4.60 (d, J) = Hz, 1H), 6.64 (d, J = 8Hz, 1H), 6.77 (d, J = 8Hz, 1H).

(7) (4R, 4aS, 7S, 7aR, 12bS) -7,9-dimethoxy-3-((1-methoxycyclopropyl) methyl) -1,2,3,4,7,7a-hexahydro-4a, Synthesis of 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinolin-6-yl trifluoromethanesulfonate (241)

The title compound 241 was obtained from compound 240, according to the method described in Reference Example 3.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.39 to 0.53 (m, 2 H), 0.69 to 0.79 (m, 1 H), 0.80 to 0.87 (m) , 2H), 1.04 (ddd, J = 6, 13, 13 Hz, 1 H), 1.38-1.48 (m, 1 H), 1.601-1.69 (m, 1 H), 1.75 -1.83 (m, 1H), 1.94 (ddd, J = 6, 13, 13 Hz, 1 H), 2.40 (dd, J = 6, 18 Hz, 1 H), 2.45 (ddd, J = 4, 12, 12 Hz, 1 H), 2.59-2.65 (m, 1 H), 2.61 (d, J = 13 Hz, 1 H), 2.69 (d, J = 13 Hz, 1 H), 3. 07 (d, J = 18 Hz, 1 H), 3.36 (s, 3 H), 3. 45 (d, J = 7 Hz, 1 H), 3.57 (s, 3 H), 3. 90 s, 3H), 4.62 (d, J = 2 Hz, 1 H), 6.57 (s, 1 H), 6.61 (d, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1H).

(8) 2,4,6-Trichlorophenyl (4R, 4aS, 7R, 7aR, 12bS) -7, 9-Dimethoxy-3-((1-methoxycyclopropyl) methyl) -1,2,3,4, Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxylate (242)

The title compound 242 was obtained from compound 241, according to the method described in Reference Example 4.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.45 to 0.55 (m, 2 H), 0.73 to 0.88 (m, 3 H), 0.96 to 1.06 (m) , 1H), 1.46 to 1.56 (m, 1H), 1.67-1.75 (m, 2H), 1.82 (ddd, J = 6, 12, 12 Hz, 1H), 2.43 (Dd, J = 7, 18 Hz, 1 H), 2.50 (ddd, J = 4, 12, 12 Hz, 1 H), 2.62-2.74 (m, 3 H), 3.10 (d, J = 18 Hz, 1 H), 3.38 (s, 3 H), 3.50-3.55 (m, 1 H), 3.55 (s, 3 H), 3.91 (s, 3 H), 4.64 (d , J = 2 Hz, 1 H), 6.63 (d, J = 8 Hz, 1 H), 6.77 (d, J = 8 Hz, 1 H), 7.39 (s, 2 H), 8. 10 (s, 1 H) .

(9) (4R, 4aS, 7R, 7aR, 12bS) -N-benzyl-7,9-dihydroxy-3-((1-hydroxycyclopropyl) methyl) -N-methyl-1,2,3,4, Synthesis of 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (243)

The title compound 243 was obtained from compound 242 according to the methods described in Examples 1 and 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.34 to 0.47 (m, 2 H), 0.69 to 1.08 (m, 4 H), 1.67 to 1.98 (m) , 4H), 2.30 to 2.55 (m, 3H), 2.72 to 2.91 (m, 2H), 2.95 to 3. 10 (m, 1H), 2.98 (s, 1) .5 H), 3.06 (s, 1.5 H), 3.08-3. 37 (m, 1 H), 4.59 (d, J = 2 Hz, 1 H), 4.62-4. 88 (m , 3H), 6.52-6.62 (m, 1 H), 6.75-6. 81 (m, 2 H), 7.20-7. 42 (m, 5 H).

(Example 181)
(4R, 4aS, 7R, 7aR, 12bS) -N-((3-hydroxypyridin-2-yl) methyl) -7,9-dimethoxy-3-((1-methoxycyclopropyl) methyl) -N-methyl Synthesis of -1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (244)

The title compound 244 was obtained from compound 242 and compound 111 according to the method described in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.44 to 0.55 (m, 2 H), 0.67 to 0.91 (m, 3 H), 0.98 (dd, J = 6) , 13, 13 Hz, 1 H), 1.60-1. 70 (m, 1 H), 1.71-1. 96 (m, 2 H), 1. 90 (ddd, J = 6, 13, 13 Hz, 1 H) , 2.38 (dd, J = 6, 18 Hz, 1 H), 2.43 (ddd, J = 3, 12, 12 Hz, 1 H), 2.54-2.69 (m, 3 H), 3.07 (m, 3 H) d, J = 18 Hz, 1 H), 3. 19 (s, 3 H), 3.33 (s, 3 H), 3. 40 (s, 3 H), 3. 44 (d, J = 6 Hz, 1 H), 3 .89 (s, 3 H), 4.62 (d, J = 14 Hz, 1 H), 4. 65 (d, J = 1 Hz, 1 H), 4. 80 (d, J = 14 Hz, 1 H) , 6.60 (d, J = 8 Hz, 1 H), 6.74 (d, J = 8 Hz, 1 H), 6.76 (s, 1 H), 7.19 (dd, J = 5, 8 Hz, 1 H) , 7.25-7.29 (m, 1 H), 8.05-8.09 (m, 1 H), 9.99 (br s, 1 H).

(Example 182)
(4R, 4aS, 7R, 7aR, 12bS) -7,9-dihydroxy-3-((1-hydroxycyclopropyl) methyl) -N-((3-hydroxypyridin-2-yl) methyl) -N-methyl Synthesis of 1--1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (245)

The title compound 245 was obtained from compound 244 according to the method described in Example 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.34 to 0.47 (m, 2 H), 0.70 to 0.90 (m, 4 H), 0.97 (ddd, J = 6) , 13, 13 Hz, 1 H), 1.23-1. 33 (m, 1 H), 1.67-1. 78 (m, 2 H), 1. 83 (ddd, J = 5, 13, 13 Hz, 1 H) , 2.39-2.54 (m, 3 H), 2. 76-2.83 (m, 1 H), 2. 85 (d, J = 18 Hz, 1 H), 3.05 (d, J = 18 Hz, 1H), 3.32 (s, 3H), 4.50 (s, 1H), 4.65 (d, J = 14 Hz, 1 H), 4.82 (d, J = 14 Hz, 1 H), 6.57 (D, J = 8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 6.88 (s, 1 H), 7.19-7.23 (m, 1 H), 7.26 7.30 (m, 1H), 8.10 (dd, J = 1,4Hz, 1H), 9.94 (br s, 1H).

(Example 183)
(4R, 4aS, 7R, 7aR, 12bS) -7,9-dihydroxy-3-((1-hydroxycyclopropyl) methyl) -N-methyl-N-((6- (trifluoromethyl) pyridine-2-) Synthesis of (Ill) methyl) -1,2,3,4,7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-6-carboxamide (246)

The title compound 246 was obtained from compound 242 and compound 108 according to the methods described in Examples 1 and 2.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.32 to 0.45 (m, 2 H), 0.69 to 1.05 (m, 5 H), 1.12 to 1.40 (m , 1H), 1.60 to 1.94 (m, 3H), 2.29 to 2.54 (m, 3H), 2.70 to 2.92 (m, 1.6 H), 2.98-3. .14 (m, 0.4 H), 3.08 (s, 1.8 H), 3.20 (d, J = 6 Hz, 0.6 H), 3.24 (s, 1.2 H), 3.34 (D, J = 6 Hz, 0.4 H), 4.58 (s, 1 H), 4.78 (d, J = 15 Hz, 0.6 H), 4. 81 (d, J = 16 Hz, 0.4 H) , 4.94 (d, J = 15 Hz, 0.6 H), 5.02 (d, J = 16 Hz, 0.4 H), 6.55 (d, J = 8 Hz, 0.4 H), 6.57 ( d, J = 8 Hz, 0. H), 6.71-6.79 (m, 1.4 H), 6.86 (s, 0.6 H), 7.54-7.65 (m, 2 H), 7.86 (t, J = 8 Hz, 0.6 H), 7.95 (t, J = 8 Hz, 0.4 H).

(Example 184)
(4R, 4aS, 7R, 7aR, 12bS) -6- (benzyl (methyl) carbamoyl) -3- (cyclopropylmethyl) -7,9-dihydroxy-1,2,3,4,7,7a-hexahydro- Synthesis of 4a, 7-Ethano-4,12-methanobenzofuro [3,2-e] isoquinoline 3-oxide (247)

To a solution of compound 60 (19.7 mg, 0.040 mmol) in chloroform (1 mL), m-chloroperbenzoic acid (6.8 mg, 0.040 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dimethyl sulfide (2.9 μL, 0.040 mmol) and water and extracted three times with chloroform. 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 = 91: 9) to give the title compound 247 (17.5 mg, 86%) as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.33 to 0.44 (m, 2 H), 0.74 to 0.89 (m, 3 H), 0.95 to 1.05 (m) , 1 H), 1.13-1.23 (m, 1 H), 1.43-1. 79 (m, 3 H), 2.40-2.50 (m, 0.4 H), 2.59-2. .69 (m, 0.6 H), 2.81 (s, 1.2 H), 2.82-3.03 (m, 2 H), 3.07 (s, 1.8 H), 3.10-3 .22 (m, 1 H), 3.30-3.64 (m, 3 H), 4.20 (d, J = 6 Hz, 1 H), 4.30 (s, 0.4 H), 4.44 (s) , 0.6 H), 4.45-45. 53 (m, 1 H), 4.59 (d, J = 14 Hz, 0.6 H), 5.09 (d, J = 15 Hz, 0.4 H), 6 .47-6.54 (m, 1 H), .75-6.81 (m, 1H), 7.11-7.29 (m, 5H), 7.80 (s, 0.6H), 7.84 (s, 0.4H).

(Test Example 1)
Opioid Receptor Functional Test The functional activity of the compound of the present invention for the κ opioid receptor was examined.
Method: Performed according to a predetermined method using Lance Ultra cAMP kit (Perkin Elmer). For the evaluation of agonist activity, assay buffer (1 × HBSS, 5 mM HEPES, pH 7.4, in the presence of 10 μM forskolin, a human opioid 受 容 receptor-expressing CHO cell (Catalog No. CT4606, accession No. NM_000912) and a test compound The reaction was carried out for 30 minutes in 0.5 mM IBMX (Isobutylmethylxanthine), 0.1% BSA. Subsequently, the cAMP detection reagent in the kit was added, and one hour later, time-resolved fluorescence measurement was performed using an EnVision plate reader (Perkin Elmer). The evaluation of the test compounds was performed in the κ opioid receptor function test at a concentration range of 10 ⁻¹⁴ to 10 ⁻⁷ M.

As shown in Table 1, the compounds of the present invention were confirmed to exhibit potent agonist activity at the opioid kappa receptor.

(Test Example 2)
Metabolic stability test (test method)
The human liver microsomes and the test substance were reacted for a certain period of time (0 to 60 minutes), and the residual amount of the test substance in the reaction sample was measured to determine the residual rate. 100% residual rate at reaction time 0 hour, log-linear plot the residual rate after incubation against time, regression line (y = 100e- ^kt , k = slope of linear: elimination rate constant) The metabolic clearance CL _int (mL / min / kg) was calculated using the following equation.
Moreover, comparison was performed using the compound (C) described in paragraph [0007] as a comparison compound. The comparative compound (C) was synthesized by the method described in Non-Patent Document 1 or the like.

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

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

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

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

Claims (17)

1. The following general formula (I),
   

   

   (Wherein, R ¹ represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _3-6 cycloalkyl C _1-6 alkyl group which may have a substituent, a substituent Represents an acyl group which may have an amino protecting group,
   Whether R ² and R ³ are the same or different and hydrogen atom, hydroxy group, C _1-6 alkoxy group which may have a substituent, halogen atom or R ² and R ³ together represent a carbonyl group R ² and R ³ combine to represent a cyclic ketal,
   R ⁴ is a hydrogen atom, a halogen atom, a hydroxy group, a C _1-6 alkoxy group which may have a substituent, an amino group, a C _1-6 alkylamino group, a di C _1-6 alkylamino group, a cyano group , A carbamoyl group, a C _1-6 alkyl carbamoyl group, a di C _1-6 alkyl carbamoyl group,
   R ⁵ represents a hydrogen atom, a hydroxy group, or a C _1-6 alkoxy group which may have a substituent,
   R ⁶ represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a hydroxy group, a C _1-6 alkoxy group which may have a substituent,
   R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or R ⁷ and R ⁸ on the same carbon are bonded to have a substituent good C _3-6 saturated hydrocarbon ring optionally either show a good saturated heterocyclic ring optionally having a substituent, substituents bonded to R ⁷ each other on different carbons when n is 2 or 3 And a C _3-6 saturated hydrocarbon ring which may have one or more substituents, and a saturated heterocyclic ring which may have one or more substituents,
   R ⁹ 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, a C _2-4 alkenyl group, C _2-4 An alkynyl group, a C _1-6 alkoxy group which may have a substituent, a hydroxy group, a C _6-10 aryl group which may have a substituent (provided that R ¹ is cyclopropylmethyl, R ² and When R ³ is a hydrogen atom, R ⁴ and R ⁵ are a hydroxy group, R ⁶ is a hydrogen atom, C _1-6 alkyl group, R ⁷ and R ⁸ are a hydrogen atom, R ⁹ is a phenyl group, and n is 0 to 2 A heteroaryl group which may have a substituent, a cyclic amino group which may have a substituent, or a saturated complex which R ⁶ and R ⁹ may be bonded to have a substituent Indicates an unsaturated heterocyclic ring which may have a ring or a substituent,
   X represents a nitrogen atom or N-oxide,
   Y represents an oxygen atom or a sulfur atom,
   n represents an integer of 0 to 3. )
   A morphinan derivative represented by the following, a tautomer, stereoisomer, deuterium substitution product or a pharmaceutically acceptable salt of the compound, or a solvate thereof.
2. The morphinan derivative according to claim 1, wherein R ⁴ and R ⁵ are a hydroxy group and / or a C _1-6 alkoxy group, a tautomer, stereoisomer, deuterium substitution product or pharmaceutically acceptable form of the compound. Salts or solvates thereof.
3. The morphinan derivative according to claim 1 or 2, wherein R ⁴ and R ⁵ are a hydroxy group, a tautomer, stereoisomer, deuterium substitution product or a pharmaceutically acceptable salt thereof of the compound, or a solvate thereof object.
4. The morphinan derivative according to any one of claims 1 to 3 wherein R ² and R ³ are a hydrogen atom, a tautomer, stereoisomer, deuterium substitution product or a pharmaceutically acceptable salt thereof of the compound or a solvate thereof object.
5. The morphinan derivative according to any one of claims 1 to 4, wherein R ⁶ is a C _1-6 alkyl group which may have a substituent, a tautomer, stereoisomer, deuterium substitution product or a pharmaceutical thereof of the compound Salts or solvates thereof.
6. The morphinan derivative according to any one of claims 1 to 5, wherein n is 1, a tautomer, stereoisomer, deuterium substitution product or a pharmaceutically acceptable salt thereof or a solvate thereof of the compound.
7. Morphinan derivative according to claim 1 to 6, wherein R ⁷ and R ⁸ is a hydrogen atom, a tautomer, stereoisomer, deuterium substitutions or a pharmaceutically acceptable salt thereof or a solvated object.
8. The morphinan derivative according to any one of claims 1 to 7, wherein R ⁹ is a C _6-10 aryl group which may have a substituent or a heteroaryl group which may have a substituent, a tautomer of the compound Or a stereoisomer, a deuterium substitution product or a pharmaceutically acceptable salt thereof or a solvate thereof.
9. A morphinan derivative according to any one of claims 1 to 8 wherein said optionally substituted C _6-10 aryl group is a phenyl group, a tautomer, stereoisomer or deuterium substitution of said compound Body or pharmaceutically acceptable salt or solvate thereof.
10. A morphinan derivative according to any one of claims 1 to 8, wherein the heteroaryl group which may have a substituent according to claim 8 is a pyridyl group, a pyrimidyl group, a pyridazyl group, a pyrazyl group or an oxodihydropyridyl group. A mutant, a stereoisomer, a deuterium substitution product or a pharmaceutically acceptable salt thereof or a solvate thereof.
11. 11. The morphinan derivative according to any one of claims 1 to 10, wherein Y is an oxygen atom, a tautomer, stereoisomer, deuterium substitution product or a pharmaceutically acceptable salt thereof or a solvate thereof of the compound.
12. The morphinan according to any one of claims 1 to 11, wherein R ¹ is a C _1-6 alkyl group which may have a substituent or a C _3-6 cycloalkyl C _1-6 alkyl group which may have a substituent. A derivative, a tautomer, stereoisomer, deuterium substitution product or pharmaceutically acceptable salt of the compound or a solvate thereof.
13. The morphinan derivative according to any one of claims 1 to 12, wherein X is a nitrogen atom, a tautomer, stereoisomer, deuterium substitution product or a pharmaceutically acceptable salt of the compound, or a solvate thereof.
14. A morphinan derivative according to any one of claims 1 to 13, a tautomer, stereoisomer, deuterium substitution product of the compound or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. Pharmaceutical composition.
15. The medicament according to claim 14, which is an agent for treating, ameliorating or preventing a disease associated with an opioid κ receptor.
16. The medicine according to claim 14 or 15, which is an analgesic.
17. The medicine according to claim 14 or 15, which is an antipruritic.