TECHNICAL FIELD

The present invention relates to an azepane derivative having a κ opioid receptor agonistic effect.

The present application claims priority based on JP 2019-179727 A filed in Japan on Sep. 30, 2019, the content of which is incorporated herein by reference.

BACKGROUND ART

Three types of opioid receptors are known: μ, δ, and κ. Morphine, which exhibits a high affinity for μ opioid receptors, has been used as an analgesic for a long time. However, μ opioid receptor agonists such as morphine are known to cause adverse events such as dependence and respiratory depression via μ opioid receptors.

Meanwhile, κ opioid receptor agonists are also known to exhibit an analgesic effect, but are not involved in such adverse events caused by morphine.

On the other hand, it is known that κ opioid receptor agonists generally exhibit a sedative effect and a drug-aversion effect. The only κ opioid receptor agonist from which drug-aversion has been separated is Nalfurafine (Patent Literature 1). However, since Nalfurafine exhibits a sedative effect in an analgesic dose, it has been approved as an antipruritic drug, but has not been approved as an analgesic. That is, there is still no κ opioid receptor-selective agonist approved as an analgesic.

Accordingly, a κ opioid receptor-selective agonist not exhibiting a sedative effect or a drug-aversion effect is expected as an excellent treating, improving or preventing drug for diseases or symptoms related to κ opioid receptors such as an analgesic.

Patent Literature 2 discloses that a compound represented by the following formula (A):

[Image Omitted]

has a κ opioid receptor agonistic activity. However, the activity is not sufficient.

Furthermore, Patent Literature 3 reports a compound represented by the following formula (B):

[Image Omitted]

It is described that this compound has a κ opioid receptor selective binding effect and an analgesic effect. However, the analgesic activity is far from satisfactory.

In addition, Patent Literature 4 and Non Patent Literature 1 disclose that a compound (C) represented by the following formula:

[Image Omitted]

has extremely high activity. However, the compound has had insufficient in vivo stability. When the compound is unstable in vivo, it is difficult to develop the compound as a pharmaceutical product due to the fact that expected drug efficacy is not exhibited, the influence of the decomposed product is exerted on the living body, and the like. Accordingly, in vivo stability is an important requirement in the development of pharmaceutical products.

Among analgesics on the market, there is still no drug having high κ opioid receptor agonist activity.

Therefore, in order to aim for an analgesic, a compound is desired that exhibits selectivity and high activity for κ opioid receptors, is excellent in in vivo stability, and has little sedative effect and drug-aversion effect.

CITATION LIST
Patent Literature

Patent Literature 1: WO 1993/5081 A

Patent Literature 2: JP 2008-179554 A

Patent Literature 3: JP 2525552 B2

Patent Literature 4: U.S. Pat. No. 963,460

Non Patent Literature

Non Patent Literature 1: Symposium Program and Abstract of 36th Annual Meeting of Japanese Narcotics Research Conference (JNRC 2016), page 37, Japanese Narcotics Research Conference

SUMMARY OF INVENTION
Technical Problem

An object of the present invention is to provide a medicine effective for treatment, improvement, or prevention of various diseases and symptoms related to κ opioid receptors, in which the sedative effect and the drug-aversion effect are suppressed.

Solution to Problem

Under such circumstances, as a result of intensive studies, the present inventors have found that a specific azepane derivative exhibits potent agonist activity against κ opioid receptors and high in vivo stability. Furthermore, it has been revealed that the present azepane derivative exhibits a potent analgesic effect, and does not exhibit a sedative effect even at a dose higher than that of Nalfurafine (Patent Literature 1). As described above, the present inventors have found an azepane derivative that is a highly safe κ opioid receptor agonist intended for an analgesic, and completed the present invention.

[1] That is, the present invention relates to an azepane derivative represented by the following formula (I):

[Image Omitted]

wherein R¹represents a hydrogen atom, a C_1-6alkyl group optionally having a substituent, a C_3-6cycloalkyl group optionally having a substituent, a C_3-6cycloalkyl C_1-6alkyl group optionally having a substituent, a C_6-10aryl group optionally having a substituent, a heteroaryl group optionally having a substituent, an aralkyl group optionally having a substituent, a heteroarylalkyl group optionally having a substituent, a C_2-6alkenyl group optionally having a substituent, a C_2-6alkynyl group optionally having a substituent, an acyl group optionally having a substituent, or an amino protecting group,

R²and R³are the same or different and each represent a hydrogen atom, a C_1-6alkyl group optionally having a substituent, a C_1-6alkoxy group optionally having a substituent, a halogen atom, an optionally protected hydroxy group, a carbonyl group in which R²and R³are together with each other, or a C_3-6saturated hydrocarbon ring optionally having a substituent or a cyclic ketal optionally having a substituent in which R²and R³are bonded to each other,

R⁴and R⁵are the same or different and each represent a hydrogen atom, a C_1-6alkyl group optionally having a substituent, a C_1-6alkoxy group optionally having a substituent, a C_3-6cycloalkyl group optionally having a substituent, an amino group optionally having a substituent, a protected amino group, a halogen atom, an optionally protected hydroxy group, a carboxy group, a carboxylic acid ester group, or a carbamoyl group optionally having a substituent,

R⁶represents a hydrogen atom, a C_1-6alkoxy group optionally having a substituent, an amino group optionally having a substituent, a protected amino group, a halogen atom, an optionally protected hydroxy group, a tetrazolyloxy group optionally having a substituent, a cyano group, a carboxy group, a carboxylic acid ester group, a carbamoyl group optionally having a substituent, a C_6-10aryl group optionally having a substituent, a heteroaryl group optionally having a substituent, a C_6-10aryloxy group, or a saccharide,

R⁷and R⁸are the same or different and each represent a hydrogen atom, a C_1-6alkyl group optionally having a substituent, a C_1-6alkoxy group optionally having a substituent, a halogen atom, an optionally protected hydroxy group, a carbonyl group or a thiocarbonyl group in which R⁷and R⁸are together with each other, or a C_3-6saturated hydrocarbon ring optionally having a substituent or a cyclic ketal optionally having a substituent in which R⁷and R⁸are bonded to each other,

R⁹and R¹⁰are the same or different and each represent a hydrogen atom, a C_1-6alkyl group optionally having a substituent, a C_1-6alkoxy group optionally having a substituent, a halogen atom, an optionally protected hydroxy group, a carbonyl group or a thiocarbonyl group in which R⁹and R¹⁰are together with each other, or a C_3-6saturated hydrocarbon ring optionally having a substituent or a cyclic ketal optionally having a substituent in which R⁹and R¹⁰are bonded to each other,

R¹¹represents a hydrogen atom, a C_1-6alkyl group optionally having a substituent, a C_1-6alkoxy group optionally having a substituent, an aralkyloxy group optionally having a substituent, an amino group optionally having a substituent, a protected amino group, a halogen atom, an optionally protected hydroxy group, or a cyano group,

A and B are different from each other and each represent NR¹⁸(R¹⁸represents a hydrogen atom or an amino protecting group), a methylene group, a carbonyl group, or a group represented by the following formula (II):

[Image Omitted]

wherein R¹²and R¹³are the same or different and each represent a hydrogen atom, a halogen atom or a C_1-6alkyl group optionally having a substituent, or a C_3-6saturated hydrocarbon ring optionally having a substituent or a saturated heterocyclic ring optionally having a substituent in which R¹²and R¹³on the same carbon are bonded to each other, or may form a C_3-6saturated hydrocarbon ring optionally having a substituent or a saturated heterocyclic ring optionally having a substituent in which a pair of adjacent R¹²s are bonded to each other when n is 2 to 3,

R¹⁴represents a hydrogen atom, a C_1-6alkyl group optionally having a substituent, a C_3-6cycloalkyl group optionally having a substituent, a C_2-6alkenyl group optionally having a substituent, a C_2-6alkynyl group optionally having a substituent, a C_1-6alkoxy group optionally having a substituent, an amino group optionally having a substituent, a protected amino group, a halogen atom, an optionally protected hydroxy group, a C_6-10aryl group optionally having a substituent, a heteroaryl group optionally having a substituent, a saturated heterocyclic group optionally having a substituent, or a cyclic amino group optionally having a substituent, and * represents a bond, provided that one of A or B represents the formula (II),

X represents a nitrogen atom or an N-oxide,

Y represents a methylene group optionally having a substituent, a carbonyl group or a thiocarbonyl group,

Z represents NR¹⁵, an oxygen atom, a bond, an ethenylene group optionally having a substituent, or an ethynylene group, provided that when m is 0, n does not represent 0 and Z does not represent NR¹⁵,

R¹⁵represents a hydrogen atom, a C_1-6alkyl group optionally having a substituent, or a nitrogen-containing saturated heterocyclic ring optionally having a substituent in which R¹⁵and R¹⁴are bonded to each other,

R¹⁷represents a hydrogen atom, a halogen atom, an optionally protected hydroxy group, an alkoxy group optionally having a substituent, or a tetrazolyloxy group optionally having a substituent,

m represents an integer of 0 to 1, and

n represents an integer of 0 to 3,

provided that when Z is a bond, m and n do not simultaneously represent 0,

and a pharmaceutically acceptable salt thereof.

[2] The present invention also relates to the azepane derivative and the pharmaceutically acceptable salt thereof according to [1], in which R⁶is a hydroxy group, a C_1-6alkoxy group optionally having a substituent, or a carbamoyl group optionally having a substituent.

[3] The present invention also relates to the azepane derivative and the pharmaceutically acceptable salt thereof according to [1] or [2], in which R⁶is a hydroxy group.

[4] The present invention also relates to the azepane derivative and the pharmaceutically acceptable salt thereof according to [1] to [3], in which R¹is a C_1-6alkyl group optionally having a substituent or a C_3-6cycloalkyl C_1-6alkyl group optionally having a substituent.

[5] The present invention also relates to the azepane derivative and the pharmaceutically acceptable salt thereof according to [1] to [4], in which Z is a bond.

[6] The present invention also relates to the azepane derivative and the pharmaceutically acceptable salt thereof according to [1] to [5], in which n is 1 to 3.

[7] The present invention also relates to the azepane derivative and the pharmaceutically acceptable salt thereof according to [1] to [6], in which R¹⁴is a heteroaryl group optionally having a substituent.

[8] The present invention also relates to the azepane derivative and the pharmaceutically acceptable salt thereof according to [1] to [7], in which A represents a group represented by the formula (II) according to claim 1, and B represents a methylene group.

[9] The present invention also relates to the azepane derivative and the pharmaceutically acceptable salt thereof according to [1] to [8], in which R¹¹is a hydroxy group.

[10] The present invention also relates to a pharmaceutical composition containing the azepane derivative and the pharmaceutically acceptable salt thereof according to any one of [1] to [9] as an active ingredient.

[11] The present invention also relates to a medicament according to [10], being a treating, improving, or preventing agent for a disease related to opioid κ receptors.

[12] The present invention also relates to the medicament according to [10] or [11], being an analgesic.

[13] The present invention also relates to the medicament according to [10] or [11], being an antipruritic drug.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a diagram showing the results of a test for confirming a sedative effect by oral administration of a compound of Example 22 (500 μg/kg).

FIG. 2 is a diagram showing the results of a test for confirming a sedative effect by oral administration of a compound of Example 50 (7000 μg/kg).

FIG. 3 is a diagram showing the results of a test for confirming a sedative effect by oral administration of Nalfurafine (30, 100, 300 μg/kg).

FIG. 4 is a diagram showing the results of a test for confirming a sedative effect by subcutaneous administration of a compound of Example 77 (400 μg/kg).

FIG. 5 is a diagram showing the results of a test for confirming a sedative effect by subcutaneous administration of Nalfurafine (3, 10, 30 μg/kg).

DESCRIPTION OF EMBODIMENTS

Next, a description is made of the present invention in more detail.

The azepane derivative represented by the above-mentioned formula (I) and a pharmaceutically acceptable salt thereof include tautomers, stereoisomers and solvates thereof.

In the C_1-6alkyl groups optionally having a substituent represented by R¹to R⁵and R⁷to R¹⁵, the C_1-6alkyl group includes a linear or branched alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, or a hexyl group, preferably a methyl group, an ethyl group, or a propyl group, more preferably a methyl group.

In the C_1-6alkyl groups optionally having a substituent, the substituent includes a halogen atom such as a fluorine atom or a chlorine atom; a hydroxy group; an amino group optionally having a substituent such as a C_1-6alkylamino group, a di C_1-6alkylamino group, or an acylamino group; a protected amino group; an acyl group such as a formyl group, an acetyl group, a cyclopropylcarbonyl group, or a benzoyl group; a cyclic amino group such as an azetidinyl group, a pyrrolidinyl group, a piperazinyl group, or a morpholinyl group; a cyclic lactam group such as β-lactam, γ-lactam, or δ-lactam, a carboxy group, or a carboxylic acid ester group (the same as described in [0032]).

In the C_3-6cycloalkyl groups optionally having a substituent represented by R¹, R⁴, R⁵, and R¹⁴, the C_3-6cycloalkyl group includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, preferably a cyclopropyl group.

In the C_3-6cycloalkyl groups optionally having a substituent represented by R¹, R⁴, R⁵, and R¹⁴, the substituent includes a C_1-6alkyl group such as a methyl group, an ethyl group or a propyl group; a halogenated methyl group such as a fluoromethyl group, a difluoromethyl group, or a trifluoromethyl group; a halogen atom such as a fluorine atom or a chlorine atom; a hydroxy group; an amino group optionally having a substituent such as a C_1-6alkylamino group, a di C_1-6alkylamino group, or an acylamino group; a protected amino group; an acyl group such as a formyl group, an acetyl group, a cyclopropylcarbonyl group, or a benzoyl group; a cyclic amino group such as an azetidinyl group, a pyrrolidinyl group, a piperazinyl group, or a morpholinyl group; or a cyclic lactam group such as β-lactam, γ-lactam, or δ-lactam.

In the C_1-6alkoxy groups optionally having a substituent represented by R²to R¹¹, R¹⁴, and R¹⁷, the C_1-6alkoxy group includes a linear or branched alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, or an isobutoxy group, preferably a methoxy group.

In the C_1-6alkoxy groups optionally having a substituent, the substituent includes a C_1-6alkoxy group such as a methoxy group or an ethoxy group; a phenoxy group; or a halogen atom such as a fluorine atom or a chlorine atom, preferably a fluorine atom, and examples thereof include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, or a 2,2,2-trifluoroethoxy group.

The C_6-10aryl groups optionally having a substituent represented by R¹, R⁶, and R¹⁴, and the C_6-10aryl group in the C_6-10aryloxy group optionally having a substituent represented by R⁶include a phenyl group or a naphthyl group.

In the heteroaryl groups optionally having a substituent represented by R¹, R⁶, and R¹⁴, examples of the heteroaryl group include a 5-membered heteroaryl group such as a furanyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazolyl group, or a tetrazolyl group; a 6-membered heteroaryl group such as a pyridyl group, a pyridazinyl group, a pyrazinyl group, or a pyrimidyl group; or a monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as a ring-constituting atom, such as a bicyclic heteroaryl group such as a quinolyl group, an isoquinolyl group, a quinazolyl group, a quinoxalyl group, an indolyl group, an indazolyl group, a benzimidazolyl group, a benzofuranyl group, a benzothienyl group, a benzoxazolyl group, a benzothiazolyl group, an imidazopyridinyl group, a pyrazolopyridinyl group, or an indazolyl group.

In addition, a tautomer may exist depending on the substituent on these heteroaryl groups. For example, when a hydroxy group is substituted on a pyridyl group, a 6-hydroxypyridin-2-yl group includes a 6-oxo-1,6-dihydropyridin-2-yl group as the tautomer thereof, and a 4-hydroxypyridin-2-yl group includes a 4-oxo-1,4-dihydropyridin-2-yl group as the tautomer thereof.

Preferable R¹includes a 6-membered heteroaryl group such as a pyridyl group, a pyridazinyl group, a pyrazinyl group, or a pyrimidyl group.

Preferable R¹⁴includes a furanyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, a triazole group, a pyridyl group, a pyridazinyl group, a pyrazinyl group, a pyrimidyl group, a quinolyl group, an isoquinolyl group, an indolyl group, an indazolyl group, a benzoxazolyl group, a benzothiazolyl group, an imidazopyridinyl group, a pyrazolopyridinyl group, or an indazole group, more preferably a furan-2-yl group, a thiazol-2-yl group, a thiazol-4-yl group, a 1H-imidazol-4-yl group, a 1H-pyrazol-3-yl group, a 1H-pyrazol-1-yl group, a 2H-1,2,3-triazol-2-yl group, a pyridin-2-yl group, a pyrimidin-2-yl group, a pyrazin-2-yl group, a 1H-indazol-3-yl group, an imidazo[1,2-a]pyridin-2-yl group, a pyrazolo[1,5-a]1H-indazol-1-yl group, a quinolin-2-yl group, an isoquinolin-3-yl group, an indolin-1-yl group, or a benzo[d]thiazol-2-yl group.

The C₆-1c aryl groups optionally having a substituent represented by R¹, R⁶, and R¹⁴, and the heteroaryl groups optionally having a substituent represented by R¹, R⁶, and R¹⁴may have 1 to 3 substituents on the ring, and the substituents include a linear or branched C_1-6alkyl group such as a methyl group, an ethyl group, or a propyl group; a linear or branched halogenated alkyl group such as a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, or a trifluoromethyl group; a hydroxyalkyl group such as a hydroxymethyl group; a hydroxyethyl group, or a 1-hydroxypropyl group; a C_3-6cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group; a linear or branched C_1-6alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or a butoxy group; a linear or branched halogenated C_1-6alkoxy group such as a trifluoromethoxy group or a 2,2,2-trifluoroethoxy group; a halogen atom such as a fluorine atom or a chlorine atom; a hydroxy group; a nitro group; a cyano group; an amino group optionally having a substituent such as a C_1-6alkylamino group, a di C_1-6alkylamino group, or an acylamino group; a protected amino group; an acyl group such as a formyl group, an acetyl group, a cyclopropylcarbonyl group, or a benzoyl group; a cyclic amino group such as an azetidinyl group, a pyrrolidinyl group, a piperazinyl group, or a morpholinyl group; or a cyclic lactam group such as β-lactam, γ-lactam, or δ-lactam.

In the C_3-6cycloalkyl C_1-6alkyl group optionally having a substituent represented by R¹, the C_3-6cycloalkyl C_1-6alkyl group includes a cyclopropylmethyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylmethyl group, a cyclobutylethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclopentylpropyl group, a cyclohexylmethyl group, a cyclohexylethyl group, or a cyclohexylpropyl group, preferably a cyclopropylmethyl group, a cyclopropylethyl group, a cyclobutylmethyl group, a cyclobutylethyl group, a cyclopentylmethyl group, or a cyclopentylethyl group, more preferably a cyclopropylmethyl group, a cyclobutylmethyl group, or a cyclopentylmethyl group, most preferably a cyclopropylmethyl group.

In the C_3-6cycloalkyl C_1-6alkyl group optionally having a substituent, the substituent includes a fluorine atom, a halogen atom such as a chlorine atom, or a hydroxy group.

The aralkyl group optionally having a substituent represented by R¹, and the aralkyl in the aralkyloxy group optionally having a substituent represented by R¹¹include one in which the carbon number of the aryl moiety is C_6-10and the carbon number of the alkylene moiety is C_1-5, and examples thereof include a benzyl group, a phenylethyl group, or a 1-naphthylmethyl group, preferably a benzyl group.

In the heteroarylalkyl group optionally having a substituent represented by R¹, the heteroaryl moiety includes a heteroaryl containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as a ring-constituting atom, and the alkyl moiety includes a C_1-6alkyl group such as a methyl group, an ethyl group, or a propyl group, and examples thereof include a monocyclic heteroarylalkyl group such as a (pyridin-2-yl)methyl group, a (pyridin-3-yl)methyl group, a (pyridin-4-yl)methyl group, a 2-(pyridin-2-yl)ethyl group, a (furan-2-yl)methyl group, a (furan-3-yl)methyl group, an (imidazol-2-yl)methyl group, an (imidazol-4-yl)methyl group, an (imidazol-5-yl)methyl group, a (thiazol-2-yl)methyl group, a (thiazol-4-yl)methyl group, a (thiazol-5-yl)methyl group, a (thiophen-2-yl)methyl group, or a 2-(thiophen-2-yl)ethyl group, or a bicyclic heteroarylalkyl group such as a (quinolin-3-yl)methyl group or a (indol-3-yl)methyl group.

The aryl in the aralkyloxy group optionally having a substituent represented by R¹¹, and the aryl and heteroaryl in the aralkyl group optionally having a substituent and the heteroarylalkyl group optionally having a substituent represented by R¹optionally have a substituent, and examples of the substituent include the same substituents as those in the C_6-10aryl group optionally having a substituent described in paragraph [0020].

In the C_2-6alkenyl groups optionally having a substituent represented by R¹and R¹⁴, the C_2-6alkenyl group includes a C_2-6linear or branched alkenyl group, and examples thereof include an alkenyl group such as an allyl group, a vinyl group, a 1-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, or a 5-hexenyl group.

In the C_2-6alkynyl groups optionally having a substituent represented by R¹and R¹⁴, the C_2-6alkynyl group represents a C_2-6linear or branched alkynyl group, and examples thereof include an ethynyl group, a propynyl group, or a butynyl group.

A group that may be substituted into the alkenyl group and the alkynyl group includes a C_1-6alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, or a propoxycarbonyl group, or an aralkyl group such as a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group, or a 4-phenylbutyl group; a C_1-6alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, or a butoxy group; an aralkyloxy group such as a benzyloxy group or a 2-phenylethyloxy group; an amino group optionally substituted with a C_1-6linear or branched alkyl group; a halogen atom such as a fluorine atom or a chlorine atom; a carboxy group or a hydroxy group.

The acyl group optionally having a substituent represented by R¹includes a C_1-6alkanoyl group such as a formyl group, an acetyl group, a propionyl group, a butanoyl group, a pentanoyl group, or a hexanoyl group; a C_4-7cycloalkanoyl group such as a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, or a cyclopentylcarbonyl group; an aroyl group such as a benzoyl group or a naphthoyl group; a 5 to 6 membered heteroaroyl group such as a furoyl group, a thiophene carbonyl group, a nicotinyl group, or an isonicotinoyl group.

In addition, the substituent in the C_1-6alkanoyl group and the C_4-7cycloalkanoyl group includes the same substituents as those described in paragraph [0015], and the substituent in the aroyl group and the heteroaroyl group includes the same substituents as those described in paragraph [0020].

The substituent in the carbamoyl groups optionally having a substituent represented by R⁴to R⁶, the substituent in the amino groups optionally having a substituent represented by R⁴to R⁶, R¹, and R¹⁴, and the substituent in the tetrazolyloxy groups optionally having a substituent represented by R⁶and R¹⁷include a C_1-6alkyl group optionally having a substituent such as a methyl group, an ethyl group, a propyl group, or an isopropyl group, or an aryl group such as a phenyl group. In the C_1-6alkyl group optionally having a substituent, the substituent includes substituents described in paragraph [0015], and 1 or 2 of these substituents may be contained.

In the amino-protecting groups represented by R¹and R¹⁸and the protected amino groups represented by R⁴to R⁶, R¹¹, and R¹⁴, the protecting group includes a carbamate-based protecting group such as a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a tert-amyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group, a p-methoxybenzylcarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-methoxyphenylazobenzyloxycarbonyl group, a 3,5-dimethoxybenzyloxycarbonyl group, a 3,4,5-trimethoxybenzyloxycarbonyl group, a p-biphenylisopropyloxycarbonyl group, a diisopropylmethyloxycarbonyl group, a 2-(trimethylsilyl)ethoxycarbonyl group, or a 9-fluorenylmethyloxycarbonyl group; a sulfonamide-based protecting group such as a p-toluenesulfonyl group or a 2-nitrobenzenesulfonyl group; an imide-based protecting group such as a phthaloyl group; a C_7-19aralkyl group such as a benzyl group, a phenylethyl group, a phenylpropyl group, a trityl group, or a naphthylmethyl group.

The halogen atoms represented by R²to R¹⁴and R¹⁷include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.

In the carboxylic acid ester groups represented by R⁴to R⁶, the ester-forming group includes a linear or branched C_1-6alkyl group such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, or a hexyl group; a C_2-6alkenyl group such as a vinyl group, an allyl group, a 1-propenyl group, a butenyl group, a pentenyl group, or a hexenyl group; an aralkyl group such as a benzyl group; an aryl group such as a phenyl group or a naphthyl group, or a C_1-6alkanoyloxy C_1-4lower alkyl group such as an acetoxymethyl group or a pivaloyloxymethyl group.

In the cyclic amino group optionally having a substituent represented by R¹⁴, the cyclic amino group includes an azetidinyl group, a pyrrolidinyl group, an azepanyl group, a piperidinyl group, a piperazinyl group, a morphonyl group, a thiomorpholinyl group, an oxazabicyclooctyl group, an azasilinyl group, an indolinyl group or an isoindolyl group, preferably a 1-pyrrolidinyl group, a 1-piperidinyl group, a 2-oxa-5-azabicyclo[2.2.2]octan-5-yl group, a 3-oxa-8-azabicyclo[3.2.1]octan-8-yl group, an azasilinan-1-yl group, or a 1-indolinyl group, more preferably a 1-pyrrolidinyl group, a 1-piperidinyl group, an azasilinan-1-yl group, or a 1-indolinyl group.

The substituent includes a C_1-6alkyl group optionally having a substituent such as a methyl group or an ethyl group; a C_1-6alkoxy group optionally having a substituent such as a methoxy group, an ethoxy group, or a propoxy group; a halogen atom such as a fluorine atom or a chlorine atom; or a hydroxy group.

In the C_1-6alkyl group optionally having a substituent, the substituent includes substituents described in paragraph [0015], and in the C_1-6alkoxy group optionally having a substituent, the substituent includes substituents described in paragraph [0017].

In the C_3-6saturated hydrocarbon ring optionally having a substituent formed by bonding of R²and R³or R⁷and R⁸, the C_3-6saturated hydrocarbon ring optionally having a substituent formed by bonding of R⁹and R¹⁰, and the C_3-6saturated hydrocarbon ring optionally having a substituent formed by bonding of R¹²and R¹³on the same carbon or bonding of a pair of adjacent R¹²s when n is 2 to 3, the C_3-6saturated hydrocarbon rings include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring.

The saturated heterocyclic ring optionally having a substituent formed by bonding of R¹²and R¹³on the same carbon or bonding of a pair of adjacent R¹²s when n is 2 to 3, and the saturated heterocyclic ring optionally having a substituent represented by R¹⁴include a 3 to 6 membered saturated heterocyclic ring, and examples thereof include a cyclic amine such as aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, or thiomorpholine, a cyclic ether such as epoxide, oxetane, tetrahydrofuran, tetrahydropyran, or dioxane, or a cyclic thioether such as thietane, thiolane, or thiane.

When having a nitrogen atom as a constituting atom of the ring, the saturated heterocyclic ring optionally further has a linear or branched C_1-6alkyl group, a substituent such as an acyl group, or an amino-protecting group on the nitrogen. These substituents and the like represent those described in paragraphs [0015], [0028], and [0030].

The nitrogen-containing saturated heterocyclic ring optionally having a substituent formed by bonding of R¹⁴and R¹⁵includes a 3 to 6 membered nitrogen-containing saturated heterocyclic ring, and examples thereof include a cyclic amino group such as aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, or thiomorpholine.

These nitrogen-containing saturated heterocyclic rings are optionally further condensed with a saturated hydrocarbon ring, a saturated heterocyclic ring, an unsaturated hydrocarbon ring, or an unsaturated heterocyclic ring, and examples thereof include decahydroquinoline, decahydroisoquinoline, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, benzomorpholine, or benzothiomorpholine.

When having a nitrogen atom as a constituting atom of the ring in addition to the nitrogen atom to which R¹⁵is bonded, the nitrogen-containing heterocyclic ring optionally further has a linear or branched C_1-6alkyl group and a substituent such as an acyl group, or an amino-protecting group on the nitrogen atom. These substituents and the like represent those described in paragraphs [0015], [0028], and [0030].

In the C_3-6saturated hydrocarbon ring optionally having a substituent formed by bonding of R¹²and R¹³on the same carbon, the saturated heterocyclic ring optionally having a substituent formed by bonding of R¹²and R¹³on the same carbon, the C_3-6saturated hydrocarbon ring optionally having a substituent or the saturated heterocyclic ring optionally having a substituent formed by bonding of a pair of adjacent R¹²s when n is 2 to 3, and the nitrogen-containing saturated heterocyclic ring optionally having a substituent formed by bonding of R¹⁴and R¹⁵, the substituent includes the same substituents as those in the cyclic amino group described in paragraph [0033].

The cyclic ketals optionally having a substituent formed by bonding of R²and R³, R⁷and R⁸, and R⁹and R¹⁰include dioxolane or dioxane. The substituent includes a C_1-6alkyl group such as a methyl group, an ethyl group, or a propyl group.

In the optionally protected hydroxy groups represented by R²to R¹¹, R¹⁴, and R¹⁷, the hydroxy-protecting group includes an acetal-based protecting group such as an aralkyl group optionally having a substituent such as a benzyl group, a 4-methoxybenzyl group, or a trityl group, an alkanoyl group such as an acetyl group, a trimethylsilyl group such as a methoxymethyl group, a 2-tetrahydropyranyl group, or an ethoxyethyl group, a silyl group having a substituent such as tert-butyldimethylsilyl, or a sulfonyl-based protecting group such as a methanesulfonyl group, a p-toluenesulfonyl group, or a trifluoromethanesulfonyl group.

The saccharide represented by R⁶includes glucuronic acid.

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

Y represents a methylene group optionally having a substituent, a carbonyl group, or a thiocarbonyl group, preferably a methylene group optionally having a substituent or a carbonyl group, particularly preferably a carbonyl group.

The substituent in the methylene group optionally having a substituent includes a C_1-6alkyl group, an optionally protected hydroxy group (the protecting group includes protecting groups in paragraph [0039]), a halogen atom (such as a fluorine atom), or a C_1-6alkyl group substituted with a halogen atom (such as a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, or a dichloromethyl group).

Z represents NR¹⁵, an oxygen atom, a bond, an ethenylene group, or an ethynylene group, preferably NR¹⁵, an oxygen atom, a bond, or an ethenylene group optionally having a substituent.

In the ethenylene group optionally having a substituent, the substituent includes substituents described in paragraph [0027].

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

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

A preferable aspect of the compound (I) used in the present invention includes a case where R¹is a C_1-6alkyl group optionally having a substituent or a C_3-6cycloalkyl C_1-6alkyl group optionally having a substituent, R²and R³are the same or different and are each a hydrogen atom or a C_1-6alkyl group optionally having a substituent, a C_1-6alkoxy group optionally having a substituent, a halogen atom, or a hydroxy group, R⁴and R⁵are the same or different and are each a hydrogen atom, a C_1-6alkyl group optionally having a substituent, a C_1-6alkoxy group optionally having a substituent, an amino group optionally having a substituent, a halogen atom, or a hydroxy group, R⁶is a hydroxy group, a C_1-6alkoxy group optionally having a substituent, or a carbamoyl group optionally having a substituent, R⁷and R⁸are the same or different and are each a hydrogen atom, a C_1-6alkyl group optionally having a substituent, a C_1-6alkoxy group optionally having a substituent, a halogen atom, or a hydroxy group, R⁹and R¹⁰are the same or different and are each a hydrogen atom, a C_1-6alkyl group optionally having a substituent, a C_1-6alkoxy group optionally having a substituent, a halogen atom, or a hydroxy group, R¹¹is a hydrogen atom or a hydroxy group, R¹²and R¹³are the same or different and are each a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R¹⁴is a C_6-10aryl group optionally having a substituent, a heteroaryl group optionally having a substituent, or a cyclic amino group optionally having a substituent, X is a nitrogen atom or an N-oxide, Y is a methylene group optionally having a substituent or a carbonyl group, Z is NR¹⁵, an oxygen atom, a bond, an ethenylene group optionally having a substituent, or an ethynylene group, R¹⁵is a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R¹⁷is a hydrogen atom, a halogen atom, an optionally protected hydroxy group, or an alkoxy group optionally having a substituent, m is an integer of 0 or 1, and n is an integer of 0 to 3.

A preferable aspect of the compound (I) used in the present invention includes a case where R¹is a C_1-6alkyl group optionally having a substituent or a C_3-6cycloalkyl C_1-6alkyl group optionally having a substituent, R²and R³are the same or different and are each a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R⁴and R⁵are the same or different and are each a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R⁶is a hydroxy group, a C_1-6alkoxy group optionally having a substituent, or a carbamoyl group optionally having a substituent, R⁷and R⁸are the same or different and are each a hydrogen atom, a C_1-6alkyl group optionally having a substituent, or a C_1-6alkoxy group optionally having a substituent, R⁹and R¹⁰are the same or different and are each a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R¹¹is a hydrogen atom or a hydroxy group, R¹²and R¹³are the same or different and are each a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R¹⁴is a C_6-10aryl group optionally having a substituent, a heteroaryl group optionally having a substituent, or a cyclic amino group optionally having a substituent, X is a nitrogen atom or an N-oxide, Y is a methylene group optionally having a substituent or a carbonyl group, Z is NR¹⁵, an oxygen atom, a bond, or an ethenylene group optionally having a substituent, R¹⁵is a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R¹⁷is a hydrogen atom, an optionally protected hydroxy group, or an alkoxy group optionally having a substituent, m is an integer of 0 or 1, and n is an integer of 0 to 3.

Furthermore, a preferable aspect of the compound (I) used in the present invention includes a case where R¹is a C_1-6alkyl group optionally having a substituent or a C_3-6cycloalkyl C_1-6alkyl group optionally having a substituent, R²and R³are the same or different and are each a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R⁴and R⁵are a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R⁶is a hydroxy group, R⁷and R⁸are the same or different and are each a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R⁹and R¹⁰are the same or different and are each a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R¹¹is a hydrogen atom or a hydroxy group, R¹²and R¹³are the same or different and are each a hydrogen atom or a C_1-6alkyl group optionally having a substituent, R¹⁴is a heteroaryl group optionally having a substituent, X is a nitrogen atom, Y is a methylene group optionally having a substituent or a carbonyl group, Z is a bond, R¹⁷is a hydrogen atom, m is 0, and n is 1 to 2.

In the azepane derivative represented by the formula (I) and the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt preferably includes an acid addition salt, and examples of the acid addition salt include (i) a salt with a mineral acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, (ii) a salt with an organic carboxylic acid such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid, maleic acid, or tartaric acid, or (iii) a salt with a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, or naphthalenesulfonic acid.

The azepane derivative represented by the formula (I) and the pharmaceutically acceptable salt thereof include a tautomer, or a stereoisomer such as a cis/trans isomer, a racemate, or an optical active material.

The azepane derivative represented by the formula (I) and the pharmaceutically acceptable salt thereof can also be present as a hydrate or a solvate. Accordingly, the compound of the present invention includes all crystal types and hydrates or solvates thereof.

Hereinafter, a reference is made of a method for producing the azepane derivative represented by the formula (I) and the pharmaceutically acceptable salt thereof.

(i) A production method in a case where in the formula (I), X represents a nitrogen atom, one of A or B represents NH, and the other represents CH₂.

(Method A) The compounds (f) and (g) of the present invention can be obtained by the method described below using a compound (a) as the starting material.

[Image Omitted]

(wherein L represents a methanesulfonyl group, a p toluenesulfonyl group, a trifluoromethanesulfonyl group, a 2-nitrobenzenesulfonyl group, or the like, and R¹to R¹¹and R¹⁷represent the same as those described above)

(First Step)

A compound (b) can be synthesized by reacting the raw material (a) with hydroxylamine hydrochloride, hydroxylamine sulfate, or the like in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; an alcohol such as methanol or ethanol; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; a protic solvent such as water or acetic acid; an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, or in a mixed solvent thereof, in the presence or absence of a base such as potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), lithium hydride, sodium hydride, or potassium hydride; an organic base such as trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; or an inorganic base such as lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or sodium acetate, at room temperature to heating under reflux for 1 to 24 hours.

(Second Step)

A compound (c) can be synthesized by reacting the compound (b) with the reagent represented by L-Cl or L₂O in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; or an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, in the presence of a base such as potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), lithium hydride, sodium hydride, or potassium hydride; an organic base such as trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; or an inorganic base such as lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide, at −78° C. to heating under reflux for 1 to 24 hours.

(Third Step)

Compounds (d) and (e) can be individually synthesized by reacting the compound (c) with a Brønsted acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid; or a Lewis acid such as a boron trifluoride-diethyl ether complex, aluminum chloride, iron (III) chloride, zinc chloride, or titanium (IV) chloride in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; an alcohol such as methanol or ethanol; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; a solvent such as water or acetic acid; an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, or in a mixed solvent thereof, or in the absence of a solvent, at room temperature to heating under reflux for 1 to 72 hours.

(Fourth Step)

The compounds (f) and (g) of the present invention can be synthesized by reacting the compounds (d) and (e) with a reducing agent such as lithium aluminum hydride, a borane-tetrahydrofuran complex, or a borane-dimethyl sulfide complex, respectively, in an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme, at 0° C. to heating under reflux for 1 to 24 hours.

(Method B) The synthetic intermediates (d) and (e) described in Method A can also be synthesized from the compound (b) in one step as described below.

[Image Omitted]

(wherein R¹to R¹¹and R¹⁷represent the same as those described above.)

Compounds (d) and (e) can be individually synthesized by reacting the compound (b) in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; an alcohol such as methanol or ethanol; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; a solvent such as water or acetic acid; an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, or in a mixed solvent thereof, or in the absence of a solvent, in the presence or absence of an acid such as a Brønsted acid such as hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid, or a Lewis acid such as a boron trifluoride-diethyl ether complex, aluminum chloride, iron chloride, or zinc chloride, at room temperature to heating under reflux for 1 to 72 hours.

(Method C) The synthetic intermediates (d) and (e) described in Method A can also be synthesized from the compound (a) in one step by using sodium azide or trimethylsilyl azide as described below.

[Image Omitted]

(wherein R¹to R¹¹and R¹⁷represent the same as those described above.)

Compounds (d) and (e) can be individually synthesized by reacting the raw material (a) with sodium azide (NaN₃) or trimethylsilyl azide (TMSN₃) in the presence or absence of a Brønsted acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, polyphosphoric acid, an Eaton reagent, methanesulfonic acid, or p-toluenesulfonic acid; or a Lewis acid such as a boron trifluoride-diethyl ether complex, aluminum chloride, iron chloride, zinc chloride, or titanium (IV) chloride, in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; an alcohol such as methanol or ethanol; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; a solvent such as water; an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, or in a mixed solvent thereof, or in the absence of a solvent, at 0° C. to heating under reflux for 1 to 24 hours.

(ii) A production method in a case where in the formula (I), X represents a nitrogen atom, one of A or B represents N—R¹⁶(R¹⁶is a C_1-10alkyl group, an aralkyl group (the number of carbon atoms in the aryl moiety is C_6-10, and the number of carbon atoms in the alkylene moiety is C_1-5), or a heteroarylalkyl group optionally having a substituent, and the other represents a carbonyl group.

(Method D) The compounds (d-1) and (e-1) of the present invention can be individually synthesized by the method described below using a compound (a) as the starting material.

[Image Omitted]

(wherein R¹⁶represents a C_1-10alkyl group, an aralkyl group (the number of carbon atoms in the aryl moiety is C_6-10, and the number of carbon atoms in the alkylene moiety is C_1-6), or a heteroarylalkyl group optionally having a substituent, and R¹to R¹¹and R¹⁷represent the same as those described above.)

The compounds (d-1) and (e-1) of the present invention can be individually synthesized by reacting the raw material (a) with an azide represented by R¹⁶—N₃in the presence or absence of a Brønsted acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, polyphosphoric acid, an Eaton reagent, methanesulfonic acid, or p-toluenesulfonic acid; or a Lewis acid such as a boron trifluoride-diethyl ether complex, aluminum chloride, iron chloride, zinc chloride, or titanium (IV) chloride, in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; an alcohol such as methanol or ethanol; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; a solvent such as water; an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, or in a mixed solvent thereof, or in the absence of a solvent, at 0° C. to heating under reflux for 1 to 24 hours.

(iii) A production method in a case where in the formula (I), X represents a nitrogen atom, either A or B represents a carbonyl group, m represents 0, and Z represents a bond

(Method E) The compound (h) of the present invention can be synthesized by an alkylation reaction of the compound (d) or (e) (both are collectively referred to as (d-e)) obtained in the above (i).

[Image Omitted]

(wherein L′ represents a leaving group such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or halogen, and R′ to R¹⁴, R¹⁷, and n represent the same as those described above. * represents a bond.)

The compound (h) of the present invention can be synthesized by reacting the compound (d) or (e) (both are collectively referred to as (d-e)) obtained in the above (i) with an alkylating agent represented by (r-1) in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; an alcohol such as methanol or ethanol; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; or an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, in the presence of a base such as potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), lithium hydride, sodium hydride, or potassium hydride; an organic base such as trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; or an inorganic base such as sodium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide, in the presence or absence of potassium iodide or sodium iodide, at room temperature to heating under reflux for 1 to 24 hours.

(iv) A production method in a case where in the formula (I), X represents a nitrogen atom, Y represents a carbonyl group or a thiocarbonyl group, Z represents a bond, an ethenylene group optionally having a substituent, or an ethynylene group, and m represents 1,

(Method F) The compounds (i) and (j) of the present invention can be obtained by a reaction of the compound (f) or (g) (both are collectively referred to as (f-g)) of the present invention obtained in the above (i) with (r-2) or (r-3).

[Image Omitted]

(wherein one of Ah or Bh represents NH, the other represents CH₂, hal represents a halogen atom, Z represents a bond and an ethenylene group optionally having a substituent or an ethynylene group, and n, R¹to R¹⁴, and R¹⁷represent the same as those described above. * represents a bond.)

(First Step)

The compound (i) of the present invention can be synthesized by reacting the carboxylic acid represented by (r-2) or the acid halide represented by (r-3) with the compound (f) or (g) (both are collectively referred to as (f-g)) of the present invention obtained in the above (i) in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an alcohol such as methanol or ethanol; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; or an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, in the presence of an organic base such as N,N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine; or an inorganic base such as potassium carbonate or lithium carbonate, in the presence or absence of a condensing agent such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), N,N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC), or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM), at 0° C. to heating under reflux for 1 to 12 hours.

(Second Step)

The compound (i) of the present invention can be converted into the compound (j) of the present invention by a reaction in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; or an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin, using a sulfurizing agent such as diphosphorus pentasulfide, Lawesson's reagent, Davy reagent, Japanese reagent, or Belleau's reagent, at 0° C. to heating under reflux for 1 to 12 hours.

(v) A production method in a case where in the formula (I), X represents a nitrogen atom, m represents 0, and Z represents a bond

(Method G) The compound (k) of the present invention can be obtained by a reductive amination reaction of the compound (f) or (g) (both are collectively referred to as (f-g)) of the present invention obtained in the above (i) with an aldehyde (r-4).

[Image Omitted]

(wherein one of Ah or Bh represents NH, the other represents CH₂, and R¹to R¹⁴, R¹⁷, and n represent the same as those described above. * represents a bond.) The compound (k) of the present invention can be synthesized by reacting the compound (f) or (g) (both are collectively referred to as (f-g)) of the present invention obtained in the above (i) with the aldehyde represented by (r-4) in a solvent such as an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an alcohol such as methanol or ethanol; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; an aprotic polar solvent such as acetonitrile, N N-dimethylformamide, or dimethylsulfoxide; or acetic acid, or a mixed solvent thereof, in the presence of a hydride reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium tri(sec-butyl)borohydride, or potassium tri(sec-butyl)borohydride, at 0° C. to heating under reflux for 1 to 12 hours.

(Method H) The compound (k) of the present invention can be obtained by an S_N2 reaction of the compound (f) or (g) (both are collectively referred to as (f-g)) of the present invention obtained in the above (i) with an alkylating agent (r-1).

[Image Omitted]

(wherein one of Ah or Bh represents NH, the other represents CH, and R¹to R¹⁴, R¹⁷, L′, and n represent the same as those described above. * represents a bond.)

The compound (k) of the present invention can be synthesized by reacting the compound (f) or (g) (both are collectively referred to as (f-g)) of the present invention obtained in the above (i) with an alkylating agent represented by (r-1) in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; an alcohol such as methanol or ethanol; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, in the presence of a base such as potassium bis(trimethylsilyl)amide (KHMDS) or lithium diisopropylamide (LDA); an organic base such as trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxide, sodium ethoxide, or potassium tert-butoxide; or an inorganic base such as sodium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide, in the presence or absence of potassium iodide or sodium iodide, at room temperature to heating under reflux for 1 to 24 hours.

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

[Image Omitted]

(wherein R¹to R¹⁴and R¹⁷or n represent the same as those described above. * represents a bond.)

The compounds (k) of the present invention can be synthesized by reacting the compound (i) of the present invention obtained in the above (iv) with a reducing agent such as lithium aluminum hydride, a borane-tetrahydrofuran complex, or a borane-dimethyl sulfide complex, in an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme, at 0° C. to heating under reflux for 1 to 24 hours.

(J method) The compound (f¹-g¹) of the present invention can also be synthesized by a reduction reaction of the compound (d-1) or (e-1) (both are collectively referred to as (d¹-e¹)) of the present invention obtained in the above (ii), when one of A or B represents N—R¹⁶(R¹⁶represents a C_1-10alkyl group optionally having a substituent, an aralkyl group (the number of carbon atoms in the aryl moiety is C_6-10, and the number of carbon atoms in the alkylene moiety is C_1-5), or a heteroaryl group,) and the other represents CH₂.

[Image Omitted]

(wherein R¹to R¹¹R¹⁶, and R¹⁷represent the same as those described above.)

The compound (f¹-g¹) of the present invention can be synthesized by performing the same reaction as in the fourth step of (Method A) on the compound (d-1) or (e-1) (both are collectively referred to as (d¹-e¹)) of the present invention obtained in the above (ii).

(vi) A production method in a case where in the formula (I), X represents a nitrogen atom, Y represents a carbonyl group, Z represents NR¹⁵or an oxygen atom, and m represents 1.

(Method K) The compound (n) of the present invention can be obtained by the method described below using the compound (f) or (g) (both are collectively referred to as (f-g)) of the present invention obtained in the above (i).

[Image Omitted]

(wherein one of Ah or Bh represents NH, the other represents CH₂, Z represents NR¹⁵or an oxygen atom, R¹to R¹⁵, R¹⁷, L′, and n represent the same as those described above, and L⁻ represents the counter anion. * represents a bond.)

(First Step)

The compound of the present invention (1) can be synthesized by reacting the compound (f) or (g) (both are collectively referred to as (f-g)) of the present invention obtained in the above (i) with carbodiimidazole in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an alcohol such as methanol or ethanol; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; or an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, in the presence of an organic base such as N,N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine; or an inorganic base such as potassium carbonate or lithium carbonate at 0° C. to heating under reflux for 1 to 12 hours.

(Second Step)

The compound (m) of the present invention can be synthesized by reacting the compound (1) of the present invention with a methylating agent such as methyl iodide, dimethyl sulfate, trifluoromethanesulfonylmethane, or a Meerwein reagent in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an alcohol such as methanol or ethanol; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; or an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, in the presence or absence of an organic base such as N,N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine; or an inorganic base such as potassium carbonate or lithium carbonate, at 0° C. to heating under reflux for 12 to 48 hours.

(Third Step)

The compound (n) of the present invention can be synthesized by reacting the compound (m) of the present invention with an amine represented by (r-5) or an alcohol represented by (r-6) in an aromatic hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; or an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide, in the presence of an organic base such as N,N-dimethylaminopyridine, trimethylamine, triethylamine, N,N-diisopropylethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine; or an inorganic base such as potassium carbonate or lithium carbonate, at 0° C. to heating under reflux for 1 to 12 hours.

(vii) A production method in a case where in the formula (I), R⁶represents a hydroxy group

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

[Image Omitted]

(wherein R^6arepresents a C_1-10alkoxy group, and R¹to R¹⁴, R¹⁷, n, m, Y, and Z represent the same as those described above. * represents a bond.)

The compound (p) of the present invention can be synthesized by reacting the compound (o) of the present invention obtained in the above (i) to (vi) with boron tribromide, trimethylsilyl iodide, hydrogen bromide, pyridinium hydrochloride, or the like in a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; a protic organic solvent such as acetic acid; or an aprotic polar solvent such as acetonitrile or ethyl acetate, or in the absence of a solvent, at −30 to 180° C. for 30 minutes to 24 hours, or reacting 1-propanethiol, 1-dodecanethiol, or the like in an aprotic polar solvent such as N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, or dimethylsulfoxide, in the presence of an organic base such as potassium tert-butoxide or sodium tert-butoxide, at 100° C. to 180° C. for 30 minutes to 24 hours.

(viii) A production method in a case where in the formula (I), X represents N-oxide

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

[Image Omitted]

(wherein R¹to R¹⁴, R¹⁷, n, m, Y, and Z represent the same as those described above. * represents a bond.)

The compound (s) of the present invention can be synthesized by reacting the compound (q) of the present invention obtained in the above (i) to (vii) with 1 to 2 equivalents of an oxidizing agent such as a hydrogen peroxide (H₂O₂) aqueous solution or m-chloroperbenzoic acid (mCPBA), in a halogenated hydrocarbon solvent such as dichloromethane, chloroform, or carbon tetrachloride, at 0° C. to room temperature for 30 minutes to 24 hours.

The compound obtained in each of the steps can be purified by, for example, silica gel column chromatography, if necessary.

Furthermore, if necessary, an acid addition salt can be formed by a normal method. For example, this formation is performed at room temperature or by appropriately heating the compound (I) of the present invention in an organic solvent such as ethyl acetate; an alcohol such as methanol or ethanol; or a polar solvent such as water, in the presence of a mineral acid such as hydrochloric acid, sulfuric acid, or phosphoric acid; an organic carboxylic acid such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid, or maleic acid; an organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, or naphthalenesulfonic acid; or the like.

The azepane derivative represented by the formula (I) and the pharmaceutically acceptable salt thereof can be formulated into a composition together with a pharmaceutically acceptable carrier for parenteral administration, oral administration in a solid or liquid form, or the like to humans. In addition, the azepane derivative represented by the formula (I) and the pharmaceutically acceptable salt thereof can be used in combination with another analgesic.

The solid formulation for oral administration includes a capsule, a tablet, a pill, a powder, and a granule. In preparation of the solid formulation, an excipient, a disintegrator, a binder, a lubricant, a pigment, or the like can be used. Here, the excipient includes lactose, D-mannitol, crystalline cellulose, or glucose. The disintegrator includes starch or carboxymethylcellulose calcium (CMC-Ca). The lubricant includes magnesium stearate or talc. The binder includes hydroxypropyl cellulose (HPC), gelatin, or polyvinyl pyrrolidone (PVP). In the case of capsule, tablet, or pill, a buffer may be further used. The tablet and pill may be provided with an enteric coating.

The form of the composition of the present invention for injection includes a pharmaceutically acceptable sterile water, non-aqueous solution, suspension, or emulsion form. Examples of a suitable non-aqueous carrier, a diluent, a solvent or a vehicle include propylene glycol, polyethylene glycol, a vegetable oil such as an olive oil, or an injectable organic ester such as ethyl oleate. Such compositions may also contain an auxiliary such as an antiseptic, a wetting agent, an emulsifier, a soothing agent, a buffering agent, a preservative, or a dispersing agent.

These compositions can be sterilized, for example, by filtration through a bacteria-retaining filter, or by mixing a sterilizing agent, or a sterilizing agent in the form of a sterile solid composition capable of dissolving in some other sterilizable and injectable media just prior to use.

In preparation for ophthalmic administration, in addition to the compound of the present invention, a solubilizing auxiliary, a preservative, an isotonizing agent, a thickener, or the like can be preferably added.

A liquid formulation for oral administration includes an inert diluent commonly used by those skilled in the art, e.g., a water-containing pharmaceutically acceptable emulsion, solution, suspension, syrup, or elixir. In addition to such inert diluents, the composition can also include an auxiliary such as a wetting agent, an emulsifying agent, or a suspension; and a sweetening agent, a flavoring agent, or a perfuming agent.

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

In an adult, usually, the dosage of the azepane derivative represented by the formula (I), a tautomer of the compound, a stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient is 0.01 μg to 1 g/day, preferably 0.0001 to 200 mg/day in injection, and 0.1 μg to 10 g/day, preferably 0.001 to 2000 mg/day in oral administration. However, the dosage can be increased or decreased depending on age, symptom, or the like. If desired, the daily dose can be divided in 2 or 4 doses for administration.

Examples of the diseases and symptoms related to κ opioid receptors include cardiovascular system disorders, digestive system diseases, blood system diseases, respiratory system diseases, liver diseases, nervous system disorders, urinary system disorders, pain, cough, pruritus, and ischemic brain diseases. The compound of the present invention is effective for treatment, improvement, and prevention of these diseases and symptoms because of its κ opioid receptor selectivity and strong agonist activity for κ opioid receptors.

EXAMPLES

Next, a description is made of the present invention in more detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto.

Reference Example 1
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-yl trifluoromethanesulfonate

[Image Omitted]

In N,N-dimethylformamide (250 mL) were dissolved (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthrene-6(7H)-one (synthesized by the method described in Tetrahedron Lett., 2010, 51, 2359) (17.87 g, 50 mmol), N-phenylbis(trifluoromethanesulfonimide) (35.73 g, 100 mmol), and potassium carbonate (20.73 g, 150 mmol), followed by stirring at room temperature for 18 hours. To the reaction solution, chloroform (750 mL) was added, and the resultant solution was washed with a 1 M aqueous sodium hydroxide solution and water, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was recrystallized from ethyl acetate to yield the title compound (21.31 g) as a white crystal. The recrystallization mother liquor (2.63 g) was purified by silica gel column chromatography (0 to 10% methanol/chloroform), followed by recrystallization from a mixed solvent of ethyl acetate and heptane to yield the title compound 4 (1.245 g, 92% in total) as a white crystal.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.09-0.18 (m, 2H), 0.52-0.59 (m, 2H), 0.81-0.93 (m, 1H), 1.65-1.87 (m, 3H), 2.03-2.14 (m, 2H), 2.20 (ddd, J=5, 13, 13 Hz, 1H), 2.39 (d, J=7 Hz, 2H), 2.66-2.73 (m, 1H), 2.77 (ddd, J=8, 13, 14 Hz, 1H), 2.88 (dd, J=7, 19 Hz, 1H), 3.01-3.18 (m, 3H), 3.52 (dd, J=2, 14 Hz, 1H), 3.80 (s, 3H), 4.75 (s, 1H), 6.85 (d, J=8 Hz, 1H), 7.05 (d, J=8 Hz, 1H).

Reference Example 2
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one

[Image Omitted]

To the compound (22.55 g, 46 mmol) obtained in Reference Example 1, 1,3-bis(diphenylphosphino)propane (1.90 g, 4.6 mmol), and palladium acetate (1.03 g, 4.6 mmol) dissolved in N,N-dimethylformamide (230 mL) were added formic acid (5.22 mL, 138 mmol) and triethylamine (32.1 mL, 230 mmol), followed by stirring at 80° C. for 30 minutes. To the reaction solution, a 1 M aqueous sodium hydroxide solution was added, then the resultant solution was extracted three times with chloroform, and the combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0 to 10% methanol/chloroform) to yield the title compound (13.95 g, 89% in total) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.09-0.18 (m, 2H), 0.50-0.59 (m, 2H), 0.80-0.93 (m, 1H), 1.13-1.27 (m, 1H), 1.72-1.93 (m, 2H), 2.02-2.22 (m, 3H), 2.40 (d, J=7 Hz, 2H), 2.55-2.63 (m, 1H), 2.70-2.86 (m, 3H), 3.01-3.17 (m, 3H), 3.77 (s, 3H), 4.87 (br s, 1H), 6.69 (d, J=9 Hz, 1H), 6.80 (s, 1H), 6.99 (d, J=9 Hz, 1H).

Reference Example 3
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one oxime

[Image Omitted]

To a mixed solution of the compound (4.51 g, 13.2 mmol) obtained in Reference Example 2 in ethanol (111 mL) and water (28 mL) was added hydroxyamine hydrochloride (1.84 g, 26.4 mmol), followed by heating under reflux for 4 hours. After allowed to cool, the reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and then washed once with a saturated aqueous sodium bicarbonate solution and twice with a saturated saline solution. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (2 to 25% methanol/ethyl acetate) to yield the title compound (4.1 g, 87%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.17 (m, 2H), 0.48-0.58 (m, 2H), 0.79-0.90 (m, 1H), 1.10-1.21 (m, 1H), 1.50-1.67 (m, 2.3H), 2.07-2.26 (m, 2.7H), 2.33-2.42 (m, 2.7H), 2.53-2.81 (m, 3.3H), 2.98-3.14 (m, 2.3H), 3.73 (d, J=16 Hz, 0.7H), 3.76 (s, 0.9H), 3.77 (s, 2.1H), 4.80 (br s, 1H), 6.67-6.71 (m, 1H), 6.84 (d, J=3 Hz, 0.3H), 6.92-7.02 (m, 2H), 7.10 (d, J=3 Hz, 0.7H).

Example 1
Synthesis of mixture of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one (isomer A) and (5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepin-3(4H)-one (isomer B)

[Image Omitted]

To a solution of the compound (4.06 g, 11.4 mmol) obtained in Reference Example 3 in chloroform (120 mL) were added triethylamine (3.33 mL, 23.9 mmol) and p-toluenesulfonyl chloride (4.34 g, 22.8 mmol) under ice cooling, followed by stirring at room temperature for 18 hours. p-Toluenesulfonyl chloride (2.0 g, 10.5 mmol) was added, followed by further stirring at room temperature for 3 and a half hours. After allowed to cool, the reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and then washed twice with a saturated aqueous sodium bicarbonate solution and once with a saturated saline solution. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. To a solution of the obtained concentrated residue in tetrahydrofuran (80 mL) was added 2 M hydrochloric acid (40 mL), followed by stirring at room temperature for 2 hours. After tetrahydrofuran was distilled off under reduced pressure, the resultant solution was made basic with potassium carbonate, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0 to 5% methanol/chloroform) to yield a mixture of the title isomers A and B (2.95 g, 73%) as a slightly brown amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.19 (m, 2H), 0.46-0.57 (m, 2H), 0.77-0.90 (m, 1H), 0.93-1.01 (m, 0.3H), 1.11-1.18 (m, 0.7H), 1.50-1.61 (m, 1H), 1.68-1.84 (m, 1H), 1.98-2.19 (m, 2.3H), 2.30-2.45 (m, 2H), 2.54-2.67 (m, 1.7H), 2.73-3.23 (m, 4H), 3.45-3.53 (m, 1H), 3.76 (s, 0.9H), 3.79 (s, 2.1H), 3.82-3.89 (m, 0.7H), 4.06-4.15 (m, 0.3H), 5.99 (br s, 0.7H), 6.20 (br s, 0.3H), 6.52 (d, J=3 Hz, 0.3H), 6.68-6.72 (m, 1H), 6.96 (d, J=8 Hz, 0.7H), 7.01 (d, J=8 Hz, 0.3H), 7.14-7.16 (m, 0.7H).

Example 2
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol (isomer C) and (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepin-5a(1H)-ol (isomer D)

[Image Omitted]

To a solution of the mixture of isomers A and B (662 mg, 1.86 mmol) obtained in Example 1 in tetrahydrofuran (8 mL) was added a 0.91 M borane-tetrahydrofuran complex-tetrahydrofuran solution (20.4 mL, 18.6 mmol), followed by heating under reflux for 14 hours. After allowed to cool, the reaction mixture was concentrated under reduced pressure. To the concentrated residue, 6 M hydrochloric acid (12 mL) was added, followed by heating under reflux for 16 hours. After allowed to cool, potassium carbonate was added to make the reaction mixture basic, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 10% methanol/chloroform) to individually yield the title isomer C (283 mg, 29%) and isomer D (236 mg, 24%) as colorless solids.

(Isomer C)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.15 (m, 2H), 0.46-0.55 (m, 2H), 0.80-0.87 (m, 1H), 1.04-1.11 (m, 1H), 1.57 (ddd, J=4, 4, 14 Hz, 1H), 1.68-1.79 (m, 1H), 1.96-2.08 (m, 3H), 2.27-2.39 (m, 3H), 2.49-2.56 (m, 1H), 2.76-2.87 (m, 2H), 2.89-3.03 (m, 4H), 3.05-3.14 (m, 1H), 3.78 (s, 3H), 4.51 (br s, 1H), 6.69-6.74 (m, 2H), 7.02 (d, J=8 Hz, 1H).

(Isomer D)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.16 (m, 2H), 0.45-0.56 (m, 2H), 0.77-0.91 (m, 1H), 0.94-1.01 (m, 1H), 1.46-1.72 (m, 3H), 1.91 (ddd, J=5, 12, 12 Hz, 1H), 1, 98 (ddd, J=3, 12, 12 Hz, 1H), 2.19-2.32 (m, 1H), 2.34 (dd, J=7, 13 Hz, 1H), 2.38 (dd, J=6, 13 Hz, 1H), 2.53-2.61 (m, 1H), 2.70 (ddd, J=7, 9, 14 Hz, 1H), 2.80 (dd, J=6, 18 Hz, 1H), 2.91 (d, J=6 Hz, 1H), 2.94-3.02 (m, 1H), 2.98 (d, J=18 Hz, 1H), 3.14 (d, J=15 Hz, 1H), 3.18 (d, J=15 Hz, 1H), 3.78 (s, 3H), 4.65 (br s, 1H), 6.73 (dd, J=2, 8 Hz, 1H), 6.75 (d, J=2 Hz, 1H), 7.03 (d, J=8 Hz, 1H).

Example 3
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol (compound E) and 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)ethan-1-one (compound F)

[Image Omitted]

To a solution of the isomer C (2.38 g, 6.9 mmol) obtained in Example 2 in N,N-dimethylacetamide (70 mL) were added 1-dodecanethiol (16.6 mL, 69 mmol) and potassium tert-butoxide (7.80 g, 69 mmol), followed by stirring at 160° C. for 4 hours. After allowed to cool, the reaction solution was added to 1 M hydrochloric acid under ice cooling, followed by washing with heptane. Then, potassium carbonate was added to make the resultant solution basic, followed by extraction three times with a mixed solvent of chloroform/isopropanol (3/1). The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 50% methanol/chloroform) to individually yield the title compound E (1.74 g, 76%) and compound F (606 mg, 24%) as colorless amorphous forms.

(Compound E)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.14 (m, 2H), 0.47-0.55 (m, 2H), 0.75-0.88 (m, 1H), 1.04-1.14 (m, 1H), 1.47-1.58 (m, 1H), 1.70-1.82 (m, 1H), 1.92-2.14 (m, 3H), 2.15-2.27 (m, 1H), 2.34 (d, J=7 Hz, 2H), 2.48-2.59 (m, 1H), 2.67-2.86 (m, 3H), 2.89 (d, J=6 Hz, 1H), 2.97 (d, J=18 Hz, 1H), 3.07 (ddd, J=4, 4, 14 Hz, 1H), 3.18 (ddd, J=3, 13, 13 Hz, 1H), 4.54 (br s, 1H), 6.56 (d, J=2 Hz, 1H), 6.63 (dd, J=2, 8 Hz, 1H), 6.92 (d, J=8 Hz, 1H).

(Compound F)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.18 (m, 2H), 0.45-0.58 (m, 2H), 0.75-2.41 (m, 13H), 2.49-3.07 (m, 5H), 3.22-3.98 (m, 2.3H), 4.35 (dd, J=5, 15 Hz, 0.7H), 6.45 (dd, J=3, 8 Hz, 0.3H), 6.60 (d, J=3 Hz, 0.3H), 6.69 (dd, J=3, 8 Hz, 0.7H), 6.86 (d, J=8 Hz, 0.3H), 6.95 (d, J=8 Hz, 0.7H), 7.00 (d, J=2 Hz, 0.7H).

Example 4
Synthesis of ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl) (3-hydroxypyridin-2-yl)methanone

[Image Omitted]

To a solution of the isomer C (12.2 mg, 0.036 mmol) obtained in Example 2 in N,N-dimethylformamide (1 mL) were added 3-hydroxypicolinic acid (14.9 mg, 0.11 mmol), N,N-dimethyl-4 aminopyridine (2.2 mg, 0.018 mmol), N,N-diisopropylethylamine (18.6 μL, 0.11 mmol), 1-hydroxybenzotriazole monohydrate (16.4 mg, 0.11 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (20.5 mg, 0.11 mmol), followed by stirring at room temperature for 3 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction once with ethyl acetate. The organic layer was washed with saturated saline and water, dried over sodium sulfate, and then concentrated under reduced pressure. To a solution of the obtained crude product (6 mg, 0.013 mmol) in chloroform (1 mL) was added a 1 M boron tribromide-dichloromethane solution (65 μL, 0.065 mmol) under ice cooling, followed by stirring at room temperature for 25 minutes. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:methanol=5:1) to yield the title compound (4.5 mg, 28%) as a colorless solid.

¹H-NMR (400 MHz, CD₃OD) δ (ppm): 0.13-0.22 (m, 2H), 0.50-0.61 (m, 2H), 0.84-0.96 (m, 1H), 0.98-1.05 (m, 0.5H), 1.09-1.13 (m, 0.5H), 1.49-1.56 (m, 0.5H), 1.66-1.73 (m, 0.5H), 1.93-2.23 (m, 4H), 2.25-2.36 (m, 0.5H), 2.38-2.59 (m, 2.5H), 2.60-2.69 (m, 1H), 2.78-2.89 (m, 1H), 2.98-3.09 (m, 2H), 3.31-3.45 (m, 1.5H), 3.53-3.67 (m, 1H), 3.74-3.83 (m, 0.5H), 3.92-4.02 (m, 0.5H), 4.07-4.15 (m, 0.5H), 6.42 (d, J=2 Hz, 0.5H), 6.58 (dd, J=2, 8 Hz, 0.5H), 6.62 (dd, J=2, 8 Hz, 0.5H), 6.68 (d, J=2 Hz, 0.5H), 6.96 (d, J=8 Hz, 0.5H), 6.98 (d, J=8 Hz, 0.5H), 7.06-7.19 (m, 2H), 7.69 (d, J=4 Hz, 0.5H), 7.74 (d, J=4 Hz, 0.5H).

Example 5
Synthesis of ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl) (pyrimidin-2-yl)methanone

[Image Omitted]

To a solution of the isomer C (15 mg, 0.044 mmol) obtained in Example 2 and pyrimidine-2-carboxylic acid (8.2 mg, 0.066 mmol) in N,N-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (22 μL, 0.13 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (20 mg, 0.053 mmol), followed by stirring at room temperature for 2 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 1 to 10% methanol/chloroform) to yield the title compound (16 mg, 80%) as a yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.18 (m, 2H), 0.41-0.58 (m, 2H), 0.73-0.91 (m, 1H), 0.98-1.16 (m, 1H), 1.21-1.80 (m, 1H), 1.84-2.12 (m, 4H), 2.16-2.63 (m, 4H), 2.71-3.07 (m, 3H), 3.22-3.52 (m, 2H), 3.60-3.83 (m, 3.5H), 3.86-3.93 (m, 1H), 4.24-4.34 (m, 0.5H), 6.36 (d, J=2 Hz, 0.5H), 6.65-6.78 (m, 1.5H), 6.99-7.08 (m, 1H), 7.26-7.35 (m, 1H), 8.73-8.82 (m, 2H).

Example 6
Synthesis of ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl) (pyrimidin-2-yl) methanone

[Image Omitted]

To a solution of the compound (16 mg, 0.035 mmol) in chloroform (1 mL) obtained in Example 5 was added a 1 M boron tribromide-dichloromethane solution (211 μL, 0.21 mmol) under ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added under ice cooling, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (11 mg, 71%) as a pale yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.18 (m, 2H), 0.38-0.58 (m, 2H), 0.71-0.94 (m, 1H), 0.96-1.18 (m, 1H), 1.19-1.80 (m, 1H), 1.83-2.12 (m, 3.5H), 2.14-2.66 (m, 4.5H), 2.67-3.04 (m, 3H), 3.24-3.52 (m, 2H), 3.69-3.82 (m, 0.5H), 3.83-3.93 (m, 1H), 4.23-4.38 (m, 0.5H), 6.33 (d, J=3 Hz, 0.5H), 6.67-6.69 (m, 1H), 6.78-6.84 (m, 0.5H), 6.91-7.00 (m, 1H), 7.28-7.34 (m, 1H), 8.75-8.83 (m, 2H).

Example 7
Synthesis of ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl) (oxazol-2-yl)methanone

[Image Omitted]

To the isomer C (13 mg, 0.038 mmol) obtained in Example 2 dissolved in N,N-dimethylformamide (1.0 mL) were added oxazole-2-carboxylic acid (7.0 mg, 0.062 mmol), N,N-diisopropylethylamine (33 μL, 0.19 mmol), 1-hydroxybenzotriazole monohydrate (10 mg, 0.076 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14 mg, 0.075 mmol), and N,N-dimethyl-4-aminopyridine (1.0 mg, 0.0080 mmol), followed by stirring at room temperature for 22 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added under ice cooling to stop the reaction, followed by extraction with ethyl acetate. The combined extracts were washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0 to 10% methanol/chloroform) to yield the title compound (12 mg, 74%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.17 (m, 2H), 0.45-0.56 (m, 2H), 0.76-0.93 (m, 1H), 1.03-1.15 (m, 1H), 1.64-1.74 (m, 1H), 1.93-2.14 (m, 3.6H), 2.21 (dd, J=5, 16 Hz, 0.4H), 2.28-2.68 (m, 4H), 2.83 (ddd, J=6, 12, 18 Hz, 1H), 2.91-3.05 (m, 2H), 3.43 (dd, J=12, 12 Hz, 0.4H), 3.64 (s, 1.8H), 3.67-3.84 (m, 1H), 3.79 (s, 1.2H), 3.96-4.04 (m, 0.6H), 4.06-4.23 (m, 2H), 6.46-6.55 (m, 0.6H) 6.60-6.67 (m, 0.6H), 6.69-6.74 (m, 0.8H), 7.00 (d, J=7 Hz, 0.6H), 7.02 (d, J=8 Hz, 0.4H), 7.20 (s, 0.4H), 7.22 (s, 0.6H), 7.68 (s, 0.6H), 7.71 (s, 0.4H).

Example 8
Synthesis of ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl) (oxazol-2-yl) methanone

[Image Omitted]

The title compound was obtained from the compound obtained in Example 7 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.17 (m, 2H), 0.43-0.57 (m, 2H), 0.73-0.93 (m, 1H), 1.04-1.09 (m, 0.4H), 1.13-1.19 (m, 0.6H), 1.64-1.76 (m, 1H), 1.93-2.14 (m, 4H), 2.27-2.48 (m, 3H), 2.49-2.62 (m, 1H), 2.83 (dd, J=6, 9 Hz, 0.6H), 2.78 (dd, J=6, 9 Hz, 0.4H), 2.89-3.05 (m, 2H), 3.40 (dd, J=12, 15 Hz, 0.6H), 3.72-3.81 (m, 0.8H), 3.98 (ddd, J=4, 4, 14 Hz, 0.6H), 4.03-4.21 (m, 0.8H), 4.22-4.29 (m, 0.6H), 4.31-4.40 (m, 0.6H), 6.51 (d, J=2 Hz, 0.4H), 6.57 (dd, J=2, 8 Hz, 0.4H), 6.70 (dd, J=2, 8 Hz, 0.6H), 6.93 (d, J=8 Hz, 0.4H), 6.97 (d, J=8 Hz, 0.6H), 7.00 (d, J=2 Hz, 0.6H), 7.22 (s, 0.4H), 7.24 (s, 0.6H), 7.71 (s, 0.4H), 7.77 (s, 0.6H).

Example 9
Synthesis of ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl) (pyridin-3-yl) methanone

[Image Omitted]

To a solution of the isomer C (9.5 mg, 0.029 mmol) obtained in Example 2 in tetrahydrofuran (1 mL) were added triethylamine (12.1 μL, 0.087 mmol) and nicotinic acid chloride hydrochloride (15.4 mg, 0.087 mmol), followed by stirring at room temperature for 30 minutes. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:methanol=10:1) to yield the title compound (12.8 mg, 99%) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.15 (m, 2H), 0.48-0.55 (m, 2H), 0.76-0.90 (m, 1H), 0.97-1.02 (m, 0.7H), 1.12-1.16 (m, 0.3H), 1.49 (ddd, J=4, 4, 15 Hz, 0.3H), 1.68-1.96 (m, 2.7H), 2.02-2.12 (m, 2H), 2.20-2.48 (m, 2.7H), 2.50-2.60 (m, 1H), 2.67-2.81 (m, 1H), 2.82-2.87 (m, 0.3H), 2.88-2.95 (m, 1H), 2.96-3.04 (m, 1H), 3.23-3.32 (m, 0.7H), 3.47 (s, 2.1H), 3.49-3.54 (m, 1.3H), 3.60-3.69 (m, 0.7H), 3.71-3.79 (m, 0.3H), 3.80 (s, 0.9H), 3.95-4.03 (m, 0.7H), 4.14-4.21 (m, 0.3H), 4.53 (br s, 1H), 6.20 (d, J=3 Hz, 0.7H), 6.70 (dd, J=3, 8 Hz, 0.7H), 6.72-6.77 (m, 0.6H), 7.03 (d, J=8 Hz, 0.7H), 7.05 (d, J=8 Hz, 0.3H), 7.15-7.25 (m, 1.4H), 7.28-7.32 (m, 0.3H), 7.71 (ddd, J=2, 2, 8 Hz, 0.3H), 8.27-8.29 (m, 0.7H), 8.58-8.61 (m, 1.3H).

Example 10
Synthesis of ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl) (pyridin-3-yl)methanone

[Image Omitted]

The title compound was obtained from the compound obtained in Example 9 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.16 (m, 2H), 0.47-0.55 (m, 2H), 0.76-0.86 (m, 1H), 0.97-1.04 (m, 0.7H), 1.13-1.18 (m, 0.3H), 1.49 (ddd, J=3, 3, 15 Hz, 0.3H), 1.69-1.77 (m, 1.4H), 1.88-2.16 (m, 3.3H), 2.20-2.41 (m, 2.7H), 2.49-2.59 (m, 1H), 2.70-2.87 (m, 1.3H), 2.87-2.94 (m, 1H), 2.95-3.04 (m, 1H), 3.25-3.33 (m, 0.7H), 3.38-3.47 (m, 1.3H), 3.61-3.80 (m, 1H), 4.05-4.11 (m, 1H), 4.58 (br s, 1H), 6.19 (d, J=2 Hz, 0.7H), 6.67 (dd, J=2, 8 Hz, 0.7H), 6.68-6.70 (m, 0.3H), 6.85 (d, J=2 Hz, 0.3H), 6.96 (d, J=8 Hz, 0.7H), 6.97 (d, J=8 Hz, 0.3H), 7.29-7.34 (m, 1H), 7.41 (ddd, J=2, 2, 8 Hz, 0.7H), 7.73 (ddd, J=2, 2, 8 Hz, 0.3H), 8.01 (d, J=1 Hz, 0.7 Hz), 8.50 (dd, J=1, 5 Hz, 0.7H), 8.59-8.62 (m, 0.6H).

Example 11
Synthesis of ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl) (imidazo[1,2-a]pyrimidin-3-yl)methanone

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and imidazo[1,2-a]pyridine-3-carboxylic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.19 (m, 2H), 0.44-0.61 (m, 2H), 0.76-0.93 (m, 1H), 1.02-1.19 (m, 1H), 1.58-1.78 (m, 2H), 1.90-2.14 (m, 3H), 2.24-2.44 (m, 3H), 2.47-2.59 (m, 1H), 2.81-3.08 (m, 4H), 3.39-3.56 (m, 1H), 3.73-3.87 (m, 1H), 3.91-4.05 (m, 1H), 4.70-4.93 (m, 1H), 6.38-6.50 (m, 1H), 6.59 (s, 1H), 6.86-7.02 (m, 2H), 7.68 (s, 1H), 8.26-8.39 (m, 1H), 8.61 (s, 1H).

Example 12
Synthesis of (5aS,6R,11bS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

To a solution of the isomer C (5 mg, 0.015 mmol) obtained in Example 2 and benzaldehyde (5 μL, 0.045 mmol) in dichloromethane (0.5 mL) was added sodium triacetoxyborohydride (13 mg, 0.06 mmol) under ice cooling, followed by stirring at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, water, and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=90:10) to yield the title compound (5 mg, 77%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.03 (d, J=13 Hz, 1H), 1.45-1.55 (m, 1H), 1.80-1.90 (m, 2H), 1.99 (ddd, J=3, 11, 12 Hz, 1H), 2.10 (ddd, J=5, 13, 13 Hz, 1H), 2.30-2.70 (m, 6H), 2.75-2.90 (m, 2H), 2.90-3.00 (m, 2H), 3.00-3.10 (m, 1H), 3.54 (s, 2H), 3.68 (s, 3H), 4.80 (br s, 1H), 6.61 (d, J=2 Hz, 1H), 6.71 (dd, J=2, 8 Hz, 1H), 7.00-7.10 (m, 3H), 7.15-7.25 (m, 3H).

Example 13
Synthesis of (5aS,6R,11bS)-3-benzyl-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol dihydrochloride

[Image Omitted]

A free form of the title compound (3.4 mg) was obtained as a colorless amorphous form from the compound obtained in Example 12 according to the method described in Example 6. To the obtained free form dissolved in methanol (0.5 mL), a 1 M hydrochloric acid-diethyl ether solution (50 μL) was added, followed by concentration under reduced pressure. To the obtained concentrated residue, water (0.2 mL) was added, and the resultant solution was frozen, followed by freeze-drying, to yield the title compound (4.0 mg, 54%) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ (ppm): 0.40-0.60 (m, 2H), 0.70-1.00 (m, 4H), 1.00-1.15 (m, 1H), 1.20-1.45 (m, 2H), 1.80-2.70 (m, 4H), 2.80-3.00 (m, 1H), 3.00-3.60 (m, 6H), 3.60-3.90 (m, 2H), 4.10-4.50 (m, 2H), 6.61 (s, 1H), 6.77 (d, J=8 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 7.40-7.60 (m, 5H).

Example 14
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(pyridin-2-ylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and picolinaldehyde according to the method described in Example 12.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.17 (m, 2H), 0.44-0.56 (m, 2H), 0.78-0.91 (m, 1H), 1.01-1.09 (m, 1H), 1.51 (ddd, J=2, 5, 14 Hz, 1H), 1.81-1.97 (m, 2H), 1.98-2.03 (m, 1H), 2.10 (ddd, J=5, 13, 13 Hz, 1H), 2.34 (dd, J=6.13 Hz, 1H), 2.36 (dd, J=6, 13 Hz, 1H), 2.44-2.59 (m, 3H), 2.68 (ddd, J=4, 4, 13 Hz, 1H), 2.79-2.95 (m, 2H), 2.95 (d, J=6 Hz, 1H), 2.99 (d, J=18 Hz, 1H), 3.19 (ddd, J=2, 12, 14 Hz, 1H), 3.68 (s, 3H), 3.70 (d, J=14 Hz, 1H), 3.74 (d, J=14 Hz, 1H), 6.62 (d, J=2 Hz, 1H), 6.72 (dd, J=2, 8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 7.02-7.06 (m, 1H), 7.07 (ddd, J=1, 5, 7 Hz, 1H), 7.47 (ddd, J=2, 7, 7 Hz, 1H), 8.45 (ddd, J=1, 2, 5 Hz, 1H).

Example 15
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(pyridin-2-ylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 14 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.15 (m, 2H), 0.42-0.57 (m, 2H), 0.76-0.89 (m, 1H), 0.91-1.00 (m, 1H), 1.46 (ddd, J=2, 5, 14 Hz, 1H), 1.53 (ddd, J=2, 5, 16 Hz, 1H), 1.85 (ddd, J=3, 12, 14 Hz, 1H), 1.93-2.07 (m, 2H), 2.28-2.40 (m, 3H), 2.47-2.81 (m, 5H), 2.88 (d, J=6 Hz, 1H), 2.93 (d, J=18 Hz, 1H), 3.22 (ddd, J=1, 11, 13 Hz, 1H), 3.76 (s, 2H), 4.73 (br s, 1H), 6.25 (d, J=2 Hz, 1H), 6.56 (dd, J=2, 8 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 7.12 (ddd, J=1, 5, 8 Hz, 1H), 7.16-7.21 (m, 1H), 7.57 (ddd, J=2, 8, 8 Hz, 1H), 8.48 (ddd, J=1, 2, 5 Hz, 1H).

Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(pyridin-4-ylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and isonicotinaldehyde according to the method described in Example 12.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.17 (m, 2H), 0.45-0.56 (m, 2H), 0.78-0.91 (m, 1H), 1.02-1.10 (m, 1H), 1.49 (ddd, J=2, 5, 14 Hz, 1H), 1.77-1.84 (m, 1H), 1.88 (ddd, J=3, 12, 15 Hz, 1H), 1.99 (ddd, J=2, 13, 13 Hz, 1H), 2.03 (ddd, J=4, 13, 13 Hz, 1H), 2.35 (dd, J=6, 13 Hz, 1H), 2.35 (dd, J=6, 13 Hz, 1H), 2.43 (ddd, J=4, 4, 13 Hz, 1H), 2.47-2.60 (m, 3H), 2.85-2.95 (m, 1H), 2.86 (dd, J=6, 18 Hz, 1H), 2.94 (d, J=6 Hz, 1H), 3.00 (d, J=18 Hz, 1H), 3.11 (ddd, J=1, 11, 13 Hz, 1H), 3.51 (d, J=15 Hz, 1H), 3.56 (d, J=15 Hz, 1H), 3.69 (s, 3H), 6.61 (d, J=3 Hz, 1H), 6.75 (dd, J=3, 8 Hz, 1H), 6.86-6.91 (m, 2H), 7.06 (d, J=8 Hz, 1H), 8.35-8.41 (m, 2H).

Example 17
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(pyridin-4-ylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 16 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.44-0.57 (m, 2H), 0.78-0.88 (m, 1H), 1.00-1.07 (m, 1H), 1.54 (dd, J=4, 14 Hz, 1H), 1.65 (ddd, J=2, 5, 16 Hz, 1H), 1.98 (ddd, J=3, 12, 14 Hz, 1H), 1.99-2.10 (m, 2H), 2.32-2.40 (m, 1H), 2.33 (dd, J=6, 13 Hz, 1H), 2.36 (dd, J=6, 13 Hz, 1H), 2.45-2.61 (m, 3H), 2.81-2.91 (m, 2H), 2.94 (d, J=6 Hz, 1H), 2.97 (d, J=18 Hz, 1H), 3.19 (dd, J=12, 12 Hz, 1H), 3.52 (d, J=15 Hz, 1H), 3.66 (d, J=15 Hz, 1H), 6.48 (d, J=2 Hz, 1H), 6.70 (dd, J=2, 8 Hz, 1H), 6.84-6.91 (m, 2H), 6.96 (d, J=8 Hz, 1H), 8.30-8.42 (m, 2H).

Example 18
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(pyrimidin-2-ylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and pyrimidine-2-carbaldehyde according to the method described in Example 12.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.42-0.56 (m, 2H), 0.79-0.92 (m, 1H), 0.98-1.10 (m, 1H), 1.48 (ddd, J=2, 5, 14 Hz, 1H), 1.84-2.03 (m, 3H), 2.12 (ddd, J=5, 13, 13 Hz, 1H), 2.33-2.44 (m, 3H), 2.56 (ddd, J=2, 5, 12 Hz, 1H), 2.73-2.84 (m, 2H), 2.85-3.02 (m, 4H), 3.32 (ddd, J=3, 11, 13 Hz, 1H), 3.75 (s, 3H), 3.92 (d, J=15 Hz, 1H), 3.96 (d, J=15 Hz, 1H), 6.63 (d, J=3 Hz, 1H), 6.69 (dd, J=3, 8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 7.13 (t, J=5 Hz, 1H), 8.68 (d, J=5 Hz, 2H).

Example 19
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(pyrimidin-2-ylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 18 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.14 (m, 2H), 0.46-0.53 (m, 2H), 0.78-0.92 (m, 1H), 0.96-1.03 (m, 1H), 1.47 (ddd, J=2, 5, 15 Hz, 1H), 1.75 (dd, J=5, 15 Hz, 1H), 1.87 (ddd, J=3, 11, 14 Hz, 1H), 1.98 (ddd, J=3, 12, 12 Hz, 1H), 2.08 (ddd, J=4, 12, 12 Hz, 1H), 2.29-2.40 (m, 3H), 2.55 (dd, J=3, 11 Hz, 1H), 2.74 (dd, J=5, 18 Hz, 1H), 2.80-2.98 (m, 5H), 3.32 (ddd, J=2, 11, 13 Hz, 1H), 3.95 (d, J=14 Hz, 1H), 4.00 (d, J=14 Hz, 1H), 6.44 (d, J=3 Hz, 1H), 6.57 (dd, J=3, 8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 7.15 (t, J=5 Hz, 1H), 8.69 (d, J=5 Hz, 2H).

Example 20
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyrimidin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(pyrimidin-2-yl)acetic acid according to the method described in Example 4.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.47-0.55 (m, 2H), 0.76-0.92 (m, 1H), 1.00-1.13 (m, 1H), 1.53-1.66 (m, 1H), 1.81 (ddd, J=3, 12, 15 Hz, 0.4H), 1.86-2.10 (m, 3.6H), 2.18-2.24 (m, 1H), 2.26-2.40 (m, 2H), 2.50-2.63 (m, 1H), 2.68-3.09 (m, 2.6H), 2.74 (ddd, J=6, 16, 16 Hz, 1H), 3.33-3.45 (m, 1.4H), 3.63-3.76 (m, 0.4H), 3.84 (d, J=15 Hz, 0.4H), 3.90-4.01 (m, 1H), 3.96 (d, J=15 Hz, 0.4H), 4.11 (s, 1.2H), 4.26-4.35 (m, 0.6H), 4.48 (br s, 1H), 6.57-6.64 (m, 1.4H), 6.83 (d, J=2 Hz, 0.6H), 6.91 (d, J=8 Hz, 1H), 7.17 (t, J=5 Hz, 0.4H), 7.18 (t, J=5 Hz, 0.6H), 8.67 (d, J=5 Hz, 0.8H), 8.70 (d, J=5 Hz, 1.2H).

Example 21
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 7.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.43-0.56 (m, 2H), 0.76-0.87 (m, 1H), 1.00-1.12 (m, 1H), 1.55 (ddd, J=3, 4, 15 Hz, 0.5H), 1.63 (ddd, J=2, 5, 15 Hz, 0.5H), 1.75 (ddd, J=4, 12, 14 Hz, 0.5H), 1.82 (ddd, J=2, 12, 14 Hz, 0.5H), 1.92-2.11 (m, 2.5H), 2.12 (ddd, J=2, 5, 16 Hz, 0.5H), 2.24-2.40 (m, 2.5H), 2.46 (ddd, J=6, 10, 16 Hz, 0.5H), 2.51-2.60 (m, 1H), 2.70 (dd, J=6, 18 Hz, 0.5H), 2.80 (dd, J=6, 18 Hz, 0.5H), 2.86 (d, J=6 Hz, 0.5H), 2.92 (d, J=6 Hz, 0.5H), 2.96 (d, J=18 Hz, 0.5H), 2.98 (d, J=18 Hz, 0.5H), 3.23 (ddd, J=2, 12, 14 Hz, 0.5H), 3.48 (ddd, J=4, 4, 13 Hz, 0.5H), 3.53 (ddd, J=2, 12, 14 Hz, 0.5H), 3.57-3.67 (m, 1H), 3.68 (d, J=15 Hz, 0.5H), 3.76 (s, 1.5H), 3.78 (s, 1.5H), 3.80-3.94 (m, 2.5H), 4.10 (ddd, J=3, 6, 15 Hz, 0.5H), 4.47 (br s, 1H), 6.63 (d, J=2 Hz, 0.5H), 6.66-6.73 (m, 1.5H), 6.99 (d, J=9 Hz, 0.5H), 7.01 (d, J=9 Hz, 0.5H), 7.09-7.15 (m, 1.5H), 7.18-7.22 (m, 0.5H), 7.55 (ddd, J=2, 6, 8 Hz, 0.5H), 7.57 (ddd, J=2, 6, 8 Hz, 0.5H), 8.49 (ddd, J=1, 2, 5 Hz, 0.5H), 8.49 (ddd, J=1, 2, 5 Hz, 0.5H).

Example 22
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 21 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.15 (m, 2H), 0.43-0.56 (m, 2H), 0.75-0.88 (m, 1H), 1.00-1.12 (m, 1H), 1.53 (ddd, J=4, 4, 15 Hz, 0.5H), 1.59 (ddd, J=1, 5, 15 Hz, 0.5H), 1.72-2.07 (m, 3.5H), 2.13 (ddd, J=2, 6, 16 Hz, 0.5H), 2.20-2.39 (m, 2.5H), 2.47 (dd, J=6, 12 Hz, 0.5H), 2.49-2.58 (m, 1H), 2.65 (dd, J=6, 18 Hz, 0.5H), 2.76 (dd, J=6, 19 Hz, 0.5H), 2.83 (d, J=6 Hz, 0.5H), 2.90 (d, J=6 Hz, 0.5H), 2.92 (d, J=19 Hz, 0.5H), 2.95 (d, J=18 Hz, 0.5H), 3.28 (ddd, J=2, 12, 14 Hz, 0.5H), 3.32-3.43 (m, 1H), 3.48 (ddd, J=3, 3, 14 Hz, 0.5H), 3.69 (d, J=15 Hz, 0.5H), 3.72-3.81 (m, 0.5H), 3.78 (d, J=15 Hz, 0.5H), 3.82-3.94 (m, 1H), 3.88 (d, J=15 Hz, 0.5H), 3.93 (d, J=15 Hz, 0.5H), 4.08 (ddd, J=2, 5, 15 Hz, 0.5H), 4.44 (br s, 0.5H), 4.51 (br s, 0.5H), 6.63 (dd, J=2, 8 Hz, 0.5H), 6.64 (dd, J=2, 8 Hz, 0.5H), 6.71 (d, J=2 Hz, 0.5H), 6.81 (d, J=2 Hz, 0.5H), 6.89 (d, J=8 Hz, 0.5H), 6.90 (d, J=8 Hz, 0.5H), 7.13 (ddd, J=1, 5, 8 Hz, 0.5H), 7.15-7.21 (m, 1H), 7.22-7.26 (m, 0.5H), 7.57 (ddd, J=2, 8, 8 Hz, 0.5H), 7.62 (ddd, J=2, 8, 8 Hz, 0.5H), 8.46-8.50 (m, 1H).

Example 23
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(thiophen-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(thiophen-2-yl)acetic acid according to the method described in Example 7.

¹H-NMR (400 MHz, CD₃Cl) δ (ppm): 0.06-0.17 (m, 2H), 0.45-0.55 (m, 2H), 0.76-0.89 (m, 1H), 1.01-1.13 (m, 1H), 1.57-1.67 (m, 1H), 1.76-1.85 (m, 1H), 1.92-2.40 (m, 6H), 2.52-2.61 (m, 1.5H), 2.68-3.03 (m, 2.5H), 3.11-3.18 (m, 0.5H), 3.36-3.53 (m, 1.5H), 3.60 (dd, J=1, 16 Hz, 0.5H), 3.68-3.82 (m, 1H), 3.78 (s, 3H), 3.86-3.95 (m, 2H), 4.11-4.20 (m, 0.5H), 4.50 (br s, 1H), 6.64 (d, J=3 Hz, 0.5H), 6.68-6.74 (m, 2H), 6.78-6.80 (m, 0.5H), 6.87-6.91 (m, 1H), 6.99-7.02 (m, 1H), 7.13-7.17 (m, 1H).

Example 24
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(2-(thiophen-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

To a solution of the compound (24.3 mg, 0.052 mmol) obtained in Example 23 in tetrahydrofuran (3 mL) was added a 0.9 M borane-tetrahydrofuran complex-tetrahydrofuran solution (578.6 μL, 0.52 mmol), followed by heating under reflux for 2 hours. After allowed to cool, the reaction mixture was concentrated under reduced pressure. To the concentrated residue, 2 M hydrochloric acid (3 mL) was added, followed by heating under reflux for 2 hours. After allowed to cool, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution to be basic, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 2% methanol/ethyl acetate) to yield the title compound (21.1 mg, 89%) as a colorless oily matter.

¹H-NMR (400 MHz, CD₃Cl) δ (ppm): 0.05-0.16 (m, 2H), 0.44-0.58 (m, 2H), 0.78-0.92 (m, 1H), 1.05-1.08 (m, 1H), 1.45-1.54 (m, 1H), 1.76-2.14 (m, 5H), 2.31-2.42 (m, 3H), 2.48-2.60 (m, 2H), 2.67-2.79 (m, 3H), 2.80-3.02 (m, 5H), 3.12-3.21 (m, 1H), 3.77 (s, 3H), 4.67 (br s, 1H), 6.66-6.74 (m, 3H), 6.82-6.87 (m, 1H), 6.97-7.06 (m, 2H).

Example 25
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(thiophen-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 24 according to the method described in Example 6.

¹H-NMR (400 MHz, CD₃Cl) δ (ppm): 0.04-0.15 (m, 2H), 0.45-0.53 (m, 2H), 0.78-0.90 (m, 1H), 0.99-1.07 (m, 1H), 1.47-1.54 (d, J=4, 15 Hz, 1H), 1.77-1.87 (m, 2H), 1.97-2.08 (m, 2H), 2.30-2.39 (m, 3H), 2.48-2.58 (m, 1H), 2.68-3.08 (m, 10H), 3.21 (dd, J=11, 11 Hz, 1H), 4.82 (br s, 1H), 6.42 (d, J=2 Hz, 1H), 6.56 (dd, J=2, 8 Hz, 1H), 6.77 (d, J=3 Hz, 1H), 6.87-6.91 (m, 2H), 7.09 (dd, J=1, 5 Hz, 1H).

Example 26
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-pyrazol-3-yl)ethan-1-one

[Image Omitted]

To a solution of the compound E (20 mg, 0.061 mmol) obtained in Example 3, 2-(1H-pyrazol-1-yl)acetic acid (12 mg, 0.17 mmol) and N,N-diisopropylethylamine (31 μL, 0.18 mmol) in N,N-dimethylformamide (0.5 mL) was added 0-(7-azabenzotriazol-3-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (24 mg, 0.064 mmol) under ice cooling, followed by stirring at room temperature for 16 hours. To the reaction mixture were added potassium carbonate (83 mg, 0.61 mmol) and methanol (1 mL), followed by further stirring for 1 hour. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, water, and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:methanol=10:1) to yield the title compound (27 mg, 100%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.01 (d, J=10 Hz, 0.5H), 1.10 (d, J=13 Hz, 0.5H), 1.50-2.40 (m, 7.5H), 2.40-2.60 (m, 1.5H), 2.72 (ddd, J=4, 12, 12 Hz, 1H), 2.80-3.00 (m, 2H), 3.28 (t, J=12 Hz, 1H), 3.37 (t, J=12 Hz, 0.5H), 3.45-3.55 (m, 1H), 3.60-4.00 (m, 3.5H), 6.11 (s, 1H), 6.55-6.70 (m, 1.5H), 6.76 (s, 0.5H), 6.87 (d, J=8 Hz, 0.5H), 6.91 (d, J=8 Hz, 0.5H), 7.44 (s, 0.5H), 7.49 (s, 0.5H).

Example 27
Synthesis of (5aS,6R,11bS)-3-(2-(1H-pyrazol-3-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 26 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.15 (m, 1H), 1.20-1.40 (m, 2H), 1.57 (d, J=14 Hz, 1H), 1.80-2.00 (m, 1H), 2.00-2.10 (m, 3H), 2.20-2.40 (m, 3H), 2.40-3.10 (m, 9H), 3.16 (ddd, J=7, 19, 19 Hz, 1H), 5.98 (s, 1H), 6.67 (d, J=8 Hz, 1H), 6.73 (s, 1H), 6.97 (d, J=8 Hz, 1H), 7.43 (s, 1H).

Example 28
Synthesis of (E)-1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(furan-3-yl)prop-2-en-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and (E)-3-(furan-3-yl)acrylic acid according to the method described in Example 4.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.18 (m, 2H), 0.43-0.58 (m, 2H), 0.76-0.90 (m, 1H), 1.04-1.09 (m, 0.2H), 1.16-1.23 (m, 0.8H), 1.61-1.71 (m, 1H), 1.83-2.48 (m, 7H), 2.55 (dd, J=4, 12 Hz, 1H), 2.79 (dd, J=6, 18 Hz, 1H), 2.88-2.96 (m, 1.2H), 2.99-3.10 (m, 1.6H), 3.48 (ddd, J=3, 3, 12 Hz, 0.8H), 3.52-3.68 (m, 0.4H), 3.76-3.85 (m, 0.2H), 3.91 (ddd, J=3, 3, 14 Hz, 0.2H), 4.11 (ddd, J=3, 12, 12 Hz, 0.8H), 4.51 (dd, J=6, 14 Hz, 0.8H), 6.51 (d, J=16 Hz, 0.2H), 6.55 (dd, J=3, 8 Hz, 0.2H), 6.57 (s, 0.8H), 6.64 (d, J=15 Hz, 0.8H), 6.65-6.68 (m, 0.2H), 6.71 (dd, J=2, 8 Hz, 0.8H), 6.89 (d, J=8 Hz, 0.2H), 6.97 (d, J=8 Hz, 0.8H), 7.10-7.15 (m, 0.8H), 7.24-7.32 (m, 0.4H), 7.38 (s, 0.2H), 7.40 (s, 0.8H), 7.54 (d, J=15 Hz, 0.8H), 7.55 (s, 0.2H), 7.65 (s, 0.8H).

Example 29
Synthesis of ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl) (phenyl)methanone

[Image Omitted]

A solution of the isomer C (14 mg, 0.040 mmol) obtained in Example 2 in dichloromethane (1.0 mL) was cooled to 0° C., and to the solution were added triethylamine (17 μL, 0.12 mmol) and benzoic anhydride (18 mg, 0.079 mmol), followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture to stop the reaction, followed by extraction twice with chloroform. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 10% methanol/chloroform) to yield the title compound (17 mg, 96%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.17 (m, 2H), 0.45-0.58 (m, 2H), 0.75-0.91 (m, 1H), 0.96-1.02 (m, 0.7H), 1.10-1.16 (m, 0.3H), 1.46 (ddd, J=3, 3, 14 Hz, 0.3H), 1.71 (dd, J=4, 14 Hz, 0.7H), 1.74-2.14 (m, 3.7H), 2.21 (dd, J=5, 15 Hz, 0.3H), 2.27-2.61 (m, 3.3H), 2.69 (ddd, J=6, 12, 17 Hz, 0.7H), 2.76 (dd, J=6, 18 Hz, 0.3H), 2.83-3.04 (m, 2.7H), 3.26-3.36 (m, 0.6H), 3.40-3.67 (m, 2.1H), 3.42 (s, 2.1H), 3.71-3.82 (m, 0.3H), 3.80 (s, 0.9H), 4.01 (ddd, J=2, 4, 14 Hz, 0.7H), 4.17 (ddd, J=1, 5, 14 Hz, 0.3H), 6.20 (d, J=2 Hz, 0.7H), 6.66-6.78 (m, 1.3H), 6.92-6.98 (m, 1.3H), 7.02 (d, J=8 Hz, 0.7H), 7.04 (d, J=8 Hz, 0.3H), 7.24-7.40 (m, 3.7H).

Example 30
Synthesis of ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl) (phenyl)methanone

[Image Omitted]

The title compound was obtained from the compound obtained in Example 29 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.15 (m, 2H), 0.42-0.55 (m, 2H), 0.74-0.92 (m, 1H), 0.93-1.00 (m, 0.4H), 1.15-1.23 (m, 0.6H), 1.48 (ddd, J=4, 4, 15 Hz, 0.6H), 1.66-1.79 (m, 0.8H), 1.88-2.13 (m, 3.4H), 2.26-2.66 (m, 4.4H), 2.73 (dd, J=6, 18 Hz, 0.6H), 2.79-3.04 (m, 2.4H), 3.24-3.36 (m, 1.2H), 3.38-3.60 (m, 1H), 3.81 (ddd, J=4, 13, 13 Hz, 0.6H), 3.93-4.01 (m, 0.4H), 4.29-4.38 (m, 0.6H), 6.20 (d, J=2 Hz, 0.4H), 6.61 (dd, J=2, 8 Hz, 0.4H), 6.65 (dd, J=2, 8 Hz, 0.6H), 6.94 (d, J=8 Hz, 0.6H), 6.95 (d, J=8 Hz, 0.4H), 6.97-7.02 (m, 0.6H), 7.06 (d, J=2 Hz, 0.6H), 7.29-7.45 (m, 4.4H).

Example 31
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(thiazol-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To the compound E (30 mg, 0.091 mmol) obtained in Example 3 and 2-(thiazol-2-yl)ethyl methanesulfonate (synthesized by the method described in WO 2010105179) (23 mg, 0.11 mmol) dissolved in acetonitrile (1 mL) was added N,N-diisopropylethylamine (47 μL, 0.27 mmol), followed by stirring at 80° C. for 12 hours and then stirring at room temperature for 4 days. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction twice with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=85:15) to yield the title compound (26 mg, 65%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.45-0.56 (m, 2H), 0.77-0.92 (m, 1H), 0.97-1.08 (m, 1H), 1.17-1.73 (m, 1H), 1.76-1.93 (m, 2H), 1.94-2.11 (m, 2H), 2.28-3.00 (m, 12H), 3.01-3.23 (m, 3H), 4.64 (br s, 1H), 6.53-6.59 (m, 1H), 6.61 (dd, J=3, 8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 7.09 (d, J=3 Hz, 1H), 7.61 (d, J=4 Hz, 1H).

Example 32
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(furan-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To a solution of 2-(furan-2-yl)ethan-1-ol (7 mg, 0.06 mmol) in dichloromethane (1 mL) was added triethylamine (18 μL, 0.12 mmol), then was added mesylic anhydride (11 mg, 0.066 mmol) under ice cooling, followed by stirring for 1 hour under ice cooling. Under ice cooling, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure to yield a crude product of 2-(furan-2-yl)ethyl methanesulfonate. A solution of the obtained crude product in N,N-dimethylformamide (0.25 mL) was added dropwise to a solution of the compound E (10 mg, 0.03 mmol) obtained in Example 3 and N,N-diisopropylethylamine (21 μL, 0.12 mmol) in N,N-dimethylformamide (0.5 mL) under ice cooling, followed by stirring at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, water, and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=90:10) to yield the title compound (2.1 mg, 17%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.04 (d, J=11 Hz, 1H), 1.40-1.60 (m, 1H), 1.80-1.95 (m, 2H), 1.95-2.10 (m, 3H), 2.20-2.40 (m, 3H), 2.50-2.60 (m, 1H), 2.70-3.00 (m, 10H), 3.20-3.45 (m, 1H), 5.96 (d, J=3 Hz, 1H), 6.20-6.25 (m, 1H), 6.50-6.55 (m, 1H), 6.58 (dd, J=3, 8 Hz, 1H), 6.90 (d, J=8 Hz, 1H)

Example 33
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(thiazol-4-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(thiazol-4-yl)acetic acid according to the method described in Example 7.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.14 (m, 2H), 0.43-0.56 (m, 2H), 0.76-0.87 (m, 1H), 1.01-1.15 (m, 1H), 1.53-1.65 (m, 1H), 1.77-2.10 (m, 3H), 2.16-2.40 (m, 3H), 2.48-2.60 (m, 1.4H), 2.69 (dd, J=6, 18 Hz, 0.6H), 2.77 (dd, J=6, 18 Hz, 0.4H), 2.86 (d, J=6 Hz, 0.6H), 2.91 (d, J=6 Hz, 0.4H), 2.92 (d, J=18 Hz, 0.4H), 2.97 (d, J=18 Hz, 0.6H), 3.12-3.30 (m, 1.4H), 3.37-3.46 (m, 0.6H), 3.49 (ddd, J=4, 4, 13 Hz, 0.6H), 3.67 (d, J=16 Hz, 0.4H), 3.72-3.83 (m, 0.4H), 3.84 (d, J=16 Hz, 0.4H), 3.85-3.99 (m, 1H), 3.90 (d, J=16 Hz, 0.6H), 4.00 (d, J=16 Hz, 0.6H), 4.11-4.19 (m, 0.6H), 6.61 (dd, J=3, 8 Hz, 0.4H), 6.63-6.68 (m, 1H), 6.85 (d, J=3 Hz, 0.6H), 6.90 (d, J=8 Hz, 0.4H), 6.92 (d, J=8 Hz, 0.6H), 7.07-7.11 (m, 1H), 8.73 (d, J=2 Hz, 0.6H), 8.74 (d, J=2 Hz, 0.4H).

Example 34
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(thiazol-4-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 33 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.42-0.56 (m, 2H), 0.76-0.88 (m, 1H), 0.98-1.08 (m, 1H), 1.49 (dd, J=5, 14 Hz, 1H), 1.75-1.86 (m, 2H), 1.94-2.08 (m, 2H), 2.28-2.41 (m, 3H), 2.49-2.58 (m, 1H), 2.68-2.80 (m, 2H), 2.73 (dd, J=6, 18 Hz, 1H), 2.85-3.05 (m, 7H), 3.16 (dd, J=12, 12 Hz, 1H), 4.72 (br s, 1H), 6.46 (s, 1H), 6.59 (d, J=8 Hz, 1H), 6.84 (s, 1H), 6.89 (d, J=8 Hz, 1H), 8.68 (s, 1H).

Example 35
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.20 (m, 2H), 0.45-0.61 (m, 2H), 0.76-0.92 (m, 1H), 1.01-1.10 (m, 1H), 1.21-1.91 (m, 2.5H), 1.93-2.44 (m, 5.5H), 2.47-2.62 (m, 1.5H), 2.69-3.07 (m, 3H), 3.08-3.20 (m, 0.5H), 3.36-3.97 (m, 10.5H), 4.06-4.17 (m, 0.5H), 6.41 (s, 0.5H), 6.54 (s, 0.5H), 6.62-6.75 (m, 2H), 6.97-7.06 (m, 1H).

Example 36
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 35 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.18 (m, 2H), 0.47-0.59 (m, 2H), 0.75-0.94 (m, 1H), 0.99-1.17 (m, 1H), 1.22-2.40 (m, 8H), 2.47-2.64 (m, 1.4H), 2.66-2.83 (m, 1H), 2.84-3.07 (m, 2H), 3.09-3.27 (m, 0.6H), 3.35-3.59 (m, 2H), 3.62-3.81 (m, 1.6H), 3.83-4.01 (m, 4H), 4.07-4.22 (m, 0.4H), 4.38-4.57 (m, 1H), 6.45 (s, 0.4H), 6.53 (s, 0.6H), 6.56-6.67 (m, 1.4H), 6.79 (d, J=2 Hz, 0.6H), 6.88-6.97 (m, 1H).

Example 37
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 36 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.18 (m, 2H), 0.41-0.57 (m, 2H), 0.74-0.91 (m, 1H), 0.97-2.15 (m, 6H), 2.26-2.42 (m, 3H), 2.45-2.60 (m, 1H), 2.67-3.02 (m, 10H), 3.10-3.25 (m, 1H), 3.88 (s, 3H), 4.74 (br s, 1H), 6.35 (s, 1H), 6.45 (d, J=2 Hz, 1H), 6.55 (dd, J=2, 8 Hz, 1H), 6.89 (d, J=8 Hz, 1H).

Example 38
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-imidazol-4-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(1H-imidazol-4-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.17 (m, 2H), 0.46-0.58 (m, 2H), 0.77-0.90 (m, 1H), 1.01-1.17 (m, 1H), 1.48-3.19 (m, 13H), 3.36-4.82 (m, 8H), 6.56-6.88 (m, 3H), 6.97-7.09 (m, 1H), 7.48-7.54 (m, 1H).

Example 39
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-imidazol-4-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 38 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.43-0.55 (m, 2H), 0.72-0.89 (m, 1H), 0.98-1.13 (m, 1H), 1.51-1.64 (m, 1H), 1.69-3.00 (m, 11H), 3.23-3.91 (m, 6H), 6.56-6.69 (m, 3H), 6.85 (d, J=8 Hz, 0.6H), 6.97 (d, J=8 Hz, 0.4H), 7.37 (s, 0.6H), 7.40 (s, 0.4H).

Example 40
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1-methyl-1H-imidazol-4-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(1-methyl-1H-imidazol-4-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.15 (m, 2H), 0.45-0.54 (m, 2H), 0.73-0.92 (m, 1H), 0.99-1.14 (m, 1H), 1.51-1.65 (m, 1H), 1.71-2.60 (m, 8H), 2.73 (ddd, J=2, 8, 8 Hz, 1H), 2.82-3.03 (m, 2H), 3.14-3.25 (m, 0.4H), 3.28-3.99 (m, 8.2H), 4.04-4.17 (m, 0.4H), 6.63 (dd, J=3, 8 Hz, 0.6H), 6.67 (dd, J=3, 8 Hz, 0.4H), 6.70-6.77 (m, 1.6H), 6.82 (d, J=3 Hz, 0.4H), 6.87 (d, J=8 Hz, 0.6H), 6.91 (d, J=8 Hz, 0.4H), 7.31 (s, 0.4H), 7.36 (s, 0.6H).

Example 41
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(1-methyl-1H-imidazol-4-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 40 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.15 (m, 2H), 0.41-0.58 (m, 2H), 0.72-1.56 (m, 3H), 1.74-2.12 (m, 4H), 2.24-2.39 (m, 3H), 2.47-2.58 (m, 1H), 2.66-3.02 (m, 10H), 3.17-3.30 (m, 1H), 3.58 (s, 3H), 6.51 (s, 1H), 6.54 (s, 1H), 6.60 (d, J=8 Hz, 1H), 6.87 (d, J=8 Hz, 1H), 7.29 (s, 1H).

Example 42
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(1H-pyrazol-1-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.15 (m, 1H), 1.50-1.70 (m, 2H), 1.75-1.90 (m, 1H), 1.90-2.40 (m, 3H), 2.50-2.65 (m, 1.4H), 2.70-3.10 (m, 4.6H), 3.30-3.60 (m, 1.4H), 3.60-3.70 (m, 0.6H), 3.75-3.95 (m, 4.6H), 4.10-4.20 (m, 0.4H), 4.49 (br s, 1H), 4.59 (d, J=16 Hz, 0.6H), 4.80-5.05 (m, 1.4H), 6.20-6.30 (m, 1H), 6.65-6.80 (m, 2H), 7.00-7.10 (m, 1H), 7.40-7.55 (m, 2H).

Example 43
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

To a solution of the compound E (7.6 mg, 0.023 mmol) obtained in Example 3 in N,N-dimethylformamide (1.0 mL) were added 2-(1H-pyrazol-1-yl)acetic acid (8.8 mg, 0.069 mmol), N,N-diisopropylethylamine (12.1 μL, 0.069 mmol), 1-hydroxybenzotriazole monohydrate (10.6 mg, 0.069 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.3 mg, 0.069 mmol), and N,N-dimethyl-4-aminopyridine (1.4 mg, 0.012 mmol), followed by stirring at room temperature for 2 hours. To the reaction mixture, a 2 M aqueous sodium hydroxide solution (1 mL) was added, followed by stirring at room temperature for 17 hours. The reaction mixture was diluted with water, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol=10:1) to yield the title compound (9.9 mg, 98%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.13 (m, 2H), 0.47-0.54 (m, 2H), 0.76-0.86 (m, 1H), 1.03-1.10 (m, 1H), 1.52-1.63 (m, 1H), 1.76-2.25 (m, 4.5H), 2.26-2.39 (m, 2H), 2.50-2.65 (m, 1.5H), 2.68-2.79 (m, 1H), 2.86-2.95 (m, 1.5H), 2.98 (d, J=18 Hz, 0.5H), 3.09-3.19 (m, 0.5H), 3.25-3.39 (m, 1.5H), 3.62-3.73 (m, 0.5H), 3.81-3.89 (m, 1H), 4.01-4.09 (m, 0.5H), 4.52 (br s, 1H), 4.66 (d, J=16 Hz, 0.5H), 4.81 (d, J=16 Hz, 0.5H), 4.95 (d, J=16 Hz, 0.5H), 4.99 (d, J=16 Hz, 0.5H), 6.26-6.29 (m, 1H), 6.62-6.68 (m, 2H), 6.90-6.95 (m, 1H), 7.33 (dd, J=2, 2 Hz, 0.5H), 7.41 (d, J=2 Hz, 0.5H), 7.55 (dd, J=2, 4 Hz, 1H).

Example 44
Synthesis of (5aS,6R,11bS)-3-(2-(1H-pyrazol-1-yl)ethyl)-14-(cyclopropylmethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 42 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.03 (d, J=13 Hz, 1H), 1.40-1.50 (m, 1H), 1.75 (ddd, J=3, 11, 14 Hz, 1H), 1.86 (ddd, J=4, 4, 12 Hz, 1H), 1.90-2.10 (m, 2H), 2.34 (d, J=6 Hz, 2H), 2.40-2.50 (m, 2H), 2.50-2.60 (m, 1H), 2.64 (dt, J=13, 4 Hz, 1H), 2.70-2.90 (m, 3H), 2.90-3.00 (m, 3H), 3.14 (ddd, J=1, 11, 12 Hz, 1H), 3.76 (s, 3H), 4.00-4.10 (m, 2H), 4.59 (br s, 1H), 6.04 (t, J=2 Hz, 1H), 6.68 (d, J=2 Hz, 1H), 6.72 (dd, J=2, 8 Hz, 1H), 6.91 (d, J=2 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 7.40 (d, J=2 Hz, 1H).

Example 45
Synthesis of (5aS,6R,11bS)-3-(2-(1H-pyrazol-1-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 44 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.85 (m, 1H), 1.00 (d, J=11 Hz, 1H), 1.44 (dd, J=3, 15 Hz, 1H), 1.70-1.85 (m, 2H), 1.90-2.10 (m, 3H), 2.30-2.45 (m, 3H), 2.45-2.55 (m, 2H), 2.61 (dt, J=13, 4 Hz, 1H), 2.75 (dd, J=6, 18 Hz, 1H), 2.80-3.00 (m, 4H), 3.10-3.20 (m, 1H), 4.05-4.15 (m, 2H), 6.09 (t, J=2 Hz, 1H), 6.55 (d, J=2 Hz, 1H), 6.61 (dd, J=2, 8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 7.05 (d, J=2 Hz, 1H), 7.41 (d, J=2 Hz, 1H).

Example 46
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(3-methyl-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(4-methyl-1H-pyrazol-1-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.07 (d, J=12 Hz, 1H), 1.50-1.65 (m, 1H), 1.70-2.40 (m, 9.4H), 2.50-2.80 (m, 2.6H), 2.80-3.15 (m, 2.6H), 3.20-3.40 (m, 1.4H), 3.60-3.75 (m, 0.6H), 3.75-3.90 (m, 1H), 4.00-4.15 (m, 0.4H), 4.53 (br s, 1H), 4.60 (d, J=16 Hz, 0.6H), 4.70 (d, J=16 Hz, 0.6H), 4.85 (d, J=16 Hz, 0.4H), 4.90 (d, J=16 Hz, 0.4H), 6.05 (s, 1H), 6.60-6.70 (m, 2H), 6.85-7.00 (m, 1H), 7.20-7.35 (m, 1H).

Example 47
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(3-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 46 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.03 (d, J=11 Hz, 1H), 1.48 (dd, J=8.14 Hz, 1H), 1.70-1.85 (m, 2H), 1.90-2.10 (m, 2H), 2.23 (s, 3H), 2.30-2.45 (m, 3H), 2.50-2.70 (m, 3H), 2.70-3.00 (m, 6H), 3.10-3.25 (m, 1H), 3.95-4.10 (m, 2H), 5.88 (d, J=2 Hz, 1H), 6.55 (d, J=2 Hz, 1H), 6.62 (dd, J=2, 8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 6.99 (s, 1H).

Example 48
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(4-methyl-1H-pyrazol-1-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.15 (m, 2H), 0.47-0.55 (m, 2H), 0.77-0.88 (m, 1H), 1.04-1.12 (m, 1H), 1.56-1.63 (m, 1H), 1.77-1.87 (m, 1H), 1.92-2.02 (m, 1.5H), 2.04 (s, 1.5H), 2.07 (s, 1.5H), 2.09-2.22 (m, 1.5H), 2.27-2.40 (m, 2H), 2.52-2.62 (m, 1H), 2.713.00 (m, 3.5H), 3.02-3.10 (m, 0.5H), 3.35 (ddd, J=4, 4, 13 Hz, 0.5H), 3.39-3.47 (m, 0.5H), 3.48-3.54 (m, 0.5H), 3.59-3.72 (m, 0.5H), 3.77 (s, 1.5H), 3.79 (s, 1.5H), 3.80-3.91 (m, 1.5H), 4.10-4.17 (m, 0.5H), 4.51 (d, J=16 Hz, 0.5H), 4.83 (d, J=16 Hz, 0.5H), 4.87 (d, J=16 Hz, 0.5H), 4.93 (d, J=16 Hz, 0.5H), 6.67 (d, J=6 Hz, 0.5H), 6.68 (d, J=6 Hz, 0.5H), 6.70-6.75 (m, 1H), 7.01-7.05 (m, 1.5H), 7.20 (s, 0.5H), 7.27 (s, 0.5H), 7.30 (s, 0.5H).

Example 49
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 48 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.14 (m, 2H), 0.48-0.54 (m, 2H), 0.77-0.86 (m, 1H), 1.02-1.11 (m, 1H), 1.55-1.62 (m, 1H), 1.75-1.88 (m, 1.5H), 1.91-2.08 (m, 2.5H), 2.04 (s, 1.5H), 2.06 (s, 1.5H), 2.10-2.40 (m, 3.5H), 2.50-2.65 (m, 1.5H), 2.85-3.00 (m, 2H), 3.09-3.16 (m, 0.5H), 3.22-3.30 (m, 1H), 3.31-3.39 (m, 0.5H), 3.64-3.74 (m, 0.5H), 3.78-3.87 (m, 1H), 4.00-4.07 (m, 0.5H), 4.56 (d, J=16 Hz, 0.5H), 4.74 (d, J=16 Hz, 0.5H), 4.86 (d, J=16 Hz, 0.5H), 4.91 (d, J=16 Hz, 0.5H), 6.62-6.68 (m, 2H), 6.90-6.95 (m, 1H), 7.11 (s, 0.5H), 7.16 (s, 0.5H), 7.29 (m, 0.5H), 7.30 (s, 0.5H).

Example 50
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 49 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.02 (d, J=11 Hz, 1H), 1.45 (dd, J=3, 14 Hz, 1H), 1.70-1.85 (m, 2H), 1.90-2.10 (m, 2H), 2.00 (s, 3H), 2.30-2.40 (m, 3H), 2.50-2.70 (m, 3H), 2.75 (dd, J=6, 18 Hz, 1H), 2.80-3.00 (m, 5H), 3.13-3.25 (m, 1H), 4.00-4.15 (m, 2H), 6.54 (d, J=3 Hz, 1H), 6.61 (dd, J=3, 8 Hz, 1H), 6.85-6.95 (m, 2H), 7.24 (s, 1H).

Example 51
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(5-methyl-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

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

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.80-0.90 (m, 1H), 1.06 (d, J=11 Hz, 1H), 1.50-1.90 (m, 3H), 1.90-2.10 (m, 2H), 2.01 (s, 1.2H), 2.08 (s, 1.8H), 2.20-2.40 (m, 4H), 2.50-2.80 (m, 2H), 2.80-3.00 (m, 1.6H), 3.15-3.50 (m, 1.4H), 3.60-4.00 (m, 2H), 4.53 (d, J=16 Hz, 0.6H), 4.72 (d, J=16 Hz, 0.6H), 4.85 (d, J=16 Hz, 0.4H), 4.90 (d, J=16 Hz, 0.4H), 5.99 (s, 0.4H), 6.02 (s, 0.6H), 6.60-6.75 (m, 2H), 6.90-7.00 (m, 1H), 7.38 (s, 0.4H), 7.41 (s, 0.6H).

Example 52
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(5-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 51 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.02 (d, J=10 Hz, 1H), 1.40-1.50 (m, 1H), 1.75-1.90 (m, 2H), 1.95-2.10 (m, 3H), 2.20 (s, 3H), 2.20-2.40 (m, 3H), 2.50-2.80 (m, 4H), 2.80-3.00 (m, 4H), 3.15-3.35 (m, 1H), 4.07 (t, J=8 Hz, 2H), 5.95 (s, 1H), 6.54 (s, 1H), 6.60-6.65 (m, 1H), 6.91 (d, J=8 Hz, 1H), 7.36 (s, 1H).

Example 53
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.05-1.15 (m, 1H), 1.50-2.40 (m, 7H), 2.50-2.70 (m, 1.5H), 2.70-2.85 (m, 1.5H), 2.85-3.05 (m, 2H), 3.05-3.15 (m, 0.5H), 3.30-3.50 (m, 1.5H), 3.60-3.75 (m, 0.5H), 3.80-3.90 (m, 1H), 4.00-4.15 (m, 0.5H), 4.72 (d, J=16 Hz, 0.5H), 4.89 (d, J=16 Hz, 0.5H), 5.01 (d, J=16 Hz, 0.5H), 5.02 (d, J=16 Hz, 0.5H), 6.51 (d, J=2 Hz, 0.5H), 6.54 (d, J=2 Hz, 0.5H), 6.60-6.70 (m, 2H), 6.95 (s, 0.5H), 6.97 (s, 0.5H), 7.37 (d, J=1 Hz, 0.5H), 7.50 (d, J=1 Hz, 0.5H).

Example 54
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 53 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.70-1.00 (m, 1H), 1.02 (d, J=13 Hz, 1H), 1.40-1.55 (m, 1H), 1.65-1.85 (m, 2H), 1.90-2.10 (m, 2H), 2.30-2.65 (m, 6H), 2.75-3.05 (m, 6H), 3.05-3.20 (m, 1H), 4.00-4.15 (m, 2H), 6.26 (s, 1H), 6.60-6.70 (m, 2H), 6.86 (s, 1H), 6.98 (d, J=8 Hz, 1H).

Example 55
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(3,5-dimethyl-1H-pyrazol-1-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.80-0.90 (m, 1H), 1.00-1.10 (m, 1H), 1.45-1.70 (m, 1.6H), 1.75-1.90 (m, 1.4H), 1.90-2.40 (m, 4.6H), 1.94 (s, 1.2H), 2.01 (s, 1.8H), 2.17 (s, 1.2H), 2.22 (s, 1.8H), 2.45-3.00 (m, 4.4H), 3.15-3.45 (m, 2H), 3.60-4.00 (m, 2H), 4.47 (d, J=16 Hz, 0.6H), 4.62 (d, J=16 Hz, 0.6H), 4.75 (d, J=16 Hz, 0.4H), 4.82 (d, J=16 Hz, 0.4H), 5.77 (s, 0.4H), 5.80 (s, 0.6H), 6.60-6.70 (m, 2H), 6.85-6.95 (m, 1H).

Example 56
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 55 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.70-0.90 (m, 1H), 1.00-1.10 (m, 1H), 1.40-1.50 (m, 1H), 1.70-1.90 (m, 2H), 1.95-2.10 (m, 2H), 2.14 (s, 3H), 2.19, (s, 3H), 2.20-2.40 (m, 3H), 2.50-2.60 (m, 1H), 2.60-3.00 (m, 8H), 3.20-3.30 (m, 1H), 4.00 (t, J=7 Hz, 2H), 5.74 (s, 1H), 6.53 (s, 1H), 6.61 (d, J=8 Hz, 1H), 6.90 (d, J=8 Hz, 1H).

Example 57
Synthesis of 2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)-1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.10 (d, J=12 Hz, 1H), 1.75-1.90 (m, 1H), 1.90-2.40 (m, 6H), 2.50-3.10 (m, 5H), 3.15-3.25 (m, 0.5H), 3.30-3.55 (m, 1.5H), 3.65-3.75 (m, 0.5H), 3.80-3.90 (m, 1H), 3.95-4.05 (m, 0.5H), 4.72 (d, J=16 Hz, 0.5H), 4.98 (d, J=16 Hz, 0.5H), 5.00 (d, J=16 Hz, 0.5H), 5.15 (d, J=16 Hz, 0.5H), 6.40-6.80 (m, 5H), 6.90-7.00 (m, 1H).

Example 58
Synthesis of (5aS,6R,11bS)-3-(2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 57 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.00 (d, J=10 Hz, 1H), 1.40-1.50 (m, 1H), 1.65-2.10 (m, 4H), 2.20-2.40 (m, 2H), 2.45-2.60 (m, 2H), 2.62 (ddd, J=4, 5, 13 Hz, 1H), 2.75 (dd, J=6, 8 Hz, 1H), 2.80-3.00 (m, 5H), 3.18 (ddd, J=2, 12, 12 Hz, 1H), 3.55-3.80 (m, 1H), 4.16 (t, J=6 Hz, 2H), 6.50-6.90 (m, 5H), 6.93 (d, J=8 Hz, 1H).

Example 59
Synthesis of 2-(4-bromo-1H-pyrazol-1-yl)-1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(4-bromo-1H-pyrazol-1-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.15 (m, 1H), 1.55-1.65 (m, 1H), 1.75-2.40 (m, 7H), 2.50-3.10 (m, 4.5H), 3.30-3.55 (m, 1.5H), 3.60-3.75 (m, 0.5H), 3.75-3.90 (m, 1H), 3.78 (s, 1.5H), 3.79 (s, 1.5H), 4.10-4.20 (m, 0.5H), 4.40-4.60 (br s, 1H), 4.54 (d, J=16 Hz, 0.5H), 4.84 (d, J=16 Hz, 0.5H), 4.94 (d, J=16 Hz, 0.5H), 4.94 (d, J=16 Hz, 0.5H), 6.65-6.70 (m, 1H), 6.70-6.75 (m, 1H), 7.00-7.05 (m, 1H), 7.25 (s, 0.5H), 7.42 (s, 0.5H), 7.45 (s, 0.5H), 7.47 (s, 0.5H).

Example 60
Synthesis of 2-(4-bromo-1H-pyrazol-1-yl)-1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(4-bromo-1H-pyrazol-1-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.15 (m, 1H), 1.50-1.70 (m, 1H), 1.70-2.45 (m, 7H), 2.50-2.85 (m, 2H), 2.85-3.00 (m, 2H), 3.12-3.22 (m, 0.5H), 3.30-3.45 (m, 1.5H), 3.65-3.75 (m, 0.5H), 3.75-3.90 (m, 1H), 3.95-4.05 (m, 0.5H), 4.61 (d, J=16 Hz, 0.5H), 4.79 (d, J=16 Hz, 0.5H), 4.92 (s, 1H), 6.60-6.70 (m, 2H), 6.90-7.00 (m, 1H), 7.33 (s, 0.5H), 7.43 (s, 1H), 7.46 (s, 0.5H).

Example 61
Synthesis of (5aS,6R,11bS)-3-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 60 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.65 (m, 2H), 0.75-0.90 (m, 1H), 1.02 (d, J=10 Hz, 1H), 1.40-1.50 (m, 1H), 1.65-1.85 (m, 2H), 1.90-2.10 (m, 2H), 2.25-2.40 (m, 3H), 2.40-2.60 (m, 3H), 2.70-3.20 (m, 7H), 3.80-3.95 (m, 1H), 3.95-4.05 (m, 1H), 6.60-6.70 (m, 2H), 6.71 (s, 1H), 7.03 (d, J=8 Hz, 1H), 7.35 (s, 1H).

Example 62
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-imidazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(1H-imidazol-1-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.10-1.25 (m, 2H), 1.80-2.00 (m, 2.8H), 2.00-2.15 (m, 2.2H), 2.25-2.45 (m, 2H), 2.50-2.65 (m, 0.8H), 2.70-2.95 (m, 3.2H), 3.00-3.10 (m, 0.2H), 3.13-3.22 (m, 0.8H), 3.25-3.35 (m, 0.2H), 3.40 (dd, J=8, 14 Hz, 0.8H), 3.70-3.80 (m, 0.2H), 3.85-4.05 (m, 1.8H), 4.43 (d, J=16 Hz, 0.8H), 4.67 (d, J=16 Hz, 0.2H), 4.75-4.90 (m, 1H), 6.57 (d, J=2 Hz, 0.2H), 6.65-6.75 (m, 1H), 6.81 (dd, J=2, 8 Hz, 0.8H), 6.85-6.95 (m, 1.8H), 6.95-7.05 (m, 1.2H), 7.35 (s, 0.8H), 7.48 (s, 0.2H).

Example 63
Synthesis of (5aS,6R,11bS)-3-(2-(1H-imidazol-1-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 62 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.70-0.90 (m, 1H), 1.04 (d, J=10 Hz, 1H), 1.51 (dd, J=5, 14 Hz, 1H), 1.65-1.75 (m, 1H), 1.82 (ddd, J=3, 11, 14 Hz, 1H), 1.95-2.05 (m, 2H), 2.30-2.45 (m, 3H), 2.45-2.55 (m, 3H), 2.60-2.75 (m, 2H), 2.80-3.00 (m, 4H), 3.08-3.18 (m, 1H), 3.78 (t, J=6 Hz, 2H), 6.60 (s, 1H), 6.64 (d, J=3 Hz, 1H), 6.73 (dd, J=3, 8 Hz, 1H), 6.91 (s, 1H), 6.97 (d, J=8 Hz, 1H), 7.08 (s, 1H).

Example 64
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(2H-1,2,3-triazol-2-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.10 (m, 1H), 1.50-1.70 (m, 1H), 1.75-1.85 (m, 0.4H), 1.90-2.20 (m, 3.6H), 2.25-2.45 (m, 2H), 2.50-2.70 (m, 1.4H), 2.70-3.10 (m, 4.6H), 3.20-3.35 (m, 0.4H), 3.35-3.50 (m, 0.6H), 3.60-3.70 (m, 0.4H), 3.76 (s, 1.8H), 3.81 (s, 1.2H), 3.85-3.95 (m, 1H), 4.20-4.30 (m, 0.6H), 4.50 (br s, 1H), 4.94 (d, J=16 Hz, 0.4H), 5.19 (d, J=16 Hz, 0.4H), 5.28 (d, J=16 Hz, 0.6H), 5.38 (d, J=16 Hz, 0.6H), 6.60-6.80 (m, 2H), 7.00-7.10 (m, 1H), 7.61 (s, 0.8H), 7.66 (s, 1.2H).

Example 65
Synthesis of (5aS,6R,11bS)-3-(2-(2H-1,2,3-triazol-2-yl)ethyl)-14-(cyclopropylmethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 64 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.02 (d, J=11 Hz, 1H), 1.40-1.50 (m, 1H), 1.70-2.10 (m, 4H), 2.20-2.40 (m, 3H), 2.50-2.60 (m, 2H), 2.65-3.10 (m, 7H), 3.11-3.23 (m, 1H), 3.77 (s, 3H), 4.35-4.50 (m, 2H), 6.63 (d, J=2 Hz, 1H), 6.68 (dd, J=2, 8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 7.52 (s, 2H).

Example 66
Synthesis of (5aS,6R,11bS)-3-(2-(2H-1,2,3-triazol-2-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 65 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.03 (d, J=11 Hz, 1H), 1.20-1.30 (m, 1H), 1.40-1.50 (m, 1H), 1.70-1.90 (m, 2H), 1.90-2.10 (m, 3H), 2.20-2.40 (m, 4H), 2.50-3.25 (m, 7H), 4.40-4.60 (m, 2H), 6.51 (d, J=2 Hz, 1H), 6.59 (dd, J=2, 8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 7.54 (s, 2H).

Example 67
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(pyridin-2-yl)propan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 3-(pyridin-2-yl)propanoic acid according to the method described in Example 7.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.45-0.57 (m, 2H), 0.76-0.88 (m, 1H), 1.01-1.12 (m, 1H), 1.54-1.65 (m, 1H), 1.78 (ddd, J=2, 12, 15 Hz, 0.5H), 1.87 (ddd, J=4, 12, 16 Hz, 0.5H), 1.91-2.23 (m, 3.5H), 2.29 (dd, J=6, 12 Hz, 0.5H), 2.30-2.40 (m, 1.5H), 2.41-2.60 (m, 2H), 2.66-3.18 (m, 7H), 3.34 (ddd, J=4, 4, 14 Hz, 0.5H), 3.39-3.49 (m, 0.5H), 3.50 (ddd, J=4, 4, 14 Hz, 0.5H), 3.61-3.73 (m, 0.5H), 3.70 (s, 1.5H), 3.77 (s, 1.5H), 3.80-3.92 (m, 1H), 4.17 (ddd, J=3, 5, 15 Hz, 0.5H), 4.48 (br s, 1H), 6.63 (d, J=2 Hz, 0.5H), 6.64-6.73 (m, 1.5H), 7.00 (d, J=8 Hz, 0.5H), 7.01 (d, J=8 Hz, 0.5H), 7.04-7.10 (m, 1H), 7.13 (d, J=8 Hz, 0.5H), 7.20 (d, J=8 Hz, 0.5H), 7.51-7.59 (m, 1H), 8.46-8.51 (m, 1H).

Example 68
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(3-(pyridin-2-yl)propyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

A solution of the compound (14 mg, 0.030 mmol) obtained in Example 67 in tetrahydrofuran (1.0 mL) was cooled to −20° C., and to the cooled solution, lithium aluminum hydride (3.1 mg, 0.082 mmol) was added, followed by stirring at −20° C. for 2 hours, and then heating to 0° C. and stirring for 1 hour. Thereafter, lithium aluminum hydride (3.1 mg, 0.082 mmol) was added, followed by stirring at 0° C. for 25 hours. Thereafter, lithium aluminum hydride (3.1 mg, 0.082 mmol) was further added, followed by stirring at room temperature for 1 hour. After the reaction mixture was cooled to 0° C., a saturated Rochelle's salt aqueous solution was added to stop the reaction, and the temperature was raised to room temperature. Subsequently, the resultant mixture was stirred overnight and extracted three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (18 to 60% 2 M ammonia-methanol solution/ethyl acetate) to yield the title compound (3.0 mg, 22%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.44-0.55 (m, 2H), 0.79-0.91 (m, 1H), 1.00-1.09 (m, 1H), 1.50 (ddd, J=3, 5, 15 Hz, 1H), 1.74-2.03 (m, 5H), 2.09 (ddd, J=5, 13, 13 Hz, 1H), 2.29-2.52 (m, 6H), 2.55 (ddd, J=2, 6, 11 Hz, 1H), 2.59-2.69 (m, 3H), 2.75-2.86 (m, 2H), 2.95 (d, J=6 Hz, 1H), 2.98 (d, J=18 Hz, 1H), 3.09 (ddd, J=2, 10, 13 Hz, 1H), 3.76 (s, 3H), 6.64-6.71 (m, 2H), 6.97-7.01 (m, 1H), 7.00 (d, J=8 Hz, 1H), 7.06 (ddd, J=1, 5, 7 Hz, 1H), 7.54 (ddd, J=2, 7, 7 Hz, 1H), 8.49 (ddd, J=1, 2, 5 Hz, 1H).

Example 69
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(3-(pyridin-2-yl)propyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 68 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.17 (m, 2H), 0.45-0.55 (m, 2H), 0.77-0.88 (m, 1H), 0.97-1.07 (m, 1H), 1.47 (ddd, J=1, 6, 14 Hz, 1H), 1.73-1.90 (m, 4H), 1.95-2.09 (m, 3H), 2.32-2.68 (m, 9H), 2.76 (dd, J=6, 18 Hz, 1H), 2.90 (d, J=6 Hz, 1H), 2.94-3.08 (m, 2H), 2.95 (d, J=18 Hz, 1H), 4.73 (br s, 1H), 6.59 (dd, J=2, 8 Hz, 1H), 6.62 (d, J=2 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 7.07-7.12 (m, 1H), 7.11 (dd, J=5, 8 Hz, 1H), 7.58 (ddd, J=2, 8, 8 Hz, 1H), 8.48-8.51 (m, 1H).

Example 70
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(pyridin-3-yl)propan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 3-(pyridin-3-yl)propanoic acid according to the method described in Example 7.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.16 (m, 2H), 0.46-0.57 (m, 2H), 0.77-0.88 (m, 1H), 1.01-1.12 (m, 1H), 1.57 (ddd, J=3, 3, 14 Hz, 0.5H), 1.63 (ddd, J=2, 5, 15 Hz, 0.5H), 1.78 (ddd, J=2, 12, 14 Hz, 0.5H), 1.84-2.23 (m, 4.5H), 2.24-2.86 (m, 7H), 2.87-3.05 (m, 3.5H), 3.24 (ddd, J=4, 4, 13 Hz, 0.5H), 3.32-3.43 (m, 1H), 3.65-3.76 (m, 0.5H), 3.70 (s, 1.5H), 3.79 (s, 1.5H), 3.83 (ddd, J=3, 13, 13 Hz, 0.5H), 3.91 (ddd, J=3, 4, 14 Hz, 0.5H), 4.22 (ddd, J=2, 5, 14 Hz, 0.5H), 6.62 (d, J=2 Hz, 0.5H), 6.67 (dd, J=2, 8 Hz, 0.5H), 6.69-6.74 (m, 1H), 7.01 (d, J=8 Hz, 0.5H), 7.03 (d, J=8 Hz, 0.5H), 7.18 (dd, J=5, 8 Hz, 1H), 7.45 (ddd, J=2, 2, 8 Hz, 0.5H), 7.53 (ddd, J=2, 2, 8 Hz, 0.5H), 8.38-8.49 (m, 2H).

Example 71
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(3-(pyridin-3-yl)propyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 70 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.45-0.56 (m, 2H), 0.79-0.91 (m, 1H), 1.02-1.09 (m, 1H), 1.51 (ddd, J=3, 4, 14 Hz, 1H), 1.59-1.72 (m, 2H), 1.84 (ddd, J=4, 11, 14 Hz, 1H), 1.90 (ddd, J=4, 4, 16 Hz, 1H), 1.98 (ddd, J=3, 11, 12 Hz, 1H), 2.09 (ddd, J=4, 12, 12 Hz, 1H), 2.32-2.46 (m, 8H), 2.52-2.62 (m, 2H), 2.78-2.90 (m, 2H), 2.96 (d, J=6 Hz, 1H), 2.99 (d, J=18 Hz, 1H), 3.06 (ddd, J=2, 12, 13 Hz, 1H), 3.75 (s, 3H), 6.67 (dd, J=2, 8 Hz, 1H), 6.71 (d, J=2 Hz, 1H), 7.01 (d, J=8 Hz, 1H), 7.16 (dd, J=5, 8 Hz, 1H), 7.35 (ddd, J=2, 2, 8 Hz, 1H), 8.29-8.31 (m, 1H), 8.38-8.41 (m, 1H).

Example 72
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(3-(pyridin-3-yl)propyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 71 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.44-0.55 (m, 2H), 0.77-0.89 (m, 1H), 0.98-1.06 (m, 1H), 1.51 (dd, J=5, 14 Hz, 1H), 1.59-1.77 (m, 3H), 1.78-1.87 (m, 1H), 1.96-2.07 (m, 2H), 2.28-2.47 (m, 7H), 2.49-2.58 (m, 3H), 2.78 (dd, J=6, 18 Hz, 1H), 2.84-2.95 (m, 1H), 2.90 (d, J=6 Hz, 1H), 2.95 (d, J=18 Hz, 1H), 2.98-3.07 (m, 1H), 4.72 (br s, 1H), 6.56-6.61 (m, 2H), 6.91 (d, J=8 Hz, 1H), 7.18 (dd, J=5, 7 Hz, 1H), 7.41 (d, J=7 Hz, 1H), 8.18 (s, 1H), 8.38 (d, J=5 Hz, 1H).

Example 73
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(pyridin-4-yl)propan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 3-(pyridin-4-yl)propanoic acid according to the method described in Example 7.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.45-0.58 (m, 2H), 0.76-0.91 (m, 1H), 1.01-1.13 (m, 1H), 1.58 (ddd, J=4, 4, 14 Hz, 0.5H), 1.63 (ddd, J=2, 5, 15 Hz, 0.5H), 1.77 (ddd, J=3, 12, 15 Hz, 0.5H), 1.84-2.23 (m, 4H), 2.25-3.06 (m, 11H), 3.25 (ddd, J=4, 4, 13 Hz, 0.5H), 3.36 (ddd, J=1, 12, 14 Hz, 0.5H), 3.41 (ddd, J=3, 6, 14 Hz, 0.5H), 3.66-3.80 (m, 0.5H), 3.69 (s, 1.5H), 3.78 (s, 1.5H), 3.83 (ddd, J=3, 13, 13 Hz, 0.5H), 3.91 (ddd, J=3, 5, 14 Hz, 0.5H), 4.22 (ddd, J=3, 5, 14 Hz, 0.5H), 6.63 (d, J=3 Hz, 0.5H), 6.67 (dd, J=3, 8 Hz, 0.5H), 6.69-6.75 (m, 1H), 6.99-7.06 (m, 2H), 7.11-7.14 (m, 1H), 8.44-8.48 (m, 2H).

Example 74
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(3-(pyridin-4-yl)propyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 73 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.17 (m, 2H), 0.45-0.56 (m, 2H), 0.78-0.90 (m, 1H), 1.01-1.09 (m, 1H), 1.51 (ddd, J=3, 5, 14 Hz, 1H), 1.55-1.72 (m, 2H), 1.84 (ddd, J=4, 11, 14 Hz, 1H), 1.89 (ddd, J=4, 4, 16 Hz, 1H), 1.98 (ddd, J=3, 11, 11 Hz, 1H), 2.09 (ddd, J=5, 13, 13 Hz, 1H), 2.29-2.46 (m, 8H), 2.52-2.61 (m, 2H), 2.82 (dd, J=6, 18 Hz, 1H), 2.82-2.91 (m, 1H), 2.95 (d, J=6 Hz, 1H), 2.99 (d, J=18 Hz, 1H), 3.04 (ddd, J=2, 12, 14 Hz, 1H), 3.75 (s, 3H), 6.66 (dd, J=2, 8 Hz, 1H), 6.71 (d, J=2 Hz, 1H), 6.94-6.98 (m, 2H), 7.01 (d, J=8 Hz, 1H), 8.41-8.45 (m, 2H).

Example 75
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(3-(pyridin-4-yl)propyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 74 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.45-0.55 (m, 2H), 0.78-0.88 (m, 1H), 0.95-1.05 (m, 1H), 1.51 (dd, J=5, 14 Hz, 1H), 1.63-1.81 (m, 3H), 1.83 (ddd, J=3, 12, 14 Hz, 1H), 1.95-2.08 (m, 2H), 2.29-2.50 (m, 7H), 2.51-2.62 (m, 3H), 2.77 (dd, J=6, 18 Hz, 1H), 2.85-2.94 (m, 1H), 2.90 (d, J=6 Hz, 1H), 2.94 (d, J=18 Hz, 1H), 2.99-3.08 (m, 1H), 4.74 (br s, 1H), 6.53 (d, J=2 Hz, 1H), 6.56 (dd, J=2, 8 Hz, 1H), 6.88 (d, J=8 Hz, 1H), 6.97-7.00 (m, 2H), 8.41-8.44 (m, 2H).

Example 76
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(2-(pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

(Method 1)

The title compound was obtained from the isomer C obtained in Example 2 and 2-(pyridin-2-yl)ethyl 4-methylbenzenesulfonate (synthesized by the method described in Journal of Medicinal Chemistry, 2015, 58, 5842) according to the method described in Example 31.

(Method 2)

To a solution of the isomer C (257.7 mg, 0.75 mmol) obtained in Example 2 in ethanol (10 mL) were added acetic acid (430.1 μL, 7.52 mmol) and 2-vinylpyridine (807.3 μL, 7.52 mmol), followed by heating under reflux for 3.5 hours.

After allowed to cool, the reaction solution was concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 3% methanol/chloroform) to yield the title compound (357.3 mg, quantitative) as a pale yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.13 (m, 2H), 0.44-0.55 (m, 2H), 0.79-0.90 (m, 1H), 1.00-1.07 (m, 1H), 1.49 (ddd, J=3, 4, 14 Hz, 1H), 1.81 (ddd, J=4, 11, Hz, 1H), 1.91-2.02 (m, 2H), 2.08 (ddd, J=4, 12, 12 Hz, 1H), 2.28-2.40 (m, 3H), 2.50-2.61 (m, 2H), 2.71-2.91 (m, 7H), 2.94 (d, J=6 Hz, 1H), 2.97 (d, J=18 Hz, 1H), 3.20 (ddd, J=3, 10, 13 Hz, 1H), 3.77 (s, 3H), 4.68 (br s, 1H), 6.66-6.71 (m, 2H), 6.98-7.04 (m, 2H), 7.05 (dd, J=5, 8 Hz, 1H), 7.50 (ddd, J=2, 8, 8 Hz, 1H), 8.45-8.49 (m, 1H).

Example 77
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 76 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.44-0.54 (m, 2H), 0.76-0.89 (m, 1H), 1.00-1.08 (m, 1H), 1.50 (ddd, J=2, 6, 15 Hz, 1H), 1.78-1.89 (m, 2H), 1.96-2.08 (m, 2H), 2.25-2.39 (m, 3H), 2.48-2.58 (m, 1H), 2.72-2.84 (m, 2H), 2.73 (dd, J=6, 18 Hz, 1H), 2.86-3.00 (m, 7H), 3.21 (ddd, J=2, 11, 11 Hz, 1H), 4.73 (br s, 1H), 6.48 (d, J=2 Hz, 1H), 6.57 (dd, J=2, 8 Hz, 1H), 6.87 (d, J=8 Hz, 1H), 7.08-7.13 (m, 2H), 7.56 (ddd, J=2, 8, 8 Hz, 1H), 8.46-8.49 (m, 1H).

Example 78
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-3-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(pyridin-3-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.03 (d, J=13 Hz, 1H), 1.45-1.55 (m, 1H), 1.80-1.90 (m, 2H), 1.99 (ddd, J=4, 11, 11 Hz, 1H), 2.10 (ddd, J=3, 13, 13 Hz, 1H), 2.30-2.70 (m, 6H), 2.70-2.90 (m, 2H), 2.90-3.00 (m, 2H), 3.07 (ddd, J=3, 11, 13 Hz, 1H), 3.54 (s, 2H), 3.68 (s, 3H), 4.78 (br s, 1H), 6.62 (d, J=2 Hz, 1H), 6.71 (dd, J=2, 8 Hz, 1H), 7.00-7.10 (m, 3H), 7.10-7.25 (m, 2H).

Example 79
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(2-(pyridin-3-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 78 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.10 (m, 1H), 1.20-1.30 (m, 1H), 1.65-1.80 (m, 2H), 1.80-1.95 (m, 2H), 1.95-2.10 (m, 1H), 2.30-2.45 (m, 2H), 2.50-2.55 (m, 1H), 2.60-2.85 (m, 7H), 2.85-3.10 (m, 3H), 3.10-3.25 (m, 1H), 3.77 (s, 3H), 6.55-6.65 (m, 2H), 7.00-7.05 (m, 2H), 7.05-7.10 (m, 1H), 7.10-7.15 (m, 1H), 7.25-7.40 (m, 1H).

Example 80
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(pyridin-3-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 79 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.80-0.90 (m, 1H), 1.04 (d, J=11 Hz, 1H), 1.50 (dd, J=5, 14 Hz, 1H), 1.70-1.90 (m, 2H), 1.95-2.10 (m, 3H), 2.30-2.40 (m, 3H), 2.50-2.60 (m, 1H), 2.60-2.80 (m, 6H), 2.85-3.00 (m, 3H), 3.15-3.25 (m, 1H), 6.56 (d, J=2 Hz, 1H), 6.63 (dd, J=2, 8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 7.16 (dd, J=6, 8 Hz, 1H), 7.42 (ddd, J=2, 2, 6 Hz, 1H), 8.35 (d, J=2 Hz, 1H), 8.40 (dd, J=2, 6 Hz, 1H).

Example 81
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-4-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(pyridin-4-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.10 (m, 1H), 1.50-1.70 (m, 1H), 1.70-1.90 (m, 1H), 1.90-2.50 (m, 5H), 2.50-2.75 (m, 1.5H), 2.75-3.05 (m, 2.5H), 3.10-3.25 (m, 0.5H), 3.25-3.35 (m, 0.5H), 3.35-3.50 (m, 2H), 3.65-4.00 (m, 3.5H), 3.75 (s, 1.5H), 3.79 (s, 1.5H), 4.05-4.20 (m, 0.5H), 4.50 (br s, 1H), 6.61 (d, J=3 Hz, 0.5H), 6.65-6.75 (m, 1.5H), 6.90-7.00 (m, 1H), 7.03 (d, J=8 Hz, 1H), 7.08 (d, J=6 Hz, 1H), 8.40-8.50 (m, 2H).

Example 82
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(pyridin-4-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 81 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.10 (m, 1H), 1.45-1.55 (m, 1H), 1.70-1.90 (m, 2H), 1.90-2.10 (m, 3H), 2.20-2.50 (m, 3H), 2.50-2.85 (m, 7H), 2.85-3.15 (m, 4H), 4.65 (br s, 1H), 6.52-6.65 (m, 2H), 6.93 (d, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 2H), 8.37 (d, J=5 Hz, 2H).

Example 83
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(pyrimidin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(pyrimidin-2-yl)ethan-1-ol according to the method described in Example 32.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.05 (d, J=10 Hz, 1H), 1.51 (dd, J=6, 15 Hz, 1H), 1.80-2.10 (m, 4H), 2.25-2.40 (m, 3H), 2.54 (d, J=7 Hz, 1H), 2.73 (dd, J=6, 17 Hz, 1H), 2.80-3.00 (m, 5H), 3.10-3.25 (m, 4H), 3.25-3.40 (t, J=11 Hz, 1H), 6.52 (s, 1H), 6.55 (d, J=8 Hz, 1H), 6.86 (d, J=8 Hz, 1H), 7.10 (t, J=5 Hz, 1H), 8.62 (d, J=5 Hz, 2H).

Example 84
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(pyrazin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(pyrazin-2-yl)ethyl methanesulfonate (synthesized by the method described in WO 2017223239) according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.02 (d, J=9 Hz, 1H), 1.50 (dd, J=4, 14 Hz, 1H), 1.70-1.90 (m, 2H), 1.90-2.10 (m, 2H), 2.30-2.40 (m, 3H), 2.50-2.60 (m, 1H), 2.70-2.85 (m, 3H), 2.85-3.05 (m, 7H), 3.24 (t, J=12 Hz, 1H), 6.49 (d, J=2 Hz, 1H), 6.57 (dd, J=2, 8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 8.30-8.40 (m, 2H), 8.40-8.50 (m, 1H).

Example 85
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(6-methoxypyridin-2-yl)ethan-1-one

[Image Omitted]

A solution of the compound E (7.8 mg, 0.0237 mmol) obtained in Example 3, 2-(6-methoxypyridin-2-yl)acetic acid (10 mg, 0.0609 mmol), N,N-dimethylaminopyridine (1.9 mg, 0.0152 mmol), 1-hydroxybenztriazole monohydrate (6.0 mg, 0.0395 mmol), N,N-diisopropylethylamine (26 μL, 0.152 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.6 mg, 0.0395 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature overnight. Then, to the solution, a suspension of potassium carbonate (50 mg, 0.36 mmol) in methanol (1 mL) was added, followed by stirring at room temperature for 4 hours. The reaction mixture was extracted four times with ethyl acetate, and then the combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (3 to 15% methanol/chloroform) to yield the title compound (11 mg, 97%) as a white powder.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.18 (m, 2H), 0.43-0.58 (m, 2H), 0.75-0.93 (m, 1H), 0.98-1.15 (m, 1H), 1.17-2.21 (m, 5.5H), 2.24-3.04 (m, 6.5H), 3.25-3.34 (m, 0.5H), 3.40-3.99 (m, 7.5H), 4.02-4.18 (m, 1H), 6.51-6.84 (m, 4H), 6.88-6.98 (m, 1H), 7.39-7.50 (m, 1H).

Example 86
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(6-methoxypyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 85 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.17 (m, 2H), 0.41-0.56 (m, 2H), 0.76-0.91 (m, 1H), 0.94-2.11 (m, 6H), 2.26-2.40 (m, 3H), 2.47-2.58 (m, 1H), 2.67-3.03 (m, 10H), 3.13-3.25 (m, 1H), 3.89 (s, 3H), 4.73 (br s, 1H), 6.44-6.53 (m, 2H), 6.56 (dd, J=2, 8 Hz, 1H) 6.65 (d, J=7 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 7.37-7.45 (m, 1H).

Example 87
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid according to the method described in Example 85.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.44-0.57 (m, 2H), 0.74-0.93 (m, 1H), 1.01-1.13 (m, 1H), 1.19-1.69 (m, 1H), 1.70-1.89 (m, 1H), 1.90-2.19 (m, 3H), 2.22-2.42 (m, 2.6H), 2.45-2.59 (m, 1.4H), 2.61-3.02 (m, 3H), 3.24-3.48 (m, 1H), 3.49-3.61 (m, 1H), 3.64-4.08 (m, 4H), 4.28-4.60 (m, 1H), 6.58-6.68 (m, 1.4H), 6.73 (d, J=2 Hz, 0.6H), 6.87-6.97 (m, 1H), 7.37-7.45 (m, 1H), 7.49-7.56 (m, 1H), 7.75 (dd, J=8, 8 Hz, 1H).

Example 88
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(6-(trifluoromethyl)pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 87 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.02-0.16 (m, 2H), 0.41-0.56 (m, 2H), 0.75-0.91 (m, 1H), 0.95-1.07 (m, 1H), 1.15-2.11 (m, 5H), 2.26-2.42 (m, 3H), 2.46-2.57 (m, 1H), 2.66 (ddd, J=3, 5, 13 Hz, 1H), 2.69-2.80 (m, 2H), 2.85-3.03 (m, 7H), 3.10-3.22 (m, 1H), 4.68 (br s, 1H), 6.48-6.60 (m, 2H), 6.94 (d, J=8 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.44 (d, J=8 Hz, 1H), 7.65 (dd, J=8, 8 Hz, 1H).

Example 89
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-phenethyl-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and phenethyl 4-methylbenzenesulfonate (synthesized by the method described in Journal of the American Chemical Society, 2012, 134, 11408) according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.79-0.91 (m, 1H), 1.01-1.08 (m, 1H), 1.50 (ddd, J=3, 5, 15 Hz, 1H), 1.84 (ddd, J=4, 12, Hz, 1H), 1.92-2.03 (m, 2H), 2.09 (ddd, J=5, 13, 13 Hz, 1H), 2.29-2.38 (m, 3H), 2.52-2.60 (m, 2H), 2.62-2.83 (m, 6H), 2.87 (ddd, J=2, 11, 13 Hz, 1H), 2.94 (d, J=6 Hz, 1H), 2.98 (d, J=18 Hz, 1H), 3.21 (ddd, J=3, 12, 13 Hz, 1H), 3.77 (s, 3H), 4.72 (br s, 1H), 6.68-6.73 (m, 2H), 6.99-7.04 (m, 1H), 7.07-7.17 (m, 3H), 7.19-7.25 (m, 2H).

Example 90
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-phenethyl-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 89 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.13 (m, 2H), 0.43-0.54 (m, 2H), 0.75-0.87 (m, 1H), 0.97-1.06 (m, 1H), 1.41-1.52 (m, 1H), 1.70-1.85 (m, 2H), 1.92-2.04 (m, 2H), 2.16-2.37 (m, 3H), 2.45-2.55 (m, 1H), 2.62-2.97 (m, 10H), 3.07-3.21 (m, 1H), 4.79 (br s, 1H), 6.42 (s, 1H), 6.53 (d, J=8 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 7.10-7.19 (m, 3H), 7.23 (d, J=8 Hz, 2H).

Example 91
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-phenylpropan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 3-phenylpropanoic acid according to the method described in Example 7.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.46-0.56 (m, 2H), 0.76-0.88 (m, 1H), 1.01-1.12 (m, 1H), 1.56 (ddd, J=3, 3, 15 Hz, 0.5H), 1.63 (ddd, J=2, 5, 15 Hz, 0.5H), 1.79 (ddd, J=3, 12, 15 Hz, 0.5H), 1.83-2.03 (m, 2H), 2.08 (ddd, J=5, 13, 13 Hz, 0.5H), 2.15-2.20 (m, 1H), 2.26-2.66 (m, 5.5H), 2.68 (ddd, J=4, 6, Hz, 0.5H), 2.73-3.05 (m, 5.5H), 3.25 (ddd, J=4, 4, 13 Hz, 0.5H), 3.34-3.45 (m, 1H), 3.64-3.74 (m, 0.5H), 3.69 (s, 1.5H), 3.79 (s, 1.5H), 3.83 (ddd, J=3, 12, 12 Hz, 0.5H), 3.91 (ddd, J=2, 4, 14 Hz, 0.5H), 4.21 (ddd, J=3, 5, 14 Hz, 0.5H), 6.62 (d, J=3 Hz, 0.5H), 6.68 (dd, J=3, 8 Hz, 0.5H), 6.70-6.74 (m, 1H), 7.01 (d, J=8 Hz, 0.5H), 7.02 (d, J=8 Hz, 0.5H), 7.12-7.32 (m, 5H).

Example 92
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(3-phenylpropyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 91 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.45-0.54 (m, 2H), 0.80-0.91 (m, 1H), 1.01-1.09 (m, 1H), 1.50 (ddd, J=3, 4, 15 Hz, 1H), 1.62-1.72 (m, 2H), 1.84 (ddd, J=4, 12, 15 Hz, 1H), 1.89-2.02 (m, 2H), 2.10 (ddd, J=5, 13, 13 Hz, 1H), 2.29-2.48 (m, 8H), 2.55 (ddd, J=2, 5, 11 Hz, 1H), 2.62 (ddd, J=4, 4, 13 Hz, 1H), 2.76-2.85 (m, 2H), 2.96 (d, J=6 Hz, 1H), 2.98 (d, J=18 Hz, 1H), 3.07 (ddd, J=3, 11, 13 Hz, 1H), 3.76 (s, 3H), 4.79 (br s, 1H), 6.67 (dd, J=3, 8 Hz, 1H), 6.70 (d, J=3 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 7.06-7.10 (m, 2H), 7.14 (tt, J=2, 7 Hz, 1H), 7.21-7.27 (m, 2H).

Example 93
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(3-phenylpropyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 92 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.17 (m, 2H), 0.46-0.54 (m, 2H), 0.78-0.88 (m, 1H), 0.95-1.03 (m, 1H), 1.48 (ddd, J=2, 6, 15 Hz, 1H), 1.71-1.88 (m, 4H), 1.98-2.04 (m, 2H), 2.25-2.39 (m, 3H), 2.48-2.64 (m, 5H), 2.66-2.77 (m, 3H), 2.83-2.92 (m, 1H), 2.88 (d, J=6 Hz, 1H), 2.93 (d, J=18 Hz, 1H), 3.05-3.15 (m, 1H), 4.80 (br s, 1H), 6.42 (d, J=3 Hz, 1H), 6.53 (dd, J=3, 8 Hz, 1H), 6.87 (d, J=8 Hz, 1H), 7.11-7.18 (m, 3H), 7.21-7.28 (m, 2H).

Example 94
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-fluorophenethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(2-fluorophenyl)ethan-1-ol according to the method described in Example 32.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.04 (d, J=14 Hz, 1H), 1.45-1.55 (m, 1H), 1.75-1.90 (m, 1H), 1.90-2.15 (m, 3H), 2.25-2.40 (m, 2H), 2.50-2.60 (m, 2H), 2.60-3.00 (m, 9H), 3.15-3.25 (m, 1H), 3.77 (s, 3H), 3.80-3.90 (m, 1H), 4.70 (br s, 1H), 6.65-6.75 (m, 2H), 6.90-7.20 (m, 5H).

Example 95
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-fluorophenethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 94 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.04 (d, J=11 Hz, 1H), 1.52 (dd, J=4, 15 Hz, 1H), 1.80-1.90 (m, 2H), 1.95-2.10 (m, 2H), 2.25-2.40 (m, 3H), 2.50-2.60 (m, 1H), 2.70-3.10 (m, 10H), 3.18-3.33 (m, 1H), 4.75 (br s, 1H), 6.47 (d, J=3 Hz, 1H), 6.57 (dd, J=3, 8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 6.95-7.05 (m, 2H), 7.10-7.20 (m, 2H).

Example 96
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-methoxyphenethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-methoxyphenethyl 4-methylbenzenesulfonate (synthesized by the method described in WO 2010021149) according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.45-0.54 (m, 2H), 0.77-0.88 (m, 1H), 1.00-1.07 (m, 1H), 1.52 (ddd, J=2, 6, 14 Hz, 1H), 1.78-1.88 (m, 2H), 1.96-2.09 (m, 2H), 2.27-2.41 (m, 3H), 2.46-2.61 (m, 1H), 2.69-3.04 (m, 10H), 3.26 (dd, J=12, 12 Hz, 1H), 3.78 (s, 3H), 4.79 (br s, 1H), 6.47 (d, J=2 Hz, 1H), 6.56 (dd, J=2, 8 Hz, 1H), 6.79-6.90 (m, 3H), 7.10 (dd, J=1, 7 Hz, 1H), 7.16 (ddd, J=1, 8, 8 Hz, 1H).

Example 97
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(3-methoxypyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(3-methoxypyridin-2-yl)acetic acid according to the method described in Example 7.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.16 (m, 2H), 0.43-0.57 (m, 2H), 0.76-0.87 (m, 1H), 1.00-1.11 (m, 1H), 1.52 (ddd, J=4, 4, 15 Hz, 0.6H), 1.52-1.61 (m, 0.4H), 1.76-1.90 (m, 1H), 1.91-2.08 (m, 2.4H), 2.09-2.18 (m, 0.6H), 2.19-2.43 (m, 2.6H), 2.47-2.59 (m, 1.4H), 2.69 (dd, J=6, 18 Hz, 0.6H), 2.76 (dd, J=6, 18 Hz, 0.4H), 2.84 (d, J=6 Hz, 0.6H), 2.88-2.95 (m, 0.8H), 2.96 (d, J=18 Hz, 0.6H), 3.08-3.23 (m, 0.6H), 3.27-3.45 (m, 1.4H), 3.64 (d, J=16 Hz, 0.4H), 3.64-3.76 (m, 0.4H), 3.73 (s, 3H), 3.80 (d, J=16 Hz, 0.4H), 3.85-3.98 (m, 2.2H), 4.22 (ddd, J=2, 5, 14 Hz, 0.6H), 6.59 (dd, J=2, 8 Hz, 0.6H), 6.61 (dd, J=2, 8 Hz, 0.4H), 6.66 (d, J=2 Hz, 0.4H), 6.80 (d, J=2 Hz, 0.6H), 6.88 (d, J=8 Hz, 0.4H), 6.89 (d, J=8 Hz, 0.6H), 7.07-7.17 (m, 2H), 8.06-8.10 (m, 1H).

Example 98
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(3-methoxypyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 97 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.14 (m, 2H), 0.44-0.54 (m, 2H), 0.77-0.88 (m, 1H), 1.01-1.07 (m, 1H), 1.51 (ddd, J=2, 5, 14 Hz, 1H), 1.80-1.92 (m, 2H), 1.96-2.09 (m, 2H), 2.26-2.39 (m, 3H), 2.50-2.55 (m, 1H), 2.72 (dd, J=6, 18 Hz, 1H), 2.81-3.10 (m, 9H), 3.21-3.30 (m, 1H), 3.78 (s, 3H), 4.78 (br s, 1H), 6.47 (d, J=2 Hz, 1H), 6.55 (dd, J=2, 8 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 7.08 (dd, J=2, 8 Hz, 1H), 7.10 (dd, J=4, 8 Hz, 1H), 8.07 (dd, J=2, 4 Hz, 1H).

Example 99
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(3-fluoropyridin-2-yl)ethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(3-fluoropyridin-2-yl)ethyl 4-methylbenzenesulfonate according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.14 (m, 2H), 0.44-0.55 (m, 2H), 0.78-0.90 (m, 1H), 0.98-1.07 (m, 1H), 1.51 (ddd, J=3, 4, 15 Hz, 1H), 1.82 (ddd, J=4, 12, Hz, 1H), 1.92-2.01 (m, 2H), 2.08 (ddd, J=5, 13, 13 Hz, 1H), 2.25-2.40 (m, 3H), 2.54 (ddd, J=2, 4, 11 Hz, 1H), 2.61 (ddd, J=4, 4, 13 Hz, 1H), 2.72-3.02 (m, 9H), 3.20 (ddd, J=3, 12, 13 Hz, 1H), 3.77 (s, 3H), 4.67 (br s, 1H), 6.65-6.69 (m, 2H), 6.98 (d, J=9 Hz, 1H), 7.09 (ddd, J=4, 4, 8 Hz, 1H), 7.26 (ddd, J=1, 8, 10 Hz, 1H), 8.29 (ddd, J=1, 1, 4 Hz, 1H).

Example 100
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(3-fluoropyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 99 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.43-0.54 (m, 2H), 0.77-0.88 (m, 1H), 0.99-1.09 (m, 1H), 1.51 (ddd, J=2, 5, 15 Hz, 1H), 1.78-1.90 (m, 2H), 1.96-2.09 (m, 2H), 2.27-2.39 (m, 3H), 2.49-2.59 (m, 1H), 2.73 (dd, J=6, 18 Hz, 1H), 2.82 (ddd, J=3, 6, 13 Hz, 1H), 2.85-3.09 (m, 8H), 3.19-3.28 (m, 1H), 4.73 (br s, 1H), 6.45 (d, J=3 Hz, 1H), 6.54 (dd, J=3, 8 Hz, 1H), 6.86 (d, J=8 Hz, 1H), 7.12 (ddd, J=4, 4, 8 Hz, 1H), 7.29 (ddd, J=1, 8, 10 Hz, 1H), 8.29 (ddd, J=1, 1, 4 Hz, 1H).

Example 101
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(2-(3-methylpyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(3-methylpyridine-2-yl)ethan-1-ol according to the method described in Example 32.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.45-0.55 (m, 2H), 0.79-0.90 (m, 1H), 1.01-1.09 (m, 1H), 1.50 (ddd, J=3, 5, 15 Hz, 1H), 1.84 (ddd, J=4, 12, Hz, 1H), 1.93-2.03 (m, 2H), 2.10 (ddd, J=5, 13, 13 Hz, 1H), 2.27 (s, 3H), 2.29-2.39 (m, 3H), 2.52-2.59 (m, 1H), 2.64 (ddd, J=4, 4, 13 Hz, 1H), 2.73-3.04 (m, 9H), 3.28 (ddd, J=3, 12, 13 Hz, 1H), 3.77 (s, 3H), 4.75 (br s, 1H), 6.66-6.72 (m, 2H), 6.97-7.03 (m, 2H), 7.34-7.39 (m, 1H), 8.32 (dd, J=1, 5 Hz, 1H).

Example 102
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(3-methylpyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 101 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.16 (m, 2H), 0.43-0.54 (m, 2H), 0.77-0.89 (m, 1H), 0.98-1.09 (m, 1H), 1.51 (ddd, J=2, 5, 15 Hz, 1H), 1.80-1.93 (m, 2H), 1.95-2.11 (m, 2H), 2.23 (s, 3H), 2.26-2.40 (m, 3H), 2.48-2.59 (m, 1H), 2.73 (dd, J=6, 18 Hz, 1H), 2.83-3.04 (m, 9H), 3.23-3.32 (m, 1H), 4.76 (br s, 1H), 6.49 (d, J=2 Hz, 1H), 6.58 (dd, J=2, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.05 (dd, J=5, 8 Hz, 1H), 7.38-7.43 (m, 1H), 8.33 (dd, J=1, 5 Hz, 1H).

Example 103
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(2-(6-methylpyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(6-methylpyridin-2-yl)ethyl 4-methylbenzenesulfonate (synthesized by the method described in WO 9905095) according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.14 (m, 2H), 0.45-0.54 (m, 2H), 0.79-0.90 (m, 1H), 0.99-1.07 (m, 1H), 1.49 (ddd, J=3, 4, 15 Hz, 1H), 1.82 (ddd, J=4, 11, Hz, 1H), 1.90-2.03 (m, 2H), 2.09 (ddd, J=5, 13, 13 Hz, 1H), 2.28-2.40 (m, 3H), 2.49 (s, 3H), 2.51-2.61 (m, 2H), 2.71-2.90 (m, 7H), 2.94 (d, J=6 Hz, 1H), 2.97 (d, J=18 Hz, 1H), 3.18 (ddd, J=3, 11, 13 Hz, 1H), 3.76 (s, 3H), 4.69 (br s, 1H), 6.67-6.71 (m, 2H), 6.82 (d, J=8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 6.98-7.02 (m, 1H), 7.38 (dd, J=8, 8 Hz, 1H).

Example 104
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(6-methylpyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 103 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.16 (m, 2H), 0.44-0.55 (m, 2H), 0.77-0.89 (m, 1H), 0.98-1.11 (m, 1H), 1.49 (ddd, J=2, 5, 14 Hz, 1H), 1.78-1.89 (m, 2H), 1.96-2.09 (m, 2H), 2.24-2.39 (m, 3H), 2.49-2.56 (m, 1H), 2.51 (s, 3H), 2.65-2.97 (m, 10H), 3.16-3.26 (m, 1H), 4.73 (br s, 1H), 6.48 (d, J=2 Hz, 1H), 6.56 (dd, J=2, 8 Hz, 1H), 6.86 (d, J=8 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 6.96 (d, J=8 Hz, 1H), 7.45 (dd, J=8, 8 Hz, 1H).

Reference Example 4
Synthesis of (E)-2-(2-methoxyvinyl)-4-methylpyridine (isomer G) and (Z)-2-(2-methoxyvinyl)-4-methylpyridine (isomer H)

[Image Omitted]

To 4-methylpicolinaldehyde (363.4 mg, 3.0 mmol) and (methoxymethyl) triphenylphosphonium chloride (3.09 g, 9.0 mmol) dissolved in tetrahydrofuran (60 mL) was added sodium hydride (55% oil dispersion) (600 mg, 13.8 mmol) at −20° C., followed by stirring at −20° C. for 30 minutes and at room temperature for 18 hours. The reaction mixture was poured into ice water, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, then dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10 to 100% ethyl acetate/heptane) to individually yield the title isomers G (70.2 mg, 16%) and H (73.9 mg, 17%).

(Isomer G)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.29 (s, 3H), 3.73 (s, 3H), 5.83 (d, J=13 Hz, 1H), 6.84 (dd, J=1, 5 Hz, 1H), 6.90 (d, J=1 Hz, 1H), 7.56 (d, J=13 Hz, 1H), 8.29 (d, J=5 Hz, 1H).

(Isomer H)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.33 (s, 3H), 3.84 (s, 3H), 5.47 (d, J=7 Hz, 1H), 6.32 (d, J=7 Hz, 1H), 6.85 (dd, J=1, 5 Hz, 1H), 7.70 (d, J=1 Hz, 1H), 8.36 (d, J=5 Hz, 1H).

Example 105
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-methylpyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To a solution of the isomer G (14.9 mg, 0.10 mmol) obtained in Reference Example 4 in methanol (1 mL) was added 2 M hydrochloric acid (1 mL), followed by heating under reflux for 8 hours. After allowed to cool, a saturated aqueous sodium bicarbonate solution was added to make the reaction solution basic, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure to yield a crude product of 2-(4-methylpyridin-2-yl)acetaldehyde. The title compound was obtained from the compound E obtained in Example 3 and the crude product of 2-(4-methylpyridin-2-yl)acetaldehyde according to the method described in Example 12.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.42-0.56 (m, 2H), 0.76-1.12 (m, 2H), 1.42-2.11 (m, 5H), 2.20-2.41 (m, 6H), 2.46-2.60 (m, 1H), 2.66-3.01 (m, 10H), 3.17-3.27 (m, 1H), 4.74 (br s, 1H), 6.48 (d, J=2 Hz, 1H), 6.57 (dd, J=2, 8 Hz, 1H), 6.87 (d, J=8 Hz, 1H), 6.90-6.97 (m, 2H), 8.33 (d, J=5 Hz, 1H).

Example 106
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2,2-difluoro-2-(pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2,2-difluoro-2-(pyridin-2-yl)ethyl trifluoromethanesulfonate (synthesized by the method described in WO 2011045383) according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.12 (m, 2H), 0.45-0.51 (m, 2H), 0.76-0.84 (m, 1H), 0.94-1.00 (m, 1H), 1.26-1.33 (m, 1H), 1.46 (ddd, J=3, 11, 15 Hz, 1H), 1.71 (ddd, J=3, 3, 16 Hz, 1H), 1.90-2.02 (m, 2H), 2.23-2.33 (m, 3H), 2.46-2.52 (m, 1H), 2.56 (ddd, J=4, 4, 13 Hz, 1H), 2.62 (dd, J=6, 18 Hz, 1H), 2.76-2.83 (m, 2H), 2.90 (d, J=18 Hz, 1H), 2.94-3.02 (m, 1H), 3.13-3.21 (m, 1H), 3.23-3.42 (m, 2H), 4.64 (br s, 1H), 6.51 (d, J=2 Hz, 1H), 6.60 (dd, J=2, 8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 7.24-7.30 (m, 2H), 7.63 (ddd, J=2, 8, 8 Hz, 1H), 8.57-8.62 (m, 1H).

Example 107
Synthesis of ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl) (1-(pyridin-2-yl)cyclopropyl)methanone

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 1-(pyridin-2-yl)cyclopropane-1-carboxylic acid according to the method described in Example 85.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.15 (m, 2H), 0.38-0.54 (m, 2.4H), 0.74-0.97 (m, 1.8H), 1.14-1.30 (m, 1.2H), 1.38 (ddd, J=3, 3, 15 Hz, 0.6H), 1.41-1.49 (m, 0.6H), 1.52-1.80 (m, 2.8H), 1.83-2.11 (m, 2.6H), 2.19-2.58 (m, 4.6H), 2.62 (dd, J=6, 18 Hz, 0.6H), 2.76 (dd, J=6, 18 Hz, 0.4H), 2.78 (d, J=6 Hz, 0.6H), 2.87 (d, J=6 Hz, 0.4H), 2.90 (d, J=18 Hz, 0.4H), 2.94-3.04 (m, 0.4H), 2.96 (d, J=18 Hz, 0.6H), 3.08 (ddd, J=4, 4, 14 Hz, 0.6H), 3.21 (dd, J=12, 14 Hz, 0.6H), 3.40 (ddd, J=2, 12, 14 Hz, 0.4H), 3.78 (ddd, J=4, 14, 14 Hz, 0.4H), 3.90-4.01 (m, 1H), 4.25-4.38 (m, 1H), 4.51 (br s, 1H), 6.55 (d, J=3 Hz, 0.4H), 6.63 (dd, J=3, 8 Hz, 0.4H), 6.69 (d, J=2, 8 Hz, 0.6H), 6.89 (d, J=8 Hz, 0.4H), 6.93 (d, J=8 Hz, 0.6H), 7.01-7.09 (m, 1.2H), 7.10 (d, J=2 Hz, 0.6H), 7.13 (ddd, J=1, 5, 7 Hz, 0.4H), 7.19-7.23 (m, 0.4H), 7.48 (ddd, J=2, 8, 8 Hz, 0.6H), 7.60 (ddd, J=2, 8, 8 Hz, 0.4H), 8.44 (ddd, J=1, 2, 5 Hz, 0.6H), 8.45 (ddd, J=1, 2, 5 Hz, 0.4H).

Example 108
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-((1-(pyridin-2-yl)cyclopropyl)methyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 107 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.14 (m, 2H), 0.45-0.51 (m, 2H), 0.74-0.87 (m, 2H), 0.92-0.98 (m, 1H), 1.15-1.23 (m, 2H), 1.38-1.45 (m, 1H), 1.65-1.77 (m, 1H), 1.90-2.04 (m, 2H), 2.20-2.29 (m, 1H), 2.31 (d, J=7 Hz, 2H), 2.46-2.53 (m, 1H), 2.62-2.73 (m, 3H), 2.78 (d, J=13 Hz, 1H), 2.78-2.84 (m, 1H), 2.85 (d, J=Hz, 1H), 2.88 (d, J=18 Hz, 1H), 2.91 (d, J=13 Hz, 1H), 2.95-3.04 (m, 1H), 3.67-3.74 (m, 2H), 6.33 (d, J=3 Hz, 1H), 6.50 (dd, J=3, 8 Hz, 1H), 6.83 (d, J=8 Hz, 1H), 6.93 (ddd, J=1, 5, 8 Hz, 1H), 7.23-7.28 (m, 1H), 7.38 (ddd, J=2, 8, 8 Hz, 1H), 8.35-8.38 (m, 1H).

Example 109
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-indol-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(1H-indol-2-yl)acetic acid according to the method described in Example 7.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.15 (m, 2H), 0.49-0.55 (m, 2H), 0.78-0.90 (m, 1H), 1.04-1.11 (m, 1H), 1.56-1.67 (m, 1.4H), 1.78-1.90 (m, 0.6H), 1.91-2.08 (m, 3H), 2.12-2.40 (m, 3H), 2.46-2.58 (m, 1.4H), 2.68 (dd, J=6, 18 Hz, 0.6H), 2.81 (dd, J=7, 19 Hz, 0.4H), 2.88-2.96 (m, 1.6H), 2.97-3.00 (m, 0.4H), 3.20 (ddd, J=3, 11, 14 Hz, 0.6H), 3.49 (ddd, J=4, 4, 13 Hz, 0.6H), 3.54-3.64 (m, 1H), 3.65-3.72 (m, 0.4H), 3.74-3.76 (m, 0.4H), 3.76 (s, 1.2H), 3.79 (s, 1.8H), 3.80-3.90 (m, 1.6H), 3.97 (ddd, J=3, 12, 12 Hz, 0.6H), 4.06-4.14 (m, 0.4H), 6.21-6.25 (m, 1H), 6.62-6.70 (m, 2H), 6.90 (d, J=8 Hz, 0.6H), 6.99-7.13 (m, 2.4H), 7.26-7.30 (m, 1H), 7.49-7.53 (m, 1H), 8.94 (br s, 0.4H), 9.23 (br s, 0.6H).

Example 110
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-indol-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 109 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.47-0.57 (m, 2H), 0.78-0.90 (m, 1H), 1.00-1.12 (m, 1H), 1.56-1.67 (m, 1.2H), 1.79-2.12 (m, 3.8H), 2.13-2.40 (m, 3.8H), 2.44-2.56 (m, 1.2H), 2.62 (dd, J=5, 18 Hz, 0.8H), 2.77 (dd, J=6, 18 Hz, 0.2H), 2.86-2.99 (m, 2H), 3.12-3.30 (m, 0.8H), 3.41-3.59 (m, 1.2H), 3.65-3.75 (m, 0.2H), 3.79-3.92 (m, 1.8H), 3.96-4.17 (m, 1H), 4.82 (br s, 1H), 6.17 (s, 0.2H), 6.27 (s, 0.8H), 6.49 (d, J=8 Hz, 0.2H), 6.60-6.72 (m, 1H), 6.73-6.81 (m, 0.8H), 6.86-6.92 (m, 1H), 6.99-7.13 (m, 2H), 7.15-7.20 (m, 0.2H), 7.21-7.29 (m, 0.8H), 7.43-7.52 (m, 1H), 8.83 (br s, 0.2H), 9.49 (br s, 0.8H).

Reference Example 5
Synthesis of tert-butyl 3-(2-hydroxyethyl)-1H-indazole-1-carboxylate

[Image Omitted]

To a solution of 2-(1H-indazol-3-yl)ethan-1-ol (13 mg, 0.077 mmol) in chloroform (2 mL) were added triethylamine (32 μL, 0.23 mmol), di-tert-butyl dicarbonate (20 mg, 0.093 mmol) and N,N-dimethylaminopyridine (1 mg, 0.0077 mmol), followed by stirring at room temperature for 17 hours. Water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (60 to 80% ethyl acetate/heptane) to yield the title compound (16 mg, 80%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.72 (s, 9H), 2.63 (t, J=6 Hz, 1H), 3.23 (t, J=6 Hz, 2H), 4.13 (dt, J=6, 6 Hz, 2H), 7.32 (t, J=8 Hz, 1H), 7.51-7.56 (m, 1H), 7.70 (d, J=8 Hz, 1H), 8.12 (d, J=9 Hz, 1H).

Reference Example 6
Synthesis of tert-butyl 3-(2-(tosyloxy)ethyl)-1H-indazole-1-carboxylate

[Image Omitted]

To a solution of the compound (16 mg, 0.060 mmol) obtained in Reference Example 5 in chloroform (1 mL) were added triethylamine (25 μL, 0.18 mmol) and p-toluenesulfonyl chloride (14 mg, 0.072 mmol) under ice cooling, followed by stirring at room temperature for 17 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added under ice cooling, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (15 to 35% ethyl acetate/heptane) to yield the title compound (25 mg, 99%) as a pale yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.72 (s, 9H), 2.41 (s, 3H), 3.56 (t, J=7 Hz, 2H), 4.47 (t, J=7 Hz, 2H), 7.17-7.34 (m, 3H), 7.52 (ddd, J=1, 7, 9 Hz, 1H), 7.61-7.68 (m, 3H), 8.05 (d, J=9 Hz, 1H).

Example 111
Synthesis of tert-butyl 3-(2-((5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)ethyl)-1H-indazole-1-carboxylate

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and the compound obtained in Reference Example 6 according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.18 (m, 2H), 0.46-0.55 (m, 2H), 0.77-0.92 (m, 1H), 0.99-1.10 (m, 1H), 1.20-1.65 (m, 1H), 1.72 (s, 9H), 1.79-2.14 (m, 4H), 2.30-2.45 (m, 3H), 2.50-2.59 (m, 1H), 2.61-2.71 (m, 1H), 2.73-3.12 (m, 9H), 3.19-3.33 (m, 1H), 3.76 (s, 3H), 6.62-6.69 (m, 2H), 6.98 (d, J=9 Hz, 1H), 7.21-7.31 (m, 1H), 7.48 (ddd, J=1, 7, 8 Hz, 1H), 7.63 (d, J=8 Hz, 1H), 8.05 (d, J=8 Hz, 1H).

Example 112
Synthesis of (5aS,6R,11bS)-3-(2-(1H-indazol-3-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 111 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.17 (m, 2H), 0.44-0.56 (m, 2H), 0.77-0.95 (m, 1H), 0.99-1.08 (m, 1H), 1.18-2.13 (m, 5H), 2.24-2.39 (m, 3H), 2.49-2.58 (m, 1H), 2.59-2.69 (m, 1H), 2.70-2.81 (m, 2H), 2.83-3.02 (m, 5H), 3.06-3.17 (m, 2H), 3.19-3.32 (m, 1H), 4.79 (br s, 1H), 6.56-6.66 (m, 2H), 6.93 (d, J=9 Hz, 1H), 7.07-7.14 (m, 1H), 7.30-7.38 (m, 1H), 7.43-7.52 (m, 1H), 7.66 (d, J=8 Hz, 1H).

Reference Example 7
Synthesis of 2-(1-methyl-1H-indazol-3-yl)ethyl methanesulfonate

[Image Omitted]

To a solution of 2-(1-methyl-1H-indazol-3-yl)ethan-1-ol (6.9 mg, 0.039 mmol) in chloroform (1 mL) were added triethylamine (16 μL, 0.12 mmol) and methanesulfonic anhydride (10 mg, 0.059 mmol) under ice cooling, followed by stirring at the same temperature for 1 hour. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added under ice cooling, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure to yield a crude product of the title compound (8.9 mg, 89%) as a pale yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.92 (s, 3H), 3.43 (t, J=7 Hz, 2H), 4.03 (s, 3H), 4.63 (t, J=7 Hz, 2H), 7.16 (ddd, J=1, 6, 8 Hz, 1H), 7.33-7.44 (m, 2H), 7.70 (d, J=8 Hz, 1H).

Example 113
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(1-methyl-1H-indazol-3-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 7 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.17 (m, 2H), 0.43-0.56 (m, 2H), 0.75-0.93 (m, 1H), 0.95-1.08 (m, 1H), 1.12-2.10 (m, 5H), 2.25-2.41 (m, 3H), 2.45-2.59 (m, 1H), 2.74 (dd, J=6, 18 Hz, 1H), 2.80-3.07 (m, 7H), 3.10-3.33 (m, 3H), 3.98 (s, 3H), 4.75 (br s, 1H), 6.43-6.61 (m, 2H), 6.89 (d, J=8 Hz, 1H), 7.03-7.12 (m, 1H), 7.27-7.39 (m, 2H), 7.63 (d, J=8 Hz, 1H).

Example 114
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-indazol-3-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(1H-indazol-3-yl)acetic acid according to the method described in Example 85.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.19 (m, 2H), 0.43-0.59 (m, 2H), 0.74-1.12 (m, 2H), 1.13-2.18 (m, 6H), 2.23-2.44 (m, 2H), 2.46-2.81 (m, 2H), 2.83-3.02 (m, 2H), 3.11-3.30 (m, 1H), 3.46-4.08 (m, 5H), 6.58-6.76 (m, 2H), 6.88 (d, J=8 Hz, 1H), 7.02-7, 13 (m, 1H), 7.24-7.45 (m, 2H), 7.63 (d, J=8 Hz, 0.4H), 7.72 (d, J=8 Hz, 0.6H).

Example 115
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(imidazo[1,2-a]pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from 2-(imidazo[1,2-a]pyridin-2-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.18 (m, 2H), 0.41-0.59 (m, 2H), 0.71-0.92 (m, 1H), 0.96-1.10 (m, 1H), 1.49-1.66 (m, 1H), 1.73-2.14 (m, 5H), 2.23-2.97 (m, 6H), 3.26-4.01 (m, 6H), 4.52 (br s, 1H), 6.59 (dd, J=2, 8 Hz, 0.6H), 6.64 (dd, J=3, 8 Hz, 0.4H), 6.68-6.82 (m, 2.4H), 6.86 (d, J=8 Hz, 0.6H), 7.07-7.19 (m, 1H), 7.38 (s, 0.4H), 7.43 (s, 0.6H), 7.48 (d, J=9 Hz, 0.4H), 7.52 (d, J=9 Hz, 0.6H), 7.94-8.04 (m, 1H).

Example 116
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(imidazo[1,2-a]pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 115 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.15 (m, 2H), 0.42-0.53 (m, 2H), 0.74-1.04 (m, 2H), 1.42-1.54 (m, 1H), 1.67-1.91 (m, 2H), 1.92-2.09 (m, 2H), 2.26-2.38 (m, 3H), 2.43-2.99 (m, 11H), 3.10-3.26 (m, 1H), 6.54 (d, J=2 Hz, 1H), 6.65 (dd, J=2, 8 Hz, 1H), 6.70 (ddd, J=1, 1, 7 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 7.09 (ddd, J=1, 7, 9 Hz, 1H), 7.19 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.98-8.04 (m, 1H).

Example 117
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(pyrazolo[1,5-a]pyridin-2-yl)acetic acid according to the method described in Example 85.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 0.95-1.10 (m, 1H), 1.50-1.65 (m, 1H), 1.70-1.90 (m, 3H), 1.90-2.05 (m, 2H), 2.20-2.40 (m, 3H), 2.45-2.65 (m, 2H), 2.70-3.00 (m, 2H), 3.20-3.55 (m, 2H), 3.60-4.00 (m, 3H), 4.05-4.15 (m, 1H), 6.32 (s, 0.5H), 6.33 (s, 0.5H), 6.50-6.75 (m, 2.5H), 6.80-6.95 (m, 1.5H), 7.00-7.10 (m, 1H), 7.40 (d, J=3 Hz, 1H), 8.30-8.40 (m, 1H).

Example 118
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(pyrazolo[1,5-a]pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 117 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 0.95-1.10 (m, 1H), 1.40-1.60 (m, 1H), 1.75-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.30-2.40 (m, 3H), 2.45-2.55 (m, 1H), 2.70-2.85 (m, 3H), 2.85-3.05 (m, 7H), 3.15-3.28 (m, 1H), 4.74 (br s, 1H), 6.23 (s, 1H), 6.51 (d, J=3 Hz, 1H), 6.57 (dd, J=3, 8 Hz, 1H), 6.65 (ddd, J=1, 6, 6 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 7.00-7.10 (m, 1H), 7.39 (d, J=8 Hz, 1H), 8.33 (d, J=6 Hz, 1H).

Example 119
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(2H-indazol-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(2H-indazol-2-yl)acetic acid according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.04 (d, J=10 Hz, 1H), 1.50-1.90 (m, 2H), 1.90-2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.50-2.70 (m, 2H), 2.70-3.00 (m, 2H), 3.10-3.25 (m, 2.6H), 3.37 (ddd, J=4, 4, 12 Hz, 0.4H), 3.77 (ddd, J=5, 12, 12 Hz, 0.6H), 3.80-4.00 (m, 2.4H), 4.80 (d, J=16 Hz, 0.6H), 5.02 (d, J=16 Hz, 0.6H), 5.19 (s, 0.8H), 6.50-6.75 (m, 2H), 6.88 (d, J=8 Hz, 0.4H), 6.97 (d, J=8 Hz, 0.6H), 7.10-7.35 (m, 4H), 7.68 (d, J=8 Hz, 1H).

Example 120
Synthesis of (5aS,6R,11bS)-3-(2-(2H-indazol-2-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 119 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.80-0.90 (m, 1H), 1.01 (d, J=9 Hz, 1H), 1.35-1.45 (m, 1H), 1.60-1.80 (m, 2H), 1.90-2.10 (m, 3H), 2.30-2.65 (m, 5H), 2.77 (dd, J=6, 18 Hz, 1H), 2.85-3.10 (m, 5H), 3.10-3.20 (m, 1H), 4.20-4.40 (m, 2H), 6.60-6.70 (m, 2H), 7.00-7.10 (m, 2H), 7.20-7.30 (m, 1H), 7.36 (s, 1H), 7.56 (d, J=8 Hz, 1H), 7.63 (d, J=8 Hz, 1H).

Example 121
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-indazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(1H-indazol-1-yl)acetic acid according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.80-0.90 (m, 1H), 1.00-1.05 (m, 1H), 1.50-2.10 (m, 5H), 2.15-2.40 (m, 3H), 2.50-2.70 (m, 2H), 2.70-3.00 (m, 2.6H), 3.10-3.35 (m, 1.4H), 3.35-3.45 (m, 0.4H), 3.60-3.70 (m, 0.6H), 3.80-3.90 (m, 0.6H), 3.90-4.00 (m, 0.4H), 4.87 (d, J=16 Hz, 0.6H), 5.03 (d, J=16 Hz, 0.6H), 5.20 (d, J=16 Hz, 0.4H), 5.26 (d, J=16 Hz, 0.4H), 6.60-6.70 (m, 2H), 6.85-6.95 (m, 1H), 7.00-7.10 (m, 1H), 7.10-7.20 (m, 1H), 7.60-7.70 (m, 2H), 7.84 (s, 0.6H), 7.92 (s, 0.4H).

Example 122
Synthesis of (5aS,6R,11bS)-3-(2-(1H-indazol-1-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 121 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.01 (d, J=9 Hz, 1H), 1.20-1.90 (m, 3H), 1.90-2.10 (m, 3H), 2.25-2.45 (m, 3H), 2.50-2.80 (m, 3H), 2.80-3.10 (m, 5H), 3.15-3.30 (m, 1H), 4.30-4.50 (m, 2H), 6.50-6.70 (m, 2H), 6.91 (d, J=8 Hz, 1H), 7.11 (dd, J=6, 6 Hz, 1H), 7.20-7.40 (m, 2H), 7.69 (d, J=8 Hz, 1H), 7.96 (s, 1H).

Example 123
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(isoquinolin-3-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from 2-(isoquinolin-3-yl)acetaldehyde and the compound E obtained in Example 3 according to the method described in Reference Example 4 and Example 105.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.15 (m, 2H), 0.40-0.55 (m, 2H), 0.74-0.92 (m, 1H), 0.97-1.09 (m, 1H), 1.51 (dd, J=3, 15 Hz, 1H), 1.80-2.10 (m, 4H), 2.26-2.40 (m, 3H), 2.44-2.56 (m, 1H), 2.72 (dd, J=2, 18 Hz, 1H), 2.81-3.17 (m, 9H), 3.22-3.33 (m, 1H), 4.75 (br s, 1H), 6.48 (d, J=3 Hz, 1H), 6.55 (dd, J=3, 8 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 7.47 (s, 1H), 7.48-7.56 (m, 1H), 7.60-7.68 (m, 1H), 7.72 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 9.15 (s, 1H).

Example 124
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(quinolin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from 2-(quinolin-2-yl)acetaldehyde and the compound E obtained in Example 3 according to the method described in Reference Example 4 and Example 105.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.15 (m, 2H), 0.44-0.55 (m, 2H), 0.75-0.90 (m, 1H), 0.95-1.07 (m, 1H), 1.42-1.60 (m, 1H), 1.75-1.90 (m, 2H), 1.94-2.09 (m, 2H), 2.26-2.41 (m, 3H), 2.49-2.59 (m, 1H), 2.73 (dd, J=6, 18 Hz, 1H), 2.77-3.18 (m, 9H), 3.22-3.33 (m, 1H), 6.51 (d, J=2 Hz, 1H), 6.59 (dd, J=3, 8 Hz, 1H), 6.86 (d, J=8 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.45-7.53 (m, 1H), 7.62-7.70 (m, 1H), 7.77 (dd, J=1, 8 Hz, 1H), 8.03 (d, J=8 Hz, 2H).

Example 125
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-indol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(1H-indol-1-yl)acetic acid according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.10 (m, 1H), 1.40-1.50 (m, 1H), 1.60-1.85 (m, 2H), 1.90-2.15 (m, 2H), 2.15-2.40 (m, 3H), 2.50-3.00 (m, 4.4H), 3.10-3.35 (m, 1.8H), 3.72 (ddd, J=6, 13, 13 Hz, 0.4H), 3.84 (ddd, J=3, 13, 13 Hz, 0.4H), 3.90-4.00 (m, 1H), 4.51 (d, J=16 Hz, 0.6H), 4.64 (d, J=16 Hz, 0.6H), 4.82 (d, J=16 Hz, 0.4H), 4.90 (d, J=16 Hz, 0.4H), 6.48 (d, J=8 Hz, 0.4H), 6.50 (d, J=8 Hz, 0.6H), 6.54 (d, J=2 Hz, 0.4H), 6.59 (d, J=2 Hz, 0.6H), 6.65 (ddd, J=3, 8, 8 Hz, 1H), 6.88 (d, J=3 Hz, 1H), 6.90-7.00 (m, 2H), 7.00-7.20 (m, 2H), 7.59 (t, J=8 Hz, 1H).

Example 126
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(indolin-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 125 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 2H), 0.45-0.60 (m, 2H), 0.75-1.00 (m, 2H), 1.40-1.90 (m, 5H), 1.90-2.05 (m, 2H), 2.20-2.40 (m, 3H), 2.45-2.60 (m, 1H), 2.65-3.00 (m, 9H), 3.10-3.40 (m, 4H), 4.72 (br s, 1H), 6.45 (d, J=8 Hz, 1H), 6.50 (d, J=3 Hz, 1H), 6.56 (dd, J=3, 8 Hz, 1H), 6.61 (dd, J=8, 8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 7.00-7.05 (m, 2H).

Example 127
Synthesis of (5aS,6R,11bS)-3-(2-(benzo[d]thiazol-2-yl)ethyl)-14-(cyclopropylmethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 2-(benzo[d]thiazol-2-yl)ethan-1-ol according to the method described in Example 32.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.17 (m, 2H), 0.45-0.55 (m, 2H), 0.78-0.90 (m, 1H), 1.01-1.08 (m, 1H), 1.55 (ddd, J=2, 5, 14 Hz, 1H), 1.86-2.03 (m, 3H), 2.09 (ddd, J=5, 13, 13 Hz, 1H), 2.35 (dd, J=6, 13 Hz, 1H), 2.367 (dd, J=6, 13 Hz, 1H), 2.45-2.58 (m, 2H), 2.61 (ddd, J=3, 5, 13 Hz, 1H), 2.72 (ddd, J=4, 4, 13 Hz, 1H), 2.78-2.91 (m, 3H), 2.95 (d, J=6 Hz, 1H), 2.98 (d, J=18 Hz, 1H), 3.04 (ddd, J=3, 12, 12 Hz, 1H), 3.12-3.21 (m, 3H), 3.72 (s, 3H), 6.68-6.72 (m, 2H), 6.99-7.03 (m, 1H), 7.31 (ddd, J=1, 7, 8 Hz, 1H), 7.40 (ddd, J=1, 7, 8 Hz, 1H), 7.75-7.79 (m, 1H), 7.88-7.92 (m, 1H).

Example 128
Synthesis of (5aS,6R,11bS)-3-(2-(benzo[d]thiazol-2-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 127 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.42-0.56 (m, 2H), 0.76-0.88 (m, 1H), 0.96-1.06 (m, 1H), 1.51 (dd, J=4, 14 Hz, 1H), 1.71-1.80 (m, 1H), 1.89 (ddd, J=3, 12, 14 Hz, 1H), 1.95-2.09 (m, 2H), 2.34 (dd, J=6, 12 Hz, 1H), 2.34 (dd, J=6, 12 Hz, 1H), 2.42 (ddd, J=4, 12, 16 Hz, 1H), 2.48-2.58 (m, 1H), 2.59-2.70 (m, 2H), 2.76 (dd, J=6, 18 Hz, 1H), 2.83-2.98 (m, 5H), 3.10-3.22 (m, 3H), 4.70 (br s, 1H), 6.55 (d, J=2 Hz, 1H), 6.62 (dd, J=2, 8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 7.30 (dd, J=8, 8 Hz, 1H), 7.39 (dd, J=8, 8 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.91 (d, J=8 Hz, 1H).

Example 129
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(2-(piperidin-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer C obtained in Example 2 and 1-(2-chloroethyl)piperidine hydrochloride according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.44-0.55 (m, 2H), 0.77-0.94 (m, 1H), 0.98-1.09 (m, 1H), 1.19-1.71 (m, 10 Hz), 1.75-2.15 (m, 3H), 2.22-2.42 (m, 8H), 2.46-2.88 (m, 6H), 2.90-3.02 (m, 2H), 3.06-3.21 (m, 1H), 3.77 (s, 3H), 6.63-6.71 (m, 2H), 6.99 (d, J=8 Hz, 1H).

Example 130
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(piperidin-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To a solution of the compound (5.3 mg, 0.0117 mmol) in chloroform (1 mL) obtained in Example 129 was added a 1 M boron tribromide-dichloromethane solution (70 μL, 0.070 mmol) under ice cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added under ice cooling, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. To the obtained concentrated residue dissolved in methanol (1 mL), 10% palladium-activated carbon (55% wet) (3.4 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 15 hours. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=4:1) to yield the title compound (4.0 mg, 78%) as a pale yellow solid substance.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.44-0.55 (m, 2H), 0.76-0.92 (m, 1H), 0.95-1.08 (m, 1H), 1.14-1.91 (m, 10H), 1.93-2.10 (m, 2H), 2.14-3.02 (m, 17H), 3.07-3.22 (m, 1H), 4.75 (br s, 1H), 6.46 (d, J=2 Hz, 1H), 6.55 (dd, J=2, 8 Hz, 1H), 6.89 (d, J=8 Hz, 1H).

Example 131
Synthesis of 2-((5aS,6R,11bS)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-1-(piperidin-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-chloro-1-(piperidin-1-yl)ethan-1-one (synthesized by the method described in WO 2018148576) according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.17 (m, 2H), 0.43-0.56 (m, 2H), 0.75-0.91 (m, 1H), 0.96-1.06 (m, 1H), 1.08-2.15 (m, 12H), 2.33 (d, J=6 Hz, 1H), 2.42-2.61 (m, 4H), 2.72-2.84 (m, 1H), 2.85-3.20 (m, 6H), 3.15 (d, J=13 Hz, 1H), 3.23 (d, J=13 Hz, 1H), 3.33-3.51 (m, 2H), 4.63 (br s, 1H), 6.57-6.70 (m, 2H), 6.91 (d, J=8 Hz, 1H).

Example 132
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)ethan-1-one

[Image Omitted]

To a solution of the compound E (10 mg, 0.030 mmol) obtained in Example 3 in chloroform (1 mL) were added N,N-diisopropylethylamine (21 μL, 0.12 mmol) and chloroacetyl chloride (4.8 μL, 0.061 mmol) under ice cooling, followed by stirring at room temperature for 1 hour. Next, to the reaction mixture were added 4,4-dimethyl-1,4-azasilinane (16 mg, 0.12 mmol), sodium iodide (10 mg, 0.061 mmol), and acetonitrile (1 mL), followed by stirring at 60° C. for 6 hours. Thereafter, a suspension of potassium carbonate (28 mg, 0.204 mmol) in methanol (1 mL) was added, followed by stirring at room temperature for 18 hour. Water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 5% methanol/chloroform) to yield the title compound (14 mg, 95%) as a pale yellow solid substance.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.15 (m, 8H), 0.46-0.56 (m, 2H), 0.61-0.92 (m, 5H), 1.01-1.13 (m, 1H), 1.22-1.86 (m, 2H), 1.89-2.19 (m, 3H), 2.25-2.41 (m, 2.6H), 2.48-2.69 (m, 5.4H), 2.71-2.84 (m, 1H), 2.86-3.27 (m, 4H), 3.28-3.48 (m, 1H), 3.51-3.71 (m, 1.4H), 3.72-3.85 (m, 1H), 3.89-4.00 (m, 0.6H), 4.49-4.534.51 (m, 1H), 6.54-6.69 (m, 1.4H), 6.76-6.81 (m, 0.6H), 6.90-6.96 (m, 1H).

Example 133
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 132 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.19 (m, 8H), 0.43-0.55 (m, 2H), 0.66-0.90 (m, 5H), 0.95-1.07 (m, 1H), 1.16-2.11 (m, 5H), 2.23-2.41 (m, 3H), 2.45-2.98 (m, 15H), 3.09-3.22 (m, 1H), 4.76 (br s, 1H), 6.46 (d, J=2 Hz, 1H), 6.56 (dd, J=2, 8 Hz, 1H), 6.89 (d, J=8 Hz, 1H).

Example 134
Synthesis of mixture of (5aR,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepin-3(4H)-one (isomer G) and (5aR,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one (isomer H)

[Image Omitted]

A mixture of the title isomers G and H was obtained as a colorless amorphous form using (4bS,8aR,9R)-11-(cyclopropylmethyl)-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one (synthesized by the method described in Bioorganic Medicinal Chemistry, 2012, 20, 949) according to the method described in Reference Example 3 and Example 1.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.20-1.80 (m, 3H), 1.86 (ddd, J=5, 12, 12 Hz, 1H), 1.90-2.10 (m, 2H), 2.25-2.35 (m, 1H), 2.35-2.70 (m, 3H), 2.70-2.90 (m, 2.5H), 3.00-3.05 (m, 0.5H), 3.05-3.15 (m, 1.5H), 3.30-3.40 (m, 0.5H), 3.40-3.60 (m, 1H), 3.76 (s, 1.5H), 3.79 (s, 1.5H), 5.81 (br s, 0.5H), 5.92 (br s, 0.5H), 6.52 (d, J=3 Hz, 0.5H), 6.68 (dd, J=3, 8 Hz, 1H), 6.94 (d, J=8 Hz, 0.5H), 6.99 (d, J=8 Hz, 0.5H), 7.10 (d, J=3 Hz, 0.5H).

Example 135
Synthesis of (5aR,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepine

[Image Omitted]

The title compound was obtained as a colorless amorphous form from the isomers G and H described in Example 134 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.00-0.20 (m, 2H), 0.45-0.55 (m, 2H), 0.75-0.90 (m, 1H), 1.20-1.50 (m, 3H), 1.65-2.20 (m, 6H), 2.30 (dd, J=7, 12 Hz, 1H), 2.55 (dd, J=6, 13 Hz, 1H), 2.60-2.70 (m, 2H), 2.70-2.90 (m, 3H), 3.04 (dd, J=5, 13 Hz, 1H), 3.18 (br s, 1H), 3.45 (d, J=14 Hz, 1H), 3.78 (s, 3H), 6.50-6.70 (m, 2H), 7.02 (d, J=8 Hz, 1H).

Example 136
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-2-(2-(pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer D obtained in Example 2 and 2-(pyridin-2-yl)ethyl 4-methylbenzenesulfonate according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.43-0.55 (m, 2H), 0.78-1.00 (m, 2H), 1.45-1.69 (m, 3H), 1.71-1.82 (m, 1H), 1.91-2.14 (m, 3H), 2.28-2.40 (m, 2H), 2.51-2.85 (m, 5H), 2.86-3.31 (m, 6H), 3.73 (s, 3H), 6.67 (dd, J=3, 8 Hz, 1H), 6.78 (d, J=3 Hz, 1H), 6.96 (d, J=8 Hz, 1H), 7.08 (dd, J=5, 8 Hz, 1H), 7.14-7.18 (m, 1H), 7.54 (ddd, J=2, 8, 8 Hz, 1H), 8.52 (ddd, J=1, 2, 5 Hz, 1H).

Example 137
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-2-(2-(pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 136 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.18 (m, 2H), 0.44-0.55 (m, 2H), 0.78-0.99 (m, 2H), 1.39-1.47 (m, 1H), 1.56-1.65 (m, 1H), 1.69 (ddd, J=2, 12, 13 Hz, 1H), 1.88 (ddd, J=6, 13, 13 Hz, 1H), 2.14 (ddd, J=4, 12, 12 Hz, 1H), 2.23-2.42 (m, 3H), 2.54-2.81 (m, 6H), 2.84-3.09 (m, 5H), 3.44 (d, J=15 Hz, 1H), 6.72 (dd, J=2, 8 Hz, 1H), 6.88 (d, J=2 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 7.08-7.13 (m, 1H), 7.18 (ddd, J=1, 5, 8 Hz, 1H), 7.63 (ddd, J=2, 8, 8 Hz, 1H), 8.53-8.58 (m, 1H).

Example 138
Synthesis of 1-((5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepin-2(1H)-yl)-2-(pyrimidin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the isomer D obtained in Example 2 and 2-(pyrimidin-2-yl)acetic acid according to the method described in Example 7.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.17 (m, 2H), 0.45-0.57 (m, 2H), 0.77-0.92 (m, 1H), 1.06-1.13 (m, 1H), 1.55-1.72 (m, 2H), 1.76 (dd, J=6, 13 Hz, 1H), 1.92-2.10 (m, 2H), 2.23-2.42 (m, 3H), 2.55-2.63 (m, 1H), 2.79 (dd, J=6, 18 Hz, 1H), 2.90-3.06 (m, 3H), 3.64 (d, J=15 Hz, 1H), 3.69-3.81 (m, 1H), 3.71 (s, 3H), 3.95 (d, J=15 Hz, 1H), 4.09 (d, J=15 Hz, 1H), 4.79 (d, J=15 Hz, 1H), 6.69 (dd, J=3, 8 Hz, 1H), 6.89 (d, J=3 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 7.15 (t, J=5 Hz, 1H), 8.65 (d, J=5 Hz, 2H).

Example 139
Synthesis of 1-((5aS,6R,11bS)-14-(cyclopropylmethyl)-5a,10-dihydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepin-2(1H)-yl)-2-(pyrimidin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 138 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.17 (m, 2H), 0.45-0.58 (m, 2H), 0.78-0.93 (m, 1H), 1.10-1.17 (m, 1H), 1.52-1.63 (m, 1H), 1.65-1.74 (m, 1H), 1.78 (dd, J=6, 13 Hz, 1H), 2.02 (ddd, J=4, 12, 12 Hz, 1H), 2.11 (ddd, J=3, 12, 12 Hz, 1H), 2.19-2.32 (m, 1H), 2.35 (dd, J=6, 13 Hz, 1H), 2.36 (dd, J=7, 13 Hz, 1H), 2.55-2.63 (m, 1H), 2.65-2.74 (m, 1H), 2.78 (dd, J=7, 18 Hz, 1H), 2.98 (d, J=7 Hz, 1H), 3.00 (d, J=18 Hz, 1H), 3.54 (dd, J=4, 12 Hz, 1H), 3.78 (d, J=15 Hz, 1H), 3.89 (d, J=16 Hz, 1H), 3.96 (d, J=16 Hz, 1H), 4.62 (d, J=15 Hz, 1H), 6.65 (d, J=3 Hz, 1H), 6.74 (dd, J=3, 8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 7.29 (t, J=5 Hz, 1H), 8.76 (d, J=5 Hz, 2H).

Example 140
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

Single Isomer A

To a solution of the compound (14 g, 39.3 mmol) obtained in Reference Example 3 in chloroform (400 mL) were added triethylamine (16.4 mL, 117.8 mmol) and p-toluenesulfonyl chloride (22.5 g, 117.8 mmol) under ice cooling, followed by stirring at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and to a solution of the obtained concentrated residue in tetrahydrofuran (250 mL) was added 2 M hydrochloric acid (160 mL), followed by stirring at room temperature for 71 hours. After the reaction solution was washed three times with a mixed solution of ethyl acetate and heptane (2/1), the aqueous layer was made basic with potassium carbonate, then extracted twice with ethyl acetate, and extracted once with chloroform. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was suspended in ethyl acetate (50 mL), followed by stirring for 1 hour. Subsequently, insoluble matter was collected by filtration to yield 4-methylbenzenesulfonate (5.15 g, 25%) of the title compound as a colorless solid. Subsequently, a reaction similar to the method described in Example 24 was performed on 4-methylbenzenesulfonate of the title compound to yield the title compound (509.3 mg, 10% recovery) as a colorless amorphous form as an unreacted recovery raw material.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.08-0.16 (m, 2H), 0.50-0.57 (m, 2H), 0.78-0.92 (m, 1H), 1.10-1.18 (m, 1H), 1.23-1.33 (m, 1H), 1.78 (ddd, J=2, 11, 14 Hz, 1H), 2.07-2.13 (m, 2H), 2.34-2.42 (m, 2H), 2.56-2.63 (m, 2H), 2.72-2.82 (m, 1H), 2.83-2.97 (m, 2H), 3.02 (d, J=18 Hz, 1H), 3.51 (d, J=15 Hz, 1H), 3.80 (s, 3H), 3.87 (ddd, J=3, 11, 15 Hz, 1H), 5.62-5.71 (m, 1H), 6.71 (dd, J=3, 8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 7.15 (d, J=3 Hz, 1H).

Example 141
Synthesis of (5aS,6R,11bR)-3-benzyl-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

To a solution of the compound (14.3 mg, 0.04 mmol) obtained in Example 140 in N,N-dimethylformamide (1 mL) was added sodium hydride (55% oil dispersion, 16 mg, 0.37 mmol), followed by stirring at room temperature for 10 minutes. Benzyl bromide (47.5 μL, 0.4 mmol) was then added, followed by stirring at room temperature for 1 hour. To the reaction solution, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0 to 10% methanol/chloroform) to yield the title compound (14.4 mg, 79%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.44-0.53 (m, 2H), 0.72-0.91 (m, 1H), 1.15-1.49 (m, 3H), 2.00-2.15 (m, 2H), 2.33 (d, J=7 Hz, 2H), 2.52-2.66 (m, 2H), 2.77 (d, J=15 Hz, 1H), 2.78-2.92 (m, 2H), 2.94 (d, J=18 Hz, 1H), 3.62 (d, J=15 Hz, 1H), 3.82 (d, J=15 Hz, 1H), 3.85 (s, 3H), 4.06 (dd, J=11, 15 Hz, 1H), 5.05 (d, J=15 Hz, 1H), 6.62 (d, J=8 Hz, 2H), 6.79 (dd, J=3, 8 Hz, 1H), 6.97 (d, J=9 Hz, 1H), 7.01 (t, J=8 Hz, 2H), 7.09 (t, J=7 Hz, 1H), 7.32 (d, J=3 Hz, 1H).

Example 142
Synthesis of (5aS,6R,11bR)-3-benzyl-14-(cyclopropylmethyl)-5a,10-dihydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 141 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.12 (m, 2H), 0.44-0.55 (m, 2H), 0.71-0.93 (m, 1H), 1.08-1.50 (m, 3H), 2.02-2.12 (m, 2H), 2.33 (d, J=6 Hz, 2H), 2.50-2.64 (m, 2H), 2.71 (d, J=15 Hz, 1H), 2.78-2.98 (m, 3H), 3.60 (d, J=15 Hz, 1H), 3.84 (d, J=15 Hz, 1H), 4.07 (dd, J=11, 15 Hz, 1H), 5.03 (d, J=14 Hz, 1H), 6.65 (d, J=8 Hz, 2H), 6.78 (dd, J=3, 8 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 7.03 (t, J=7 Hz, 2H), 7.11 (t, J=7 Hz, 1H), 7.18 (d, J=2 Hz, 1H).

Example 143
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.05-1.15 (m, 1H), 1.30-2.50 (m, 7H), 2.50-2.85 (m, 2.5H), 2.90-3.15 (m, 2.5H), 3.30-3.40 (m, 1H), 3.40-3.50 (m, 1H), 3.70-3.80 (m, 0.5H), 3.80-3.95 (m, 1H), 4.05-4.15 (m, 0.5H), 4.66 (d, J=16 Hz, 0.5H), 4.86 (d, J=16 Hz, 0.5H), 4.94 (d, J=16 Hz, 0.5H), 5.00 (d, J=16 Hz, 0.5H), 6.60-6.70 (m, 2H), 6.90-7.00 (m, 1H), 7.59 (s, 0.5H), 7.66 (s, 0.5H), 7.69 (m, 0.5H), 7.78 (s, 0.5H).

Example 144
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 143 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-1.00 (m, 1H), 1.00-1.10 (m, 1H), 1.40-2.20 (m, 4H), 2.25-2.50 (m, 5H), 2.50-2.70 (m, 2H), 2.75-3.15 (m, 6H), 3.15-3.30 (m, 1H), 3.90-4.05 (m, 1H), 4.10-4.20 (m, 1H), 6.60-6.70 (m, 2H), 6.99 (d, J=8 Hz, 1H), 7.17 (s, 1H), 7.62 (s, 1H).

Example 145
Synthesis of (5aS,6R,11bR)-3-(2-cyclohexylethyl)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 140 and (2-bromoethyl)cyclohexane according to the method described in Example 141.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.65-1.77 (m, 17H), 1.99-2.12 (m, 2H), 2.35 (dd, J=7, 13 Hz, 1H), 2.36 (dd, J=7, 13 Hz, 1H), 2.53-2.61 (m, 1H), 2.66 (d, J=15 Hz, 1H), 2.74 (dd, J=6, 18 Hz, 1H), 2.83-2.97 (m, 3H), 3.01 (d, J=18 Hz, 1H), 3.46-3.64 (m, 2H), 3.81 (s, 3H), 4.06 (dd, J=11, 15 Hz, 1H), 6.68 (dd, J=3, 8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 7.20 (d, J=3 Hz, 1H).

Example 146
Synthesis of (5aS,6R,11bR)-3-(2-cyclohexylethyl)-14-(cyclopropylmethyl)-5a,10-dihydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 145 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.14 (m, 2H), 0.46-0.55 (m, 2H), 0.64-0.90 (m, 4H), 0.97-1.30 (m, 6H), 1.35-1.46 (m, 1H), 1.47-1.65 (m, 5H), 1.67-1.79 (m, 1H), 1.96-2.12 (m, 2H), 2.35 (dd, J=7, 13 Hz, 1H), 2.36 (dd, J=7, 13 Hz, 1H), 2.51-2.61 (m, 1H), 2.66 (d, J=15 Hz, 1H), 2.73 (dd, J=6, 18 Hz, 1H), 2.84-3.04 (m, 4H), 3.44-3.58 (m, 2H), 4.07 (dd, J=11, 15 Hz, 1H), 6.68 (dd, J=2, 8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 7.16 (d, J=2 Hz, 1H).

Example 147
Synthesis of 2-chloro-1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)ethan-1-one

[Image Omitted]

To the compound E (40 mg, 0.12 mmol) obtained in Example 3 and N,N-diisopropylethylamine (125 μL, 0.73 mmol) dissolved in tetrahydrofuran (1.5 mL) was added chloroacetyl chloride (32 μL, 0.40 mmol) under ice cooling, followed by stirring for 1 hour under a nitrogen atmosphere. After the reaction solution was diluted with ethyl acetate and then washed with a saturated aqueous sodium bicarbonate solution, the obtained organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 1 to 20% methanol/chloroform) to yield the title compound (40 mg, 81%) as a yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-1.00 (m, 1H), 1.08 (d, J=12 Hz, 0.3H), 1.16 (d, J=12 Hz, 0.7H), 1.40-2.50 (m, 8H), 2.55-2.70 (m, 1.3H), 2.75-2.85 (m, 1H), 2.90-3.15 (m, 2.7H), 3.30-4.00 (m, 4.3H), 4.17 (s, 1H), 4.20-4.30 (m, 0.7H), 6.55-6.65 (m, 0.6H), 6.71 (dd, J=3, 8 Hz, 0.7H), 6.90 (d, J=3 Hz, 0.7H), 6.94 (d, J=8 Hz, 0.3H), 6.98 (d, J=8 Hz, 0.7H).

Example 148
Synthesis of 2-(4-(tert-butyl)-1H-pyrazol-1-yl)-1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)ethan-1-one

[Image Omitted]

The compound (20 mg, 0.049 mmol) obtained in Example 147, potassium carbonate (102 mg, 0.735 mmol), 4-tert-butylpyrazole (61 mg, 0.490 mmol), and sodium iodide (9 mg, 0.059 mmol) were dissolved in acetonitrile (1 mL), followed by stirring at 60° C. for 16 hours under a nitrogen atmosphere. After the reaction solution was diluted with ethyl acetate and then washed with a saturated aqueous sodium bicarbonate solution, the obtained organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 1 to 20% methanol/chloroform) to yield the title compound (10 mg, 41%) as a yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-1.00 (m, 1H), 1.00-1.10 (m, 1H), 1.22 (s, 6.3H), 1.24 (s, 2.7H), 1.40-2.20 (m, 8H), 2.25-2.50 (m, 1.3H), 2.50-2.70 (m, 1H), 2.70-2.90 (m, 0.7H), 2.90-3.30 (m, 3H), 3.30-3.40 (m, 0.3H), 3.70-3.80 (m, 0.7H), 3.80-3.95 (m, 0.7H), 4.05-4.15 (m, 0.3H), 4.57 (d, J=16 Hz, 0.7H), 4.69 (d, J=16 Hz, 0.7H), 4.88 (s, 0.6H), 6.60-6.70 (m, 2H), 6.94 (d, J=8 Hz, 0.7H), 6.98 (d, J=8 Hz, 0.3H), 7.16 (s, 0.7H), 7.24 (s, 0.3H), 7.36 (s, 0.7H), 7.37 (s, 0.3H).

Example 149
Synthesis of (5aS,6R,11bS)-3-(2-(4-(tert-butyl)-1H-pyrazol-1-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 148 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-1.00 (m, 1H), 1.03 (d, J=11 Hz, 1H), 1.21 (s, 9H), 1.40-2.10 (m, 5H), 2.20-2.40 (m, 3H), 2.50-2.70 (m, 3H), 2.74 (dd, J=6, 18 Hz, 1H), 2.80-3.00 (m, 5H), 3.10-3.30 (m, 1H), 4.00-4.10 (m, 2H), 6.54 (d, J=3 Hz, 1H), 6.60 (dd, J=3, 8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 7.10 (s, 1H), 7.25 (s, 1H).

Example 150
Synthesis of 2,2,2-trichloroethyl (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

To a solution of the isomer C (342 mg, 1.0 mmol) obtained in Example 2 in tetrahydrofuran (10 mL) were added N,N-diisopropylethylamine (348 μL, 2.0 mmol) and 2,2,2-trichloroethyl chloroformate (165 μL, 1.2 mmol), followed by stirring at room temperature for 1 hour. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0 to 20% methanol/chloroform) to yield the title compound (481 mg, 93%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.45-0.55 (m, 2H), 0.76-0.88 (m, 1H), 0.96-2.12 (m, 6H), 2.26-2.59 (m, 4H), 2.73-3.05 (m, 3H), 3.51-3.77 (m, 4H), 3.77 (s, 1.5H), 3.79 (s, 1.5H), 4.47 (d, J=12 Hz, 0.5H), 4.52 (br s, 1H), 4.62 (s, 1H), 4.79 (d, J=12 Hz, 0.5H), 6.64-6.71 (m, 2H), 6.95-7.02 (m, 1H).

Example 151
Synthesis of 2,2,2-trichloroethyl (5aS,6R,11bR)-5a-acetoxy-14-(cyclopropylmethyl)-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

Acetic anhydride (10 mL) was added to the compound (481 mg, 0.93 mmol) obtained in Example 150, followed by heating under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, and to the concentrated reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0 to 20% methanol/chloroform) to yield the title compound (410 mg, 79%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.02-0.11 (m, 2H), 0.38-0.52 (m, 2H), 0.68-0.91 (m, 1H), 1.05-3.80 (m, 15H), 2.09 (s, 1.5H), 2.13 (s, 1.5H), 3.79 (s, 3H), 3.86-3.99 (m, 1H), 4.22 (d, J=6 Hz, 0.5H), 4.27 (d, J=6 Hz, 0.5H), 4.62 (d, J=12 Hz, 0.5H), 4.69 (d, J=12 Hz, 0.5H), 4.71 (d, J=12 Hz, 0.5H), 4.90 (d, J=12 Hz, 0.5H), 6.69-6.76 (m, 2H), 6.97-7.07 (m, 1H).

Example 152
Synthesis of 2,2,2-trichloroethyl (5aS,6R,11bR)-14-acetyl-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

To a solution of the compound (410 mg, 0.73 mmol) obtained in Example 151 in toluene (7 mL) was added diisopropyl azodicarboxylate (40% toluene solution, about 1.9 mol/L, 768 μL, 1.46 mmol), followed by stirring at 100° C. for 90 minutes. The reaction mixture was concentrated under reduced pressure, and to the concentrated reaction mixture, ethanol (14 mL) and pyridine hydrochloride (888 mg, 7.7 mmol) were added, followed by stirring at 40° C. for 18 hours. To the reaction mixture, water and potassium carbonate were added to adjust the pH to 11, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (50 to 100% ethyl acetate/heptane) to yield the title compound (346 mg, 93%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.04-1.30 (m, 1H), 1.52-4.84 (m, 19H), 3.79 (s, 1.5H), 3.80 (s, 1.5H), 6.67-6.77 (m, 2H), 6.96-7.15 (m, 1H).

Example 153
Synthesis of 1-((5aS,6R,11bS)-5a-hydroxy-10-methoxy-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-14-yl)ethan-1-one

[Image Omitted]

To a solution of the compound (346 mg, 0.68 mmol) obtained in Example 152 in acetic acid (30 mL) was added a zinc powder (895 mg, 13.7 mmol), followed by stirring at room temperature for 4 hours. The reaction mixture was filtered through celite to remove zinc, followed by concentration under reduced pressure. To the obtained crude product, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 50% methanol/chloroform) to yield the title compound (187 mg, 83%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.04-1.14 (m, 1H), 1.50-2.47 (m, 6H), 2.11 (s, 1.5H), 2.20 (s, 1.5H), 2.53-3.00 (m, 4H), 3.02-3.14 (m, 1H), 3.24-3.36 (m, 1H), 3.42-3.50 (m, 0.5H), 3.80 (s, 3H), 3.89 (d, J=7 Hz, 0.5H), 4.33-4.40 (m, 0.5H), 4.87 (d, J=6 Hz, 0.5H), 6.76 (dd, J=2, 8 Hz, 1H), 6.80-6.83 (m, 1H), 7.05 (d, J=8 Hz, 0.5H), 7.06 (d, J=8 Hz, 0.5H).

Example 154
Synthesis of 1-((5aS,6R,11bS)-5a-hydroxy-10-methoxy-3-(2-(pyridin-2-yl)ethyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-14-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 153 according to the method described in Example 76 (Method 1).

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.97-1.11 (m, 1H), 1.50-3.15 (m, 15H), 2.09 (s, 1.5H), 2.18 (s, 1.5H), 3.19-3.33 (m, 1H), 3.39-3.48 (m, 0.5H), 3.79 (s, 1.5H), 3.79 (s, 1.5H), 3.85 (d, J=6 Hz, 0.5H), 4.31-4.38 (m, 0.5H), 4.87 (d, J=6 Hz, 0.5H), 6.71-6.77 (m, 1H), 6.78-6.82 (m, 1H), 7.01-7.07 (m, 1H), 7.10-7.20 (m, 2H), 7.57-7.65 (m, 1H), 8.49-8.56 (m, 1H).

Example 155
Synthesis of (5aS,6R,11bR)-10-methoxy-3-(2-(pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

To a solution of the compound (87.0 mg, 0.20 mmol) obtained in Example 154 in ethanol (5 mL) was added 2 M aqueous sodium hydroxide solution (5 mL, 10 mmol), followed by heating under reflux for 40 hours. After allowed to cool, to the resultant solution was added water, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 50% methanol/chloroform) to yield the title compound (69.3 mg, 88%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.92-1.00 (m, 1H), 1.48 (dd, J=7, 14 Hz, 1H), 1.72-1.93 (m, 3H), 2.28 (dd, J=4, 15 Hz, 1H), 2.40-2.71 (m, 5H), 2.82-3.00 (m, 7H), 3.19 (dd, J=7, 18 Hz, 1H), 3.79 (s, 3H), 4.81 (br s, 1H), 6.72 (dd, J=3, 8 Hz, 1H), 6.75 (d, J=3 Hz, 1H), 7.06 (d, J=8 Hz, 1H), 7.12-7.20 (m, 2H), 7.63 (ddd, J=2, 7, 7 Hz, 1H), 8.54-8.57 (m, 1H).

Example 156
Synthesis of (5aS,6R,11bR)-3-(2-(pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol (compound I) and (5aS,6R,11bS)-14-methyl-3-(2-(pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol (compound J)

[Image Omitted]

The title compounds I and J were individually obtained from the compound obtained in Example 155 according to the method described in Example 6.

(Compound I)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.93-1.03 (m, 1H), 1.47 (dd, J=7, 15 Hz, 1H), 1.60-1.71 (m, 1H), 1.77-1.92 (m, 2H), 2.19 (dd, J=4, 15 Hz, 1H), 2.32-2.63 (m, 5H), 2.75-3.01 (m, 7H), 3.18 (dd, J=7, 18 Hz, 1H), 6.64 (dd, J=2, 8 Hz, 1H), 6.69 (d, J=2 Hz, 1H), 6.96 (d, J=8 Hz, 1H), 7.14-7.22 (m, 2H), 7.66 (ddd, J=2, 8, 8 Hz, 1H), 8.53-8.58 (m, 1H).

(Compound J)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.96-1.08 (m, 1H), 1.41-1.54 (m, 1H), 1.76-2.09 (m, 4H), 2.16-2.38 (m, 2H), 2.33 (s, 3H), 2.61 (d, J=6 Hz, 1H), 2.63-2.96 (m, 8H), 3.03 (d, J=18 Hz, 1H), 3.11-3.23 (m, 1H), 4.58 (br s, 1H), 6.53 (d, J=2 Hz, 1H), 6.59 (dd, J=2, 8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 7.07-7.14 (m, 2H), 7.56 (ddd, J=2, 7, 7 Hz, 1H), 8.46-8.51 (m, 1H).

Example 157
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(1H-pyrazol-1-yl)propan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 3-(1H-pyrazol-1-yl)propanoic acid hydrochloride according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.15 (m, 2H), 0.48-0.53 (m, 2H), 0.78-0.88 (m, 1H), 1.06-1.14 (m, 1H), 1.52-1.65 (m, 1.3H), 1.78-1.93 (m, 1.7H), 1.94-2.20 (m, 2.3H), 2.26-2.48 (m, 2.7H), 2.50-2.58 (m, 1H), 2.68-2.81 (m, 1.3H), 2.82-2.99 (m, 3.7H), 3.00-3.22 (m, 1.3H), 3.26-3.33 (m, 0.7H), 3.67-3.82 (m, 1H), 3.86-3.99 (m, 1.3H), 4.07 (br s, 0.3H), 4.20-4.29 (m, 0.7H), 4.40-4.48 (m, 1H), 4.53 (br s, 0.7H), 6.17 (s, 0.3H), 6.22 (s, 0.7H), 6.65-6.76 (m, 1.3H), 6.77-6.81 (m, 0.7H), 6.91-6.98 (m, 1H), 7.37 (s, 0.7H), 7.42 (s, 0.3H), 7.47 (s, 0.3H), 7.56 (s, 0.7H), 7.89 (br s, 0.7H).

Example 158
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(thiazol-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(thiazol-2-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.08-0.12 (m, 2H), 0.49-0.53 (m, 2H), 0.77-0.88 (m, 1H), 1.05-1.10 (m, 1H), 1.23-1.28 (m, 1H), 1.60-1.64 (m, 1H), 1.79-2.15 (m, 4H), 2.24-2.39 (m, 2H), 2.52-2.64 (m, 1H), 2.69-2.80 (m, 1H), 2.88-3.00 (m, 2H), 3.25-3.50 (m, 2H), 3.82-4.15 (m, 4H), 6.60 (dd, J=2, 8 Hz, 0.6H), 6.65 (dd, J=2, 8 Hz, 0.4H), 6.69 (d, J=2 Hz, 0.6H), 6.72 (d, J=2 Hz, 0.4H), 6.88-6.92 (m, 1H), 7.25-7.28 (m, 1H), 7.67-7.69 (m, 1H).

Example 159
Synthesis of (5aS,6R,11bS)-14-propyl-3-(2-(pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To a solution of the compound I (10 mg, 0.026 mmol) obtained in Example 156 in N,N-dimethylformamide (1 mL) were added 1-bromopropane (4.6 μL, 0.051 mmol) and N,N-diisopropylethylamine (13.2 μL, 0.076 mmol), followed by stirring at room temperature for 18 hours. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in chloroform (2 mL) was added a 1 M boron tribromide-dichloromethane solution (500 μL, 0.50 mmol) under ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture, a 28% aqueous ammonia solution was added under ice cooling, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (4.9 mg, 45%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.90 (t, J=7 Hz, 3H), 0.98-1.05 (m, 1H), 1.41-1.52 (m, 3H), 1.79-2.05 (m, 4H), 2.27-2.44 (m, 4H), 2.66 (d, J=6 Hz, 1H), 2.75 (dd, J=6, 18 Hz, 1H), 2.80-3.02 (m, 8H), 3.32 (dd, J=11, 11 Hz, 1H), 6.49 (d, J=3 Hz, 1H), 6.58 (dd, J=3, 8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 7.07-7.14 (m, 2H), 7.55 (ddd, J=2, 8, 8 Hz, 1H), 8.45-8.48 (m, 1H).

Example 160
Synthesis of 2-(4-cyclopropyl-1H-pyrazol-1-yl)-1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(4-cyclopropyl-1H-pyrazol-1-yl)acetic acid according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 4H), 0.75-0.95 (m, 3H), 1.00-1.15 (m, 1H), 1.50-2.40 (m, 8.4H), 2.50-2.65 (m, 1.6H), 2.65-2.85 (m, 1H), 2.85-3.05 (m, 2H), 3.05-3.40 (m, 2H), 3.60-3.75 (m, 0.6H), 3.75-3.90 (m, 1H), 4.00-4.10 (m, 0.4H), 4.55 (d, J=16 Hz, 0.6H), 4.70 (d, J=16 Hz, 0.6H), 4.85 (d, J=16 Hz, 0.4H), 4.89 (d, J=16 Hz, 0.4H), 6.60-6.70 (m, 2H), 6.85-7.00 (m, 1H), 7.10 (s, 0.6H), 7.16 (s, 0.4H), 7.26 (s, 1H).

Example 161
Synthesis of (5aS,6R,11bS)-14-(cyclobutylmethyl)-10-methoxy-3-(2-(pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

To a solution of the compound (10 mg, 0.025 mmol) obtained in Example 155 in N,N-dimethylformamide (1.0 mL) were added (bromomethyl)cyclobutane (4.6 μL, 0.042 mmol) and N,N-diisopropylethylamine (13.2 μL, 0.076 mmol), followed by stirring at room temperature for 18 hours and then stirring at 80° C. for 6 hours. After allowed to cool, to the reaction mixture was added a saturated sodium bicarbonate aqueous solution, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (7.1 mg, 62%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.94-1.07 (m, 1H), 1.20-1.32 (m, 1H), 1.40-1.51 (m, 1H), 1.58-2.11 (m, 10H), 2.27-2.68 (m, 7H), 2.71-2.95 (m, 6H), 3.01 (d, J=18 Hz, 1H), 3.14-3.26 (m, 1H), 3.76 (s, 3H), 4.63 (br s, 1H), 6.66 (d, J=2 Hz, 1H), 6.69 (dd, J=3, 8 Hz, 1H), 6.98-7.08 (m, 3H), 7.49 (ddd, J=2, 8, 8 Hz, 1H), 8.44-8.47 (m, 1H).

Example 162
Synthesis of (5aS,6R,11bS)-14-(cyclobutylmethyl)-3-(2-(pyridin-2-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 161 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.96-1.03 (m, 1H), 1.20-1.28 (m, 1H), 1.41-1.52 (m, 1H), 1.56-1.69 (m, 2H), 1.75-2.10 (m, 8H), 2.28-2.50 (m, 5H), 2.60 (d, J=6 Hz, 1H), 2.73 (dd, J=6, 18 Hz, 1H), 2.80-3.04 (m, 7H), 3.31 (dd, J=12, 12 Hz, 1H), 6.47 (d, J=2 Hz, 1H), 6.58 (dd, J=2, 8 Hz, 1H), 6.88 (d, J=8 Hz, 1H), 7.07-7.15 (m, 2H), 7.56 (ddd, J=2, 8, 8 Hz, 1H), 8.44-8.47 (m, 1H).

Example 163
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(4-methyl3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.08-0.13 (m, 2H), 0.49-0.54 (m, 2H), 0.79-0.84 (m, 1H), 1.07-1.10 (m, 1H), 1.23-1.28 (m, 1H), 1.56-2.07 (m, 5H), 2.11 (s, 1.5H), 2.14 (s, 1.5H), 2.20-2.39 (m, 2H), 2.53-2.67 (m, 1H), 2.75 (ddd, J=6, 19, 19 Hz, 1H), 2.88-3.02 (m, 2H), 3.12-3.18 (m, 0.5H), 3.32-3.42 (m, 1.5H), 3.65-3.75 (m, 0.5H), 3.79-3.86 (m, 1H), 4.02-4.07 (m, 0.5H), 4.64 (d, J=16 Hz, 0.5H), 4.79 (d, J=16 Hz, 0.5H), 4.90 (d, J=16 Hz, 0.5H), 4.95 (d, J=16 Hz, 0.5H), 5.90 (br s, 0.5H), 6.62-6.67 (m, 2H), 6.95 (dd, J=2, 8 Hz, 1H), 7.16 (s, 0.5H).

Example 164
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 163 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.09-0.13 (m, 2H), 0.49-0.53 (m, 2H), 0.81-0.89 (m, 1H), 1.01-1.04 (m, 1H), 1.22-1.28 (m, 1H), 1.46 (dd, J=4, 14 Hz, 1H), 1.72-1.85 (m, 2H), 2.00-2.05 (m, 2H), 2.05 (s, 3H), 2.37-3.03 (m, 11H), 3.20 (dd, J=12, 12 Hz, 1H), 3.99-4.13 (m, 2H), 6.60 (s, 1H), 6.62 (d, J=8 Hz, 1H), 6.83 (s, 1H), 6.97 (d, J=8 Hz, 1H).

Example 165
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (synthesized by the method described in Journal of Medicinal Chemistry 2018, 61, 8797) according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.09-0.14 (m, 2H), 0.49-0.55 (m, 2H), 0.79-0.87 (m, 1H), 1.09-1.12 (m, 1H), 1.20-1.28 (m, 6H), 1.58-1.66 (m, 1H), 1.81-2.11 (m, 4H), 2.22-2.39 (m, 2.2H), 2.54-2.80 (m, 3H), 2.90-3.07 (m, 3.2H), 3.30-3.42 (m, 1.6H), 3.85-3.97 (m, 1.6H), 4.12-4.15 (m, 0.4H), 4.56 (br s, 1H), 4.67 (d, J=16 Hz, 0.6H), 5.12 (d, J=16 Hz, 0.4H), 5.25 (d, J=16 Hz, 0.4H), 5.29 (d, J=16 Hz, 0.6H), 6.65-6.69 (m, 1H), 6.78 (s, 0.6H), 6.91-6.95 (m, 1.4H), 7.26 (s, 0.6H), 7.39 (s, 0.4H).

Reference Example 8
Synthesis of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1H-pyrrole

[Image Omitted]

To 3-methyl-1H-pyrrole (97 mg, 1.20 mmol) dissolved in N,N-dimethylformamide (3 mL) were added sodium hydride (55% oil dispersion) (156.5 mg, 3.59 mmol) and (2-bromoethoxy) (tert-butyl)dimethylsilane (765.6 μL, 3.59 mmol) under ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction solution, a saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (2 to 12% ethyl acetate/heptane) to yield the title compound (314 mg, quantitative) as a yellow liquid.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.90 (s, 9H), 0.93 (s, 3H), 1.59 (s, 3H), 2.10 (s, 3H), 3.78-3.85 (m, 2H), 3.89-3.95 (m, 2H), 5.94-5.98 (m, 1H), 6.43-6.47 (m, 1H), 6.56-6.59 (m, 1H).

Reference Example 9
Synthesis of 2-(3-methyl-1H-pyrrol-1-yl)ethan-1-ol

[Image Omitted]

To the compound (304.9 mg, 1.27 mmol) obtained in Reference Example 8 dissolved in tetrahydrofuran (1 mL), a 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (3.82 mL, 3.82 mmol) was added, followed by stirring at room temperature for 10 minutes. To the reaction solution, a saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed once with a saturated aqueous sodium bicarbonate solution, twice with saturated saline, and once with water, then dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (34 to 54% ethyl acetate/heptane) to yield the title compound (69.5 mg, 44%) as a pale yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.10 (s, 3H), 3.83 (t, J=5 Hz, 2H), 3.95 (t, J=5 Hz, 2H), 5.98-6.02 (m, 1H), 6.46-6.49 (m, 1H), 6.58-6.61 (m, 1H).

Reference Example 10
Synthesis of 2-(3-methyl-1H-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 9 according to the method described in Reference Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.04 (s, 3H), 2.44 (s, 3H), 4.05 (t, J=6 Hz, 2H), 4.20 (t, J=6 Hz, 2H), 5.90-5.94 (m, 1H), 6.30-6.33 (m, 1H), 6.44-6.48 (m, 1H), 7.29 (d, J=8 Hz, 2H), 7.66 (d, J=8 Hz, 2H).

Example 166
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(3-methyl-1H-pyrrol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 10 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.16 (m, 2H), 0.46-0.54 (m, 2H), 0.76-0.90 (m, 1H), 0.98-1.07 (m, 1H), 1.42-1.51 (m, 1H), 1.74-1.84 (m, 2H), 1.95-2.06 (m, 2H), 2.05 (s, 3H), 2.28-2.39 (m, 3H), 2.49-2.57 (m, 1H), 2.62-2.98 (m, 8H), 3.13-3.22 (m, 1H), 3.85 (t, J=7 Hz, 2H), 4.72 (br s, 1H), 5.89 (dd, J=2, 2 Hz, 1H), 6.30-6.34 (m, 1H), 6.42-6.45 (m, 1H), 6.45-6.48 (m, 1H), 6.58 (dd, J=2, 8 Hz, 1H), 6.92 (d, J=8 Hz, 1H).

Example 167
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2,2,2-trifluoroethan-1-one

[Image Omitted]

To a solution of the compound E (20 mg, 0.061 mmol) obtained in Example 3 in chloroform (1 mL) were added N,N-diisopropylethylamine (49 μL, 0.29 mmol) and trifluoroacetic anhydride (16 μL, 0.12 mmol) under ice cooling, followed by stirring at room temperature for 23 hours. To the reaction mixture were added potassium carbonate (60 mg, 0.43 mmol) and methanol (1 mL), followed by further stirring for 1 hour. Water was added to the reaction mixture under ice cooling, followed by extraction three times with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (1 to 10% methanol/chloroform) to yield the title compound (14 mg, 54%) as a pale yellow gumlike substance.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.19 (m, 2H), 0.43-0.60 (m, 2H), 0.75-0.95 (m, 1H), 1.01-1.78 (m, 3H), 1.79-2.24 (m, 4H), 2.27-2.47 (m, 3H), 2.48-2.66 (m, 1H), 2.70-2,85 (m, 1H), 2.86-3.06 (m, 2H), 3.27-3.36 (m, 0.5H), 3.42-3.69 (m, 1.5H), 3.69-3.89 (m, 1H), 3.91-4.09 (m, 1H), 6.58 (d, J=2 Hz, 0.5H), 6.60-6.70 (m, 1.5H), 6.91-7.02 (m, 1H).

Reference Example 11
Synthesis of 3-(chloromethyl)-5-methylisothiazole

[Image Omitted]

To a solution of (5-methylisothiazol-3-yl) methanol (103 mg, 0.797 mmol) in toluene (3 mL) was added thionyl chloride (0.12 mL, 1.7 mmol), followed by stirring at 80° C. for 5 hours. After allowed to cool to room temperature, to the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (4 to 25% ethyl acetate/heptane) to yield the title compound (69.7 mg, 59%) as a pale brown oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.58 (s, 3H), 4.62 (s, 2H), 7.05 (s, 1H).

Reference Example 12
Synthesis of 2-(5-methylisothiazol-3-yl)acetonitrile

[Image Omitted]

To a solution of the compound (69.7 mg, 0.472 mmol) obtained in Reference Example 11 in dimethyl sulfoxide (1.5 mL) was added sodium cyanide (69.4 mg, 1.42 mmol), followed by stirring at room temperature for 1.5 hours and at 50° C. for 17 hours. After allowed to cool to room temperature, to the reaction mixture was added water, followed by extraction three times with tert-butyl methyl ether. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (19 to 40% ethyl acetate/heptane) to yield the title compound (42.9 mg, 66%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.59 (s, 3H), 3.86 (s, 2H), 7.01 (s, 1H).

Reference Example 13
Synthesis of 2-(5-methylisothiazol-3-yl)acetic acid

[Image Omitted]

To a solution of the compound (42.9 mg, 0.310 mmol) obtained in Reference Example 12 in acetic acid (1 mL) was added 6 M hydrochloric acid (0.5 mL), followed by stirring at 90° C. for 4.5 hours. After allowed to cool to room temperature, the reaction solution was concentrated under reduced pressure. Water was added to the obtained residue, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure to yield the title compound (42.9 mg, 88%) as a pale brown crystal.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.59 (s, 3H), 3.88 (s, 2H), 6.91 (s, 1H).

Example 168
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(5-methylisothiazol-3-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 13 according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.08-0.12 (m, 2H), 0.48-0.53 (m, 2H), 0.78-0.85 (m, 1H), 1.02-1.10 (m, 1H), 1.53-1.62 (m, 1H), 1.72-2.15 (m, 4H), 2.26-2.38 (m, 2.6H), 2.47-2.54 (m, 4.4H), 2.67 (dd, J=6, 18 Hz, 0.6H), 2.77 (dd, J=6, 18 Hz, 0.4H), 2.85-2.98 (m, 2H), 3.33-3.41 (m, 1.4H), 3.45-3.49 (m, 1.2H), 3.57 (d, J=Hz, 0.4H), 3.72 (d, J=15 Hz, 0.4H), 3.73-3.78 (m, 0.4H), 3.78 (d, J=15 Hz, 0.6H), 3.85-3.88 (m, 1H), 3.89 (d, J=15 Hz, 0.6H), 3.99-4.02 (m, 0.4H), 4.46-4.52 (m, 0.6H), 6.61-6.68 (m, 1.5H), 6.79-6.83 (m, 1.5H), 6.89-6.92 (m, 1H).

Example 169
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propanoic acid according to the method described in Example 85.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.48-0.56 (m, 2H), 0.76-0.89 (m, 1H), 1.04-1.15 (m, 1H), 1.55-1.63 (m, 1H), 1.78 (ddd, J=3, 12, 14 Hz, 0.5H), 1.87-2.25 (m, 3.5H), 2.29 (dd, J=6, 13 Hz, 0.5H), 2.32-2.39 (m, 1.5H), 2.51-3.09 (m, 7H), 3.24 (ddd, J=4, 4, 13 Hz, 0.5H), 3.26-3.34 (m, 0.5H), 3.36 (ddd, J=2, 6, 14 Hz, 0.5H), 3.63-3.90 (m, 1.5H), 4.03-4.18 (m, 1.5H), 4.32 (ddd, J=7, 7, 14 Hz, 0.5H), 4.47 (t, J=7 Hz, 1H), 6.61 (dd, J=2, 8 Hz, 0.5H), 6.64-6.69 (m, 1H), 6.75-6.80 (m, 0.5H), 6.91 (d, J=8 Hz, 0.5H), 6.96 (d, J=8 Hz, 0.5H), 7.66 (s, 0.5H), 7.69 (s, 0.5H), 7.73 (s, 0.5H), 7.81 (s, 0.5H).

Example 170
Synthesis of 2,2,2-trichloroethyl (5aS,6R,11bR)-5a-(benzoyloxy)-14-(cyclopropylmethyl)-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

To a solution of the compound (270 mg, 0.52 mmol) obtained in Example 150 in xylene (10 mL) were added benzoic anhydride (236 mg, 1.04 mmol), 4-dimethylaminopyridine (127 mg, 1.04 mmol), and N,N-diisopropylethylamine (182 μL, 1.04 mmol), followed by stirring at 140° C. for 18 hours. Thereafter, xylene (10 mL), benzoic anhydride (236 mg, 1.04 mmol), 4-dimethylaminopyridine (127 mg, 1.04 mmol), and N,N-diisopropylethylamine (182 μL, 1.04 mmol) were added, followed by stirring at 140° C. for 42 hours. After allowed to cool, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (25 to 100% ethyl acetate/heptane) to yield the title compound (213 mg, 66%) as a white amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): −0.18-0.00 (m, 2H), 0.29-0.43 (m, 2H), 0.58-0.70 (m, 1H), 0.83-2.84 (m, 11H), 3.02-3.35 (m, 3H), 3.63-3.78 (m, 1H), 3.81 (s, 1.2H), 3.81 (s, 1.8H), 3.88-4.03 (m, 1.6H), 4.40-4.51 (m, 1.4H), 4.53 (d, J=12 Hz, 0.6H), 4.63 (d, J=12 Hz, 0.4H), 6.72-6.79 (m, 2H), 7.05-7.11 (m, 1H), 7.28-7.60 (m, 3H), 8.01-8.08 (m, 2H).

Example 171
Synthesis of 2,2,2-trichloroethyl (5aS,6R,11bR)-14-benzoyl-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

The title compound was obtained from the compound obtained in Example 170 according to the method described in Example 152.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.88-1.39 (m, 1H), 1.60-3.02 (m, 9H), 3.30-3.90 (m, 5H), 3.79 (s, 1.2H), 3.80 (s, 1.8H), 4.37-4.96 (m, 3H), 6.67-6.78 (m, 2H), 6.99-7.12 (m, 1H), 7.34-7.51 (m, 5H).

Example 172
Synthesis of ((5aS,6R,11bS)-5a-hydroxy-10-methoxy-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-14-yl) (phenyl)methanone

[Image Omitted]

The title compound was obtained from the compound obtained in Example 171 according to the method described in Example 153.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.80-1.50 (m, 1H), 1.55-3.28 (m, 11H), 3.30-3.42 (m, 1H), 3.73-4.00 (m, 1H), 3.78 (s, 3H), 4.38-4.49 (m, 0.5H), 4.92-5.00 (m, 0.5H), 6.70-6.86 (m, 2H), 7.04 (d, J=8 Hz, 0.5H), 7.11 (d, J=8 Hz, 0.5H), 7.32-7.61 (m, 5H).

Example 173
Synthesis of 1-((5aS,6R,11bS)-14-benzoyl-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 172 and 2-(4-methyl-1H-pyrazol-1-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.80-4.60 (m, 15H), 2.04 (s, 1.5H), 2.07 (s, 1.5H), 3.79 (s, 1.5H), 3.81 (s, 1.5H), 4.76-4.96 (m, 2H), 6.66-6.74 (m, 1H), 6.76-6.83 (m, 1H), 6.98-7.20 (m, 2H), 7.26-7.33 (m, 1H), 7.34-7.50 (m, 5H).

Example 174
Synthesis of (5aS,6R,11bS)-14-benzyl-10-methoxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 173 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.96-1.06 (m, 1H), 1.34-1.43 (m, 1H), 1.73 (ddd, J=3, 11, 11 Hz, 1H), 1.84 (ddd, J=4, 4, 16 Hz, 1H), 1.95-2.10 (m, 2H), 1.99 (s, 3H), 2.31-2.48 (m, 3H), 2.64 (ddd, J=4, 4, 13 Hz, 1H), 2.73 (d, J=6 Hz, 1H), 2.76-2.88 (m, 3H), 2.94-3.04 (m, 1H), 3.09-3.20 (m, 2H), 3.59 (d, J=13 Hz, 1H), 3.64 (d, J=13 Hz, 1H), 3.77 (s, 3H), 3.86-4.05 (m, 2H), 4.51 (br s, 1H), 6.69 (d, J=2 Hz, 1H), 6.70-6.76 (m, 2H), 7.09 (d, J=8 Hz, 1H), 7.17-7.35 (m, 6H).

Example 175
Synthesis of (5aS,6R,11bS)-14-benzyl-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 174 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.95-1.05 (m, 1H), 1.33-1.44 (m, 1H), 1.68-1.82 (m, 2H), 1.91-2.13 (m, 2H), 1.99 (s, 3H), 2.28-2.42 (m, 2H), 2.48-2.68 (m, 2H), 2.70 (d, J=6 Hz, 1H), 2.79 (dd, J=6, 18 Hz, 1H), 2.83-2.99 (m, 3H), 3.05-3.23 (m, 2H), 3.58 (d, J=13 Hz, 1H), 3.64 (d, J=13 Hz, 1H), 3.99-4.11 (m, 2H), 6.53 (d, J=2 Hz, 1H), 6.63 (dd, J=2, 8 Hz, 1H), 6.90 (s, 1H), 6.97 (d, J=8 Hz, 1H), 7.20-7.38 (m, 6H).

Example 176
Synthesis of (5aS,6R,11bR)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To the compound (4.7 mg, 0.010 mmol) obtained in Example 175 were added 10% palladium-activated carbon (4.7 mg) and methanol (500 μL), followed by stirring under a hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was filtered through celite to remove palladium, followed by concentration under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=5:1) to yield the title compound (2.2 mg, 58%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.92-1.00 (m, 1H), 1.47 (dd, J=7, 15 Hz, 1H), 1.63-2.05 (m, 3H), 2.09 (s, 3H), 2.16 (dd, J=5, 15 Hz, 1H), 2.31-2.64 (m, 5H), 2.82-2.98 (m, 5H), 3.17 (dd, J=7, 18 Hz, 1H), 4.08-4.15 (m, 2H), 6.62-6.68 (m, 2H), 6.98 (d, J=8 Hz, 1H), 7.15 (s, 1H), 7.35 (s, 1H).

Example 177
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(5-methylisothiazol-3-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 168 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.13 (m, 2H), 0.47-0.52 (m, 2H), 0.79-0.86 (m, 1H), 1.00-1.07 (m, 1H), 1.47-1.51 (m, 1H), 1.78-1.85 (m, 2H), 1.96-2.07 (m, 2H), 2.30-2.35 (m, 3H), 2.50 (s, 3H), 2.50-2.54 (m, 1H) 2.71-2.80 (m, 3H), 2.87-2.96 (m, 7H), 3.15-3.23 (m, 1H), 4.74 (br s, 1H), 6.44-6.49 (m, 1H), 6.57 (dd, J=2, 8 Hz, 1H), 6.71 (s, 1H), 6.89 (d, J=8 Hz, 1H).

Example 178
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2,2,2-trifluoroethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 167 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.18 (m, 2H), 0.42-0.58 (m, 2H), 0.75-0.91 (m, 1H), 0.98-1.13 (m, 1H), 1.19-1.90 (m, 3H), 1.92-2.11 (m, 2H), 2.25-2.42 (m, 3H), 2.48-2.63 (m, 1H), 2.72-2.85 (m, 2H), 2.86-3.18 (m, 6H), 3.23-3.31 (m, 1H), 4.64 (br s, 1H), 6.54-6.66 (m, 2H), 6.96 (d, J=8 Hz, 1H).

Example 179
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 169 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.16 (m, 2H), 0.46-0.56 (m, 2H), 0.77-0.89 (m, 1H), 1.02-1.08 (m, 1H), 1.46-1.53 (m, 1H), 1.75-1.89 (m, 4H), 1.96-2.10 (m, 2H), 2.16-2.43 (m, 6H), 2.49-2.60 (m, 2H), 2.84 (dd, J=6, 18 Hz, 1H), 2.91-3.04 (m, 4H), 3.76 (ddd, J=7, 7, 14 Hz, 1H), 3.82 (ddd, J=7, 7, 14 Hz, 1H), 4.65 (br s, 1H), 6.58 (dd, J=2, 8 Hz, 1H), 6.72 (d, J=2 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 7.19 (s, 1H), 7.64 (s, 1H).

Example 180
Synthesis of 2-chloro-1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)ethan-1-one

[Image Omitted]

To a solution of the compound E (50 mg, 0.15 mmol) obtained in Example 3 in chloroform (1 mL) were added N,N-diisopropylethylamine (77 μL, 0.45 mmol) and chloroacetyl chloride (18 μL, 0.23 mmol) under ice cooling, followed by stirring at room temperature for 15 hours. Thereafter, potassium carbonate (207 mg, 1.5 mmol) and methanol (1 mL) were added, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture under ice cooling, followed by extraction three times with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 1 to 100% methanol/chloroform) to yield the title compound (30 mg, 50%) as a pale yellow amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.19 (m, 2H), 0.42-0.61 (m, 2H), 0.75-0.92 (m, 1H), 1.02-1.18 (m, 1H), 1.21-2.43 (m, 8H), 2.46-3.12 (m, 5H), 3.33-4.01 (m, 3H), 4.06-4.32 (m, 2H), 6.51-6.78 (m, 1.4H), 6.79-7.04 (m, 1.6H).

Example 181
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(3,3-difluoropyrrolidin-1-yl)ethan-1-one

[Image Omitted]

To a solution of the compound (15.3 mg, 0.038 mmol) obtained in Example 180 in acetonitrile (1 mL) were added N,N-diisopropylethylamine (65 μL, 0.38 mmol) and 3,3-difluoropyrrolidine (16 mg, 0.11 mmol), followed by stirring at room temperature for 42 hours. Water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 5% methanol/chloroform) to yield the title compound (16.6 mg, 92%) as a pale yellow gumlike substance.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.19 (m, 2H), 0.41-0.59 (m, 2H), 0.74-0.92 (m, 1H), 0.99-1.18 (m, 1H), 1.19-2.43 (m, 10H), 2.46-3.12 (m, 8.3H), 3.17-3.28 (m, 1H), 3.30-3.54 (m, 2.7H), 3.60-3.72 (m, 0.3H), 3.73-3.88 (m, 1H), 3.90-4.05 (m, 0.7H), 6.51-6.73 (m, 1.3H), 6.79-7.02 (m, 1.7H).

Example 182
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 181 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.18 (m, 2H), 0.43-0.57 (m, 2H), 0.76-0.92 (m, 1H), 0.96-1.08 (m, 1H), 1.17-1.91 (m, 3H), 1.94-2.09 (m, 2H), 2.11-2.26 (m, 2H), 2.27-2.41 (m, 3H), 2.46-3.00 (m, 15H), 3.01-3.16 (m, 1H), 4.73 (br s, 1H), 6.48 (d, J=2 Hz, 1H), 6.56 (dd, J=2, 8 Hz, 1H), 6.90 (d, J=8 Hz, 1H).

Example 183
Synthesis of (5aS,6R,11bS)-3-(2-(4-cyclopropyl-1H-pyrazol-1-yl)ethyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 160 according to the method described in Example 68.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 4H), 0.70-0.95 (m, 3H), 1.00-1.10 (m, 1H), 1.20-1.40 (m, 1H), 1.40-1.50 (m, 2H), 1.50-2.20 (m, 3H), 2.20-2.45 (m, 4H), 2.50-2.60 (m, 2H), 2.60-2.80 (m, 2H), 2.85-3.10 (m, 4H), 3.15-3.30 (m, 1H), 4.00-4.20 (m, 2H), 6.56 (d, J=3 Hz, 1H), 6.63 (dd, J=3, 8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 7.00 (s, 1H), 7.22 (s, 1H).

Example 184
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-fluoro-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 180 and 4-fluoro-1H-pyrazole according to the methods described in Examples 181 and 182.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-1.00 (m, 1H), 0.95-1.05 (m, 1H), 1.40-1.90 (m, 3H), 1.90-2.10 (m, 3H), 2.25-2.65 (m, 6H), 2.70-2.85 (m, 3H), 2.85-3.05 (m, 2H), 3.05-3.15 (m, 1H), 3.80-4.00 (m, 2H), 6.60-6.70 (m, 3H), 6.97 (d, J=8 Hz, 1H), 7.19 (d, J=4 Hz, 1H).

Reference Example 14
Synthesis of 2-(5-methylisoxazol-3-yl)acetic acid

[Image Omitted]

The title compound was obtained from 2-(5-methylisoxazol-3-yl)acetonitrile according to the method described in Reference Example 13.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.43 (s, 3H), 3.76 (s, 2H), 6.06 (s, 1H).

Example 185
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(5-methylisoxazol-3-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 14 according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.08-0.13 (m, 2H), 0.50-0.54 (m, 2H), 0.78-0.85 (m, 1H), 1.04-1.13 (m, 1H), 1.55-1.64 (m, 1H), 1.78-2.08 (m, 3.4H), 2.16-2.38 (m, 6.6H), 2.51-2.60 (m, 1.4H), 2.72 (dd, J=7, 19 Hz, 0.6H), 2.77 (dd, J=6, 20 Hz, 0.4H), 2.87-3.01 (m, 2H), 3.16-3.22 (m, 0.6H), 3.36-3.48 (m, 2H), 3.59 (d, J=15 Hz, 0.4H), 3.67 (d, J=15 Hz, 0.6H), 3.63-3.97 (m, 2H), 4.48 (br s, 0.6H), 5.90 (s, 0.4H), 5.97 (s, 0.6H), 6.61-6.68 (m, 1.4H), 6.82-6.84 (m, 0.6H), 6.90-6.94 (m, 1H), 7.60 (br s, 0.4H).

Example 186
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(dimethylamino)propan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 3-(dimethylamino)propanoic acid according to the method described in Example 85.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.02-0.17 (m, 2H), 0.43-0.57 (m, 2H), 0.76-0.88 (m, 1H), 1.02-1.14 (m, 1H), 1.52-1.65 (m, 1H), 1.77 (ddd, J=2, 12, 14 Hz, 0.5H), 1.86-2.11 (m, 3H), 2.13-2.47 (m, 5.5H), 2.23 (s, 3H), 2.24 (s, 3H), 2.49-2.81 (m, 4H), 2.88 (d, J=6 Hz, 0.5H), 2.92 (d, J=19 Hz, 0.5H), 2.92 (d, J=6 Hz, 0.5H), 3.00 (d, J=18 Hz, 0.5H), 3.12-3.27 (m, 1H), 3.37 (ddd, J=3, 3, 14 Hz, 0.5H), 3.40 (ddd, J=2, 6, 14 Hz, 0.5H), 3.80-3.98 (m, 1.5H), 4.07-4.16 (m, 0.5H), 4.47 (br s, 0.5H), 4.53 (br s, 0.5H), 6.58-6.63 (m, 0.5H), 6.65 (dd, J=2, 8 Hz, 0.5H), 6.68-6.71 (m, 0.5H), 6.81 (d, J=2 Hz, 0.5H), 6.90 (d, J=8 Hz, 0.5H), 6.94 (d, J=8 Hz, 0.5H).

Example 187
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-methoxypropan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 3-methoxypropanoic acid according to the method described in Example 85.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.17 (m, 2H), 0.44-0.57 (m, 2H), 0.74-0.90 (m, 1H), 0.91-0.98 (m, 0.3H), 1.02-1.11 (m, 0.7H), 1.53-1.63 (m, 1H), 1.72-2.12 (m, 4H), 2.23-2.57 (m, 6H), 2.74 (dd, J=6, 18 Hz, 1H), 2.83-2.92 (m, 1.3H), 2.98 (d, J=18 Hz, 0.7H), 3.27 (s, 2.1H), 3.29 (s, 0.9H), 3.30-3.88 (m, 6H), 4.49 (br s, 1H), 6.61 (dd, J=2, 8 Hz, 0.3H), 6.65 (d, J=2 Hz, 0.3H), 6.69 (dd, J=2, 8 Hz, 0.7H), 6.77-6.82 (m, 0.7H), 6.86 (d, J=8 Hz, 0.3H), 6.89 (d, J=8 Hz, 0.7H).

Example 188
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(5-methylisoxazol-3-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 185 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.08-0.11 (m, 2H), 0.47-0.52 (m, 2H), 0.78-0.86 (m, 1H), 1.03-1.05 (m, 1H), 1.49 (dd, J=4, 14 Hz, 1H), 1.68-1.71 (m, 1H), 1.78-1.84 (m, 2H), 1.99-2.03 (m, 2H), 2.32 (s, 3H), 2.32-2.35 (m, 2H) 2.52-2.54 (m, 1H), 2.71-2.96 (m, 9H), 3.13-3.19 (m, 1H), 3.69-3.71 (m, 2H), 4.71 (br s, 1H), 5.72 (s, 1H), 6.45 (s, 1H), 6.54-6.59 (m, 1H), 6.89 (d, J=8 Hz, 1H).

Example 189
Synthesis of 1-(2-((5aS,6R,11bS)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)ethyl)-1H-pyrazole-4-carbonitrile

[Image Omitted]

The target compound was obtained from 1-(2-hydroxyethyl)-1H-pyrazole-4-carbonitrile and the compound E obtained in Example 3 according to the methods described in Reference Example 6 and Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.03 (d, J=12 Hz, 1H), 1.15-1.25 (m, 1H), 1.77 (dd, J=5, 15 Hz, 1H), 1.90-2.10 (m, 2H), 2.15-2.25 (m, 1H), 2.25-2.40 (m, 2H), 2.45-2.70 (m, 3H), 2.70-3.05 (m, 5H), 3.05-3.20 (m, 2H), 3.65-3.80 (m, 1H), 3.85-4.05 (m, 2H), 6.65-6.80 (m, 3H), 7.12 (d, J=8 Hz, 1H), 7.63 (s, 1H).

Example 190
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(pyridin-2-yl)propan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 3-(pyridin-2-yl)propanoic acid according to the method described in Example 85.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.17 (m, 2H), 0.44-0.57 (m, 2H), 0.76-0.90 (m, 1H), 1.07-1.16 (m, 1H), 1.52-1.63 (m, 1H), 1.77-2.43 (m, 8H), 2.50-2.59 (m, 1H), 2.65-3.20 (m, 7H), 3.25-3.37 (m, 1H), 3.88 (ddd, J=3, 13, 13 Hz, 0.3H), 3.94-4.07 (m, 1.4H), 4.22 (dd, J=4, 15 Hz, 0.3H), 4.43 (br s, 0.3H), 4.55 (br s, 0.7H), 6.69 (dd, J=2, 8 Hz, 0.3H), 6.71-6.76 (m, 0.7H), 6.83 (dd, J=2, 2 Hz, 0.7H), 6.88-6.97 (m, 1.3H), 7.09 (dd, J=5, 8 Hz, 0.3H), 7.16-7.23 (m, 1.7H), 7.56 (ddd, J=2, 8, 8 Hz, 0.3H), 7.65 (ddd, J=2, 8, 8 Hz, 0.7H), 8.47-8.53 (m, 1H).

Reference Example 15
Synthesis of (5-ethylisoxazol-3-yl)methanol

[Image Omitted]

To a solution of ethyl 5-ethylisoxazole-3-carboxylate (synthesized by the method described in WO 2016040515) (410 mg, 2.42 mmol) in tetrahydrofuran (4.8 mL) was added a 4 M lithium borohydride-tetrahydrofuran solution (1.21 mL, 4.84 mmol) under ice cooling, followed by stirring at room temperature for 24.5 hours. Water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure to yield the title compound (195 mg, 63%) as a pale yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.30 (t, J=8 Hz, 3H), 2.77 (q, J=8 Hz, 2H), 4.73 (s, 2H), 6.03 (s, 1H).

Reference Example 16
Synthesis of 3-(chloromethyl)-5-ethylisoxazole

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 15 according to the method described in Reference Example 11.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.31 (t, J=8 Hz, 3H), 2.77 (q, J=8 Hz, 2H), 4.56 (s, 2H), 6.10 (s, 1H).

Reference Example 17
Synthesis of 2-(5-ethylisoxazol-3-yl)acetonitrile

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 16 according to the method described in Reference Example 12.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.31 (t, J=8 Hz, 3H), 2.79 (q, J=8 Hz, 2H), 3.78 (s, 2H), 6.10 (s, 1H).

Reference Example 18
Synthesis of 2-(5-ethylisoxazol-3-yl)acetic acid

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 17 according to the method described in Reference Example 13.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.30 (t, J=8 Hz, 3H), 2.77 (q, J=8 Hz, 2H), 3.77 (s, 2H), 6.05 (s, 1H)

Example 191
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(5-ethylisoxazol-3-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 18 according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.08-0.13 (m, 2H), 0.48-0.54 (m, 2H), 0.80-0.86 (m, 1H), 1.04-1.13 (m, 1H), 1.23-1.32 (m, 3H), 1.59-1.63 (m, 1H), 1.70-2.10 (m, 3.4H), 2.20-2.23 (m, 1H), 2.28-2.39 (m, 2H), 2.52-2.60 (m, 1.4H), 2.68-2.81 (m, 3H), 2.89-3.02 (m, 2H), 3.16 (ddd, J=4, 9, 13 Hz, 0.6H), 3.37-3.49 (m, 2H), 3.59 (d, J=15 Hz, 0.4H), 3.68 (d, J=15 Hz, 0.6H), 3.71-3.80 (m, 1H), 3.83-3.88 (m, 0.4H), 3.93 (ddd, J=3, 12, 12 Hz, 0.6H), 4.12-4.18 (m, 0.6H), 5.92 (s, 0.4H), 5.99 (s, 0.6H), 6.61-6.67 (m, 1.4H), 6.80-6.82 (m, 0.6H), 6.91-6.95 (m, 1H).

Example 192
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-ethyl-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 180 and 4-ethyl-1H-pyrazole according to the methods described in Example 181.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.10 (m, 1H), 1.10-1.30 (m, 3H), 1.50-2.10 (m, 3H), 2.10-2.25 (m, 1H), 2.25-2.40 (m, 2H), 2.40-2.70 (m, 3H), 2.70-2.85 (m, 1H), 2.85-3.15 (m, 2.4H), 3.20-3.60 (m, 1.6H), 3.60-3.75 (m, 0.6H), 3.80-4.00 (m, 1.4H), 4.05-4.25 (m, 1H), 4.52 (br s, 1H), 4.60 (d, J=16 Hz, 0.6H), 4.73 (d, J=16 Hz, 0.6H), 4.88 (d, J=16 Hz, 0.4H), 4.93 (d, J=16 Hz, 0.4H), 6.60-6.80 (m, 2H), 6.90-7.00 (m, 1H), 7.14 (s, 0.6H), 7.21 (s, 0.4H), 7.34 (s, 0.6H), 7.42 (s, 0.4H).

Example 193
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-ethyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 192 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.03 (d, J=10 Hz, 1H), 1.15 (t, J=8 Hz, 3H), 1.40-1.50 (m, 1H), 1.70-1.85 (m, 2H), 1.90-2.10 (m, 2H), 2.30-2.40 (m, 3H), 2.41 (q, J=8 Hz, 2H), 2.50-2.70 (m, 3H), 2.70-2.80 (m, 1H), 2.80-3.00 (m, 5H), 3.15-3.30 (m, 1H), 4.00-4.15 (m, 2H), 6.55 (s, 1H), 6.61 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 6.96 (s, 1H), 7.28 (s, 1H).

Example 194
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-isopropyl-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 180 and 4-isopropyl-1H-pyrazole according to the method described in Example 181.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.10 (m, 1H), 1.17 (d, J=7 Hz, 3.6H), 1.18 (d, J=7 Hz, 2.4H), 1.50-1.70 (m, 1H), 1.70-1.90 (m, 2H), 1.90-2.10 (m, 3H), 2.20-2.40 (m, 2H), 2.50-3.05 (m, 5H), 3.15-3.30 (m, 1H), 3.30-3.45 (m, 1H), 3.70-3.95 (m, 2H), 4.55 (br s, 1H), 4.57 (d, J=16 Hz, 0.6H), 4.74 (d, J=16 Hz, 0.6H), 4.78 (d, J=16 Hz, 0.4H), 4.86 (d, J=16 Hz, 0.4H), 6.60-6.70 (m, 2H), 6.90 (d, J=8 Hz, 0.6H), 6.93 (d, J=8 Hz, 0.4H), 7.15 (s, 0.4H), 7.16 (s, 0.6H), 7.34 (s, 0.4H), 7.36 (s, 0.6H).

Example 195
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-isopropyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 194 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.03 (d, J=10 Hz, 1H), 1.16 (d, J=7 Hz, 3H), 1.17 (d, J=7 Hz, 3H), 1.44 (dd, J=2, 15 Hz, 1H), 1.70-1.85 (m, 2H), 1.95-2.05 (m, 2H), 2.20-2.40 (m, 2H), 2.50-2.85 (m, 6H), 2.85-3.00 (m, 5H), 3.15-3.30 (m, 1H), 4.00-4.15 (m, 2H), 6.50 (d, J=2 Hz, 1H), 6.60 (dd, J=2, 8 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 7.05 (s, 1H), 7.31 (s, 1H).

Example 196
Synthesis of (5aS,6R,11bS)-14-allyl-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 176 and allyl bromide according to the method described in Example 161.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.95-1.10 (m, 1H), 1.35-1.50 (m, 1H), 1.70-1.85 (m, 2H), 1.95-2.08 (m, 2H), 2.00 (s, 3H), 2.28-2.53 (m, 3H), 2.54-2.62 (m, 1H), 2.68-3.02 (m, 6H), 3.07-3.19 (m, 3H), 3.94-4.08 (m, 2H), 5.08-5.21 (m, 2H), 5.72-5.85 (m, 1H), 6.56 (d, J=2 Hz, 1H), 6.62 (dd, J=2, 8 Hz, 1H), 6.86 (s, 1H), 6.95 (d, J=8 Hz, 1H), 7.23 (s, 1H).

Example 197
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(5-ethylisoxazol-3-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 191 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.08-0.11 (m, 2H), 0.48-0.52 (m, 2H), 0.80-0.87 (m, 1H), 1.03-1.05 (m, 1H), 1.23 (t, J=8 Hz, 3H), 1.46-1.49 (m, 1H), 1.77-1.87 (m, 2H), 1.96-2.08 (m, 2H), 2.31-2.38 (m, 3H), 2.53-2.55 (m, 1H), 2.65-2.83 (m, 9H), 2.88-2.97 (m, 3H), 3.13-3.19 (m, 1H), 4.69 (br s, 1H), 5.73 (s, 1H), 6.50 (d, J=2 Hz, 1H), 6.58 (dd, J=2, 8 Hz, 1H), 6.91 (d, J=8 Hz, 1H).

Example 198
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(dimethylamino)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and dimethylglycine according to the method described in Example 85.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.13 (m, 2H), 0.46-0.54 (m, 2H), 0.77-0.87 (m, 1H), 1.01-1.07 (m, 0.3H), 1.09-1.15 (m, 0.7H), 1.56-1.64 (m, 1H), 1.78-2.12 (m, 3H), 2.16-2.39 (m, 3.7H), 2.21 (s, 4.2H), 2.25 (s, 1.8H), 2.49-2.62 (m, 1.3H), 2.76 (dd, J=6, 18 Hz, 0.7H), 2.77 (dd, J=6, 18 Hz, 0.3H), 2.84-3.17 (m, 4H), 3.20-3.29 (m, 0.7H), 3.30-3.39 (m, 0.3H), 3.41-3.51 (m, 1H), 3.76 (ddd, J=4, 12, 14 Hz, 0.3H), 3.81-3.91 (m, 1H), 4.09-4.17 (m, 0.7H), 4.52 (br s, 1H), 6.54 (dd.J=3, 8 Hz, 0.3H), 6.65-6.70 (m, 1H), 6.87 (d, J=8 Hz, 0.3H), 6.92 (d, J=8 Hz, 0.7H), 6.95 (d, J=2 Hz, 0.7H).

Example 199
Synthesis of (5aS,6R,11bR)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 140 and (3-bromopropoxy) (tert-butyl)dimethylsilane according to the method described in Example 141.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): −0.04 (s, 3H), −0.03 (s, 3H), 0.02-0.16 (m, 2H), 0.46-0.55 (m, 2H), 0.80-0.95 (m, 1H), 0.84 (s, 9H), 1.08-1.18 (m, 1H), 1.33-1.82 (m, 4H), 1.99-2.12 (m, 2H), 2.28-2.45 (m, 2H), 2.53-2.60 (m, 1H), 2.64 (d, J=15 Hz, 1H), 2.73 (dd, J=6, 18 Hz, 1H), 2.88-2.99 (m, 2H), 3.00 (d, J=18 Hz, 1H), 3.06-3.21 (m, 2H), 3.33-3.56 (m, 3H), 3.81 (s, 3H), 4.10 (dd, J=11, 15 Hz, 1H), 4.72 (br s, 1H), 6.68 (dd, J=2, 8 Hz, 1H), 6.93 (d, J=9 Hz, 1H), 7.19 (d, J=2 Hz, 1H).

Example 200
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-3-(3-hydroxypropyl)-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

To a solution of the compound (138 mg, 0.26 mmol) obtained in Example 199 in tetrahydrofuran (30 mL) was added a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (2.6 mL, 2.6 mmol), followed by stirring at room temperature for 3 hours. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 50% methanol/chloroform) to yield the title compound (99.5 mg, 92%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.18 (m, 2H), 0.46-0.58 (m, 2H), 0.77-0.90 (m, 1H), 1.10-1.39 (m, 2H), 1.44-1.80 (m, 3H), 2.00-2.15 (m, 2H), 2.35 (dd, J=6, 12 Hz, 1H), 2.37 (dd, J=6, 12 Hz, 1H), 2.53-2.67 (m, 2H), 2.71 (d, J=15 Hz, 1H), 2.74 (dd, J=7, 18 Hz, 1H), 2.84-2.96 (m, 2H), 3.00 (d, J=18 Hz, 1H), 3.01-3.18 (m, 2H), 3.56 (d, J=15 Hz, 1H), 3.68-3.88 (m, 2H), 3.83 (s, 3H), 4.17 (dd, J=10, 15 Hz, 1H), 6.72 (dd, J=2, 8 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 7.19 (d, J=2 Hz, 1H).

Example 201
Synthesis of 3-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-2-oxo-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)propyl methanesulfonate

[Image Omitted]

The title compound was obtained from the compound obtained in Example 200 according to the method described in Reference Example 7.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.18 (m, 2H), 0.46-0.58 (m, 2H), 0.76-0.92 (m, 1H), 1.08-1.21 (m, 1H), 1.55-3.18 (m, 16H), 2.94 (s, 3H), 3.26-3.86 (m, 3H), 3.80 (s, 3H), 4.15 (dd, J=11, 15 Hz, 1H), 6.69 (dd, J=2, 8 Hz, 1H), 6.97 (d, J=9 Hz, 1H), 7.16 (d, J=2 Hz, 1H).

Example 202
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3-(3-(4-methyl-1H-pyrazol-1-yl)propyl)-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

To a solution of the compound (9.8 mg, 0.020 mmol) obtained in Example 201 in tetrahydrofuran (1 mL) were added 4-methylpyrazole (16.5 μL, 0.20 mmol) and sodium hydride (55% oil dispersion, 7.0 mg, 0.16 mmol), followed by stirring at room temperature for 4 hours. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 20% methanol/chloroform) to yield the title compound (8.0 mg, 84%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.15 (m, 2H), 0.48-0.56 (m, 2H), 0.76-0.90 (m, 1H), 1.10-1.20 (m, 1H), 1.56-1.77 (m, 3H), 1.83-1.96 (m, 1H), 2.00-2.14 (m, 2H), 2.04 (s, 3H), 2.35 (dd, J=7, 12 Hz, 1H), 2.36 (dd, J=7, 12 Hz, 1H), 2.53-2.62 (m, 1H), 2.68 (d, J=Hz, 1H), 2.76 (dd, J=6, 18 Hz, 1H), 2.83-2.95 (m, 3H), 3.01 (d, J=18 Hz, 1H), 3.44 (t, J=7 Hz, 2H), 3.55 (d, J=15 Hz, 1H), 3.58-3.69 (m, 1H), 3.78 (s, 3H), 4.09 (dd, J=11, 15 Hz, 1H), 4.68 (br s, 1H), 6.63 (dd, J=3, 8 Hz, 1H), 6.94 (d, J=9 Hz, 1H), 6.99 (s, 1H), 7.22 (s, 1H), 7.24 (d, J=3 Hz, 1H).

Example 203
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-3-(3-(4-methyl-1H-pyrazol-1-yl)propyl)-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 202 according to the method described in Example 6.

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.08-0.19 (m, 2H), 0.46-0.58 (m, 2H), 0.82-0.92 (m, 1H), 1.06-1.38 (m, 1H), 1.58-1.89 (m, 4H), 1.99-2.19 (m, 2H), 2.04 (s, 3H), 2.28-2.45 (m, 2H), 2.52-2.62 (m, 2H), 2.75-2.88 (m, 2H), 2.94-3.07 (m, 3H), 3.26-3.36 (m, 1H), 3.37-3.46 (m, 1H), 3.56 (d, J=15 Hz, 1H), 3.61-3.72 (m, 1H), 4.09 (dd, J=11, 15 Hz, 1H), 6.52 (dd, J=2, 8 Hz, 1H), 6.93 (d, J=9 Hz, 1H), 6.97 (d, J=3 Hz, 1H), 7.16 (s, 1H), 7.20 (s, 1H).

Example 204
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3-(3-(pyrrolidin-1-yl)propyl)-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

To a solution of the compound (9.8 mg, 0.020 mmol) obtained in Example 201 in tetrahydrofuran (1 mL) was added pyrrolidine (16.4 μL, 0.20 mmol), followed by stirring at 60° C. for 1 hour. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 20% methanol/chloroform) to yield the title compound (5.0 mg, 53%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.46-0.56 (m, 2H), 0.75-0.90 (m, 1H), 1.06-1.18 (m, 1H), 1.34-1.89 (m, 9H), 1.99-2.16 (m, 3H), 2.17-2.42 (m, 6H), 2.50-2.77 (m, 3H), 2.86-3.04 (m, 4H), 3.52 (d, J=15 Hz, 1H), 3.60-3.75 (m, 1H), 3.81 (s, 3H), 4.10 (dd, J=11, 15 Hz, 1H), 4.70 (br s, 1H), 6.66 (dd, J=2, 8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 7.21 (d, J=2 Hz, 1H).

Example 205
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-3-(3-(pyrrolidin-1-yl)propyl)-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 204 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.17 (m, 2H), 0.47-0.55 (m, 2H), 0.72-0.96 (m, 1H), 1.03-1.90 (m, 10H), 1.97-2.20 (m, 3H), 2.22-2.41 (m, 6H), 2.52-2.59 (m, 1H), 2.64 (d, J=15 Hz, 1H), 2.71 (dd, J=6, 18 Hz, 1H), 2.86-3.03 (m, 4H), 3.51 (d, J=15 Hz, 1H), 3.64-3.75 (m, 1H), 4.09 (dd, J=11, 15 Hz, 1H), 4.72 (br s, 1H), 6.64 (dd, J=2, 8 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 7.12 (d, J=2 Hz, 1H).

Example 206
Synthesis of (5aS,6R,11bR)-3-(3-(4-(tert-butyl)-1H-pyrazol-1-yl)propyl)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 201 and 4-tert-butyl-1H-pyrazole according to the methods described in Example 202.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.16 (m, 2H), 0.48-0.56 (m, 2H), 0.77-0.90 (m, 1H), 1.06-1.35 (m, 1H), 1.24 (s, 9H), 1.55-1.78 (m, 3H), 1.86-2.15 (m, 3H), 2.35 (dd, J=7, 13 Hz, 1H), 2.36 (dd, J=7, 13 Hz, 1H), 2.52-2.61 (m, 1H), 2.70 (d, J=15 Hz, 1H), 2.76 (dd, J=6, 19 Hz, 1H), 2.83-2.97 (m, 3H), 3.01 (d, J=18 Hz, 1H), 3.34-3.53 (m, 2H), 3.55 (d, J=15 Hz, 1H), 3.61-3.72 (m, 1H), 3.78 (s, 3H), 4.10 (dd, J=11, 15 Hz, 1H), 4.74 (br s, 1H), 6.65 (dd, J=2, 8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 6.98 (s, 1H), 7.25 (d, J=2 Hz, 1H), 7.30 (s, 1H).

Example 207
Synthesis of (5aS,6R,11bR)-3-(3-(4-(tert-butyl)-1H-pyrazol-1-yl)propyl)-14-(cyclopropylmethyl)-5a,10-dihydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 206 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.15 (m, 2H), 0.46-0.57 (m, 2H), 0.74-0.92 (m, 1H), 1.08-1.33 (m, 1H), 1.23 (s, 9H), 1.56-1.82 (m, 3H), 1.89-2.15 (m, 3H), 2.28-2.42 (m, 2H), 2.50-2.64 (m, 1H), 2.66 (d, J=Hz, 1H), 2.74 (dd, J=6, 18 Hz, 1H), 2.84-3.04 (m, 4H), 3.38-3.72 (m, 4H), 4.10 (dd, J=11, 15 Hz, 1H), 6.64 (dd, J=1, 8 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 6.98 (s, 1H), 7.22 (d, J=1 Hz, 1H), 7.31 (s, 1H).

Reference Example 19
Synthesis of isothiazol-3-ylmethyl methanesulfonate

[Image Omitted]

To a solution of isothiazol-3-ylmethanol (synthesized by the method described in WO 2018160878) (61.4 mg, 0.533 mmol) in tetrahydrofuran (2 mL) were added methanesulfonic anhydride (141 mg, 0.809 mmol) and N,N-diisopropylethylamine (183 μL, 1.06 mmol), followed by stirring at room temperature for 1.5 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (49 to 70% ethyl acetate/heptane) to yield the title compound (71.0 mg, 69%) as a pale brown oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 3.06 (s, 3H), 5.40 (s, 2H), 7.39 (d, J=5 Hz, 1H), 8.73 (d, J=5 Hz, 1H).

Reference Example 20
Synthesis of 2-(isothiazol-3-yl)acetonitrile

[Image Omitted]

To a solution of the compound (71.0 mg, 0.367 mmol) obtained in Reference Example 19 in dimethyl sulfoxide (2 mL) was added sodium cyanide (53.4 mg, 1.09 mmol), followed by stirring at 70° C. for 18.5 hours. After allowed to cool to room temperature, to the reaction mixture was added water, followed by extraction three times with tert-butyl methyl ether. The combined extracts were washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure to yield the title compound (30.0 mg, 66%) as a brown oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 3.98 (s, 2H), 7.32 (d, J=5 Hz, 1H), 8.74 (d, J=5 Hz, 1H).

Reference Example 21
Synthesis of 2-(isothiazol-3-yl)acetic acid

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 20 according to the method described in Reference Example 13.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 4.00 (s, 2H), 7.22 (d, J=5 Hz, 1H), 8.71 (d, J=5 Hz, 1H).

Example 208
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(isothiazol-3-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 21 according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.13 (m, 2H), 0.49-0.53 (m, 2H), 0.79-0.86 (m, 1H), 1.04-1.12 (m, 1H), 1.55-1.63 (m, 1H), 1.75-2.10 (m, 3.6H), 2.14-2.40 (m, 3H), 2.44-2.57 (m, 1.4H), 2.69 (dd, J=6, 18 Hz, 0.6H), 2.78 (dd, J=6, 18 Hz, 0.4H), 2.88-2.99 (m, 2H), 3.24-3.31 (m, 0.6H), 3.39-3.48 (m, 1.4H), 3.70-3.77 (m, 0.4H), 3.71 (d, J=16 Hz, 0.4H), 3.83-3.95 (m, 2H), 4.02 (d, J=16 Hz, 0.6H), 4.06-4.12 (m, 0.6H), 6.61-6.66 (m, 1.4H), 6.81 (s, 0.6H), 6.91-6.93 (m, 1H), 7.12-7.13 (m, 1H), 8.54-8.56 (m, 1H).

Example 209
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(isothiazol-3-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 208 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.09 (m, 2H), 0.47-0.49 (m, 2H), 0.78-0.94 (m, 2H), 1.26-1.39 (m, 2H), 1.65-1.77 (m, 2H), 1.87-2.18 (m, 2H), 2.29-2.31 (m, 2H), 2.45-3.68 (m, 13H), 6.37-6.44 (m, 2H), 6.68-6.73 (m, 1H), 6.89 (d, J=4 Hz, 1H), 8.42 (d, J=4 Hz, 1H).

Example 210
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(thiazol-2-yl)propan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 3-(thiazol-2-yl)propanoic acid according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.17 (m, 2H), 0.42-0.60 (m, 2H), 0.75-0.94 (m, 1H), 1.03-2.45 (m, 9H), 2.49-3.46 (m, 10H), 3.80-4.06 (m, 1.7H), 4.13-4.27 (m, 0.3H), 6.61-7.03 (m, 3H), 7.16 (d, J=3 Hz, 0.3H), 7.21 (d, J=3 Hz, 0.7H), 7.65 (d, J=3 Hz, 0.3H), 7.72 (d, J=3 Hz, 0.7H).

Example 211
Synthesis of (5aS,6R,11bS)-3-(3-(1H-pyrazol-1-yl)propyl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 157 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.44-0.54 (m, 2H), 0.77-0.92 (m, 1H), 0.99-1.08 (m, 1H), 1.45-1.52 (m, 1H), 1.67-1.95 (m, 4H), 2.00-2.06 (m, 2H), 2.27-2.57 (m, 8H), 2.79 (dd, J=6, 18 Hz, 1H), 2.87-3.02 (m, 4H), 3.77-3.94 (m, 2H), 4.69 (br s, 1H), 6.18 (dd, J=1, 2 Hz, 1H), 6.57 (dd, J=2, 8 Hz, 1H), 6.61 (d, J=2 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 7.15 (d, J=2 Hz, 1H), 7.48 (d, J=1 Hz, 1H).

Example 212
Synthesis of (5aS,6R,11bR)-3-(3-(1H-pyrazol-1-yl)propyl)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 201 and pyrazole according to the method described in Example 202.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.46-0.57 (m, 2H), 0.76-0.94 (m, 1H), 1.10-1.21 (m, 1H), 1.58-1.78 (m, 2H), 1.87-1.99 (m, 1H), 2.02-2.14 (m, 2H), 2.35 (dd, J=6, 13 Hz, 1H), 2.36 (dd, J=6, 13 Hz, 1H), 2.53-2.63 (m, 1H), 2.69 (d, J=15 Hz, 1H), 2.77 (dd, J=6, 18 Hz, 1H), 2.83-2.96 (m, 3H), 3.01 (d, J=18 Hz, 1H), 3.43-3.60 (m, 3H), 3.62-3.72 (m, 1H), 3.77 (s, 3H), 4.11 (dd, J=11, 15 Hz, 1H), 6.13-6.17 (m, 1H), 6.63 (dd, J=2, 9 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 7.20-7.26 (m, 2H), 7.42-7.46 (m, 1H).

Example 213
Synthesis of (5aS,6R,11bR)-3-(3-(1H-pyrazol-1-yl)propyl)-14-(cyclopropylmethyl)-5a,10-dihydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 212 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.17 (m, 2H), 0.46-0.56 (m, 2H), 0.76-0.92 (m, 1H), 1.10-1.25 (m, 1H), 1.62 (dd, J=6, 14 Hz, 1H), 1.66-1.82 (m, 2H), 1.90-2.16 (m, 3H), 2.35 (dd, J=6, 13 Hz, 1H), 2.36 (dd, J=6, 13 Hz, 1H), 2.52-2.62 (m, 1H), 2.67 (d, J=15 Hz, 1H), 2.76 (dd, J=6, 18 Hz, 1H), 2.85-2.95 (m, 3H), 3.00 (d, J=18 Hz, 1H), 3.48-3.70 (m, 4H), 4.10 (dd, J=11, Hz, 1H), 6.11-6.15 (m, 1H), 6.62 (dd, J=2, 8 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 7.23-7.28 (m, 2H), 7.42-7.46 (m, 1H).

Example 214
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(5-hydroxy-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 2,4-dihydro-3H-pyrazol-3-one according to the method described in Example 132.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.20 (m, 2H), 0.41-0.59 (m, 2H), 0.74-2.43 (m, 8H), 2.46-3.04 (m, 5H), 3.06-3.45 (m, 2H), 3.55-4.19 (m, 2.7H), 4.23-4.49 (m, 1H), 4.59-4.93 (m, 1.3H), 5.70-5.77 (m, 1H), 6.50-7.02 (m, 3H), 7.22-7.38 (m, 1H).

Reference Example 22
Synthesis of ethyl (E)-3-(5-methylisothiazol-3-yl) acrylate

[Image Omitted]

To a suspension of potassium tert-butoxide (106 mg, 0.94 mmol) in tetrahydrofuran (1 mL) was added dropwise triethyl phosphonoacetate (189 μL, 0.94 mmol) under ice cooling, followed by stirring at 0° C. for 30 minutes. Thereafter, a solution of 5-methylisothiazole-3-carbaldehyde (100 mg, 0.79 mmol) in THF (1 mL) was added dropwise, followed by stirring at room temperature for 5 hours. Under ice cooling, to the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (1 to 10% ethyl acetate/heptane) to yield the title compound (143 mg, 92%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.33 (t, J=7 Hz, 3H), 2.59 (s, 3H), 4.27 (q, J=7 Hz, 2H), 6.56 (d, J=16 Hz, 1H), 7.15 (s, 1H), 7.65 (d, J=16 Hz, 1H).

Reference Example 23
Synthesis of (E)-3-(5-methylisothiazol-3-yl)acrylic acid

[Image Omitted]

To a solution of the compound (143 mg, 0.73 mmol) obtained in Reference Example 22 in tetrahydrofuran (1 mL) was added a 2 M aqueous sodium hydroxide solution (0.73 mL, 1.45 mmol), followed by stirring at room temperature for 5 hours. To the reaction mixture, 2 M hydrochloric acid (0.73 mL, 1.45 mmol) was added, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure to yield the title compound (122 mg, 99%) as a white powder.

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm): 2.57 (s, 3H), 6.61 (d, J=16 Hz, 1H), 7.42 (d, J=16 Hz, 1H), 7, 58 (s, 1H), 12.71 (br s, 1H).

Example 215
Synthesis of (E)-1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(5-methylisothiazol-3-yl)prop-2-en-1-one

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 23 according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.18 (m, 2H), 0.41-0.57 (m, 2H), 0.75-0.93 (m, 1H), 1.02-2.16 (m, 5.6H), 2.18-2.42 (m, 3H), 2.46-3.08 (m, 7.4H), 3.11-3.24 (m, 0.6H), 3.38-3.62 (m, 1.4H), 3.85-4.00 (m, 0.6H), 4.04-4.17 (m, 0.8H), 4.29-4.40 (m, 0.6H), 6.58 (dd, J=2, 8 Hz, 0.4H), 6.65-6.73 (m, 1H), 6.84-7.12 (m, 3H), 7.13-7.24 (m, 1H), 7.55 (d, J=16 Hz, 0.6H).

Example 216
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(3,3,3-trifluoro-2-phenylpropyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and 3,3,3-trifluoro-2 phenylpropanoic acid according to the methods described in Example 5 and Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.11 (m, 2H), 0.44-0.52 (m, 2H), 0.75-0.86 (m, 1H), 0.94-1.01 (m, 1H), 1.23-1.33 (m, 1H), 1.48 (ddd, J=4, 11, 14 Hz, 1H), 1.73 (ddd, J=4, 4, 15 Hz, 1H), 1.90-2.06 (m, 2H), 2.20-2.38 (m, 4H), 2.48-2.54 (m, 1H), 2.59-2.68 (m, 2H), 2.83 (d, J=6 Hz, 1H), 2.86-2.97 (m, 1H), 2.90 (d, J=18 Hz, 1H), 2.96 (dd, J=9, 13 Hz, 1H), 3.09 (ddd, J=2, 11, 13 Hz, 1H), 3.15 (dd, J=5, 13 Hz, 1H), 3.26 (ddq, J=5, 9, 9 Hz, 1H), 6.52 (d, J=2 Hz, 1H), 6.60 (dd, J=2, 8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 7.02-7.08 (m, 2H), 7.21-7.31 (m, 3H).

Example 217
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(5-methylisothiazol-3-yl)propan-1-one

[Image Omitted]

To a solution of the compound (14 mg, 0.029 mmol) obtained in Example 215 in methanol (1 mL) was added 10% palladium-activated carbon (55% wet, 8.5 mg), followed by stirring under a hydrogen atmosphere at room temperature for 10 days. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound and a raw material compound (compound described in Example 215) (6.6 mg) as a colorless gumlike substance. To the obtained product dissolved in a methanol (1 mL) solution, 10% palladium-activated carbon (55% wet, 13.2 mg) was added, followed by stirring at room temperature for 19 hours under a hydrogen atmosphere. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 5% methanol/chloroform) to yield the title compound (5.4 mg, 39%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.19 (m, 2H), 0.43-0.59 (m, 2H), 0.76-3.27 (m, 22H), 3.28-3.44 (m, 1H), 3.80-4.04 (m, 1.4H), 4.16-4.33 (m, 0.6H), 6.57-7.11 (m, 4H).

Example 218
Synthesis of (5aS,6R,11bS)-14-((2,2-difluorocyclopropyl)methyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 176 and 2-(bromomethyl)-1,1-difluorocyclopropane according to the method described in Example 161.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.95-1.10 (m, 2H), 1.38-1.53 (m, 2H), 1.58-1.86 (m, 3H), 1.96-2.20 (m, 2H), 2.00 (s, 3H), 2.28-3.02 (m, 12H), 3.09-3.19 (m, 1H), 3.95-4.09 (m, 2H), 6.57 (d, J=3 Hz, 1H), 6.63 (dd, J=2, 8 Hz, 1H), 6.86-6.88 (m, 1H), 6.94 (d, J=8 Hz, 0.5H), 6.95 (d, J=8 Hz, 0.5H), 7.24 (s, 1H).

Example 219
Synthesis of (5aS,6R,11bS)-14-(((1S,2S)-2-fluorocyclopropyl)methyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To the compound (15.3 mg, 0.040 mmol) obtained in Example 176 were added (1S,2S)-2 fluorocyclopropane-1-carboxylic acid (5.0 mg, 0.048 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (18.3 mg, 0.048 mmol), N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (17 μL, 0.10 mmol), followed by stirring at room temperature for 1 hour. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in tetrahydrofuran (0.5 mL) was added a 0.91 M borane-tetrahydrofuran complex-tetrahydrofuran solution (0.44 mL, 0.40 mmol), followed by heating under reflux for 6 hours. After allowed to cool, the reaction mixture was concentrated under reduced pressure. To the concentrated residue, 6 M hydrochloric acid (2 mL) was added, followed by heating under reflux for 1 hour. After allowed to cool, water and potassium carbonate were added to make the reaction mixture basic, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (9.0 mg, 49%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.60 (dddd, J=3, 7, 7, 23 Hz, 1H), 0.73-0.85 (m, 1H), 0.90-1.10 (m, 2H), 1.38-1.48 (m, 1H), 1.72-1.85 (m, 2H), 1.96-2.09 (m, 2H), 1.99 (s, 3H), 2.29-2.40 (m, 1H), 2.49-2.66 (m, 4H), 2.68 (dd, J=6, 13 Hz, 1H), 2.75-3.04 (m, 6H), 3.16 (dd, J=11, 11 Hz, 1H), 3.95-4.09 (m, 2H), 4.55 (dddd, J=3, 6, 6, 65 Hz, 1H), 6.53 (d, J=3 Hz, 1H), 6.61 (dd, J=3, 8 Hz, 1H), 6.87 (s, 1H), 6.93 (d, J=8 Hz, 1H), 7.24 (s, 1H).

Example 220
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-3-(4-methyl-1H-pyrazol-1-yl)propan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 3 and 3-(4-methyl-1H-pyrazol-1-yl)propanoic acid hydrochloride according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.14 (m, 2H), 0.47-0.53 (m, 2H), 0.76-0.88 (m, 1H), 1.05-1.13 (m, 1H), 1.51-1.61 (m, 1H), 1.76-1.99 (m, 2H), 2.00-2.23 (m, 2.3H), 2.03 (s, 0.9H), 2.04 (s, 2.1H), 2.27-2.45 (m, 2.7H), 2.49-2.59 (m, 1H), 2.66-3.02 (m, 5H), 3.10-3.23 (m, 1.3H), 3.27-3.33 (m, 0.7H), 3.60-3.69 (m, 0.7H), 3.70-3.79 (m, 0.3H), 3.85-4.06 (m, 1.7H), 4.11-4.20 (m, 0.6H), 4.31-4.37 (m, 0.7H), 4.43 (br s, 0.3H), 4.53 (br s, 0.7H), 6.67 (dd, J=3, 8 Hz, 0.3H), 6.72 (dd, J=3, 8 Hz, 0.7H), 6.75 (d, J=3 Hz, 0.3H), 6.79 (d, J=3 Hz, 0.7H), 6.92 (d, J=8 Hz, 0.7H), 6.93 (d, J=8 Hz, 0.3H), 7.15 (s, 0.7H), 7.19 (s, 0.3H), 7.25-7.28 (m, 0.3H), 7.34 (s, 0.7H).

Example 221
Synthesis of (5aS,6R,11bS)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-14-((1-methylcyclopropyl)methyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 176 and 1-methylcyclopropane-1 carboxylic acid according to the method described in Example 219.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.02-0.32 (m, 4H), 0.99-1.10 (m, 1H), 1.07 (s, 3H), 1.39-1.49 (m, 1H), 1.70-1.81 (m, 2H), 1.90-2.08 (m, 2H), 1.99 (s, 3H), 2.21 (d, J=12 Hz, 1H), 2.35-2.45 (m, 1H), 2.38 (d, J=12 Hz, 1H), 2.48-2.65 (m, 3H), 2.70-3.00 (m, 6H), 3.11-3.21 (m, 1H), 3.95-4.09 (m, 2H), 6.54 (d, J=3 Hz, 1H), 6.61 (dd, J=3, 8 Hz, 1H), 6.85 (s, 1H), 6.92 (d, J=8 Hz, 1H), 7.23 (s, 1H).

Example 222
Synthesis of diastereomeric mixture (1:1) of ethyl (S)-3-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano) naphtho[1,2-d]azepin-3(4H)-yl)-4,4,4-trifluorobutanoate and ethyl (R)-3-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-4,4,4-trifluorobutanoate

[Image Omitted]

To a solution of the compound C (98.2 mg, 0.287 mmol) obtained in Example 2 in acetonitrile (3.0 mL) were added ethyl (E)-4,4,4-trifluorocrotonate (210 μL, 1.46 mmol) and cesium carbonate (467 mg, 1.43 mmol), followed by stirring at 85° C. for 2 hours. Water (10 mL) was added to the reaction mixture under ice cooling, followed by extraction three times with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (5 to 20% methanol/ethyl acetate) to yield the title compound (154 mg, quantitative) as a yellow amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.14 (m, 2H), 0.44-0.56 (m, 2H), 0.76-0.89 (m, 1H), 0.97-1.04 (m, 1H), 1.15-1.37 (m, 2H), 1.46-1.56 (m, 1H), 1.73 (ddd, J=3, 11, 14 Hz, 0.5H), 1.79 (ddd, J=3, 10, 14 Hz, 0.5H), 1.84-2.11 (m, 3H), 2.28-2.73 (m, 6.5H), 2.74-3.10 (m, 6H), 3.24 (dd, J=11, 11 Hz, 0.5H), 3.34 (dd, J=12, 12 Hz, 0.5H), 3.55-3.75 (m, 1H), 3.78 (s, 1.5H), 3.78 (s, 1.5H), 3.81-4.07 (m, 1.5H), 4.16-4.25 (m, 1H), 6.62-6.65 (m, 1H), 6.67 (dd, J=3, 8 Hz, 0.5H), 6.68 (dd, J=2, 8 Hz, 0.5H), 6.98 (d, J=8 Hz, 0.5H), 6.99 (d, J=8 Hz, 0.5H).

Example 223
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-3-(1,1,1-trifluoro-4-(4-methyl-1H-pyrazol-1-yl)butan-2-yl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol (diastereomer I) and (5aS,6R,11bR)-14-(cyclopropylmethyl)-3-(1,1,1-trifluoro-4-(4-methyl-1H-pyrazol-1-yl)butan-2-yl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol (diastereomer II)

[Image Omitted]

To a solution of the compound (154 mg, 0.301 mmol) obtained in Example 222 in tetrahydrofuran (3.0 mL) was added lithium borohydride (4 M tetrahydrofuran solution, 380 μL, 1.52 mmol), followed by stirring at room temperature for 5 hours. Thereafter, lithium borohydride (4 M tetrahydrofuran solution, 380 μL, 1.52 mmol) was added, followed by stirring at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture under ice cooling, followed by extraction three times with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. To a solution of the obtained crude product in tetrahydrofuran (3.0 mL) was added lithium borohydride (4 M tetrahydrofuran solution, 800 μL, 3.20 mmol), followed by stirring at room temperature for 18 hours. Under ice cooling, to the reaction mixture were added water (3 mL) and a saturated aqueous ammonium chloride solution (10 mL), followed by extraction three times with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure.

To a solution of the obtained crude product in chloroform (1.0 mL) were added N,N-diisopropylethylamine (31.2 μL, 179 μmol) and methanesulfonic anhydride (16.0 mg, 91.9 μmol) at 0° C., followed by stirring at 0° C. for 2.5 hours. Thereafter, methanesulfonic anhydride (6.0 mg, 34.4 μmol) was added, followed by stirring at 0° C. for 40 minutes. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution (3 mL) and water (2 mL), followed by extraction three times with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure.

To a solution of the obtained crude product in acetonitrile (1.0 mL) were added N,N-diisopropylethylamine (15.6 μL, 89.6 μmol) and 4-methyl-1H-pyrazole (5.6 μL, 67.7 μmol), followed by stirring at room temperature for 18 hours. Thereafter, N,N-diisopropylethylamine (15.6 μL, 89.6 μmol) and 4-methylpyrazole (6.0 μL, 72.6 μmol) were added, followed by stirring at 70° C. for 6.5 hours. After cooled to room temperature, to the reaction mixture was added a saturated aqueous sodium bicarbonate solution (3 mL), followed by extraction three times with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure.

The title compounds (diastereomer I (4.3 mg, 4 steps 16%) and diastereomer II (1.8 mg, 4 steps 7%)) were individually obtained from the obtained crude product according to the method described in Example 6.

(Diastereomer I)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.16 (m, 2H), 0.46-0.57 (m, 2H), 0.77-0.89 (m, 1H), 1.03-1.10 (m, 1H), 1.53 (dd, J=4, 13 Hz, 1H), 1.74-2.12 (m, 6H), 2.04 (s, 3H), 2.33 (dd, J=7, 13 Hz, 1H), 2.34 (dd, J=6, 13 Hz, 1H), 2.43-2.68 (m, 3H), 2.69-2.81 (m, 2H), 2.85 (dd, J=6, 18 Hz, 1H), 2.96 (d, J=6 Hz, 1H), 3.00 (d, J=18 Hz, 1H), 3.05-3.20 (m, 2H), 3.34-3.45 (m, 2H), 4.55 (br s, 1H), 6.52 (dd, J=2, 8 Hz, 1H), 6.77 (d, J=2 Hz, 1H), 6.78 (s, 1H), 6.93 (d, J=8 Hz, 1H), 7.03 (s, 1H).

(Diastereomer II)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.17 (m, 2H), 0.48-0.54 (m, 2H), 0.78-0.89 (m, 1H), 1.02-1.12 (m, 1H), 1.51-1.72 (m, 2H), 1.82 (ddd, J=2, 6, 16 Hz, 1H), 1.87-1.97 (m, 1H), 1.98-2.09 (m, 3H), 2.06 (s, 3H), 2.34 (dd, J=7, 13 Hz, 1H), 2.34 (dd, J=7, 13 Hz, 1H), 2.49-2.68 (m, 3H), 2.78-2.89 (m, 2H), 2.92-3.07 (m, 2H), 2.94 (d, J=6 Hz, 1H), 3.00 (d, J=18 Hz, 1H), 3.18-3.26 (m, 1H), 3.34 (ddd, J=5, 10, 19 Hz, 1H), 3.46-3.54 (m, 1H), 4.53 (br s, 1H), 6.61 (dd, J=2, 8 Hz, 1H), 6.78 (d, J=2 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 6.96 (s, 1H), 7.28 (s, 1H).

Example 224
Synthesis of (5aS,6R,11bS)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-14-(3-methylbut-2-en-1-yl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 176 and 1-bromo-3-methylbut-2-ene according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.96-1.04 (m, 1H), 1.38-1.46 (m, 1H), 1.64 (s, 3H), 1.67-1.81 (m, 2H), 1.72 (s, 3H), 1.93-2.06 (m, 2H), 1.99 (s, 3H), 2.29-2.43 (m, 2H), 2.46-2.63 (m, 2H), 2.67-3.08 (m, 8H), 3.09-3.19 (m, 1H), 3.94-4.07 (m, 2H), 4.56 (br s, 1H), 5.12-5.19 (m, 1H), 6.54 (d, J=3 Hz, 1H), 6.61 (dd, J=3, 8 Hz, 1H), 6.85 (s, 1H), 6.92 (d, J=8 Hz, 1H), 7.23 (s, 1H).

Example 225
Synthesis of (5aS,6R,11bS)-14-((1-hydroxycyclopropyl)methyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 176 and 1-hydroxycyclopropane-1 carboxylic acid according to the method described in Example 219.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.35-0.42 (m, 2H), 0.78-0.84 (m, 2H), 1.02-1.09 (m, 1H), 1.46-1.55 (m, 1H), 1.76-1.89 (m, 1H), 1.90-2.23 (m, 4H), 1.99 (s, 3H), 2.42-3.00 (m, 11H), 3.09 (ddd, J=4, 12, 12 Hz, 1H), 4.00-4.09 (m, 2H), 6.58-6.66 (m, 2H), 6.94 (d, J=8 Hz, 1H), 6.96 (s, 1H), 7.25-7.28 (m, 1H).

Example 226
Synthesis of (5aS,6R,11bS)-14-((1-fluorocyclopropyl)methyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 176 and 1-fluorocyclopropane-1 carboxylic acid according to the method described in Example 219.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.52-0.67 (m, 2H), 0.97-1.13 (m, 3H), 1.40-1.52 (m, 1H), 1.71-1.82 (m, 2H), 2.00 (s, 3H), 2.06 (ddd, J=5, 13, 13 Hz, 1H), 2.17 (ddd, J=3, 12, 12 Hz, 1H), 2.37 (ddd, J=4, 11, 11 Hz, 1H), 2.42-2.65 (m, 3H), 2.68-3.05 (m, 8H), 3.10-3.20 (m, 1H), 3.95-4.09 (m, 2H), 4.52 (br s, 1H), 6.55 (d, J=2 Hz, 1H), 6.62 (dd, J=2, 8 Hz, 1H), 6.87 (s, 1H), 6.95 (d, J=8 Hz, 1H), 7.24 (s, 1H).

Reference Example 24
Synthesis of 3-(4-methyl-1H-pyrazol-1-yl)cyclobutan-1-one

[Image Omitted]

To a solution of 4-methylpyrazole (81.9 mg, 0.997 mmol) in N,N-dimethylformamide (2.5 mL) was added sodium hydride (55% oil dispersion, 43.8 mg, 1.00 mmol), followed by stirring at 70° C. for 1 hour. After allowed to cool to room temperature, to the resultant solution was added a solution of 3-bromocyclobutan-1-one (175 mg, 1.17 mmol) in N,N-dimethylformamide (1.0 mL), followed by stirring at room temperature for 20 hours. Water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.09 (s, 3H), 3.48-3.57 (m, 2H), 3.71-3.80 (m, 2H), 4.92-4.99 (m, 1H), 7.29 (s, 1H), 7.39 (s, 1H).

Example 227
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(3-(4-methyl-1H-pyrazol-1-yl)cyclobutyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol(diastereomer I) and (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(3-(4-methyl-1H-pyrazol-1-yl)cyclobutyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol(diastereomer II)

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 24 according to the method described in Example 12.

(Diastereomer I)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.12 (m, 2H), 0.47-0.52 (m, 2H), 0.78-0.88 (m, 1H), 0.99-1.03 (m, 1H), 1.46-1.52 (m, 1H), 1.76-1.85 (m, 2H), 1.94-2.09 (m, 5H), 2.17-2.39 (m, 4H), 2.51-2.55 (m, 1H), 2.58-2.79 (m, 6H), 2.88-3.00 (m, 3H), 3.05-3.11 (m, 1H), 4.35-4.43 (m, 1H), 4.75 (br s, 1H), 6.54 (d, J=2 Hz, 1H), 6.61 (dd, J=2, 8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 7.17 (s, 1H), 7.25 (s, 1H).

(Diastereomer II)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.11 (m, 2H), 0.47-0.52 (m, 2H), 0.79-0.90 (m, 3H), 1.01-1.04 (m, 1H), 1.48 (dd, J=4, 15 Hz, 1H), 1.78-1.83 (m, 2H), 1.96-2.08 (m, 5H), 2.28-2.37 (m, 3H), 2.42-2.55 (m, 2H), 2.59-2.68 (m, 2H), 2.72-2.79 (m, 2H), 2.89 (d, J=6 Hz, 1H), 2.95 (d, J=18 Hz, 1H), 3.03-3.09 (m, 1H), 3.45-3.52 (m, 1H), 4.52-4.58 (m, 1H), 4.76 (br s, 1H), 6.55 (d, J=2 Hz, 1H), 6.59 (dd, J=2, 8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 7.17 (s, 1H), 7.34 (s, 1H).

Reference Example 25
Synthesis of (R)-1-(4-methyl-1H-pyrazol-1-yl)propan-2-ol

[Image Omitted]

To a suspension of sodium hydride (55% oil dispersion, 79 mg, 1.8 mmol) in N,N-dimethylformamide (5 mL) was added dropwise (R)-2-methyloxirane (71 μL, 1.0 mmol) under ice cooling, followed by stirring at room temperature for 30 minutes. Thereafter, 4-methyl-1H-pyrazole (100 μL, 1.2 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 18 hours. Under ice cooling, to the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction three times with ethyl acetate. The combined extracts were washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (20 to 40% ethyl acetate/heptane) to yield the title compound (35 mg, 25%) as a pale yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.21 (d, J=6 Hz, 3H), 2.08 (s, 3H), 3.57 (d, J=3 Hz, 1H), 3.92 (dd, J=8, 14 Hz, 1H), 4.05-4.23 (m, 2H), 7.18 (s, 1H), 7.33 (s, 1H).

Example 228
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-((S)-1-(4-methyl-1H-pyrazol-1-yl)propan-2-yl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 25 according to the method described in Example 32.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.02-0.17 (m, 2H), 0.42-0.57 (m, 2H), 0.75-0.93 (m, 4H), 0.97-1.07 (m, 1H), 1.45-1.56 (m, 1H), 1.74 (ddd, J=3, 11, 14 Hz, 1H), 1.82-2.12 (m, 6H), 2.24-2.40 (m, 3H), 2.43-2.59 (m, 2H), 2.62-3.23 (m, 7H), 3.77 (dd, J=7, 14 Hz, 1H), 3.98 (dd, J=6, 14 Hz, 1H), 6.57-6.66 (m, 2H), 6.84 (s, 1H), 6.95 (d, J=8 Hz, 1H), 7.23 (s, 1H).

Reference Example 26
Synthesis of (S)-1-(4-methyl-1H-pyrazol-1-yl)propan-2-ol

[Image Omitted]

The title compound was obtained from (S)-2-methyloxirane and 4-methyl-1H-pyrazole according to the method described in Reference Example 25.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.20 (d, J=6 Hz, 3H), 2.08 (s, 3H), 3.58 (br s, 1H), 3.92 (dd, J=8, 14 Hz, 1H), 4.05-4.22 (m, 2H), 7.18 (s, 1H), 7.33 (s, 1H)

Example 229
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-((R)-1-(4-methyl-1H-pyrazol-1-yl)propan-2-yl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 26 according to the method described in Example 32.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.18 (m, 2H), 0.44-0.57 (m, 2H), 0.76-0.93 (m, 4H), 0.97-1.06 (m, 1H), 1.49-1.83 (m, 2H), 1.88-2.13 (m, 6H), 2.21-2.41 (m, 3H), 2.47-2.61 (m, 2H), 2.68-2.85 (m, 3H), 2.88-3.17 (m, 4H), 3.79 (dd, J=7, 14 Hz, 1H), 4.02 (dd, J=7, 14 Hz, 1H), 4.61 (br s, 1H), 6.56-6.69 (m, 2H), 6.89-7.02 (m, 2H), 7.21 (s, 1H).

Example 230
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(3-(4-methyl-1H-pyrazol-1-yl)propyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 220 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.44-0.54 (m, 2H), 0.77-0.92 (m, 1H), 0.99-1.08 (m, 1H), 1.48 (dd, J=4, 14 Hz, 1H), 1.70-1.92 (m, 4H), 1.99-2.06 (m, 2H), 2.04 (s, 3H), 2.29-2.57 (m, 8H), 2.78 (dd, J=6, 18 Hz, 1H), 2.88-3.04 (m, 4H), 3.67-3.76 (m, 1H), 3.77-3.86 (m, 1H), 4.68 (br s, 1H), 6.59 (dd, J=2, 8 Hz, 1H), 6.64 (d, J=2 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 6.98 (s, 1H), 7.27 (s, 1H).

Reference Example 27
Synthesis of (S)-1-(benzyloxy)-3-(4-methyl-1H-pyrazol-1-yl)propan-2-ol

[Image Omitted]

The title compound was obtained from (S)-2-((benzyloxy)methyl)oxirane and 4-methyl-1H-pyrazole according to the method described in Reference Example 25.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.06 (s, 3H), 3.34 (dd, J=6, 9 Hz, 1H), 3.46 (dd, J=5, 9 Hz, 1H), 3.67 (br s, 1H), 4.08-4.30 (m, 3H), 4.51 (d, J=12 Hz, 1H), 4.55 (d, J=12 Hz, 1H), 7.14 (s, 1H), 7.26-7.42 (m, 6H).

Example 231
Synthesis of (5aS,6R,11bS)-3-((R)-1-(benzyloxy)-3-(4-methyl-1H-pyrazol-1-yl)propan-2-yl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 27 according to the method described in Example 32.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.42-0.55 (m, 2H), 0.76-0.93 (m, 1H), 0.94-1.05 (m, 1H), 1.39-1.74 (m, 2H), 1.77-1.88 (m, 1H), 1.92-2.11 (m, 5H), 2.28-2.43 (m, 3H), 2.46-2.61 (m, 2H), 2.68-2.83 (m, 2H), 2.85-3.01 (m, 3H), 3.03-3.25 (m, 2H), 3.35 (d, J=6 Hz, 2H), 3.91 (dd, J=7, 14 Hz, 1H), 4.01 (dd, J=6, 14 Hz, 1H), 4.37 (d, J=12 Hz, 1H), 4.40 (d, J=12 Hz, 1H), 6.53-6.71 (m, 3H), 6.95 (d, J=8 Hz, 1H), 7.17-7.39 (m, 6H).

Example 232
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-((R)-1-hydroxy-3-(4-methyl-1H-pyrazol-1-yl)propan-2-yl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 231 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.17 (m, 2H), 0.43-0.57 (m, 2H), 0.74-0.92 (m, 1H), 0.96-1.12 (m, 1H), 1.50-1.84 (m, 3H), 1.90-2.12 (m, 5H), 2.24-2.68 (m, 6H), 2.76-3.23 (m, 8H), 3.81 (dd, J=6, 14 Hz, 1H), 4.07 (dd, J=6, 14 Hz, 1H), 6.59 (dd, J=2, 8 Hz, 1H), 6.65 (d, J=2 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 7.04 (s, 1H), 7.27 (s, 1H).

Reference Example 28
Synthesis of (R)-1-(benzyloxy)-3-(4-methyl-1H-pyrazol-1-yl)propan-2-ol

[Image Omitted]

The title compound was obtained from (R)-2-((benzyloxy)methyl)oxirane and 4-methyl-1H-pyrazole according to the method described in Reference Example 25.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.06 (s, 3H), 3.34 (dd, J=6, 9 Hz, 1H), 3.46 (dd, J=5, 9 Hz, 1H), 3.67 (br s, 1H), 4.08-4.28 (m, 3H), 4.51 (d, J=12 Hz, 1H), 4.55 (d, J=12 Hz, 1H), 7.14 (s, 1H), 7.26-7.41 (m, 6H).

Example 233
Synthesis of (5aS,6R,11bS)-3-((S)-1-(benzyloxy)-3-(4-methyl-1H-pyrazol-1-yl)propan-2-yl)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound E obtained in Example 3 and the compound obtained in Reference Example 28 according to the method described in Example 32.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.02-0.17 (m, 2H), 0.43-0.55 (m, 2H), 0.76-0.92 (m, 1H), 0.94-1.05 (m, 1H), 1.40-1.79 (m, 2H), 1.81-2.11 (m, 6H), 2.27-2.41 (m, 3H), 2.46-2.67 (m, 2H), 2.69-3.20 (m, 7H), 3.24-3.40 (m, 2H), 4.01 (dd, J=8, 14 Hz, 1H), 4.10 (dd, J=6, 14 Hz, 1H), 4.33-4.45 (m, 2H), 6.54-6.63 (m, 2H), 6.89-6.98 (m, 2H), 7.19 (s, 1H), 7.20-7.38 (m, 5H).

Example 234
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-((S)-1-hydroxy-3-(4-methyl-1H-pyrazol-1-yl)propan-2-yl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 233 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.02-0.17 (m, 2H), 0.43-0.56 (m, 2H), 0.74-0.91 (m, 1H), 0.96-1.11 (m, 1H), 1.43-1.60 (m, 1H), 1.73-2.10 (m, 7H), 2.23-2.38 (m, 3H), 2.41-2.65 (m, 3H), 2.71-3.07 (m, 5H), 3.15-3.42 (m, 3H), 3.82 (dd, J=6, 14 Hz, 1H), 4.10 (dd, J=8, 14 Hz, 1H), 6.55-6.68 (m, 2H), 6.95 (d, J=8 Hz, 1H), 7.05 (s, 1H), 7.26 (s, 1H).

Reference Example 29
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-10-((1-phenyl-1H-tetrazol-5-yl)oxy)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

To the compound (25.2 mg, 0.058 mmol) obtained in Example 50 dissolved in N,N-dimethylformamide (1 mL) were added potassium carbonate (23.9 mg, 0.17 mmol) and 5-chloro-1-phenyl-1H-tetrazole (31.3 mg, 0.17 mmol), followed by stirring at room temperature for 19 hours. To the reaction solution, a saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed three times with saturated saline, then 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 yield the title compound (15.3 mg, 46%).

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.46-0.58 (m, 2H), 0.78-0.91 (m, 1H), 0.99-1.06 (m, 1H), 1.42-1.51 (m, 1H), 1.68 (ddd, J=3, 13, 13 Hz, 1H), 1.81 (ddd, J=3, 3, 16 Hz, 1H), 1.92-2.01 (m, 1H), 1.97 (s, 3H), 2.04-2.14 (m, 1H), 2.30-2.42 (m, 3H), 2.50 (ddd, J=5, 14, 14 Hz, 1H), 2.57 (dd, J=4, 12 Hz, 1H), 2.61-2.68 (m, 1H), 2.81-2.86 (m, 2H), 2.87-3.21 (m, 4H), 3.94-4.08 (m, 2H), 4.58 (br s, 1H), 6.72 (s, 1H), 7.11-7.26 (m, 4H), 7.49-7.62 (m, 3H), 7.78-7.84 (m, 2H).

Example 235
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

To the compound (14.9 mg, 0.026 mmol) obtained in Reference Example 29 dissolved in methanol (1 mL), 10% palladium-activated carbon (55% wet) (20 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 15 hours. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=15:1) to yield the title compound (4.3 mg, 40%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.15 (m, 2H), 0.46-0.53 (m, 2H), 0.77-0.90 (m, 1H), 0.98-1.04 (m, 1H), 1.45 (ddd, J=2, 5, 14 Hz, 1H), 1.74 (ddd, J=3, 3, 13 Hz, 1H), 1.91 (ddd, J=4, 4, 16 Hz, 1H), 1.94-2.00 (m, 1H), 1.98 (s, 3H), 2.08 (ddd, J=5, 13, 13 Hz, 1H), 2.30-2.49 (m, 4H), 2.51-2.58 (m, 1H), 2.63 (ddd, J=4, 4, 13 Hz, 1H), 2.74-3.01 (m, 5H), 3.04 (d, J=18 Hz, 1H), 3.17 (ddd, J=2, 12, 12 Hz, 1H), 3.85-4.01 (m, 2H), 4.63 (br s, 1H), 6.63 (s, 1H), 7.10-7.17 (m, 4H), 7.20 (s, 1H).

Reference Example 30
Synthesis of (1S,3S)-3-(4-methyl-1H-pyrazol-1-yl)cyclopentan-1-ol

[Image Omitted]

To a solution of 4-methylpyrazole (136 mg, 1.66 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (55% oil dispersion, 76.4 mg, 1.75 mmol), followed by stirring at 60° C. for 10 minutes. After allowed to cool to room temperature, to the reaction mixture was added a solution of (1S,3R)-3-((methylsulfonyl)oxy)cyclopentyl acetate (synthesized by the method described in Journal of Medicinal Chemistry 1996, 39, 2615, 196 mg, 0.882 mmol) in N,N-dimethylformamide (1.5 mL), followed by stirring at 60° C. for 19 hours. After allowed to cool to room temperature, water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure to yield a crude product of the title compound (173 mg) as a yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.83-0.90 (m, 1H), 1.68-1.76 (m, 1H), 1.97-2.05 (m, 1H), 2.06 (s, 3H), 2.14-2.41 (m, 3H), 4.57-4.61 (m, 1H), 4.81-4.88 (m, 1H), 7.18 (s, 1H), 7.31 (s, 1H).

Reference Example 31
Synthesis of (1S,3S)-3-(4-methyl-1H-pyrazol-1-yl)cyclopentyl methanesulfonate

[Image Omitted]

To a solution of the compound (84.2 mg, 0.395 mmol) obtained in Reference Example 30 in tetrahydrofuran (2 mL) were added N,N-diisopropylethylamine (136 μL, 0.789 mmol) and methanesulfonic anhydride (105 mg, 0.603 mmol) under ice cooling, followed by stirring at room temperature for 1 hour. Again, N,N-diisopropylethylamine (34.0 μL, 0.197 mmol) and methanesulfonic anhydride (35.0 mg, 0.201 mmol) were added, followed by stirring at room temperature for 1 hour. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (58 to 100% ethyl acetate/heptane) to yield the title compound (47.6 mg, 49%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.04-2.13 (m, 2H), 2.06 (s, 3H), 2.31-2.43 (m, 2H), 2.45-2.57 (m, 2H), 3.03 (s, 3H), 4.79-4.86 (m, 1H), 5.35-5.39 (m, 1H), 7.17 (s, 1H), 7.31 (s, 1H).

Example 236
Synthesis of diastereomeric mixture of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-((1R,3S)-3-(4-methyl-1H-pyrazol-1-yl)cyclopentyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained as a 14:1:1.5 diastereomer mixture from the compound E obtained in Example 3 and the compound obtained in Reference Example 31 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.12 (m, 2H), 0.46-0.54 (m, 2H), 0.78-0.88 (m, 1H), 0.97-1.00 (m, 1H), 1.49-1.53 (m, 1H), 1.76-2.00 (m, 6H), 2.01 (s, 3H), 2.06-2.30 (m, 2H), 2.34 (d, J=6 Hz, 2H), 2.40-2.51 (m, 2H), 2.70-2.81 (m, 3H), 2.84-2.96 (m, 4H), 3.11-3.21 (m, 2H), 4.51-4.59 (m, 1H), 4.82 (br s, 1H), 6.50 (d, J=2 Hz, 1H), 6.60 (dd, J=2, 8 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 7.11 (s, 1H), 7.25 (s, 1H).

Reference Example 32
Synthesis of (1S,3R)-3-(4-methyl-1H-pyrazol-1-yl)cyclopentyl methanesulfonate

[Image Omitted]

To a solution of 3-(4-methyl-1H-pyrazol-1-yl)cyclopentan-1-one (synthesized by the method described in the Bulletin of the Korian Chemical Society 2012, 33, 3535, 136 mg, 1.66 mmol) in ethanol (2.8 mL) was added sodium borohydride (64.4 mg, 1.70 mmol) under ice cooling, followed by stirring at room temperature for 2.5 hours. Again, sodium borohydride (63.4 mg, 1.67 mmol) was added, followed by stirring at room temperature for 19 hours. Water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. To a solution of the obtained colorless oily matter (120 mg) in tetrahydrofuran (3.5 mL) were added N,N-diisopropylethylamine (373 μL, 2.16 mmol) and methanesulfonic anhydride (189 mg, 1.08 mmol) under ice cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (67 to 100% ethyl acetate/heptane) to yield the title compound (83.2 mg, 40%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.02-2.12 (m, 1H), 2.07 (s, 3H), 2.21-2.29 (m, 3H), 2.36-2.43 (m, 1H), 2.69 (ddd, J=7, 9, 15 Hz, 1H), 3.02 (s, 3H), 4.62-4.70 (m, 1H), 5.18-5.23 (m, 1H), 7.26 (s, 1H), 7.31 (s, 1H).

Example 237
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-((1R,3R)-3-(4-methyl-1H-pyrazol-1-yl)cyclopentyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol and (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-((1S,3S)-3-(4-methyl-1H-pyrazol-1-yl)cyclopentyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained as a 1:1 diastereomer mixture from the compound E obtained in Example 3 and the compound obtained in Reference Example 32 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.13 (m, 2H), 0.47-0.52 (m, 2H), 0.78-0.88 (m, 1H), 0.98-1.05 (m, 1H), 1.46-1.52 (m, 1H), 1.56-1.66 (m, 1H), 1.76-1.82 (m, 2H), 1.87-2.37 (m, 12H), 2.49-2.57 (m, 1H), 2.70-2.96 (m, 6H), 3.09-3.18 (m, 1H), 3.30-3.37 (m, 0.5H), 3.39-3.47 (m, 0.5H), 4.53-4.60 (m, 0.5H), 4.61-4.68 (m, 0.5H), 4.79 (br s, 1H), 6.48 (d, J=2 Hz, 0.5H), 6.53 (d, J=2 Hz, 0.5H), 6.55 (dd, J=2, 8 Hz, 0.5H), 6.58 (dd, J=2, 8 Hz, 0.5H), 6.87-6.89 (m, 1H), 7.16 (s, 1H), 7.30 (s, 0.5H), 7.31 (s, 0.5H).

Example 238
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-10-yl pivalate

[Image Omitted]

To the compound (11 mg, 0.025 mmol) obtained in Example 50 dissolved in dichloromethane (1 mL) were added triethylamine (10.5 μL, 0.076 mmol) and pivaloyl chloride (9.3 μL, 0.076 mmol), followed by stirring at room temperature for 2.5 hours. To the reaction solution, a saturated sodium bicarbonate aqueous solution was added, followed by extraction 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=95:5) to yield the title compound (13.9 mg, quantitative).

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.13 (m, 2H), 0.45-0.52 (m, 2H), 0.78-0.88 (m, 1H), 0.99-1.06 (m, 1H), 1.35 (s, 9H), 1.38-1.46 (m, 1H), 1.66 (ddd, J=3, 13, 13 Hz, 1H), 1.82 (ddd, J=4, 4, 16 Hz, 1H), 1.92-2.01 (m, 1H), 1.98 (s, 3H), 2.02-2.12 (m, 1H), 2.32-2.39 (m, 3H), 2.45 (ddd, J=5, 13, 13 Hz, 1H), 2.51-2.57 (m, 1H), 2.65 (ddd, J=4, 13, 13 Hz, 1H), 2.78-2.86 (m, 3H), 2.90-3.04 (m, 3H), 3.12-3.20 (m, 1H), 3.88-4.00 (m, 2H), 4.58 (br s, 1H), 6.64 (s, 1H), 6.82 (d, J=2 Hz, 1H), 6.83-6.85 (m, 1H), 7.12 (d, J=9 Hz, 1H), 7.20 (s, 1H).

Example 239
Synthesis of tert-butyl (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate (compound K) and tert-butyl (5aS,6R,11bR)-10-((tert-butoxycarbonyl)oxy)-14-(cyclopropylmethyl)-5a-hydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate (compound L)

[Image Omitted]

To a solution of the compound E (299 mg, 0.911 mmol) obtained in Example 3 in tetrahydrofuran (3.0 mL) was added di-tert-butyl dicarbonate (1.0 mL, 4.35 mmol) under ice cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture, water and a saturated aqueous sodium bicarbonate solution were added under ice cooling, followed by extraction three times with ethyl acetate. The organic layers were combined, washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 50 to 100% ethyl acetate/heptane) to individually yield the title compound K(176 mg, 36%) and the title compound L (190 mg, 49%) as colorless amorphous forms.

(Compound K)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.14 (m, 2H), 0.47-0.55 (m, 2H), 0.76-0.88 (m, 1H), 0.99-1.09 (m, 1H), 1.29 (s, 4.5H), 1.31 (s, 4.5H), 1.44-1.67 (m, 1H), 1.76-1.90 (m, 1.5H), 1.91-2.11 (m, 2.5H), 2.29 (dd, J=7, 13 Hz, 0.5H), 2.32-2.43 (m, 2H), 2.47-2.57 (m, 1.5H), 2.74-2.85 (m, 1H), 2.88-2.97 (m, 1.5H), 2.98 (d, J=18 Hz, 0.5H), 3.31-3.41 (m, 1.5H), 3.46-3.63 (m, 2H), 3.75 (ddd, J=5, 13, 13 Hz, 0.5H), 4.51 (br s, 0.5H), 4.95 (br s, 0.5H), 5.75 (br s, 0.5H), 6.59 (dd, J=2, 8 Hz, 0.5H), 6.61-6.67 (m, 1.5H), 6.92 (d, J=8 Hz, 0.5H), 6.94 (d, J=7 Hz, 0.5H).

(Compound L)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.14 (m, 2H), 0.42-0.55 (m, 2H), 0.77-0.90 (m, 1H), 1.00-1.11 (m, 1H), 1.30 (s, 4.5H), 1.39 (s, 4.5H), 1.50-1.62 (m, 1H), 1.55 (s, 9H), 1.69-2.12 (m, 4H), 2.17-2.40 (m, 2.5H), 2.44-2.58 (m, 1.5H), 2.78-2.94 (m, 1.5H), 2.93 (d, J=6 Hz, 0.5H), 2.97 (d, J=19 Hz, 0.5H), 3.00-3.11 (m, 0.5H), 3.04 (d, J=18 Hz, 0.5H), 3.26 (ddd, J=4, 4, 14 Hz, 0.5H), 3.36-3.48 (m, 1H), 3.54-3.65 (m, 1H), 3.70 (ddd, J=3, 14, 14 Hz, 0.5H), 3.83-3.89 (m, 0.5H), 4.50 (br s, 1H), 6.90-6.94 (m, 1H), 6.97 (dd, J=2, 8 Hz, 1H), 7.07 (d, J=8 Hz, 0.5H), 7.09 (d, J=8 Hz, 0.5H).

Example 240
Synthesis of tert-butyl (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-(((trifluoromethyl)sulfonyl)oxy)-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

To the compound K(320 mg, 0.746 mmol) obtained in Example 239 dissolved in N,N-dimethylformamide (5.0 mL) were added potassium carbonate (520 mg, 3.76 mmol) and N-phenylbis(trifluoromethanesulfonimide) (804 mg, 2.25 mmol) under ice cooling, followed by stirring at room temperature for 17 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution and water were added under ice cooling to stop the reaction, followed by extraction three times with ethyl acetate. The organic layers were combined, washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 20 to 50% ethyl acetate/heptane) to yield the title compound (359 mg, 86%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.14 (m, 2H), 0.49-0.56 (m, 2H), 0.77-0.89 (m, 1H), 0.97-1.07 (m, 1H), 1.30 (s, 5.4H), 1.35 (s, 3.6H), 1.50-1.81 (m, 2.2H), 1.82-1.97 (m, 1.4H), 1.99-2.18 (m, 1.4H), 2.30 (dd, J=7, 13 Hz, 0.6H), 2.32-2.41 (m, 1.8H), 2.54-2.65 (m, 1.6H), 2.83-2.98 (m, 2H), 3.02 (d, J=19 Hz, 0.6H), 3.07 (d, J=19 Hz, 0.4H), 3.16 (ddd, J=2, 12, 14 Hz, 0.4H), 3.31 (ddd, J=4, 4, 14 Hz, 0.4H), 3.36-3.44 (m, 1.2H), 3.55-3.68 (m, 1.6H), 3.77 (ddd, J=4, 5, 15 Hz, 0.4H), 4.47 (br s, 1H), 7.00-7.07 (m, 2H), 7.16 (d, J=8 Hz, 0.6H), 7.17 (d, J=8 Hz, 0.4H).

Example 241
Synthesis of tert-butyl (5aS,6R,11bR)-10-cyano-14-(cyclopropylmethyl)-5a-hydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

The compound (299 mg, 0.533 mmol) obtained in Example 240, zinc cyanide (190 mg, 1.62 mmol), tris(dibenzylideneacetone)dipalladium (0) (48.8 mg, 53.3 μmol), and (±)-BINAP (66.9 mg, 0.107 mmol) were dissolved in N,N-dimethylformamide (3.0 mL), followed by stirring at 150° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and filtered through celite. The filtrate was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (50 to 100% ethyl acetate/heptane) to yield the title compound (184 mg, 79%) as a pale yellow amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.16 (m, 2H), 0.47-0.58 (m, 2H), 0.77-0.89 (m, 1H), 0.96-1.06 (m, 1H), 1.26 (s, 6.3H), 1.32 (s, 2.7H), 1.44-1.75 (m, 2.3H), 1.78-1.92 (m, 1.7H), 2.01-2.15 (m, 0.3H), 2.14 (ddd, J=5, 13, 13 Hz, 0.7H), 2.29 (dd, J=7, 12 Hz, 0.7H), 2.32-2.47 (m, 1.6H), 2.59 (dd, J=4, 12 Hz, 1H), 2.67 (ddd, J=6, 13, 16 Hz, 0.7H), 2.88-3.00 (m, 1H), 2.97 (d, J=7 Hz, 0.3H), 2.99 (d, J=6 Hz, 0.7H), 3.04 (d, J=19 Hz, 0.7H), 3.09 (d, J=19 Hz, 0.3H), 3.22-3.38 (m, 2H), 3.53-3.72 (m, 1.3H), 3.80 (ddd, J=5, 13, 13 Hz, 0.7H), 4.47 (br s, 1H), 7.16-7.21 (m, 0.3H), 7.18 (d, J=8 Hz, 0.7H), 7.39 (d, J=8 Hz, 1H), 7.46 (s, 1H).

Example 242
Synthesis of tert-butyl (5aS,6R,11bR)-10-carbamoyl-14-(cyclopropylmethyl)-5a-hydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

To the compound (222 mg, 0.507 mmol) obtained in Example 241, palladium acetate (24.0 mg, 0.107 mmol), and triphenylphosphine (53.5 mg, 0.204 mmol) dissolved in toluene (3.0 mL) was added acetaldoxime (93.0 μL, 1.52 mmol), followed by heating to 80° C. and stirring for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (6 to 50% 10% aqueous ammonia-methanol/50% ethyl acetate-heptane) to yield the title compound (210 mg, 91%) as a yellow amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.17 (m, 2H), 0.46-0.58 (m, 2H), 0.77-0.89 (m, 1H), 0.98-1.13 (m, 1H), 1.06 (s, 7.2H), 1.22 (s, 1.8H), 1.48 (dd, J=4, 14 Hz, 0.8H), 1.60 (dd, J=4, 14 Hz, 0.2H), 1.69-2.21 (m, 4.2H), 2.26-2.41 (m, 0.2H), 2.29 (dd, J=6, 12 Hz, 0.2H), 2.35 (dd, J=7, 12 Hz, 0.8H), 2.35 (dd, J=6, 12 Hz, 0.8H), 2.48-2.65 (m, 1.2H), 2.72 (ddd, J=9, 11, 16 Hz, 0.8H), 2.86 (dd, J=6, 19 Hz, 0.8H), 2.93-3.23 (m, 2H), 3.01 (d, J=6 Hz, 0.8H), 3.12 (d, J=19 Hz, 0.8H), 3.30-3.38 (m, 0.4H), 3.47-3.63 (m, 1H), 3.77 (ddd, J=4, 13, 13 Hz, 0.2H), 4.28-4.39 (m, 0.8H), 4.49 (br s, 0.2H), 4.58 (br s, 0.8H), 5.58 (br s, 1H), 5.82 (br s, 0.2H), 6.20 (br s, 0.8H), 7.13 (d, J=8 Hz, 0.8H), 7.14 (d, J=8 Hz, 0.2H), 7.39-7.49 (m, 1.8H), 7.73-7.75 (m, 0.2H).

Example 243
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carboxamide

[Image Omitted]

To the compound (210 mg, 0.461 mmol) obtained in Example 242 dissolved in dichloromethane (3.0 mL), trifluoroacetic acid (0.6 mL) was added under cooling, followed by stirring at 0° C. for 30 minutes and at room temperature for 1 hour. Water was added to the reaction mixture under cooling to stop the reaction, and the organic layer was separated. To the aqueous layer, a saturated aqueous sodium bicarbonate solution was added to make the aqueous layer basic, followed by extraction with dichloromethane, chloroform, chloroform/methanol (10/1), and chloroform/methanol (5/1). The combined organic layers were dried over sodium sulfate and then concentrated under reduced pressure to yield the title compound (119 mg, 73%) as a pale yellow amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.18 (m, 2H), 0.46-0.59 (m, 2H), 0.79-0.90 (m, 1H), 1.07-1.14 (m, 1H), 1.60 (ddd, J=5, 5, 15 Hz, 1H), 1.69 (ddd, J=4, 11, Hz, 1H), 1.92 (ddd, J=3, 13, 13 Hz, 1H), 2.08 (ddd, J=5, 13, 13 Hz, 1H), 2.17 (ddd, J=3, 3, 16 Hz, 1H), 2.30-2.41 (m, 3H), 2.54-2.60 (m, 1H), 2.80 (ddd, J=4, 4, 14 Hz, 1H), 2.80-2.91 (m, 1H), 2.92 (dd, J=6, 19 Hz, 1H), 2.99 (d, J=6 Hz, 1H), 3.05 (ddd, J=4, 4, 15 Hz, 1H), 3.10 (d, J=19 Hz, 1H), 3.15 (ddd, J=3, 11, 14 Hz, 1H), 4.52 (br s, 1H), 5.56 (br s, 1H), 6.08 (br s, 1H), 7.19 (d, J=8 Hz, 1H), 7.51 (dd, J=2, 8 Hz, 1H), 7.71 (d, J=2 Hz, 1H).

Reference Example 33
Synthesis of 2-(4-methyl-1H-pyrazol-1-yl)ethyl methanesulfonate

[Image Omitted]

The title compound was obtained from 2-(4-methyl-1H-pyrazol-1-yl)ethane-1-ol according to the method described in Reference Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.07 (s, 3H), 2.81 (s, 3H), 4.37 (t, J=5 Hz, 2H), 4.58 (t, J=5 Hz, 2H), 7.24 (s, 1H), 7.36 (s, 1H).

Example 244
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carboxamide

[Image Omitted]

The title compound was obtained from the compounds obtained in Example 243 and Reference Example 33 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.16 (m, 2H), 0.46-0.56 (m, 2H), 0.78-0.89 (m, 1H), 1.00-1.08 (m, 1H), 1.47 (ddd, J=2, 4, 14 Hz, 1H), 1.68 (ddd, J=3, 11, 14 Hz, 1H), 1.89 (ddd, J=3, 13, 13 Hz, 1H), 1.93-2.01 (m, 1H), 1.98 (s, 3H), 2.10 (ddd, J=5, 13, 13 Hz, 1H), 2.34 (d, J=6 Hz, 2H), 2.40 (ddd, J=4, 4, 13 Hz, 1H), 2.49 (ddd, J=5, 12, 16 Hz, 1H), 2.53-2.59 (m, 1H), 2.65 (ddd, J=4, 4, 13 Hz, 1H), 2.78 (ddd, J=6, 6, 13 Hz, 1H), 2.80 (ddd, J=6, 6, 13 Hz, 1H), 2.89 (dd, J=6, 19 Hz, 1H), 2.92-3.01 (m, 1H), 2.97 (d, J=6 Hz, 1H), 3.07 (d, J=19 Hz, 1H), 3.14 (ddd, J=2, 11, 13 Hz, 1H), 3.90 (ddd, J=6, 6, 14 Hz, 1H), 3.93 (ddd, J=6, 6, 14 Hz, 1H), 4.60 (br s, 1H), 5.57 (br s, 1H), 6.14 (br s, 1H), 6.70 (s, 1H), 7.18 (s, 1H), 7.19 (d, J=8 Hz, 1H), 7.48 (dd, J=2, 8 Hz, 1H), 7.69 (d, J=2 Hz, 1H).

Example 245
Synthesis of (2S,3R,5S,6S)-2-(((5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-10-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[Image Omitted]

To a solution of the compound (31.2 mg, 0.0717 mmol) obtained in Example 50 and 2,3,4-tri-O-acetyl-α-D-glucuronic acid methyl ester trichloroacetoimidate (68.6 mg, 0.143 mmol) in dichloromethane (1.5 mL) were added molecular sieves 4 Å (157 mg), followed by stirring at room temperature for 3 hours. To the reaction mixture was added a boron trifluoride-diethyl ether complex (36.0 μL, 0.287 mmol), followed by stirring at room temperature for 18 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol=95:5, twice) to yield the title compound (22.8 mg, 42%) as a pale yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.11 (m, 2H), 0.48-0.52 (m, 2H), 0.78-0.86 (m, 1H), 0.97-1.00 (m, 1H), 1.42-1.46 (m, 1H), 1.66-1.73 (m, 1H), 1.80 (ddd, J=4, 4, 16 Hz, 1H), 1.90-2.11 (m, 15H), 2.33 (d, J=7 Hz, 2H), 2.37-2.48 (m, 2H), 2.54 (dd, J=4, 12 Hz, 1H), 2.60 (ddd, J=4, 4, 12 Hz, 1H), 2.76-2.83 (m, 3H), 2.91-3.00 (m, 3H), 3.10-3.16 (m, 1H), 3.72 (s, 3H), 3.85-4.01 (m, 2H), 4.11-4.13 (m, 1H), 5.07 (d, J=8 Hz, 1H), 5.22-5.36 (m, 3H), 6.67 (s, 1H), 6.79-6.81 (m, 2H), 7.04 (d, J=8 Hz, 1H), 7.19 (s, 1H).

Example 246
Synthesis of (2S,3S,5R,6S)-6-(((5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-10-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[Image Omitted]

To a mixed solution of the compound (8.3 mg, 0.011 mmol) obtained in Example 245 in tetrahydrofuran/water (v/v=2/1, 1 mL) was added lithium hydroxide (9.3 mg, 0.22 mmol), followed by stirring at 60° C. for 4 hours. After allowed to cool to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by reverse phase silica gel column chromatography (0 to 100% methanol/water) to yield the title compound (8.1 mg, 100%) as a colorless oily matter.

¹H-NMR (400 MHz, D₂O) δ (ppm): 0.35-0.45 (m, 2H), 0.64-0.80 (m, 2H), 1.00-1.09 (m, 1H), 1.36-1.39 (m, 1H), 1.62-1.66 (m, 1H), 1.81-1.90 (m, 3H), 2.00 (s, 3H), 2.23-2.35 (m, 3H), 2.59 (ddd, J=4, 13, 13 Hz, 1H), 2.68-3.30 (m, 9H), 3.57-3.63 (m, 3H), 3.81-3.86 (m, 2H), 4.18-4.21 (m, 2H), 5.10 (d, J=7 Hz, 1H), 6.93 (d, J=2 Hz, 1H), 7.05 (dd, J=2, 8 Hz, 1H), 7.25 (d, J=8 Hz, 1H), 7.26 (s, 1H), 7.32 (s, 1H).

Example 247
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(pyridin-2-yl)acetyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carboxamide

[Image Omitted]

The title compound was obtained from the compound obtained in Example 243 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.17 (m, 2H), 0.45-0.59 (m, 2H), 0.76-0.89 (m, 1H), 1.01-1.11 (m, 1H), 1.52-2.15 (m, 5.4H), 2.30 (dd, J=7, 13 Hz, 0.4H), 2.33 (d, J=6 Hz, 1.2H), 2.37 (dd, J=7, 13 Hz, 0.4H), 2.50-2.73 (m, 2.6H), 2.86-2.99 (m, 0.4H), 2.95 (d, J=7 Hz, 0.6H), 2.97 (d, J=6 Hz, 0.4H), 3.04 (d, J=20 Hz, 1H), 3.27-3.39 (m, 1.4H), 3.46-3.84 (m, 3.8H), 3.88-3.97 (m, 0.4H), 4.36 (br s, 0.6H), 4.51 (br s, 0.4H), 5.75 (br s, 1H), 6.88 (d, J=8 Hz, 0.6H), 7.00 (d, J=8 Hz, 0.4H), 7.08-7.18 (m, 2H), 7.09 (br s, 1H), 7.39-7.44 (m, 0.6H), 7.45-7.53 (m, 1.6H), 7.54-7.61 (m, 0.4H), 7.65-7.68 (m, 0.4H), 8.39-8.46 (m, 1H).

Reference Example 34
Synthesis of (4bR,8aS,9R)-3-(benzyloxy)-11-(cyclopropylmethyl)-4,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one

[Image Omitted]

To (4R,4aS,7aR,12bS)-9-(benzyloxy)-3-(cyclopropylmethyl)-4a-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7(7aH)-one (synthesized by the method described in Tetrahedron Letters, 2007, 48, 7413) (1.66 g, 3.85 mmol) dissolved in ethanol (165 mL) was added ammonium chloride (2.06 g, 38.5 mmol), and then added zinc powder (2.52 g, 38.5 mmol) in 5 portions, followed by heating under reflux for 1 hour. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. A 28% aqueous ammonia solution was added to the obtained residue, followed by extraction once with ethyl acetate. The organic layer was washed with saturated saline and water, then dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was used in the next reaction without purification.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.09-0.15 (m, 2H), 0.49-0.58 (m, 2H), 0.80-0.92 (m, 1H), 1.49-1.63 (m, 1H), 1.78-1.86 (m, 1H), 1.97 (ddd, J=6, 14, 14 Hz, 1H), 2.03-2.09 (m, 2H), 2.11-2.19 (m, 1H), 2.30-2.41 (m, 2H), 2.57-2.62 (m, 1H), 2.73-2.89 (m, 2H), 2.92-3.03 (m, 2H), 3.11 (d, J=6 Hz, 1H), 3.91 (dd, J=2, 14 Hz, 1H), 4.72 (br s, 1H), 5.01 (d, J=11 Hz, 1H), 5.02 (d, J=11 Hz, 1H), 6.19 (br s, 1H), 6.55 (d, J=8 Hz, 1H), 6.73 (d, J=8 Hz, 1H), 7.32-7.42 (m, 5H).

Reference Example 35
Synthesis of (4bR,8aS,9R)-3-(benzyloxy)-11-(cyclopropylmethyl)-8a-hydroxy-4-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one

[Image Omitted]

To the compound (98.2 mg, 0.23 mmol) obtained in Reference Example 34 dissolved in N,N-dimethylformamide (4 mL) were added potassium carbonate (62.6 mg, 0.45 mmol) and methyl iodide (17 μL, 0.27 mmol), followed by stirring at room temperature for 40 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction once with ethyl acetate. The organic layer was washed three times with water, then dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0 to 5% methanol/ethyl acetate) to yield the title compound (68.6 mg, 68%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.17 (m, 2H), 0.49-0.59 (m, 2H), 0.80-0.91 (m, 1H), 1.50-1.60 (m, 1H), 1.81 (dd, J=7, 13 Hz, 1H), 1.92-2.20 (m, 4H), 2.30-2.41 (m, 2H), 2.57-2.64 (m, 1H), 2.74-2.89 (m, 2H), 2.97 (d, J=19 Hz, 1H), 3.02 (d, J=14 Hz, 1H), 3.02 (d, J=14 Hz, 1H), 3.09 (d, J=6 Hz, 1H), 3.71 (d, J=14 Hz, 1H), 3.98 (s, 3H), 5.03 (s, 2H), 6.71 (d, J=8 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 7.28-7.47 (m, 5H).

Example 248
Synthesis of (5aS,6R,11bR)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-11-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one (compound M) and (5aS,6R,11bS)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-11-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepin-3(4H)-one (compound N)

[Image Omitted]

The title compounds (M) and (N) were individually obtained from the compound obtained in Reference Example 35 according to the methods described in Reference Example 3 and Example 1.

(Compound M)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.13 (m, 2H), 0.45-0.56 (m, 2H), 0.75-0.88 (m, 1H), 1.53-1.62 (m, 2H), 1.84-1.94 (m, 1H), 1.96-2.11 (m, 2H), 2.26-2.38 (m, 2H), 2.57-2.66 (m, 1H), 2.78-2.92 (m, 4H), 3.20 (dd, J=2, 14 Hz, 1H), 3.34 (d, J=14 Hz, 1H), 3.80 (ddd, J=3, 3, 13 Hz, 1H), 3.96 (s, 3H), 4.50 (br s, 1H), 4.97 (d, J=12 Hz, 1H), 5.10 (d, J=12 Hz, 1H), 5.49-5.56 (m, 1H), 6.67 (d, J=8 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 7.27-7.46 (m, 5H).

(Compound N)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.16 (m, 2H), 0.46-0.58 (m, 2H), 0.77-0.88 (m, 1H), 1.10-1.26 (m, 1H), 1.49-1.57 (m, 1H), 1.81 (dd, J=14, 14 Hz, 1H), 2.00 (ddd, J=5, 13, 13 Hz, 1H), 2.07-2.17 (m, 2H), 2.29-2.40 (m, 2H), 2.65 (dd, J=4, 11 Hz, 1H), 2.82 (dd, J=6, 18 Hz, 1H), 2.87 (d, J=6 Hz, 1H), 2.96 (d, J=18 Hz, 1H), 3.20 (dd, J=14, 14 Hz, 1H), 3.46 (dd, J=7, 15 Hz, 1H), 3.82 (s, 3H), 4.12 (dd, J=7, 15 Hz, 1H), 4.66 (br s, 1H), 5.00 (d, J=11 Hz, 1H), 5.07 (d, J=11 Hz, 1H), 6.10 (dd, J=6, 6 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 7.30-7.47 (m, 5H).

Example 249
Synthesis of tert-butyl (5aS,6R,11bR)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-11-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

The title compound was obtained from the compound M obtained in Example 248 according to the methods described in Example 2 and Example 239.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.12 (m, 2H), 0.48-0.53 (m, 2H), 0.78-0.86 (m, 1H), 1.24 (s, 6.3H), 1.31 (s, 2.7H), 1.32-1.66 (m, 4H), 1.73-1.90 (m, 1H), 1.94-2.13 (m, 2H), 2.22-2.43 (m, 3.3H), 2.46-2.62 (m, 2H), 2.81-2.95 (m, 2.7H), 3.22-3.35 (m, 1.3H), 3.42-3.53 (m, 0.7H), 3.55-3.62 (m, 0.3H), 3.66-3.76 (m, 1H), 3.81 (s, 2.1H), 3.84 (s, 0.9H), 4.45 (br s, 0.7H), 5.00 (d, J=11 Hz, 0.7H), 5.07 (d, J=11 Hz, 0.7H), 5.09 (d, J=12 Hz, 0.3H), 5.13 (d, J=12 Hz, 0.3H), 6.69 (d, J=8 Hz, 0.3H), 6.72 (d, J=8 Hz, 0.7H), 6.77 (d, J=8 Hz, 0.3H), 6.80 (d, J=8 Hz, 0.7H), 7.30-7.49 (m, 5H).

Example 250
Synthesis of tert-butyl (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-11-methoxy-10-(((trifluoromethyl)sulfonyl)oxy)-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

To the compound (64 mg, 0.12 mmol) obtained in Example 249 dissolved in methanol (4 mL), 10% palladium-activated carbon (55% wet) (93 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 100 minutes. The reaction mixture was filtered through celite, and then the filtrate was concentrated under reduced pressure. The title compound was obtained from the obtained crude product according to the method described in Example 240.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.14 (m, 2H), 0.49-0.56 (m, 2H), 0.78-0.90 (m, 1H), 1.30-1.38 (m, 0.7H), 1.34 (s, 6.3H), 1.37 (s, 2.7H), 1.45-1.84 (m, 2.3H), 1.93 (ddd, J=3, 12, 12 Hz, 1H), 2.00-2.06 (m, 0.3H), 2.15 (ddd, J=5, 13, 13 Hz, 0.7H), 2.25-2.39 (m, 3H), 2.48-2.68 (m, 2H), 2.88-3.06 (m, 3.3H), 3.25-3.34 (m, 0.7H), 3.39-3.49 (m, 1.7H), 3.56-3.65 (m, 0.3H), 3.81-3.89 (m, 1H), 3.84 (s, 2.1H), 3.87 (s, 0.9H), 6.89 (d, J=8 Hz, 1H), 7.04-7.09 (m, 1H).

Example 251
Synthesis of tert-butyl (5aS,6R,11bR)-10-cyano-14-(cyclopropylmethyl)-5a-hydroxy-1l-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

The title compound was obtained from the compound obtained in Example 250 according to the method described in Example 241.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.15 (m, 2H), 0.49-0.55 (m, 2H), 0.76-0.88 (m, 1H), 1.26 (s, 6.3H), 1.28 (s, 2.7H), 1.32-1.79 (m, 3.7H), 1.86 (ddd, J=3, 12, 12 Hz, 1H), 1.99-2.17 (m, 1.4H), 2.23-2.39 (m, 2.3H), 2.43-2.53 (m, 0.3H), 2.59-2.70 (m, 1.7H), 2.87-3.04 (m, 3H), 3.11-3.23 (m, 1.3H), 3.37-3.56 (m, 1H), 3.69-3.80 (m, 1.3H), 4.08 (s, 2.1H), 4.14 (s, 0.9H), 6.81-6.86 (m, 1H), 7.29-7.34 (m, 1H).

Example 252
Synthesis of tert-butyl (5aS,6R,11bR)-10-carbamoyl-14-(cyclopropylmethyl)-5a-hydroxy-11-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

The title compound was obtained from the compound obtained in Example 251 according to the method described in Example 242.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.14 (m, 2H), 0.48-0.55 (m, 2H), 0.78-0.89 (m, 1H), 1.09 (s, 9H), 1.30-1.37 (m, 1H), 1.43 (dd, J=4, 14 Hz, 1H), 1.55-1.83 (m, 1H), 1.94-2.14 (m, 3H), 2.26-2.40 (m, 2H), 2.53-2.79 (m, 2H), 2.86-3.02 (m, 4H), 3.07-3.16 (m, 1H), 3.47-3.55 (m, 1H), 3.78 (s, 3H), 4.43 (ddd, J=7, 13, 13 Hz, 1H), 5.62-5.82 (m, 1H), 6.82 (d, J=8 Hz, 1H), 7.26 (d, J=8 Hz, 1H).

Example 253
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-11-methoxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carboxamide

[Image Omitted]

The title compound was obtained from the compound obtained in Example 252 according to the methods described in Example 243 and Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.45-0.56 (m, 2H), 0.77-0.92 (m, 1H), 1.30-1.37 (m, 1H), 1.44 (dd, J=5, 14 Hz, 1H), 1.60-1.73 (m, 1H), 1.97 (s, 3H), 1.98-2.04 (m, 1H), 2.06-2.18 (m, 2H), 2.27-2.42 (m, 3H), 2.53 (ddd, J=5, 13, 13 Hz, 1H), 2.60-2.68 (m, 2H), 2.69-2.79 (m, 2H), 2.89-3.03 (m, 4H), 3.09-3.18 (m, 1H), 3.75 (s, 3H), 3.84-3.97 (m, 2H), 4.53 (br s, 1H), 5.72 (br s, 1H), 6.76 (s, 1H), 6.96 (d, J=8 Hz, 1H), 7.08 (br s, 1H), 7.17 (s, 1H), 7.67 (d, J=8 Hz, 1H).

Example 254
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(isothiazol-3-yl)acetyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carboxamide

[Image Omitted]

The title compound was obtained from the compound obtained in Example 243 and the compound obtained in Reference Example 21 according to the method described in Example 5.

¹H-NMR (400 MHz, CD₃OD) δ (ppm): 0.11-0.17 (m, 2H), 0.49-0.57 (m, 2H), 0.83-0.92 (m, 1H), 1.07-1.10 (m, 1H), 1.60-1.65 (m, 1H), 1.78-1.97 (m, 2H), 2.04-2.63 (m, 5.5H), 2.84 (dd, J=6, 19 Hz, 0.5H), 2.95 (dd, J=6, 19 Hz, 0.5H), 2.99-3.18 (m, 2H), 3.43-3.55 (m, 2H), 3.59-3.71 (m, 2H), 3.78-3.86 (m, 2H), 3.94 (d, J=16 Hz, 0.5H), 6.98 (d, J=4 Hz, 0.5H), 7.00 (d, J=4 Hz, 0.5H), 7.23 (d, J=8 Hz, 0.5H), 7.27 (d, J=8 Hz, 0.5H), 7.64 (dd, J=2, 8 Hz, 0.5H), 7.69 (dd, J=2, 8 Hz, 0.5H), 7.73 (d, J=2 Hz, 0.5H), 7.78 (d, J=2 Hz, 0.5H), 8.77 (d, J=4 Hz, 0.5H), 8.78 (d, J=4 Hz, 0.5H).

Reference Example 36
Synthesis of (4′R,4a′S,7a′R,12b′S)-3′-(cyclopropylmethyl)-4a′-hydroxy-9′-methoxy-1′,2′,3′,4′,4a′,5′-hexahydrospiro[cyclopentane-1,6′-[4,12]methanobenzofuro[3,2-e]isoquinolin]-7′(7a′H)-one

[Image Omitted]

To (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (synthesized by the method described in Organic Letters 2009, 11, 539) (1.50 g, 4.22 mmol) and 1,4 dibromobutane (1.50 mL, 12.7 mmol) dissolved in toluene (42 mL) was added sodium tert-butoxide (2.37 g, 21.1 mmol), followed by heating under reflux for 24 hours under a nitrogen atmosphere. The reaction solution was allowed to cool to room temperature and filtered through celite, and the obtained filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0 to 100% ethyl acetate/chloroform and 0 to 10% methanol/ethyl acetate) to yield the title compound (650 mg, 38%) as a pale yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.90-1.00 (m, 1H), 1.20-1.80 (m, 8H), 2.00-2.10 (m, 3H), 2.15-2.25 (m, 1H), 2.30-2.50 (m, 3H), 2.50-2.60 (m, 1H), 2.60-2.70 (m, 1H), 3.03 (d, J=18 Hz, 1H), 3.09 (d, J=14 Hz, 1H), 3.35-3.50 (m, 1H), 3.92 (s, 3H), 4.86 (s, 1H), 6.58 (d, J=8 Hz, 1H), 6.68 (d, J=8 Hz, 1H).

Reference Example 37
Synthesis of (4b′R,8a′S,9′R)-11′-(cyclopropylmethyl)-4′,8a′-dihydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydrospiro[cyclopentane-1,7′-[9,4b](epiminoethano)phenanthren]-6′(5′H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 36 according to the method described in Reference Example 34.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.90-1.00 (m, 1H), 1.20-1.80 (m, 8H), 1.80-2.25 (m, 4H), 2.25-2.50 (m, 3H), 2.50-2.65 (m, 1H), 2.70-2.90 (m, 1H), 2.96 (d, J=18 Hz, 1H), 3.00-3.10 (m, 1H), 3.21 (d, J=13 Hz, 1H), 3.74 (d, J=13 Hz, 1H), 3.82 (s, 3H), 6.06 (s, 1H), 6.53 (d, J=8 Hz, 1H), 6.65 (d, J=8 Hz, 1H).

Reference Example 38
Synthesis of (4b′R,8a′S,9′R)-11′-(cyclopropylmethyl)-8a′-hydroxy-3′-methoxy-6′-oxo-5′,6′,8′,8a′,9′,10′-hexahydrospiro[cyclopentane-1,7′-[9,4b](epiminoethano)phenanthren]-4′-yl trifluoromethanesulfonate

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 37 according to the method described in Reference Example 1.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.90-1.00 (m, 1H), 1.20-1.80 (m, 8H), 1.90-2.00 (m, 1H), 2.00-2.15 (m, 3H), 2.15-2.25 (m, 1H), 2.30-2.45 (m, 2H), 2.60-2.70 (m, 1H), 2.80-2.90 (m, 1H), 3.02 (d, J=18 Hz, 1H), 3.09 (d, J=6 Hz, 1H), 3.38 (d, J=14 Hz, 1H), 3.42 (d, J=14 Hz, 1H), 3.80 (s, 3H), 6.83 (d, J=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H).

Reference Example 39
Synthesis of (4b′R,8a′S,9′R)-11′-(cyclopropylmethyl)-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydrospiro[cyclopentane-1,7′-[9,4b](epiminoethano)phenanthren]-6′(5′H)-one

[Image Omitted]

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

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 2H), 1.10-1.20 (m, 1H), 1.35-1.70 (m, 4H), 1.67 (d, J=14 Hz, 1H), 1.79 (d, J=14 Hz, 1H), 1.85-1.95 (m, 1H), 2.00-2.20 (m, 4H), 2.37 (d, J=6 Hz, 2H), 2.50-2.60 (m, 1H), 2.65-2.80 (m, 2H), 2.95-3.10 (m, 2H), 3.32 (d, J=14 Hz, 1H), 3.76 (s, 3H), 6.66 (dd, J=3, 8 Hz, 1H), 6.80 (d, J=3 Hz, 1H), 6.93 (d, J=8 Hz, 1H).

Reference Example 40
Synthesis of (4b′R,8a′S,9′R)-11′-(cyclopropylmethyl)-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydrospiro[cyclopentane-1,7′-[9,4b](epiminoethano)phenanthren]-6′(5′H)-one oxime

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 39 according to the method described in Reference Example 3.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 0.90-1.00 (m, 1H), 1.00-1.20 (m, 1H), 1.40-1.80 (m, 6H), 1.80-2.20 (m, 5H), 2.25-2.45 (m, 2H), 2.50 (d, J=14 Hz, 1H), 2.50-2.60 (m, 1H), 2.60-2.80 (m, 1H), 2.90-3.10 (m, 2H), 3.55 (s, 3H), 3.69 (d, J=14 Hz, 1H), 6.69 (dd, J=3, 8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 7.09 (d, J=3 Hz, 1H), 8.39 (br s, 1H).

Example 255
Synthesis of (5a′S,6′R,11b′R)-14′-(cyclopropylmethyl)-5a′-hydroxy-10′-methoxy-5′,5a′,6′,7′-tetrahydro-1′H-spiro[cyclopentane-1,4′-[6,11b](epiminoethano)naphtho[1,2-d]azepin]-2′(3′H)-one

[Image Omitted]

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

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.15 (m, 1H), 1.40-1.85 (m, 8H), 2.00-2.25 (m, 4H), 2.30-2.40 (m, 2H), 2.55-2.60 (m, 1H), 2.66 (dd, J=2, 15 Hz, 1H), 2.78 (dd, J=6, 18 Hz, 1H), 2.87 (d, J=6 Hz, 1H), 3.00 (d, J=18 Hz, 1H), 3.57 (d, J=15 Hz, 1H), 3.79 (s, 3H), 4.82 (br s, 1H), 5.40 (s, 1H), 6.70 (dd, J=3, 8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 7.12 (d, J=3 Hz, 1H).

Example 256
Synthesis of (5a′S,6′R,11b′S)-14′-(cyclopropylmethyl)-10′-methoxy-2′,3′,6′,7′-tetrahydro-1′H-spiro[cyclopentane-1,4′-[6,11b](epiminoethano)naphtho[1,2-d]azepin]-5a′(5′H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 255 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.15 (m, 2H), 1.40-1.70 (m, 5H), 1.70-1.85 (m, 2H), 1.85-2.10 (m, 3H), 2.25-2.45 (m, 3H), 2.50-2.65 (m, 2H), 2.76 (dd, J=6, 18 Hz, 1H), 2.85 (d, J=6 Hz, 1H), 2.95-3.10 (m, 2H), 3.79 (s, 3H), 4.46 (br s, 1H), 6.65-6.70 (m, 2H), 7.03 (d, J=8 Hz, 1H).

Example 257
Synthesis of 1-((5a′S,6′R,11b′R)-14′-(cyclopropylmethyl)-5a′-hydroxy-10′-methoxy-1′,2′,5′,5a′,6′,7′-hexahydro-3′H-spiro[cyclopentane-1,4′-[6,11b](epiminoethano)naphtho[1,2-d]azepin]-3′-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 256 and 4-methylpyrazole according to the method described in Example 132.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.00-1.10 (m, 1H), 1.30-2.60 (m, 21H), 2.80-3.00 (m, 3H), 3.30-3.60 (m, 1H), 3.79 (s, 3H), 4.60-4.80 (m, 2H), 6.70-6.80 (m, 2H), 7.00-7.10 (m, 2H), 7.20-7.30 (m, 1H).

Example 258
Synthesis of (5a′S,6′R,11b′R)-14′-(cyclopropylmethyl)-10′-methoxy-3′-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2′,3′,6′,7′-tetrahydro-1′H-spiro[cyclopentane-1,4′-[6,11b](epiminoethano)naphtho[1,2-d]azepin]-5a′(5′H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 257 according to the method described in Example 24.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.30 (m, 2H), 0.50-0.70 (m, 2H), 0.80-1.00 (m, 1H), 1.00-1.30 (m, 2H), 1.30-2.10 (m, 18H), 2.09 (s, 3H), 2.10-2.30 (m, 1H), 2.30-2.45 (m, 1H), 2.45-2.70 (m, 2H), 2.70-2.90 (m, 2H), 3.00-3.15 (m, 1H), 4.11 (br s, 1H), 6.66 (d, J=8 Hz, 1H), 6.74 (s, 1H), 6.93 (d, J=8 Hz, 1H), 7.27 (s, 1H), 7.52 (s, 1H).

Example 259
Synthesis of (5aS,6R,11bR)-9-bromo-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The compound (356 mg, 0.999 mmol) obtained in Example 140 was suspended in water (10 mL), and dissolved by adding trifluoroacetic acid (1.0 mL). Under ice cooling, N-bromosuccinimide (356 mg, 1.99 mmol) was added, followed by stirring at 0° C. for 16 hours. To the reaction mixture, a mixed solution of a 2 M aqueous sodium hydroxide solution and a saturated aqueous sodium thiosulfate solution (v/v=4/1, 10 mL) was added, followed by extraction three times with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 10% methanol/ethyl acetate) to yield the title compound (368 mg, 85%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.18 (m, 2H), 0.46-0.59 (m, 2H), 0.76-0.88 (m, 1H), 1.05-1.14 (m, 1H), 1.50-1.69 (m, 2H), 2.00-2.12 (m, 2H), 2.34 (dd, J=6, 14 Hz, 1H), 2.35 (dd, J=6, 14 Hz, 1H), 2.51-2.65 (m, 2H), 2.74 (dd, J=6, 18 Hz, 1H), 2.79-2.88 (m, 1H), 2.91 (d, J=6 Hz, 1H), 2.98 (d, J=18 Hz, 1H), 3.50 (d, J=14 Hz, 1H), 3.79-3.94 (m, 1H), 3.90 (s, 3H), 4.69 (br s, 1H), 6.04 (br s, 1H), 7.16 (s, 1H), 7.24 (s, 1H).

Example 260
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-9-methyl-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The compound (368 mg, 0.846 mmol) obtained in Example 259, potassium carbonate (351 mg, 2.54 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane adduct (345 mg, 0.423 mmol), and trimethylboroxine (0.590 mL, 4.22 mmol) were suspended in N,N-dimethylformamide (8.0 mL), followed by stirring at 80° C. for 15 hours. After allowed to cool to room temperature, a saturated aqueous sodium bicarbonate solution and water were added, followed by extraction three times with ethyl acetate. The organic layers were combined, washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0 to 20% methanol/ethyl acetate and amino group-supported silica gel, 1 to 30% methanol/ethyl acetate) to yield the title compound (244 mg, 78%) as a pale yellow amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.18 (m, 2H), 0.45-0.56 (m, 2H), 0.77-0.89 (m, 1H), 1.08-1.17 (m, 1H), 1.53 (dd, J=6, 14 Hz, 1H), 1.77 (ddd, J=2, 12, 14 Hz, 1H), 2.02-2.13 (m, 2H), 2.14 (s, 3H), 2.35 (dd, J=6, 13 Hz, 1H), 2.36 (dd, J=6, 13 Hz, 1H), 2.51-2.63 (m, 1H), 2.60 (dd, J=2, 15 Hz, 1H), 2.72 (dd, J=6, 18 Hz, 1H), 2.81-2.92 (m, 1H), 2.90 (d, J=6 Hz, 1H), 2.98 (d, J=18 Hz, 1H), 3.50 (d, J=15 Hz, 1H), 3.81-3.91 (m, 1H), 3.84 (s, 3H), 4.73 (br s, 1H), 5.63-5.72 (m, 1H), 6.82 (s, 1H), 7.06 (s, 1H).

Example 261
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-9-methyl-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 260 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.43-0.57 (m, 2H), 0.78-0.90 (m, 1H), 1.00-1.11 (m, 1H), 1.56 (ddd, J=3, 3, 15 Hz, 1H), 1.75 (ddd, J=4, 12, Hz, 1H), 1.95-2.08 (m, 3H), 2.17 (s, 3H), 2.25-2.40 (m, 3H), 2.47-2.58 (m, 1H), 2.74-2.82 (m, 2H), 2.89-3.00 (m, 1H), 2.91 (d, J=7 Hz, 1H), 2.95 (d, J=19 Hz, 1H), 3.00 (ddd, J=3, 6, 14 Hz, 1H), 3.07 (ddd, J=3, 12, 14 Hz, 1H), 3.79 (s, 3H), 4.52 (br s, 1H), 6.61 (s, 1H), 6.89 (s, 1H).

Example 262
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-9-methyl-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 261 and the compound obtained in Reference Example 33 according to the methods described in Example 31 and Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.46-0.55 (m, 2H), 0.76-0.88 (m, 1H), 0.95-1.05 (m, 1H), 1.39-1.46 (m, 1H), 1.72-1.82 (m, 2H), 1.95-2.07 (m, 2H), 2.00 (s, 3H), 2.19 (s, 3H), 2.28-2.40 (m, 3H), 2.45-2.61 (m, 3H), 2.73 (dd, J=6, 18 Hz, 1H), 2.78-2.99 (m, 5H), 3.11-3.20 (m, 1H), 3.96-4.08 (m, 2H), 4.62 (br s, 1H), 6.51 (s, 1H), 6.48 (s, 1H), 6.87 (s, 1H), 7.23 (s, 1H).

Example 263
Synthesis of (5aS,6R,11bS)-9-bromo-14-(cyclopropylmethyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 259 according to the methods described in Example 2, Example 31, and Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.43-0.57 (m, 2H), 0.76-0.88 (m, 1H), 0.96-1.03 (m, 1H), 1.45 (ddd, J=2, 5, 14 Hz, 1H), 1.72 (ddd, J=3, 11, 14 Hz, 1H), 1.77 (ddd, J=4, 4, 16 Hz, 1H), 1.92-2.09 (m, 2H), 2.01 (s, 3H), 2.31-2.38 (m, 1H), 2.34 (dd, J=7, 13 Hz, 1H), 2.39 (ddd, J=4, 11, 16 Hz, 1H), 2.45 (ddd, J=3, 5, 14 Hz, 1H), 2.51-2.58 (m, 1H), 2.59 (ddd, J=4, 4, 13 Hz, 1H), 2.76 (dd, J=6, 18 Hz, 1H), 2.80-2.95 (m, 3H), 2.89 (d, J=6 Hz, 1H), 2.94 (d, J=18 Hz, 1H), 3.13 (ddd, J=2, 11, 13 Hz, 1H), 3.97 (ddd, J=6, 6, 14 Hz, 1H), 4.01 (ddd, J=6, 6, 14 Hz, 1H), 4.58 (br s, 1H), 6.76 (s, 1H), 6.82 (s, 1H), 7.21 (s, 1H), 7.22 (s, 1H).

Example 264
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-3-(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl) propanoyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carboxamide

[Image Omitted]

The title compound was obtained from the compound obtained in Example 243 and 3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propanoic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.18 (m, 2H), 0.46-0.58 (m, 2H), 0.76-0.88 (m, 1H), 1.04-1.13 (m, 1H), 1.57-1.76 (m, 1.5H), 1.85 (ddd, J=4, 12, 12 Hz, 0.5H), 1.91-2.20 (m, 2.5H), 2.25-2.38 (m, 2.5H), 2.41-2.73 (m, 3H), 2.77-2.90 (m, 1.5H), 2.95-3.00 (m, 0.5H), 2.98 (d, J=6 Hz, 1H), 2.99 (d, J=19 Hz, 0.5H), 3.11 (d, J=19 Hz, 0.5H), 3.23-3.40 (m, 1.5H), 3.56-3.72 (m, 1.5H), 3.79 (ddd, J=4, 11, 15 Hz, 0.5H), 3.89 (ddd, J=3, 3, 14 Hz, 0.5H), 4.15-4.24 (m, 1H), 4.25-4.34 (m, 1H), 4.47 (br s, 1H), 5.40 (br s, 0.5H), 5.70 (br s, 0.5H), 6.55 (br s, 0.5H), 6.68 (br s, 0.5H), 7.02 (d, J=8 Hz, 0.5H), 7.14 (d, J=8 Hz, 0.5H), 7.23 (dd, J=2, 8 Hz, 0.5H), 7.45 (dd, J=2, 8 Hz, 0.5H), 7.53 (s, 0.5H), 7.54 (d, J=2 Hz, 0.5H), 7.63 (s, 1H), 7.69 (s, 0.5H), 7.74 (s, 0.5H).

Example 265
Synthesis of (5aS,6R,11bR)-3-(2-(1H-indazol-3-yl)acetyl)-14-(cyclopropylmethyl)-5a-hydroxy-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carboxamide

[Image Omitted]

The title compound was obtained from the compound obtained in Example 243 and 2-(1H-indazol-3-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CD₃OD) δ (ppm): 0.08-0.20 (m, 2H), 0.46-0.58 (m, 2H), 0.81-0.92 (m, 1H), 1.02-1.12 (m, 1H), 1.53-1.66 (m, 1.4H), 1.84 (ddd, J=3, 12, 15 Hz, 0.6H), 1.92 (ddd, J=3, 12, 15 Hz, 0.6H), 2.02-2.27 (m, 1.4H), 2.29-2.65 (m, 3.6H), 2.70 (dd, J=6, 19 Hz, 0.4H), 2.92-3.01 (m, 1H), 3.06 (d, J=6 Hz, 0.6H), 3.08 (d, J=19 Hz, 0.4H), 3.16 (d, J=19 Hz, 0.6H), 3.27-3.39 (m, 2H), 3.44-3.79 (m, 3H), 3.68 (d, J=16 Hz, 0.6H), 3.85 (ddd, J=7, 7, 15 Hz, 0.4H), 3.93 (d, J=16 Hz, 0.4H), 3.94 (d, J=16 Hz, 0.6H), 4.05 (d, J=16 Hz, 0.4H), 6.99-7.12 (m, 1.4H), 7.26-7.38 (m, 1.6H), 7.41-7.50 (m, 2H), 7.52 (dd, J=2, 8 Hz, 0.4H), 7.69 (dd, J=2, 7 Hz, 0.6H), 7.71 (dd, J=2, 8 Hz, 0.4H), 7.81 (d, J=2 Hz, 0.6H).

Example 266
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carboxamide

[Image Omitted]

The title compound was obtained from the compound obtained in Example 243 and 2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.19 (m, 2H), 0.50-0.59 (m, 2H), 0.78-0.90 (m, 1H), 1.07-1.17 (m, 1H), 1.59-1.83 (m, 2H), 1.91 (ddd, J=4, 12, 12 Hz, 0.5H), 1.95-2.17 (m, 2H), 2.21 (ddd, J=4, 4, 16 Hz, 0.5H), 2.31 (dd, J=7, 13 Hz, 0.5H), 2.36 (d, J=6 Hz, 1H), 2.38 (dd, J=7, 13 Hz, 0.5H), 2.47 (ddd, J=5, 11, 16 Hz, 0.5H), 2.54-2.64 (m, 1H), 2.74-2.85 (m, 0.5H), 2.86-2.90 (m, 0.5H), 2.91-2.97 (m, 0.5H), 2.99 (d, J=6 Hz, 0.5H), 3.00 (d, J=6 Hz, 0.5H), 3.05 (d, J=19 Hz, 0.5H), 3.13 (d, J=19 Hz, 0.5H), 3.26-3.50 (m, 1.5H), 3.66 (ddd, J=4, 12, 15 Hz, 0.5H), 3.71-3.82 (m, 1.5H), 3.90 (ddd, J=3, 4, 14 Hz, 0.5H), 4.50 (br s, 1H), 4.58 (d, J=16 Hz, 0.5H), 4.75 (d, J=16 Hz, 0.5H), 4.78 (d, J=16 Hz, 0.5H), 4.87 (d, J=16 Hz, 0.5H), 5.64 (br s, 1H), 6.44 (br s, 1H), 7.17 (d, J=8 Hz, 0.5H), 7.19 (d, J=7 Hz, 0.5H), 7.44 (d, J=2, 8 Hz, 0.5H), 7.45-7.52 (m, 0.5H), 7.49 (s, 0.5H), 7.55 (d, J=2 Hz, 0.5H), 7.58 (s, 0.5H), 7.62 (s, 0.5H), 7.64 (s, 0.5H), 7.76 (d, J=2 Hz, 0.5H).

Reference Example 41
Synthesis of (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-6,6-dimethyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one

[Image Omitted]

To a solution of (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (synthesized by the method described in Organic Letters 2009, 11, 539) (1.50 g, 4.22 mmol) in tetrahydrofuran (37 mL) cooled to −78° C. was added a 1.08 M lithium bis(trimethylsilyl)amide-tetrahydrofuran solution (11.7 mL, 12.6 mmol), followed by stirring for 1 hour. To the reaction mixture, a solution of methyl iodide (1.58 mL, 25.4 mmol) in tetrahydrofuran (3 mL) was added, followed by stirring at −78° C. for 1 hour and at room temperature for 18 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (47 to 68% ethyl acetate/heptane) to yield the title compound (574 mg, 36%) as a pale yellow crystal.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.12-0.16 (m, 2H), 0.53-0.57 (m, 2H), 0.82-0.88 (m, 1H), 0.95 (s, 3H), 1.44 (s, 3H), 1.52-1.62 (m, 2H), 1.73 (d, J=14 Hz, 1H), 2.09 (ddd, J=4, 12, 12 Hz, 1H), 2.32-2.50 (m, 3H), 2.57 (dd, J=6, 19 Hz, 1H), 2.63-2.71 (m, 1H), 3.02 (d, J=19 Hz, 1H), 3.11 (d, J=6 Hz, 1H), 3.92 (s, 3H), 4.87 (s, 1H), 5.45 (br s, 1H), 6.60 (d, J=8 Hz, 1H), 6.69 (d, J=8 Hz, 1H).

Reference Example 42
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-4,8a-dihydroxy-3-methoxy-7,7-dimethyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 41 according to the method described in Reference Example 34.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.09-0.13 (m, 2H), 0.50-0.54 (m, 2H), 0.82 (s, 3H), 0.82-0.88 (m, 1H), 1.40 (s, 3H), 1.65 (d, J=14 Hz, 1H), 1.81 (d, J=14 Hz, 1H), 1.97-2.11 (m, 2H), 2.31 (dd, J=6, 13 Hz, 1H), 2.37 (dd, J=6, 13 Hz, 1H), 2.56-2.60 (m, 1H), 2.83 (dd, J=6, 19 Hz, 1H), 2.96 (d, J=19 Hz, 1H), 3.06 (d, J=6 Hz, 1H), 3.23 (d, J=13 Hz, 1H), 3.73 (d, J=13 Hz, 1H), 3.82 (s, 3H), 4.87 (br s, 1H), 6.06 (s, 1H), 6.54 (d, J=8 Hz, 1H), 6.64 (d, J=8 Hz, 1H).

Reference Example 43
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7,7-dimethyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-yl trifluoromethanesulfonate

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 42 according to the method described in Reference Example 1.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.10-0.14 (m, 2H), 0.52-0.57 (m, 2H), 0.78 (s, 3H), 0.81-0.89 (m, 1H), 1.38 (s, 3H), 1.61-1.70 (m, 3H), 2.06 (ddd, J=3, 12, 12 Hz, 1H), 2.21 (ddd, J=5, 12, 12 Hz, 1H), 2.33 (dd, J=6, 12 Hz, 1H), 2.39 (dd, J=6, 12 Hz, 1H), 2.66-2.69 (m, 1H), 2.87 (dd, J=6, 18 Hz, 1H), 3.02 (d, J=18 Hz, 1H), 3.11 (d, J=6 Hz, 1H), 3.37 (d, J=14 Hz, 1H), 3.44 (d, J=14 Hz, 1H), 3.80 (s, 3H), 6.83 (d, J=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H).

Reference Example 44
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7,7-dimethyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one

[Image Omitted]

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

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.11-0.15 (m, 2H), 0.51-0.56 (m, 2H), 0.79 (s, 3H), 0.80-0.91 (m, 1H), 1.14-1.17 (m, 1H), 1.40 (s, 3H), 1.64 (d, J=14 Hz, 1H), 1.71 (d, J=14 Hz, 1H), 2.07 (ddd, J=3, 12, 12 Hz, 1H), 2.16 (ddd, J=4, 13, 13 Hz, 1H), 2.34 (dd, J=6, 13 Hz, 1H), 2.41 (dd, J=6, 13 Hz, 1H), 2.56-2.60 (m, 1H), 2.72 (d, J=14 Hz, 1H), 2.75 (dd, J=6, 18 Hz, 1H), 3.04 (d, J=18 Hz, 1H), 3.09 (d, J=6 Hz, 1H), 3.36 (d, J=14 Hz, 1H), 3.77 (s, 3H), 6.68 (dd, J=2, 8 Hz, 1H), 6.79 (d, J=2 Hz, 1H), 6.96 (d, J=8 Hz, 1H).

Reference Example 45
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7,7-dimethyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one oxime

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 44 according to the method described in Reference Example 3.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.09-0.13 (m, 2H), 0.49-0.53 (m, 2H), 0.80-0.89 (m, 1H), 0.90 (s, 3H), 1.12-1.15 (m, 1H), 1.42 (s, 3H), 1.43-1.60 (m, 2H), 2.04-2.17 (m, 2H), 2.32 (dd, J=6, 13 Hz, 1H), 2.39 (dd, J=6, 13 Hz, 1H), 2.53-2.59 (m, 2H), 2.71 (dd, J=6, 18 Hz, 1H), 2.99 (d, J=6 Hz, 1H), 3.01 (d, J=18 Hz, 1H), 3.69 (d, J=14 Hz, 1H), 3.74 (s, 3H), 6.68 (dd, J=2, 8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 6.99 (br s, 1H), 7.08 (d, J=2 Hz, 1H).

Example 267
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-4,4-dimethyl-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 45 according to the method described in Example 1.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.09-0.13 (m, 2H), 0.50-0.54 (m, 2H), 0.78-0.88 (m, 1H), 1.06-1.14 (m, 1H), 1.10 (s, 3H), 1.55 (d, J=14 Hz, 1H), 1.62 (s, 3H), 1.86 (d, J=14 Hz, 1H), 2.00-2.09 (m, 2H), 2.32 (dd, J=6, 13 Hz, 1H), 2.34 (dd, J=6, 13 Hz, 1H), 2.52-2.61 (m, 1H), 2.72 (dd, J=2, 15 Hz, 1H), 2.78 (dd, J=6, 18 Hz, 1H), 2.87 (d, J=6 Hz, 1H), 3.00 (d, J=18 Hz, 1H), 3.57 (d, J=15 Hz, 1H), 3.79 (s, 3H), 4.90 (br s, 1H), 5.39 (s, 1H), 6.71 (dd, J=2, 8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 7.10 (d, J=2 Hz, 1H).

Example 268
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-4,4-dimethyl-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 267 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.13 (m, 2H), 0.50-0.53 (m, 2H), 0.81-0.90 (m, 1H), 0.85 (s, 3H), 1.04-1.10 (m, 1H), 1.33 (s, 3H), 1.43 (d, J=15 Hz, 1H), 1.57-1.76 (m, 2H), 1.92-2.01 (m, 2H), 2.26-2.39 (m, 3H), 2.51-2.60 (m, 2H), 2.74 (dd, J=6, 18 Hz, 1H), 2.82 (d, J=6 Hz, 1H), 2.85-2.91 (m, 1H), 2.98 (d, J=18 Hz, 1H), 3.79 (s, 3H), 4.41 (s, 1H), 6.71 (dd, J=2, 8 Hz, 1H), 6.74 (d, J=2 Hz, 1H), 7.02 (d, J=8 Hz, 1H).

Example 269
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-4,4-dimethyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

To a solution of the compound (24.0 mg, 0.0648 mmol) obtained in Example 268 in tetrahydrofuran (2 mL) were added N,N-diisopropylethylamine (55.1 μL, 0.324 mmol) and chloroacetyl chloride (12.9 μL, 0.162 mmol) under ice cooling, followed by stirring at room temperature for 1.5 hours. To the reaction mixture, sodium iodide (23.9 mg, 0.159 mmol) and 4-methylpyrazole (13.4 μL, 0.162 mmol) were added, followed by stirring at 60° C. for 17 hours. After allowed to cool to room temperature, to the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:methanol=95:5, twice) to yield the title compound (9.7 mg, 30%) as a pale yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.13 (m, 2H), 0.49-0.54 (m, 2H), 0.79-0.88 (m, 1H), 1.04-1.07 (m, 1H), 1.14 (s, 3H), 1.39 (d, J=15 Hz, 1H), 1.88 (s, 3H), 1.92-2.15 (m, 4H), 2.09 (s, 3H), 2.28-2.40 (m, 3H), 2.55-2.62 (m, 1H), 2.76 (dd, J=6, 18 Hz, 1H), 2.81 (d, J=6 Hz, 1H), 2.92-2.98 (m, 1H), 3.01 (d, J=18 Hz, 1H), 3.57-3.63 (m, 1H), 3.79 (s, 3H), 4.44 (s, 1H), 4.82 (d, J=16 Hz, 1H), 4.99 (d, J=16 Hz, 1H), 6.68 (d, J=2 Hz, 1H), 6.74 (dd, J=2, 8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 7.33 (s, 1H), 7.34 (s, 1H).

Example 270
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-4,4-dimethyl-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To a solution of the compound (9.7 mg, 0.020 mmol) obtained in Example 269 in tetrahydrofuran (3 mL) was added a 0.9 M borane-tetrahydrofuran complex-tetrahydrofuran solution (0.22 mL, 0.20 mmol), followed by heating under reflux for 18 hours. After allowed to cool to room temperature, to the reaction mixture was added 2 M hydrochloric acid (3 mL), followed by stirring at 100° C. for 1 hour. After allowed to cool to room temperature, the reaction mixture was added to a saturated aqueous sodium bicarbonate solution, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. To a solution of the obtained crude product (4.5 mg) in dichloromethane (1.5 mL) was added a 1 M boron tribrominate-dichloromethane solution (0.050 mL, 0.050 mmol) under ice cooling, followed by stirring at room temperature for 17 hours. To the reaction mixture, a saturated aqueous potassium carbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M NH₃-methanol=95:5, twice) to yield the title compound (5.6 mg, 60%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.09 (m, 2H), 0.43-0.49 (m, 2H), 0.67 (s, 3H), 0.85-0.93 (m, 1H), 0.99-1.03 (m, 1H), 1.25 (s, 3H), 1.36 (d, J=15 Hz, 1H), 1.72 (d, J=15 Hz, 1H), 1.86-1.92 (m, 1H), 1.97 (ddd, J=3, 12, 12 Hz, 1H), 2.08 (s, 3H), 2.14 (ddd, J=5, 12, 12 Hz, 1H), 2.28 (dd, J=5, 15 Hz, 1H), 2.34-2.40 (m, 3H), 2.55-2.65 (m, 3H), 2.76 (dd, J=12, 14 Hz, 1H), 2.95-2.99 (m, 2H), 3.04-3.11 (m, 1H), 4.04-4.17 (m, 2H), 4.74 (br s, 1H), 6.61 (d, J=2, 8 Hz, 1H), 6.71 (d, J=2 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 7.28 (s, 1H), 7.33 (s, 1H).

Reference Example 46
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-4,8a-dihydroxy-3-methoxy-7-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one

[Image Omitted]

To a solution of (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (synthesized by the method described in Organic Letters 2009, 11, 539) (1.50 g, 4.22 mmol) in tetrahydrofuran (37 mL) cooled to −78° C. was added a 1.08 M lithium bis(trimethylsilyl)amide-tetrahydrofuran solution (11.7 mL, 12.6 mmol), followed by stirring for 1 hour. To the reaction mixture, a solution of methyl iodide (1.58 mL, 25.4 mmol) in tetrahydrofuran (3 mL) was added, followed by stirring at −78° C. for 1 hour and at room temperature for 18 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (47 to 68% ethyl acetate/heptane). To a mixed solution of the obtained pale yellow crystals (460 mg) in chloroform/water (3:2, 2.5 mL), concentrated hydrochloric acid (1.5 mL) was added, followed by stirring at room temperature for 2.5 hours. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction twice with chloroform. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. To a solution of the obtained pale yellow oily matter (307 mg) in acetic acid (8 mL), zinc powder (550 mg) was added, followed by heating under reflux for 20.5 hours. After allowed to cool to room temperature, zinc powder (555 mg) was added again, followed by heating under reflux for 8.5 hours. After allowed to cool to room temperature, zinc powder (555 mg) was added again, followed by heating under reflux for 7 hours. The reaction mixture was allowed to cool to room temperature and then filtered through celite, and the filtrate was concentrated under reduced pressure. To the obtained residue, a saturated aqueous potassium carbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (20 to 100% ethyl acetate/heptane) to yield the title compound (219 mg, 14%) as a pale yellow crystal.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.10-0.14 (m, 2H), 0.51-0.55 (m, 2H), 0.83-0.89 (m, 1H), 0.88 (d, J=7 Hz, 3H), 1.63 (dd, J=13, 14 Hz, 1H), 1.87 (dd, J=6, 13 Hz, 1H), 1.98-2.13 (m, 3H), 2.32-2.41 (m, 2H), 2.58-2.62 (m, 1H), 2.81 (dd, J=7, 18 Hz, 1H), 2.89-3.01 (m, 3H), 3.09 (d, J=7 Hz, 1H), 3.82 (s, 3H), 3.93 (d, J=13 Hz, 1H), 6.10 (s, 1H), 6.54 (d, J=8 Hz, 1H), 6.65 (d, J=8 Hz, 1H).

Reference Example 47
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-yl trifluoromethanesulfonate

[Image Omitted]

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

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.11-0.15 (m, 2H), 0.53-0.57 (m, 2H), 0.83 (d, J=6 Hz, 3H), 0.83-0.90 (m, 1H), 1.44 (dd, J=14, 14 Hz, 1H), 1.65-1.69 (m, 1H), 1.89 (dd, J=7, 14 Hz, 1H), 2.09 (dd, J=3, 12 Hz, 1H), 2.21 (ddd, J=5, 13, 13 Hz, 1H), 2.38 (d, J=7 Hz, 2H), 2.67-2.71 (m, 1H), 2.85 (dd, J=7, 18 Hz, 1H), 2.87-2.96 (m, 1H), 3.04 (d, J=18 Hz, 1H), 3.13 (d, J=7 Hz, 1H), 3.14 (d, J=14 Hz, 1H), 3.53 (d, J=14 Hz, 1H), 3.80 (s, 3H), 6.83 (d, J=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H).

Reference Example 48
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one

[Image Omitted]

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

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.12-0.16 (m, 2H), 0.52-0.57 (m, 2H), 0.83-0.91 (m, 1H), 0.87 (d, J=6 Hz, 3H), 1.16-1.20 (m, 1H), 1.54 (dd, J=13, 13 Hz, 1H), 1.85 (dd, J=6, 13 Hz, 1H), 2.05-2.20 (m, 2H), 2.36-2.44 (m, 2H), 2.57-2.61 (m, 1H), 2.74 (dd, J=6, 18 Hz, 1H), 2.83 (d, J=14 Hz, 1H), 2.88-2.98 (m, 1H), 3.05 (d, J=18 Hz, 1H), 3.08 (dd, J=1, 14 Hz, 1H), 3.12 (d, J=6 Hz, 1H), 3.77 (s, 3H), 6.68 (dd, J=2, 8 Hz, 1H), 6.81 (d, J=2 Hz, 1H), 6.97 (d, J=8 Hz, 1H).

Reference Example 49
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one oxime

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 48 according to the method described in Reference Example 3.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.10-0.15 (m, 2H), 0.50-0.55 (m, 2H), 0.82-0.90 (m, 1H), 0.94 (d, J=6 Hz, 3H), 1.15-1.18 (m, 1H), 1.39 (dd, J=13, 13 Hz, 1H), 1.66 (dd, J=5, 13 Hz, 1H), 2.06-2.16 (m, 2H), 2.33 (d, J=14 Hz, 1H), 2.33-2.42 (m, 2H), 2.55-2.60 (m, 1H), 2.71 (dd, J=6, 18 Hz, 1H), 2.81-2.90 (m, 1H), 3.03 (d, J=6 Hz, 1H), 3.04 (d, J=18 Hz, 1H), 3.77 (s, 3H), 3.78 (d, J=14 Hz, 1H), 6.69 (dd, J=2, 8 Hz, 1H), 6.87 (br s, 1H), 6.95 (d, J=8 Hz, 1H), 7.11 (d, J=2 Hz, 1H).

Example 271
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-4-methyl-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 49 according to the method described in Example 1.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.10-0.13 (m, 2H), 0.50-0.55 (m, 2H), 0.78-0.88 (m, 1H), 1.09-1.14 (m, 1H), 1.11 (d, J=6 Hz, 3H), 1.48 (d, J=14 Hz, 1H), 1.68 (dd, J=10, 14 Hz, 1H), 2.03-2.11 (m, 2H), 2.35-2.37 (m, 2H), 2.56-2.63 (m, 2H), 2.75 (dd, J=6, 18 Hz, 1H), 2.90 (d, J=6 Hz, 1H), 3.01 (d, J=18 Hz, 1H), 3.50 (d, J=14 Hz, 1H), 3.80 (s, 3H), 4.06-4.15 (m, 1H), 5.23 (s, 1H), 6.71 (dd, J=2, 8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 7.15 (d, J=2 Hz, 1H).

Example 272
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-4-methyl-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 271 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.13 (m, 2H), 0.47-0.55 (m, 2H), 0.78-0.88 (m, 1H), 0.96 (d, J=7 Hz, 3H), 1.03-1.07 (m, 1H), 1.51-1.60 (m, 2H), 1.95-2.08 (m, 3H), 2.30-2.38 (m, 3H), 2.50-2.53 (m, 1H), 2.81 (dd, J=6, 18 Hz, 1H), 2.88-3.00 (m, 4H), 3.28-3.37 (m, 1H), 3.79 (s, 3H), 4.55 (br s, 1H), 6.71 (dd, J=3, 9 Hz, 1H), 6.72 (d, J=3 Hz, 1H), 7.02 (d, J=9 Hz, 1H).

Example 273
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-4-methyl-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 272 and the compound obtained in Reference Example 33 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.13 (m, 2H), 0.46-0.54 (m, 2H), 0.78-0.87 (m, 1H), 0.81 (d, J=6 Hz, 3H), 1.00-1.08 (m, 1H), 1.40 (dd, J=4, 15 Hz, 1H), 1.65 (dd, J=12, 15 Hz, 1H), 1.86 (dd, J=6, 16 Hz, 1H), 1.99-2.02 (m, 2H), 2.05 (s, 3H), 2.14 (dd, J=10, 16 Hz, 1H), 2.32 (dd, J=6, 13 Hz, 1H), 2.38 (dd, J=6, 13 Hz, 1H), 2.49-2.57 (m, 1H), 2.62 (dd, J=6, 15 Hz, 1H), 2.74 (dd, J=6, 18 Hz, 1H), 2.83-2.89 (m, 2H), 2.98 (d, J=19 Hz, 1H), 2.98-3.11 (m, 2H), 3.16-3.24 (m, 1H), 3.78 (s, 3H), 4.03-4.15 (m, 2H), 4.69 (br s, 1H), 6.67 (d, J=2 Hz, 1H), 6.71 (dd, J=2, 8 Hz, 1H), 7.01 (d, J=8 Hz, 1H), 7.19 (s, 1H), 7.28 (s, 1H).

Example 274
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-4-methyl-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 273 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.13 (m, 2H), 0.45-0.53 (m, 2H), 0.78-0.90 (m, 1H), 0.84 (d, J=6 Hz, 3H), 1.00-1.07 (m, 1H), 1.38 (dd, J=4, 15 Hz, 1H), 1.67 (dd, J=12, 15 Hz, 1H), 1.82 (dd, J=6, 15 Hz, 1H), 1.99-2.01 (m, 2H), 2.05 (s, 3H), 2.13 (dd, J=10, 15 Hz, 1H), 2.32 (dd, J=6, 12 Hz, 1H), 2.37 (dd, J=6, 12 Hz, 1H), 2.48-2.56 (m, 1H), 2.62 (dd, J=6, 15 Hz, 1H), 2.72 (dd, J=6, 18 Hz, 1H), 2.85 (d, J=19 Hz, 1H), 2.87 (d, J=13 Hz, 1H), 2.95 (d, J=19 Hz, 1H), 2.95-3.12 (m, 2H), 3.17-3.25 (m, 1H), 4.04-4.16 (m, 2H), 4.71 (br s, 1H), 6.61 (d, J=2 Hz, 1H), 6.64 (dd, J=2, 8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 7.19 (s, 1H), 7.30 (s, 1H).

Reference Example 50
Synthesis of (4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-1,2,3,4,4a,5,6,7-octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-8(8aH)-one

[Image Omitted]

To (4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-1,2,3,4,4a,5,6,7-octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-8(8aH)-one (synthesized by the method described in Journal of Medicinal Chemistry 2004, 47, 1070) (4.88 g, 15 mmol) suspended in polyphosphoric acid (100 mL) and then heated to an internal temperature of 60 to 80° C. was added azidotrimethylsilane (3.95 mL, 30 mmol), followed by stirring at an internal temperature of 60 to 80° C. for 30 minutes. Azidotrimethylsilane (7.89 mL, 60 mmol) was added at an internal temperature of 60 to 80° C., followed by stirring at an internal temperature of 60 to 80° C. for 2 hours. The reaction mixture was poured into an ice-cooled 28% aqueous ammonia solution (300 mL), and to the resultant solution, water (1.0 L) and chloroform (500 mL) were added, followed by stirring at room temperature for 18 hours. The mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0 to 10% 2 M ammonia-methanol solution/chloroform) to yield the title compound (2.63 g, 52%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.10-0.17 (m, 2H), 0.52-0.59 (m, 2H), 0.80-0.92 (m, 1H), 1.27-1.36 (m, 1H), 1.57-1.66 (m, 1H), 1.87-1.98 (m, 1H), 2.27-2.44 (m, 3H), 2.46 (ddd, J=6, 13, 13 Hz, 1H), 2.63-2.77 (m, 2H), 2.82-2.90 (m, 2H), 3.11 (d, J=7 Hz, 1H), 3.18 (d, J=19 Hz, 1H), 4.81 (d, J=2 Hz, 1H), 4.94 (br s, 1H), 5.93-6.02 (m, 1H), 6.66 (d, J=8 Hz, 1H), 6.71 (d, J=7 Hz, 1H), 7.12 (dd, J=8, 8 Hz, 1H).

Example 275
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,11-dihydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

To a solution of the compound (250 mg, 0.73 mmol) obtained in Reference Example 50 in ethylenediamine (10 mL) was added Sodium silica gel Stage I (1 g) under ice cooling, followed by stirring at room temperature for 1 hour. Tetrahydrofuran (100 mL) was added under ice cooling, and then water (150 mL) was slowly added at the same temperature, followed by stirring. The temperature of the mixture was returned to room temperature, and to the mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (50 to 100% ethyl acetate/heptane, 0 to 5% methanol/ethyl acetate) to yield the title compound (234 mg, 93%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.15 (m, 2H), 0.48-0.55 (m, 2H), 0.75-0.87 (m, 1H), 1.40-1.62 (m, 3H), 1.87-2.01 (m, 2H), 2.30 (dd, J=7, 13 Hz, 1H), 2.35 (dd, J=6, 12 Hz, 1H), 2.50-2.62 (m, 1H), 2.77-2.90 (m, 3H), 2.92-3.04 (m, 2H), 3.55 (d, J=14 Hz, 1H), 3.78-3.90 (m, 1H), 4.66 (br s, 1H), 6.71 (d, J=7 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 6.83-6.92 (m, 1H), 7.01 (dd, J=8, 8 Hz, 1H), 8.53 (br s, 1H).

Example 276
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,11(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 275 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.76-0.91 (m, 1H), 1.48-1.82 (m, 3H), 1.88-2.04 (m, 2H), 2.27-2.34 (m, 2H), 2.40-2.60 (m, 3H), 2.77-3.04 (m, 6H), 3.12-3.23 (m, 1H), 4.53 (br s, 1H), 5.93 (br s, 1H), 6.31 (d, J=8 Hz, 1H), 6.57 (d, J=7 Hz, 1H), 6.88 (dd, J=8, 8 Hz, 1H).

Example 277
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,11(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 276 and the compound obtained in Reference Example 33 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.76-0.91 (m, 1H), 1.18-2.07 (m, 5H), 2.00 (s, 3H), 2.24-2.64 (m, 6H), 2.74-3.00 (m, 7H), 3.32 (dd, J=12, 12 Hz, 1H), 3.98-4.16 (m, 2H), 4.61 (br s, 1H), 6.47 (d, J=8 Hz, 1H), 6.65 (d, J=7 Hz, 1H), 6.91 (s, 1H), 6.92 (dd, J=8, 8 Hz, 1H), 7.23 (s, 1H).

Example 278
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(pyridin-2-yl)acetyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-10-yl trifluoromethanesulfonate

[Image Omitted]

To the compound (26 mg, 0.058 mmol) obtained in Example 22 and N-phenylbis(trifluoromethanesulfonimide) (62 mg, 0.174 mmol) dissolved in dimethylformamide (1 mL) was added potassium carbonate (32 mg, 0.232 mmol), followed by stirring at room temperature for 16 hours under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate, and then washed with a saturated aqueous sodium bicarbonate solution and saturated saline. The obtained organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 1 to 20% methanol/chloroform) to yield the title compound (32 mg, 95%) as a yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.70-0.90 (m, 1H), 1.00-1.10 (m, 1H), 1.60-1.80 (m, 4H), 1.80-2.20 (m, 3H), 2.20-2.40 (m, 2H), 2.45-2.65 (m, 1H), 2.70-3.15 (m, 2.5H), 3.40-3.60 (m, 1.5H), 3.65-3.80 (m, 1H), 3.80-4.00 (m, 2.5H), 4.10-4.25 (m, 0.5H), 4.30-4.50 (m, 1H), 6.95-7.10 (m, 2H), 7.10-7.20 (m, 2.5H), 7.20-7.30 (m, 0.5H), 7.50-7.60 (m, 1H), 8.40-8.55 (m, 1H).

Example 279
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-(6-methoxypyridin-2-yl)-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

To the compound (16 mg, 0.028 mmol) obtained in Example 278, 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine (20 mg, 0.084 mmol) and tetrakis (triphenylphosphine)palladium (0) (6 mg, 0.0056 mmol) dissolved in toluene/ethanol (v/v=5/1, 0.6 mL) was added a 2 M aqueous sodium carbonate solution (168 μL, 0.336 mmol), followed by stirring at 100° C. for 16 hours under a nitrogen atmosphere. After allowed to cool to room temperature, the reaction solution was diluted with ethyl acetate, and then washed with a saturated aqueous sodium bicarbonate solution and saturated saline. The obtained organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (11 mg, 73%) as a yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.75-0.90 (m, 1H), 1.05-1.20 (m, 1H), 1.50-1.70 (m, 1.4H), 1.70-1.90 (m, 1.6H), 1.95-2.20 (m, 2H), 2.25-2.45 (m, 3H), 2.50-2.70 (m, 1.4H), 2.70-2.85 (m, 0.6H), 2.90-3.15 (m, 3H), 3.20-3.35 (m, 0.4H), 3.40-3.70 (m, 1H), 3.74 (d, J=16 Hz, 0.6H), 3.80-4.00 (m, 2.6H), 4.00 (s, 1.8H), 4.02 (s, 1.2H), 4.15-4.20 (m, 0.4H), 6.66 (d, J=8 Hz, 1H), 6.93 (d, J=8 Hz, 0.6H), 7.01 (dd, J=2, 3 Hz, 0.6H), 7.03 (dd, J=2, 3 Hz, 0.4H), 7.15-7.25 (m, 1.4H), 7.25-7.30 (m, 1H), 7.46 (dt, J=2, 7 Hz, 0.6H), 7.56 (dt, J=2, 7 Hz, 0.4H), 7.60-7.70 (m, 1H), 7.73 (dd, J=2, 8 Hz, 0.6H), 7.78 (dd, J=2, 8 Hz, 0.4H), 7.80-7.00 (m, 1H), 8.39 (dd, J=1, 4 Hz, 0.6H), 8.49 (dd, J=1, 4 Hz, 0.4H).

Example 280
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-4-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 272 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 5.

¹H-NMR (400 MHz, CD₃D) δ (ppm): 0.10-0.18 (m, 2H), 0.48-0.57 (m, 2H), 0.83-0.92 (m, 1H), 0.92 (d, J=6 Hz, 1.5H), 0.97 (d, J=6 Hz, 1.5H), 1.06-1.09 (m, 1H), 1.63-1.80 (m, 2H), 1.88-2.09 (m, 3H), 2.28 (dd, J=6, Hz, 0.5H), 2.33-2.46 (m, 2.5H), 2.52-2.58 (m, 1H), 2.62-2.68 (m, 0.5H), 2.80 (dd, J=6, 19 Hz, 1H), 2.92-3.10 (m, 2.5H), 3.76 (s, 3H), 3.90-4.12 (m, 3H), 4.27-4.37 (m, 0.5H), 4.58-4.66 (m, 0.5H), 6.75-6.78 (m, 2H), 7.08 (d, J=8 Hz, 1H), 7.23-7.32 (m, 1H), 7.43 (d, J=8 Hz, 0.5H), 7.45 (d, J=8 Hz, 0.5H), 7.77-7.81 (m, 1H), 8.45-8.49 (m, 1H).

Example 281
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-4-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 280 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.08-0.11 (m, 2H), 0.49-0.52 (m, 2H), 0.76-0.81 (m, 1.9H), 0.90 (d, J=6 Hz, 2.1H), 1.05-1.13 (m, 1H), 1.52-1.68 (m, 2H), 1.75-1.81 (m, 0.6H), 1.85-1.95 (m, 1H), 2.02-2.15 (m, 1.4H), 2.29-2.39 (m, 3H), 2.47-2.51 (m, 1H), 2.65-2.75 (m, 1.6H), 2.83-3.02 (m, 2.4H), 3.79 (dd, J=6, 16 Hz, 0.3H), 3.86 (d, J=15 Hz, 0.3H), 3.98-4.20 (m, 2.4H), 4.35-4.41 (m, 0.7H), 4.67-4.73 (m, 0.3H), 6.61-6.69 (m, 1.3H), 6.91 (d, J=8 Hz, 0.3H), 6.94 (d, J=8 Hz, 0.7H), 7.02-7.03 (m, 0.7H), 7.15-7.22 (m, 1H), 7.45 (d, J=8 Hz, 0.7H), 7.49 (d, J=8 Hz, 0.3H), 7.64-7.71 (m, 1H), 8.52 (d, J=4 Hz, 0.3H), 8.55 (d, J=4 Hz, 0.7H).

Reference Example 51
Synthesis of (4R,4aS,8aR,13bS)-3-(cyclopropylmethyl)-4a-hydroxy-10-methoxy-1,2,3,4,4a,5,6,7-octahydro-4,13-methanobenzofuro[2,3-c]pyrido[4,3-d]azepin-8(8aH)-one

[Image Omitted]

To (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (synthesized by the method described in Organic Letters 2009, 11, 539) (5.00 g, 14 mmol) suspended in polyphosphoric acid (100 mL) and then heated to an internal temperature of 60 to 80° C. was added azidotrimethylsilane (5.55 mL, 42 mmol), followed by stirring at an internal temperature of 60 to 80° C. for 30 minutes. Azidotrimethylsilane (5.55 mL, 42 mmol) was added at an internal temperature of 60 to 80° C., followed by stirring at an internal temperature of 60 to 80° C. for 90 minutes. The reaction mixture was poured into an ice-cooled 28% aqueous ammonia solution (500 mL), and to the resultant solution, chloroform (500 mL) was added, followed by stirring at room temperature for 3 hours. The mixture was separated and then extracted twice with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 10% methanol/chloroform) to yield the title compound (2.86 mg, 55%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.09-0.17 (m, 2H), 0.51-0.57 (m, 2H), 0.80-0.91 (m, 1H), 1.28-1.36 (m, 1H), 1.59-1.67 (m, 1H), 1.92 (ddd, J=6, 14, 14 Hz, 1H), 2.28-2.42 (m, 3H), 2.46 (ddd, J=6, 13, 13 Hz, 1H), 2.64 (dd, J=7, 19 Hz, 1H), 2.72 (dd, J=5, 11 Hz, 1H), 2.80-2.99 (m, 2H), 3.06-3.17 (m, 2H), 3.89 (s, 3H), 4.86 (s, 1H), 4.95 (br s, 1H), 5.95 (t, J=7 Hz, 1H), 6.66 (d, J=8 Hz, 1H), 6.78 (d, J=8 Hz, 1H).

Example 282
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,11-dihydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 51 according to the method described in Example 275.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.15 (m, 2H), 0.47-0.55 (m, 2H), 0.75-0.88 (m, 1H), 1.43-1.71 (m, 2H), 1.80-2.05 (m, 3H), 2.32 (dd, J=6, 13 Hz, 1H), 2.34 (dd, J=6, 13 Hz, 1H), 2.54-2.63 (m, 1H), 2.80-3.00 (m, 4H), 3.15 (dd, J=2, 14 Hz, 1H), 3.52 (d, J=14 Hz, 1H), 3.81 (s, 3H), 3.84-3.96 (m, 1H), 4.63 (s, 1H), 5.85 (br s, 1H), 6.66 (d, J=8 Hz, 1H), 6.72 (d, J=8 Hz, 1H).

Example 283
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,11(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 282 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.14 (m, 2H), 0.45-0.54 (m, 2H), 0.76-0.89 (m, 1H), 1.44-1.80 (m, 3H), 1.86-2.04 (m, 2H), 2.26-2.58 (m, 5H), 2.72-2.80 (m, 1H), 2.87-3.02 (m, 5H), 3.10-3.20 (m, 1H), 3.86 (s, 3H), 4.47 (br s, 1H), 6.59 (d, J=8 Hz, 1H), 6.69 (d, J=8 Hz, 1H).

Example 284
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,11(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 283 and the compound obtained in Reference Example 33 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.15 (m, 2H), 0.45-0.53 (m, 2H), 0.76-0.88 (m, 1H), 1.38-1.50 (m, 2H), 1.79-2.02 (m, 3H), 1.99 (s, 3H), 2.24-2.58 (m, 6H), 2.68-2.96 (m, 7H), 3.27 (dd, J=11, 13 Hz, 1H), 3.84 (s, 3H), 3.92-4.06 (m, 2H), 4.54 (br s, 1H), 5.89 (s, 1H), 6.60 (d, J=9 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 6.82 (s, 1H), 7.20 (s, 1H).

38/38H

Example 285
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-11-phenoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To the compound (23.3 mg, 0.050 mmol) obtained in Example 284, a copper powder (9.5 mg, 0.15 mmol) and potassium carbonate (34.6 mg, 0.25 mmol) suspended in pyridine (2 mL), bromobenzene (26.2 μL, 0.25 mmol) was added, followed by heating under reflux for 18 hours. After allowed to cool, to the reaction mixture was added a saturated sodium bicarbonate aqueous solution, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in methanol (2 mL) was added sodium borohydride (18.9 mg, 0.50 mmol), followed by stirring at room temperature for 30 minutes. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in chloroform (2 mL) was added a 1 M boron tribromide-dichloromethane solution (0.5 mL, 0.5 mmol) under ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture, a 28% aqueous ammonia solution was added under ice cooling, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (2.4 mg, 9%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.12 (m, 2H), 0.44-0.52 (m, 2H), 0.73-0.92 (m, 2H), 1.22-1.86 (m, 5H), 1.92-2.10 (m, 2H), 2.02 (s, 3H), 2.26-2.51 (m, 4H), 2.68-3.21 (m, 7H), 3.95-4.01 (m, 2H), 6.65-6.73 (m, 2H), 6.84 (s, 1H), 6.88 (d, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 7.01 (t, J=7 Hz, 1H), 7.22 (s, 1H), 7.24-7.29 (m, 2H).

Reference Example 52
Synthesis of (4bR,8aS,9R)-3-(benzyloxy)-11-(cyclopropylmethyl)-8a-hydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one oxime

[Image Omitted]

The title compound was obtained from (4bR,8aS,9R)-3-(benzyloxy)-11-(cyclopropylmethyl)-8a-hydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one (synthesized by the method described in WO 2015097545) according to the method described in Reference Example 3.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.79-0.93 (m, 1H), 1.07-1.20 (m, 1H), 1.54-1.65 (m, 2H), 2.07-2.24 (m, 3H), 2.31-2.45 (m, 2.7H), 2.54-2.66 (m, 1.7H), 2.68-2.80 (m, 0.6H), 2.72 (dd, J=7, 19 Hz, 1H), 2.98-3.11 (m, 2.3H), 3.70 (d, J=14 Hz, 0.7H), 5.02 (s, 0.6H), 5.04 (s, 1.4H), 6.76 (dd, J=3, 8 Hz, 0.3H), 6.77 (dd, J=3, 8 Hz, 0.7H), 6.92 (d, J=3 Hz, 0.3H), 6.96 (d, J=8 Hz, 0.7H), 6.97 (d, J=8 Hz, 0.3H), 7.17 (d, J=3 Hz, 0.7H), 7.24-7.45 (m, 5H).

Example 286
Synthesis of (5aS,6R,11bR)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one (isomer O) and (5aS,6R,11bS)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepin-3(4H)-one (isomer P)

[Image Omitted]

A mixture of the title isomers 0 and P was obtained from the compound obtained in Reference Example 52 according to the method described in Example 1.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.18 (m, 2H), 0.45-0.59 (m, 2H), 0.76-0.89 (m, 1H), 0.90-0.97 (m, 0.3H), 1.04-1.15 (m, 0.7H), 1.54-1.59 (m, 1H), 1.75-1.84 (m, 0.3H), 1.79 (ddd, J=2, 11, 14 Hz, 0.7H), 1.92-2.21 (m, 2.3H), 2.29-2.41 (m, 2H), 2.52-2.64 (m, 1.7H), 2.72-2.81 (m, 0.3H), 2.76 (dd, J=6, 19 Hz, 0.7H), 2.84-2.94 (m, 1H), 2.92 (d, J=6 Hz, 0.7H), 2.95-3.05 (m, 0.6H), 3.02 (d, J=19 Hz, 0.7H), 3.11-3.20 (m, 0.3H), 3.51 (d, J=14 Hz, 0.7H), 3.87 (ddd, J=4, 12, 15 Hz, 0.7H), 4.08 (dd, J=6, 16 Hz, 0.3H), 5.01 (d, J=11 Hz, 0.3H), 5.03 (d, J=11 Hz, 0.3H), 5.06 (d, J=12 Hz, 0.7H), 5.06 (d, J=12 Hz, 0.7H), 5.57-5.63 (m, 0.3H), 5.66-5.73 (m, 0.7H), 6.53 (d, J=3 Hz, 0.3H), 6.76-6.80 (m, 0.3H), 6.78 (dd, J=2, 8 Hz, 0.7H), 6.97 (d, J=8 Hz, 0.7H), 7.01 (d, J=8 Hz, 0.3H), 7.25-7.26 (m, 0.7H), 7.27-7.49 (m, 5H).

Example 287
Synthesis of (5aS,6R,11bS)-10-(benzyloxy)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol (isomer Q) and (5aS,6R,11bS)-10-(benzyloxy)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepin-5a(1H)-ol (isomer R)

[Image Omitted]

The title isomers Q and R were individually obtained from the compound obtained in Example 286 according to the method described in Example 2.

(Isomer Q)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.44-0.56 (m, 2H), 0.78-0.89 (m, 1H), 1.00-1.12 (m, 1H), 1.56 (ddd, J=3, 3, 14 Hz, 1H), 1.73 (ddd, J=4, 12, Hz, 1H), 1.95 (ddd, J=3, 3, 15 Hz, 1H), 1.99-2.07 (m, 2H), 2.28 (ddd, J=5, 12, 16 Hz, 1H), 2.34 (dd, J=7, 13 Hz, 1H), 2.34 (dd, J=7, 13 Hz, 1H), 2.47-2.59 (m, 1H), 2.71-2.85 (m, 3H), 2.91 (ddd, J=4, 4, 14 Hz, 1H), 2.92 (d, J=7 Hz, 1H), 2.99 (d, J=18 Hz, 1H) 3.08 (ddd, J=3, 12, 14 Hz, 1H), 4.06 (br s, 1H), 5.02 (d, J=12 Hz, 1H), 5.03 (d, J=12 Hz, 1H), 6.76 (d, J=3 Hz, 1H), 6.79 (dd, J=3, 8 Hz, 1H), 7.02 (d, J=8 Hz, 1H), 7.29-7.44 (m, 5H).

(Isomer R)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.45-0.55 (m, 2H), 0.78-0.90 (m, 1H), 0.92-0.97 (m, 1H), 1.47-1.67 (m, 2H), 1.90 (ddd, J=5, 13, 13 Hz, 1H), 1.94-2.06 (m, 2H), 2.19-2.32 (m, 1H), 2.33 (dd, J=6, 13 Hz, 1H), 2.38 (dd, J=6, 13 Hz, 1H), 2.54-2.60 (m, 1H), 2.67 (ddd, J=7, 9, 14 Hz, 1H), 2.80 (dd, J=6, 18 Hz, 1H), 2.90 (d, J=6 Hz, 1H), 2.92-3.01 (m, 1H), 2.98 (d, J=18 Hz, 1H), 3.13 (d, J=15 Hz, 1H), 3.16 (d, J=Hz, 1H), 4.64 (br s, 1H), 5.03 (d, J=12 Hz, 1H), 5.04 (d, J=12 Hz, 1H), 6.80 (dd, J=3, 8 Hz, 1H), 6.83 (d, J=3 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 7.29-7.46 (m, 5H).

Example 288
Synthesis of tert-butyl (5aS,6R,11bR)-10-(benzyloxy)-9-bromo-14-(cyclopropylmethyl)-5a-hydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

The isomer Q (151 mg, 0.361 mmol) obtained in Example 287 was suspended in water (2.0 mL), and dissolved by adding trifluoroacetic acid (400 μL, 5.23 mmol). After cooled to 0° C., N-bromosuccinimide (129 mg, 0.724 mmol) was added, followed by stirring at 0° C. for 17 hours. To the reaction mixture, a mixed solution of 2 M aqueous sodium hydroxide solution/saturated aqueous sodium thiosulfate solution=4/1 (v/v) (3 mL) and water (2 mL) were added, followed by extraction five times with a mixed solution of chloroform/isopropanol=4/1 (v/v). The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure.

To a solution of the obtained crude product in chloroform (1.5 mL) were added triethylamine (250 μL, 1.79 mmol) and di-tert-butyl dicarbonate (170 μL, 0.740 mmol) at 0° C., followed by stirring at room temperature for 1.5 hours. After cooled to 0° C., to the reaction mixture were added a saturated aqueous sodium bicarbonate solution (1 mL) and water (2 mL), followed by extraction three times with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0 to 5% methanol/ethyl acetate) to yield the title compound (119 mg, 55%) as a pale yellow amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.43-0.58 (m, 2H), 0.75-0.86 (m, 1H), 0.90-0.99 (m, 1H), 1.29 (s, 4.5H), 1.31 (s, 4.5H), 1.43-1.60 (m, 2H), 1.74-2.10 (m, 3H), 2.28 (dd, J=6, 12 Hz, 0.5H), 2.30-2.41 (m, 2H), 2.45-2.59 (m, 1.5H), 2.73-2.85 (m, 1H), 2.87-2.95 (m, 1.5H), 2.96 (d, J=18 Hz, 0.5H), 3.27-3.42 (m, 2H), 3.46-3.61 (m, 2H), 5.10 (d, J=12 Hz, 0.5H), 5.12 (d, J=12 Hz, 0.5H), 5.16 (d, J=12 Hz, 0.5H), 5.20 (d, J=12 Hz, 0.5H), 6.66 (s, 0.5H), 6.69 (s, 0.5H), 7.27 (s, 1H), 7.29-7.51 (m, 5H).

Example 289
Synthesis of tert-butyl (5aS,6R,11bR)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

The title compound was obtained from the compound obtained in Example 288 according to the method described in Example 260.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.16 (m, 2H), 0.44-0.55 (m, 2H), 0.75-0.89 (m, 1H), 0.96-1.03 (m, 1H), 1.27 (s, 4.5H), 1.34 (s, 4.5H), 1.42-1.64 (m, 1H), 1.78-2.09 (m, 4H), 2.20 (s, 3H), 2.24-2.40 (m, 2.5H), 2.43-2.57 (m, 1.5H), 2.70-2.83 (m, 1H), 2.85-3.00 (m, 2H), 3.22-3.45 (m, 2H), 3.50-3.69 (m, 2H), 4.50 (br s, 1H), 5.02 (d, J=12 Hz, 0.5H), 5.05 (d, J=12 Hz, 0.5H), 5.07 (s, 1H), 6.59 (s, 0.5H), 6.61 (s, 0.5H), 6.85 (s, 0.5H), 6.86 (s, 0.5H), 7.27-7.47 (m, 5H).

Example 290
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-9-methyl-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To a solution of the compound (88.1 mg, 0.165 mmol) obtained in Example 289 in methanol (1.5 mL) was added 20% palladium hydroxide-activated carbon (50% wet) (24.4 mg, 10 mol %), followed by stirring under a hydrogen atmosphere at room temperature for 17 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.

To a solution of the obtained crude product in chloroform (2.0 mL) was added trifluoroacetic acid (0.30 mL) at 0° C., followed by stirring at room temperature for 1 hour. After cooled to 0° C., to the reaction mixture were added a 2 M aqueous sodium hydroxide solution (3 mL) and water (2 mL), followed by extraction ten times with chloroform/methanol=10/1 (v/v) and three times with chloroform/isopropanol=4/1 (v/v). The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 30 to 55% methanol/ethyl acetate) to yield the title compound (45.3 mg, 80%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.42-0.57 (m, 2H), 0.77-0.88 (m, 1H), 1.03-1.11 (m, 1H), 1.48 (ddd, J=3, 3, 15 Hz, 1H), 1.79 (ddd, J=5, 12, Hz, 1H), 1.94 (ddd, J=5, 13, 13 Hz, 1H), 2.03-2.16 (m, 3H), 2.14 (s, 3H), 2.34 (d, J=6 Hz, 2H), 2.48-2.56 (m, 1H), 2.70 (dd, J=6, 18 Hz, 1H), 2.74-2.82 (m, 2H), 2.87 (d, J=6 Hz, 1H), 3.03-3.12 (m, 1H), 3.08 (d, J=18 Hz, 1H), 3.19 (ddd, J=3, 3, 13 Hz, 1H), 4.57 (br s, 1H), 5.69 (br s, 1H), 6.48 (s, 1H), 6.80 (s, 1H).

Example 291
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 290 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.16 (m, 2H), 0.44-0.55 (m, 2H), 0.75-0.87 (m, 1H), 0.99-1.12 (m, 1H), 1.49-1.61 (m, 1H), 1.76-2.09 (m, 4H), 2.15-2.22 (m, 0.5H), 2.16 (s, 1.5H), 2.17 (s, 1.5H), 2.25-2.39 (m, 2H), 2.47-2.58 (m, 1.5H), 2.65 (dd, J=6, 18 Hz, 0.5H), 2.73 (dd, J=7, 18 Hz, 0.5H), 2.83 (d, J=6 Hz, 0.5H), 2.89 (d, J=7 Hz, 0.5H), 2.90 (d, J=18 Hz, 0.5H), 2.94 (d, J=18 Hz, 0.5H), 3.12-3.21 (m, 0.5H), 3.25-3.34 (m, 1H), 3.44 (ddd, J=4, 4, 13 Hz, 0.5H), 3.71 (d, J=15 Hz, 0.5H), 3.74 (d, J=15 Hz, 0.5H), 3.78-3.98 (m, 1.5H), 3.90 (d, J=15 Hz, 0.5H), 3.95 (d, J=15 Hz, 0.5H), 4.14-4.22 (m, 0.5H), 4.42 (br s, 0.5H), 4.51 (br s, 0.5H), 6.66 (s, 0.5H), 6.77 (s, 0.5H), 6.79 (s, 0.5H), 6.79 (s, 0.5H), 7.11-7.19 (m, 1H), 7.21-7.25 (m, 1H), 7.59 (ddd, J=2, 8, 8 Hz, 0.5H), 7.61 (ddd, J=2, 8, 8 Hz, 0.5H), 8.45-8.51 (m, 1H).

Example 292
Synthesis of tert-butyl (5aS,6R,11bR)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-9-iodo-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

The title compound was obtained from the isomer Q obtained in Example 287 and N-iodosuccinimide according to the method described in Example 288.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.12 (m, 2H), 0.47-0.54 (m, 2H), 0.75-0.85 (m, 1H), 0.85-0.99 (m, 1H), 1.27 (s, 5H), 1.31 (s, 4H), 1.41-1.56 (m, 1H), 1.71-2.12 (m, 4H), 2.23-2.41 (m, 2.5H), 2.45-2.58 (m, 1.5H), 2.69-2.85 (m, 1H), 2.86-3.00 (m, 2H), 3.25-3.65 (m, 4H), 4.45 (br s, 1H), 5.00-5.24 (m, 2H), 6.58 (s, 0.5H), 6.61 (s, 0.5H), 7.28-7.35 (m, 1H), 7.35-7.45 (m, 2H), 7.46-7.55 (m, 3H).

Example 293
Synthesis of 3-(tert-butyl) 9-(2,4,6-trichlorophenyl) (5aS,6R,11bR)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3,9(4H)-dicarboxylate

[Image Omitted]

To the compound (40.0 mg, 0.062 mmol) obtained in Example 292 dissolved in toluene (1 mL) were added triethylamine (18.0 μL, 0.12 mmol), 2,4,6-trichlorophenyl formate, Xantphos (14.4 mg, 0.025 mmol), and palladium acetate (2.8 mg, 0.012 mmol), followed by stirring at room temperature for 16 hours. To the reaction solution, a saturated aqueous sodium bicarbonate solution was added, followed by extraction 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 preparative thin layer chromatography (chloroform:methanol=20:1) to yield the title compound (25.6 mg, 56%) as a brown amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.16 (m, 2H), 0.49-0.56 (m, 2H), 0.77-0.90 (m, 1H), 0.97-1.06 (m, 1H), 1.27 (s, 4.5H), 1.29 (s, 4.5H), 1.50-1.66 (m, 1H), 1.75-2.20 (m, 4H), 2.27-2.53 (m, 2.5H), 2.54-2.68 (m, 1.5H), 2.83-2.97 (m, 1H), 2.98-3.12 (m, 2H), 3.26-3.64 (m, 3.5H), 3.73 (ddd, J=4, 14, 14 Hz, 0.5H), 5.17 (d, J=12 Hz, 0.5H), 5.23 (d, J=12 Hz, 0.5H), 5.25 (d, J=12 Hz, 0.5H), 5.32 (d, J=12 Hz, 0.5H), 6.83 (s, 0.5H), 6.86 (s, 0.5H), 7.25-7.31 (m, 1H), 7.31-7.38 (m, 2H), 7.40 (s, 2H), 7.46-7.52 (m, 2H), 7.85 (s, 0.5H), 7.86 (s, 0.5H).

Example 294
Synthesis of tert-butyl (5aS,6R,11bR)-10-(benzyloxy)-9-carbamoyl-14-(cyclopropylmethyl)-5a-hydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

To the compound (62.9 mg, 0.098 mmol) obtained in Example 292 dissolved in toluene (2 mL) were added triethylamine (27 μL, 0.20 mmol), 2,4,6-trichlorophenyl formate (44 mg, 0.20 mmol), Xantphos (22.6 mg, 0.039 mmol), and palladium acetate (4.4 mg, 0.020 mmol), followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (70 to 100% ethyl acetate/heptane) to yield a mixture (58.8 mg) of the title compound and the raw material compound (compound described in Example 292) as a brown amorphous form.

To this mixture dissolved in tetrahydrofuran (1 mL), a 28% aqueous ammonia solution (1 mL) was added, followed by stirring at 45° C. for 1 hour. To the reaction solution, a saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:methanol=20:1) to individually yield the title compound (19.5 mg, 36%) and a raw material compound (compound described in Example 292) (32.3 mg, 51%) as colorless amorphous forms.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.15 (m, 2H), 0.45-0.57 (m, 2H), 0.76-0.89 (m, 1H), 0.95-1.05 (m, 1H), 1.25 (s, 6.3H), 1.30 (s, 2.7H), 1.51 (ddd, J=3, 3, Hz, 0.7H), 1.57-1.64 (m, 0.3H), 1.71-2.14 (m, 5H), 2.23-2.42 (m, 2H), 2.46-2.61 (m, 2H), 2.79-3.11 (m, 3H), 3.31-3.49 (m, 2.7H), 3.51-3.76 (m, 1.3H), 5.14 (d, J=11 Hz, 0.3H), 5.18 (d, J=11 Hz, 0.3H), 5.23 (d, J=11 Hz, 0.7H), 5.33 (d, J=11 Hz, 0.7H), 5.63-5.75 (m, 1H), 6.79 (s, 0.3H), 6.82 (s, 0.7H), 7.34-7.49 (m, 5H), 7.66-7.77 (m, 1H), 7.93 (s, 0.7H), 7.95 (s, 0.3H).

Example 295
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-5a,10-dihydroxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-9-carboxamide

[Image Omitted]

To the compound (19 mg, 0.034 mmol) obtained in Example 294 dissolved in methanol (5 mL), 20% palladium hydroxide-activated carbon (50% wet, 24 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 21 hours. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. To the obtained concentrated residue dissolved in chloroform (2 mL), trifluoroacetic acid (0.4 mL) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the obtained concentrated residue dissolved in acetonitrile (2 mL) were added N,N-diisopropylethylamine (35.4 μL, 0.20 mmol) and the compound (10.4 mg, 0.051 mmol) obtained in Reference Example 33, followed by stirring at 60° C. for 13 hours. To the reaction solution, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:10% aqueous ammonia-methanol solution=20:1) to yield the title compound (8.2 mg, 51%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.12 (m, 2H), 0.48-0.55 (m, 2H), 0.77-0.89 (m, 1H), 1.01-1.08 (m, 1H), 1.48 (ddd, J=2, 4, 14 Hz, 1H), 1.70 (ddd, J=3, 11, 14 Hz, 1H), 1.85 (ddd, J=3, 3, 16 Hz, 1H), 1.92-2.01 (m, 1H), 1.99 (s, 3H), 2.08 (ddd, J=4, 13, 13 Hz, 1H), 2.35 (d, J=6 Hz, 2H), 2.36-2.47 (m, 2H), 2.53-2.60 (m, 1H), 2.63 (ddd, J=4, 4, 13 Hz, 1H), 2.74-2.88 (m, 3H), 2.89-3.02 (m, 3H), 3.07-3.18 (m, 1H), 3.90-4.06 (m, 2H), 6.80 (s, 1H), 6.85 (s, 1H), 7.15 (s, 1H), 7.21 (s, 1H).

Example 296
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-iodo-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 140 and N-iodosuccinimide according to the methods described in Example 6 and Example 259.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.70-0.90 (m, 1H), 0.95-1.10 (m, 1H), 1.50-2.20 (m, 4H), 2.20-2.40 (m, 2H), 2.40-2.65 (m, 2H), 2.65-2.80 (m, 1H), 2.80-3.00 (m, 3H), 3.40-3.60 (m, 1H), 3.70-3.90 (m, 1H), 6.14 (br s, 0.1H), 6.39 (br s, 0.9H), 6.98 (s, 0.1H), 7.10 (s, 0.9H), 7.36 (s, 0.9H), 7.45 (s, 0.1H), 8.94 (br s, 1H).

Example 297
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-9-iodo-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 296 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.70-0.85 (m, 1H), 1.00-1.10 (m, 1H), 1.30-1.50 (m, 1H), 1.50-1.65 (m, 2H), 1.65-1.90 (m, 1H), 1.90-2.25 (m, 4H), 2.25-2.40 (m, 2H), 2.45-2.60 (m, 1H), 2.65-3.40 (m, 5H), 6.63 (s, 1H), 7.42 (s, 1H).

Example 298
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-9-iodo-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 297 and the compound obtained in Reference Example 33 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.16 (m, 2H), 0.44-0.56 (m, 2H), 0.76-0.88 (m, 1H), 0.95-1.03 (m, 1H), 1.42-1.50 (m, 1H), 1.69-1.81 (m, 2H), 1.92-2.09 (m, 2H), 2.02 (s, 3H), 2.28-2.42 (m, 3H), 2.47-2.57 (m, 2H), 2.60 (ddd, J=4, 4, 13 Hz, 1H), 2.76 (dd, J=6, 18 Hz, 1H), 2.82-2.98 (m, 5H), 3.11-3.20 (m, 1H), 3.98-4.10 (m, 2H), 6.67 (s, 1H), 6.90 (s, 1H), 7.23 (s, 1H), 7.41 (s, 1H).

Example 299
Synthesis of tert-butyl (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-(6-oxo-1,6-dihydropyridin-2-yl)-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

The title compound was obtained from the compound obtained in Example 240 and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridin-2(1H)-one according to the method described in Example 279.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.50-0.70 (m, 2H), 0.80-1.00 (m, 1H), 1.08 (s, 6.3H), 1.16 (s, 2.7H), 1.40-2.20 (m, 10H), 2.30-2.40 (m, 2H), 2.50-2.65 (m, 1H), 2.80-3.10 (m, 1.7H), 3.10-3.30 (m, 1.3H), 3.30-3.40 (m, 0.3H), 3.50-3.60 (m, 0.7H), 4.25-4.40 (m, 1H), 6.20-6.35 (m, 1H), 6.50-6.65 (m, 2H), 7.10-7.30 (m, 2H), 7.30-7.40 (m, 1H).

Example 300
Synthesis of 6-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(pyridin-2-yl)acetyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-10-yl)pyridin-2(1H)-one

[Image Omitted]

To the compound (11 mg, 0.022 mmol) obtained in Example 299 was added 2 M hydrochloric acid (1 mL), followed by stirring at room temperature for 3 hours. The reaction solution was neutralized with a 1 M aqueous sodium hydroxide solution under ice cooling, and then the aqueous layer was extracted three times with chloroform. The obtained organic layer was dried over sodium sulfate and then concentrated under reduced pressure. To a solution of the obtained crude product in N,N-dimethylformamide (0.5 mL) were added 2-(pyridin-2-yl)acetic acid hydrochloride (5 mg, 0.033 mmol), N,N-diisopropylethylamine (15 μL, 0.088 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (9 mg, 0.023 mmol), followed by stirring at room temperature for 16 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (1.0 mg, 8%) as a pale yellow oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.30 (m, 2H), 0.50-0.70 (m, 2H), 0.80-1.00 (m, 1H), 1.00-1.90 (m, 5H), 1.90-2.20 (m, 2.5H), 2.20-2.50 (m, 2.5H), 2.50-2.80 (m, 2H), 2.80-3.20 (m, 3H), 3.20-3.80 (m, 4H), 3.80-4.00 (m, 1H), 4.20-4.50 (m, 1H), 6.31 (d, J=7 Hz, 0.5H), 6.40-6.60 (m, 1.5H), 7.00-7.30 (m, 4H), 7.30-7.55 (m, 2.5H), 7.60 (dt, J=2, 8 Hz, 0.5H), 8.35-8.45 (m, 0.5H), 8.75-8.80 (m, 0.5H).

Example 301
Synthesis of tert-butyl (5aS,6R,11bR)-10-(benzyloxy)-9-cyclopropyl-14-(cyclopropylmethyl)-5a-hydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

The title compound was obtained from the compound obtained in Example 288 and cyclopropylboronic acid according to the method described in Example 260.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.13 (m, 2H), 0.46-0.60 (m, 3H), 0.63-0.72 (m, 1H), 0.76-0.91 (m, 3H), 0.94-1.02 (m, 1H), 1.28 (s, 4.5H), 1.33 (s, 4.5H), 1.42-1.50 (m, 0.5H), 1.76-1.89 (m, 1.5H), 1.90-2.09 (m, 3H), 2.13-2.23 (m, 1H), 2.24-2.39 (m, 2.5H), 2.42-2.57 (m, 1.5H), 2.68-2.81 (m, 1H), 2.84-2.92 (m, 1.5H), 2.93 (d, J=18 Hz, 0.5H), 3.24-3.45 (m, 2H), 3.49-3.67 (m, 2H), 4.48 (br s, 1H), 5.05 (d, J=11 Hz, 0.5H), 5.08 (d, J=11 Hz, 0.5H), 5.11 (s, 1H), 6.52 (s, 0.5H), 6.53 (s, 0.5H), 6.61 (s, 0.5H), 6.63 (s, 0.5H), 7.28-7.51 (m, 5H).

Example 302
Synthesis of (5aS,6R,11bS)-9-cyclopropyl-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 301 according to the method described in Example 290.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.16 (m, 2H), 0.47-0.54 (m, 2H), 0.56-0.67 (m, 2H), 0.77-0.97 (m, 3H), 1.02-1.11 (m, 1H), 1.49 (ddd, J=3, 3, 15 Hz, 1H), 1.77 (ddd, J=5, 12, 15 Hz, 1H), 1.95 (ddd, J=5, 12, 12 Hz, 1H), 1.99-2.21 (m, 4H), 2.33 (d, J=6 Hz, 2H), 2.47-2.56 (m, 1H), 2.69 (dd, J=6, 18 Hz, 1H), 2.72-2.85 (m, 2H), 2.89 (d, J=6 Hz, 1H), 2.92 (d, J=18 Hz, 1H), 3.06 (ddd, J=4, 4, 14 Hz, 1H), 3.17 (ddd, J=3, 13, 13 Hz, 1H), 4.50 (br s, 1H), 6.54 (s, 1H), 6.55 (s, 1H).

Example 303
Synthesis of 1-((5aS,6R,11bR)-9-cyclopropyl-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 302 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.44-0.54 (m, 2H), 0.55-0.70 (m, 2H), 0.75-0.98 (m, 3H), 0.99-1.09 (m, 1H), 1.49-1.62 (m, 1H), 1.74-2.06 (m, 4.6H), 2.08-2.26 (m, 1H), 2.27-2.38 (m, 0.8H), 2.30 (dd, J=7, 13 Hz, 0.6H), 2.34 (dd, J=6, 13 Hz, 0.6H), 2.44-2.56 (m, 1.6H), 2.64 (dd, J=6, 18 Hz, 0.4H), 2.73 (dd, J=6, 18 Hz, 0.6H), 2.82 (d, J=6 Hz, 0.4H), 2.89 (d, J=18 Hz, 0.6H), 2.89 (d, J=6 Hz, 0.6H), 2.92 (d, J=18 Hz, 0.4H), 3.12-3.22 (m, 0.4H), 3.31-3.41 (m, 1H), 3.45 (ddd, J=4, 4, 14 Hz, 0.4H), 3.68 (d, J=15 Hz, 0.6H), 3.73-3.82 (m, 0.4H), 3.78 (d, J=15 Hz, 0.6H), 3.84-3.95 (m, 1.2H), 3.90 (s, 0.8H), 4.09-4.17 (m, 0.4H), 4.43 (br s, 0.4H), 4.52 (br s, 0.6H), 6.64 (s, 0.4H), 6.65 (s, 0.6H), 6.71 (s, 0.6H), 6.72 (s, 0.4H), 7.11-7.17 (m, 1H), 7.20 (d, J=8 Hz, 0.6H), 7.22 (d, J=8 Hz, 0.4H), 7.58 (ddd, J=2, 8, 8 Hz, 0.4H), 7.60 (ddd, J=2, 8, 8 Hz, 0.6H), 8.46-8.50 (m, 1H).

Example 304
Synthesis of (5aS,6R,11bS)-9-cyclopropyl-14-(cyclopropylmethyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 302 and the compound obtained in Reference Example 33 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.02-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.58-0.67 (m, 2H), 0.76-1.05 (m, 4H), 1.41 (ddd, J=2, 5, 14 Hz, 1H), 1.75 (ddd, J=3, 11, 14 Hz, 1H), 1.77-1.86 (m, 2H), 1.94-2.08 (m, 2H), 2.00 (s, 3H), 2.29-2.39 (m, 1H), 2.33 (d, J=7 Hz, 2H), 2.44 (ddd, J=4, 4, 13 Hz, 1H), 2.49-2.54 (m, 1H), 2.61 (ddd, J=4, 4, 13 Hz, 1H), 2.72 (dd, J=6, 18 Hz, 1H), 2.82 (ddd, J=6, 6, 13 Hz, 1H), 2.84 (ddd, J=6, 6, 13 Hz, 1H), 2.86-2.98 (m, 1H), 2.88 (d, J=6 Hz, 1H), 2.92 (d, J=18 Hz, 1H), 3.17 (ddd, J=2, 11, 14 Hz, 1H), 3.98 (ddd, J=6, 6, 14 Hz, 1H), 4.01 (ddd, J=6, 6, 14 Hz, 1H), 4.60 (br s, 1H), 6.61 (s, 1H), 6.75 (s, 1H), 6.79 (s, 1H), 7.22 (s, 1H).

Example 305
Synthesis of (5aS,6R,11bR)-9-chloro-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one (isomer S) and (5aS,6R,11bR)-11-chloro-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one (isomer T)

[Image Omitted]

To the compound (300 mg, 0.84 mmol) obtained in Example 140 dissolved in a 0.2 M trifluoroacetic acid aqueous solution (20 mL), N-chlorosuccinimide (225 mg, 1.68 mmol) was added, followed by stirring at 80° C. for 4 hours. To the reaction solution, sodium thiosulfate (380 mg) and a saturated sodium bicarbonate aqueous solution were added, followed by extraction three times with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 20% methanol/ethyl acetate) to individually yield an isomer S (151 mg, 46%) and an isomer T (109 mg, 33%) as white solids.

(Isomer S)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.16 (m, 2H), 0.48-0.57 (m, 2H), 0.76-0.87 (m, 1H), 1.02-1.11 (m, 1H), 1.29-1.44 (m, 1H), 1.48-1.58 (m, 1H), 1.95-2.12 (m, 2H), 2.29-2.40 (m, 2H), 2.46-2.60 (m, 2H), 2.67-2.82 (m, 2H), 2.86-2.99 (m, 2H), 3.44-3.51 (m, 1H), 3.74-3.85 (m, 1H), 3.87 (s, 3H), 4.66 (br s, 1H), 6.61-6.91 (m, 1H), 7.03 (s, 1H), 7.15 (s, 1H).

(Isomer T)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.45-0.57 (m, 2H), 0.76-0.88 (m, 1H), 1.53-1.63 (m, 1H), 1.78-2.07 (m, 4H), 2.26-2.38 (m, 2H), 2.58-3.02 (m, 5H), 3.37-3.59 (m, 2H), 3.71-3.85 (m, 1H), 3.81 (s, 3H), 4.54 (br s, 1H), 5.74-6.04 (m, 1H), 6.75 (d, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H).

Example 306
Synthesis of (5aS,6R,11bS)-9-chloro-14-(cyclopropylmethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the isomer S obtained in Example 305 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.14 (m, 2H), 0.47-0.56 (m, 2H), 0.77-0.89 (m, 1H), 1.02-1.10 (m, 1H), 1.58 (ddd, J=3, 3, 15 Hz, 1H), 1.66-1.76 (m, 1H), 1.94-2.10 (m, 3H), 2.28-2.44 (m, 3H), 2.52-2.59 (m, 1H), 2.74-3.14 (m, 7H), 3.86 (s, 3H), 4.49 (brs, 1H), 6.72 (s, 1H), 7.11 (s, 1H).

Example 307
Synthesis of 1-((5aS,6R,11bR)-9-chloro-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 306 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.13 (m, 2H), 0.47-0.55 (m, 2H), 0.75-0.86 (m, 1H), 0.96-1.09 (m, 1H), 1.51-1.59 (m, 0.5H), 1.61-1.80 (m, 1.5H), 1.87-2.12 (m, 3H), 2.25-2.46 (m, 2.5H), 2.48-2.58 (m, 1.5H), 2.62 (dd, J=6, 18 Hz, 0.5H), 2.77 (dd, J=6, 18 Hz, 0.5H), 2.84-2.95 (m, 2H), 3.44-3.67 (m, 2H), 3.74-3.96 (m, 3H), 3.81 (s, 1.5H), 3.88 (s, 1.5H), 4.40-4.51 (m, 1H), 6.53 (s, 0.5H), 6.67 (s, 0.5H), 7.03 (s, 0.5H), 7.08 (s, 0.5H), 7.09-7.16 (m, 2H), 7.52 (ddd, J=2, 8, 8 Hz, 0.5H), 7.57 (ddd, J=2, 8, 8 Hz, 0.5H), 8.40-8.50 (m, 1H).

Example 308
Synthesis of 1-((5aS,6R,11bR)-9-chloro-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

To the compound (18.7 mg, 0.038 mmol) obtained in Example 307 dissolved in chloroform (2 mL), a 1 M boron tribromide-dichloromethane solution (0.57 mL, 0.57 mmol) was added, followed by stirring at room temperature for 6 hours. To the reaction solution, a 28% aqueous ammonia solution and a saturated sodium bicarbonate aqueous solution were added, followed by extraction three times with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:10% aqueous ammonia-methanol solution=15:1) to yield the title compound (15.8 mg, 87%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.12 (m, 2H), 0.45-0.54 (m, 2H), 0.72-0.84 (m, 1H), 0.87-0.96 (m, 1H), 1.42-1.62 (m, 1.5H), 1.70-2.04 (m, 3.5H), 2.23-2.38 (m, 2.5H), 2.40-2.54 (m, 2H), 2.67-2.91 (m, 2.5H), 3.27-3.57 (m, 2H), 3.61-3.95 (m, 4H), 6.75 (s, 0.5H), 6.76 (s, 0.5H), 6.86 (s, 0.5H), 6.96-7.03 (m, 1H), 7.06-7.18 (m, 1.5H), 7.51-7.60 (m, 1H), 8.39-8.47 (m, 1H).

Example 309
Synthesis of 1-((5aS,6R,11bR)-9,11-dibromo-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2,2,2-trifluoroethan-1-one

[Image Omitted]

To a solution of the compound E (65.7 mg, 0.2 mmol) obtained in Example 3 in chloroform (2 mL) were added trifluoroacetic anhydride (141 μL, 1.0 mmol) and triethylamine (139 μL, 1.0 mmol), followed by stirring at room temperature for 1 hour. To the reaction mixture, methanol (2 mL) was added under ice cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in methanol (1 mL) were added 10% hydrobromic acid (1 mL) and iodobenzene diacetate (257 mg, 0.80 mmol), followed by stirring at room temperature for 18 hours. To the reaction mixture, a saturated aqueous sodium thiosulfate solution was added, followed by stirring at room temperature for 30 minutes, and then a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 10% methanol/chloroform) to yield the title compound (66.1 mg, 53%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.14 (m, 2H), 0.49-0.57 (m, 2H), 0.76-0.90 (m, 1H), 1.62-2.06 (m, 5H), 2.24-2.40 (m, 2H), 2.58-3.10 (m, 6H), 3.31-4.04 (m, 5H), 7.23 (s, 1H).

Example 310
Synthesis of (5aS,6R,11bS)-9,11-dibromo-14-(cyclopropylmethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

To a solution of the compound (58.2 mg, 0.10 mmol) obtained in Example 309 in N,N-dimethylformamide (1 mL) were added methyl iodide (7.5 μL, 0.12 mmol) and potassium carbonate (69.1 mg, 0.50 mmol), followed by stirring at room temperature for 1 hour. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in ethanol (2 mL) was added potassium carbonate (69.1 mg, 0.50 mmol), followed by stirring at 80° C. for 3 hours. After allowed to cool, water was added to the reaction mixture, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 50% methanol/chloroform) to yield the title compound (44.2 mg, 88%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.14 (m, 2H), 0.48-0.56 (m, 2H), 0.76-0.90 (m, 1H), 1.55-1.73 (m, 2H), 1.84-2.04 (m, 3H), 2.25-2.38 (m, 2H), 2.52-2.80 (m, 4H), 2.82-3.13 (m, 6H), 3.85 (s, 3H), 4.47 (br s, 1H), 7.29 (s, 1H).

Example 311
Synthesis of (5aS,6R,11bS)-9,11-dibromo-14-(cyclopropylmethyl)-10-methoxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 310 and the compound obtained in Reference Example 33 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.46-0.56 (m, 2H), 0.75-0.87 (m, 1H), 1.46 (dd, J=6, 14 Hz, 1H), 1.63-2.05 (m, 4H), 2.02 (s, 3H), 2.29 (dd, J=7, 13 Hz, 1H), 2.31 (dd, J=7, 13 Hz, 1H), 2.33-3.03 (m, 11H), 3.08-3.20 (m, 1H), 3.76-4.06 (m, 2H), 3.80 (s, 3H), 6.77 (s, 1H), 7.21 (s, 1H), 7.30 (s, 1H).

Example 312
Synthesis of (5aS,6R,11bS)-9,11-dibromo-14-(cyclopropylmethyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 311 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.12 (m, 2H), 0.47-0.54 (m, 2H), 0.74-0.85 (m, 1H), 1.51 (dd, J=6, Hz, 1H), 1.73-1.99 (m, 4H), 2.03 (s, 3H), 2.23-2.46 (m, 3H), 2.55-3.03 (m, 10H), 3.15-3.25 (m, 1H), 4.06-4.26 (m, 2H), 6.98 (s, 1H), 7.21 (s, 1H), 7.25 (s, 1H).

Example 313
Synthesis of (5aS,6R,11bS)-11-bromo-14-(cyclopropylmethyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To a solution of the compound (15 mg, 0.030 mmol) obtained in Example 310 in methanol (1 mL) were added potassium formate (126 mg, 1.5 mmol) and 10% palladium-activated carbon (1.5 mg), followed by stirring at room temperature for 1 hour. Then, 10% palladium-activated carbon (3.0 mg) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered through celite, and to the filtrate, a 28% aqueous ammonia solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. Although the obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1), it was so difficult to separate the crude product from the by-product that the crude product was used for the next reaction without further purification.

To a solution of the obtained crude product in acetonitrile (1 mL) were added the compound (12.1 mg, 0.060 mmol) obtained in Reference Example 33 and N,N-diisopropylethylamine (15.7 μL, 0.090 mmol), followed by stirring at 60° C. for 18 hours. After allowed to cool, to the reaction mixture was added a saturated sodium bicarbonate aqueous solution, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in chloroform (2 mL) was added a 1 M boron tribromide-dichloromethane solution (0.50 mL, 0.50 mmol) under ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture, a 28% aqueous ammonia solution was added under ice cooling, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (2.3 mg, 15%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.14 (m, 2H), 0.46-0.55 (m, 2H), 0.76-0.90 (m, 1H), 1.40-2.04 (m, 5H), 2.00 (s, 3H), 2.25-2.40 (m, 3H), 2.49-3.00 (m, 10H), 3.14 (dd, J=11, 14 Hz, 1H), 3.82-3.99 (m, 2H), 4.55 (s, 1H), 6.76 (s, 1H), 6.87 (d, J=9 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 7.19 (s, 1H).

Example 314
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(imidazo[1,2-a]pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 290 and 2-(imidazo[1,2-a]pyridin-2-yl)acetic acid according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.02-0.15 (m, 2H), 0.41-0.56 (m, 2H), 0.74-0.91 (m, 1H), 0.95-1.08 (m, 1H), 1.50-1.61 (m, 1H), 1.75-2.24 (m, 5H), 2.11 (s, 3H), 2.25-2.39 (m, 2H), 2.46-2.62 (m, 1H), 2.61 (dd, J=6, 18 Hz, 0.5H), 2.66 (dd, J=6, 18 Hz, 0.5H), 2.82 (d, J=6 Hz, 0.5H), 2.88 (d, J=18 Hz, 0.5H), 2.89 (d, J=6 Hz, 0.5H), 2.91 (d, J=18 Hz, 0.5H), 3.10-3.30 (m, 1.5H), 3.45-3.55 (m, 0.5H), 3.68 (d, J=16 Hz, 0.5H), 3.71 (d, J=16 Hz, 0.5H), 3.87 (d, J=16 Hz, 0.5H), 3.89-4.03 (m, 1.5H), 3.93 (d, J=16 Hz, 0.5H), 4.06-4.16 (m, 0.5H), 4.51 (br s, 1H), 6.70-6.80 (m, 3H), 7.07-7.18 (m, 1H), 7.42-7.54 (m, 1.5H), 7.45 (s, 0.5H), 7.98-8.04 (m, 1H).

Example 315
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-((R)-2-methylpyrrolidin-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 290 and (R)-2-methylpyrrolidine hydrochloride according to the method described in Example 132.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.17 (m, 2H), 0.45-0.56 (m, 2H), 0.76-0.90 (m, 1H), 0.99-1.13 (m, 1.6H), 1.05 (d, J=6 Hz, 2.4H), 1.22-1.44 (m, 1H), 1.50-2.20 (m, 9H), 2.17 (s, 3H), 2.21-2.40 (m, 4H), 2.42-2.65 (m, 2H), 2.72 (dd, J=6, 18 Hz, 0.8H), 2.75-2.83 (m, 0.2H), 2.79 (d, J=13 Hz, 0.8H), 2.85-2.93 (m, 0.4H), 2.87 (d, J=6 Hz, 0.8H), 2.96 (d, J=18 Hz, 0.8H), 2.97-3.06 (m, 0.2H), 3.36-3.52 (m, 1.2H), 3.53-3.65 (m, 0.2H), 3.61 (ddd, J=4, 4, 14 Hz, 0.8H), 3.66-3.84 (m, 1.2H), 3.69 (d, J=13 Hz, 0.8H), 3.93-4.04 (m, 0.8H), 4.40-4.67 (m, 1H), 6.61 (s, 0.2H), 6.79 (s, 0.8H), 6.81 (s, 0.2H), 6.85 (s, 0.8H).

Example 316
Synthesis of tert-butyl (5aS,6R,11bR)-5a-acetoxy-10-(benzyloxy)-14-(cyclopropylmethyl)-9-iodo-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

The compound (106 mg, 0.16 mmol) obtained in Example 292 was dissolved in acetic anhydride (2.5 mL), followed by heating under reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure. To the obtained concentrated residue was added a saturated aqueous sodium bicarbonate solution, followed by extraction 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 (30 to 100% ethyl acetate/heptane) to yield the title compound (79.4 mg, 70%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.01-0.09 (m, 2H), 0.39-0.51 (m, 2H), 0.68-0.79 (m, 1H), 0.93-1.03 (m, 1H), 1.41 (s, 3.6H), 1.44 (s, 5.4H), 1.80-1.90 (m, 1H), 1.92-2.07 (m, 2H), 2.08-2.18 (m, 2H), 2.10 (s, 1H), 2.12 (s, 2H), 2.19-2.45 (m, 3H), 2.48-2.56 (m, 1H), 2.60-2.78 (m, 2H), 2.92-3.16 (m, 2H), 3.42 (ddd, J=4, 13, 13 Hz, 0.4H), 3.50 (ddd, J=2, 5, 15 Hz, 0.6H), 3.60 (ddd, J=4, 13, 13 Hz, 0.6H), 3.74 (ddd, J=2, 5, 15 Hz, 0.4H), 4.18 (d, J=6 Hz, 0.4H), 4.26 (d, J=6 Hz, 0.6H), 5.00-5.20 (m, 2H), 6.58 (s, 0.4H), 6.59 (s, 0.6H), 7.28-7.35 (m, 1H), 7.36-7.43 (m, 2H), 7.44-7.51 (m, 2H), 7.54 (s, 0.4H), 7.55 (s, 0.6H).

Example 317
Synthesis of tert-butyl (5aS,6R,11bR)-5a-acetoxy-10-(benzyloxy)-14-(cyclopropylmethyl)-9-(trifluoromethyl)-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

To the compound (78 mg, 0.11 mmol) obtained in Example 316 dissolved in N,N-dimethylformamide (2.5 mL) were added copper (I) iodide (38.2 mg, 0.20 mmol) and methyl 2,2-difluoro 2-(fluorosulfonyl)acetate (73 μL, 0.58 mmol), followed by stirring at 80° C. for 1 hour. To the reaction solution, a saturated aqueous sodium bicarbonate solution was added, followed by extraction 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 (26 to 47% ethyl acetate/heptane) to yield the title compound (51.0 mg, 71%) as a white amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.01-0.10 (m, 2H), 0.41-0.51 (m, 2H), 0.68-0.80 (m, 1H), 0.94-1.04 (m, 1H), 1.39 (s, 3.6H), 1.43 (s, 5.4H), 1.75-1.86 (m, 1H), 1.95 (ddd, J=3, 12, 12 Hz, 1H), 1.98-2.09 (m, 1H), 2.11 (s, 1.2H), 2.13 (s, 1.8H), 2.14-2.34 (m, 4H), 2.35-2.49 (m, 1H), 2.50-2.58 (m, 1H), 2.64-2.84 (m, 2H), 2.97-3.18 (m, 2H), 3.40 (ddd, J=4, 13, 13 Hz, 0.4H), 3.49 (ddd, J=3, 5, 15 Hz, 0.6H), 3.58 (ddd, J=4, 13, 13 Hz, 0.6H), 3.69 (ddd, J=3, 5, 15 Hz, 0.4H), 4.23 (d, J=6 Hz, 0.6H), 4.30 (d, J=6 Hz, 0.4H), 5.08-5.24 (m, 2H), 6.76 (s, 1H), 7.28-7.50 (m, 6H).

Example 318
Synthesis of (5aS,6R,11bS)-10-(benzyloxy)-14-(cyclopropylmethyl)-9-(trifluoromethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

To the compound (22.3 mg, 0.036 mmol) obtained in Example 317 dissolved in ethanol (3 mL), a 6 M aqueous sodium hydroxide solution (2 mL) was added, followed by stirring at 80° C. for 1.5 hours. To the reaction solution, 2M hydrochloric acid and a saturated aqueous sodium bicarbonate solution were added, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the obtained concentrated residue dissolved in chloroform (1.5 mL), trifluoroacetic acid (0.5 mL) was added, followed by stirring at room temperature for 2.5 hours. To the reaction solution, a saturated aqueous sodium bicarbonate solution was added, followed by extraction with a mixed solvent of chloroform/isopropanol (4/1). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:10% aqueous ammonia-methanol solution=8:1) to yield the title compound (12.5 mg, 72%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.14 (m, 2H), 0.47-0.56 (m, 2H), 0.76-0.88 (m, 1H), 0.95-1.03 (m, 1H), 1.51-1.68 (m, 2H), 1.84 (ddd, J=3, 3, 16 Hz, 1H), 1.89-2.09 (m, 2H), 2.26-2.39 (m, 3H), 2.44-2.58 (m, 2H), 2.74 (ddd, J=4, 4, 14 Hz, 1H), 2.78-2.86 (m, 2H), 2.87-3.10 (m, 3H), 4.47 (br s, 1H), 5.12 (d, J=13 Hz, 1H), 5.21 (d, J=13 Hz, 1H), 6.75 (s, 1H), 7.28-7.48 (m, 6H).

Example 319
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-9-(trifluoromethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To the compound (21.4 mg, 0.044 mmol) obtained in Example 318 dissolved in methanol (2.5 mL), 20% palladium hydroxide-activated carbon (50% wet, 21.4 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure to yield the title compound (13.4 mg, 77%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.14 (m, 2H), 0.46-0.56 (m, 2H), 0.75-0.87 (m, 1H), 0.98-1.07 (m, 1H), 1.47-1.57 (m, 1H), 1.69-1.81 (m, 1H), 1.88-2.07 (m, 2H), 2.10-2.18 (m, 2H), 2.34 (d, J=6 Hz, 2H), 2.48-2.57 (m, 1H), 2.62-2.76 (m, 2H), 2.79-3.02 (m, 3H), 3.08-3.20 (m, 1H), 3.23-3.36 (m, 1H), 6.59 (s, 1H), 7.18 (s, 1H).

Example 320
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-(trifluoromethyl)-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 319 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.13 (m, 2H), 0.47-0.54 (m, 2H), 0.75-0.86 (m, 1H), 0.96-1.09 (m, 1H), 1.49-1.85 (m, 2H), 1.88-2.15 (m, 3H), 2.25-2.39 (m, 2H), 2.47-2.67 (m, 1.7H), 2.76 (dd, J=6, 18 Hz, 0.3H), 2.83-2.99 (m, 2.3H), 3.10-3.21 (m, 0.7H), 3.46-3.72 (m, 2.7H), 3.77-4.04 (m, 3.3H), 6.88 (s, 0.3H), 6.98 (s, 0.7H), 7.07-7.18 (m, 2.7H), 7.24-7.28 (m, 0.3H), 7.57 (ddd, J=2, 8, 8 Hz, 0.7H), 7.62 (ddd, J=2, 8, 8 Hz, 0.3H), 8.36-8.40 (m, 0.3H), 8.42-8.46 (m, 0.7H).

Example 321
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-9-(trifluoromethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 319 and the compound obtained in Reference Example 33 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.13 (m, 2H), 0.47-0.54 (m, 2H), 0.75-0.86 (m, 1H), 0.95-1.03 (m, 1H), 1.42-1.51 (m, 1H), 1.61-1.79 (m, 2H), 1.90-2.04 (m, 2H), 1.97 (s, 3H), 2.27-2.39 (m, 3H), 2.47-2.57 (m, 2H), 2.62 (ddd, J=2, 5, 13 Hz, 1H), 2.69-2.82 (m, 2H), 2.86-3.03 (m, 4H), 3.05-3.15 (m, 1H), 4.03-4.11 (m, 2H), 6.42 (s, 1H), 7.03 (s, 1H), 7.15 (s, 1H), 7.24 (s, 1H).

Example 322
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 290 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.43-0.56 (m, 2H), 0.76-0.87 (m, 1H), 0.99-1.12 (m, 1H), 1.53-1.63 (m, 0.7H), 1.79-2.09 (m, 4H), 2.12 (s, 2.1H), 2.16-2.23 (m, 1.4H), 2.18 (s, 0.9H), 2.26-2.39 (m, 2H), 2.46 (ddd, J=5, 12, 16 Hz, 0.3H), 2.48-2.56 (m, 1H), 2.66 (dd, J=6, 18 Hz, 0.7H), 2.75 (dd, J=6, 18 Hz, 0.3H), 2.84 (d, J=6 Hz, 0.7H), 2.90 (d, J=6 Hz, 0.3H), 2.91 (d, J=18 Hz, 0.3H), 2.94 (d, J=18 Hz, 0.7H), 3.12-3.21 (m, 0.7H), 3.38-3.54 (m, 1.3H), 3.67-3.77 (m, 0.3H), 3.73 (d, J=15 Hz, 0.3H), 3.82 (ddd, J=3, 4, 14 Hz, 0.3H), 3.87 (d, J=15 Hz, 0.3H), 3.90-4.01 (m, 0.3H), 3.96 (d, J=15 Hz, 0.7H), 4.02 (d, J=15 Hz, 0.7H), 4.15 (ddd, J=4, 4, 14 Hz, 0.7H), 4.41 (br s, 0.7H), 4.51 (br s, 0.3H), 6.58 (s, 0.3H), 6.77 (s, 1.4H), 6.83 (s, 0.3H), 7.38 (d, J=8 Hz, 0.3H), 7.46 (d, J=8 Hz, 0.7H), 7.52-7.56 (m, 0.3H), 7.54 (d, J=8 Hz, 0.7H), 7.75 (dd, J=8, 8 Hz, 0.3H), 7.77 (dd, J=8, 8 Hz, 0.7H).

Example 323
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(5-methylisothiazol-3-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 290 and 2-(5-methylisothiazol-3-yl)acetic acid according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.45-0.55 (m, 2H), 0.76-0.88 (m, 1H), 1.00-1.12 (m, 1H), 1.51-1.61 (m, 1H), 1.76-2.10 (m, 3.4H), 2.14-2.23 (m, 1H), 2.18 (s, 3H), 2.28 (dd, J=6, 12 Hz, 0.6H), 2.32-2.39 (m, 0.8H), 2.36 (dd, J=6, 12 Hz, 0.6H), 2.45-2.59 (m, 1.6H), 2.51 (s, 1.2H), 2.52 (s, 1.8H), 2.67 (dd, J=6, 18 Hz, 0.6H), 2.73 (dd, J=6, 18 Hz, 0.4H), 2.84 (d, J=6 Hz, 0.6H), 2.89 (d, J=6 Hz, 0.4H), 2.90 (d, J=18 Hz, 0.4H), 2.95 (d, J=18 Hz, 0.6H), 3.19 (ddd, J=4, 10, 14 Hz, 0.6H), 3.30-3.42 (m, 0.8H), 3.42 (ddd, J=4, 4, 13 Hz, 0.6H), 3.63 (d, J=15 Hz, 0.4H), 3.69 (d, J=15 Hz, 0.4H), 3.73-3.97 (m, 1.4H), 3.83 (d, J=16 Hz, 0.6H), 3.91 (d, J=16 Hz, 0.6H), 4.11-4.19 (m, 0.6H), 4.44 (br s, 0.6H), 4.52 (br s, 0.4H), 6.64 (s, 0.4H), 6.79 (s, 0.6H), 6.81 (s, 1H), 6.83 (s, 0.4H), 6.87 (s, 0.6H).

Example 324
Synthesis of 1-((5aS,6R,11bR)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2,2,2-trifluoroethan-1-one

[Image Omitted]

To the compound Q (99.8 mg, 0.24 mmol) obtained in Example 287 dissolved in chloroform (4 mL) were added N,N-diisopropylethylamine (250 μL, 1.44 mmol) and trifluoroacetic anhydride (152 μL, 1.08 mmol), followed by stirring at room temperature for 1 hour. To the reaction solution, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (5 to 20% methanol/ethyl acetate) to yield the title compound (100.1 mg, 81%) as a pale yellow amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.15 (m, 2H), 0.47-0.56 (m, 2H), 0.76-0.86 (m, 1H), 1.01-1.13 (m, 1H), 1.66 (ddd, J=4, 4, 15 Hz, 1H), 1.82-1.93 (m, 1H), 1.96-2.15 (m, 3H), 2.27-2.41 (m, 3H), 2.52-2.62 (m, 1H), 2.74-2.84 (m, 1H), 2.88-2.94 (m, 1H), 2.97-3.05 (m, 1H), 3.13-3.23 (m, 0.5H), 3.28-3.38 (m, 0.5H), 3.46-3.56 (m, 1H), 3.59-3.67 (m, 0.5H), 3.78-4.06 (m, 1.5H), 4.98-5.08 (m, 2H), 6.66 (d, J=2 Hz, 0.5H), 6.72 (d, J=2 Hz, 0.5H), 6.77-6.83 (m, 1H), 7.03 (d, J=8 Hz, 1H), 7.30-7.45 (m, 5H).

Example 325
Synthesis of (5aS,6R,11bS)-9-chloro-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol (compound U), (5aS,6R,11bS)-11-chloro-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol (compound V) and (5aS,6R,11bS)-9,11-dichloro-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol (compound UV)

[Image Omitted]

To the compound (100 mg, 0.19 mmol) obtained in Example 324 dissolved in a 2 M trifluoroacetic acid aqueous solution (4 mL), N-chlorosuccinimide (200 mg, 1.50 mmol) was added, followed by stirring at room temperature for 18.5 hours. To the reaction solution, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. To the obtained concentrated residue dissolved in ethanol (6 mL), potassium carbonate (300 mg, 2.17 mmol) was added, followed by stirring at 80° C. for 4 hours. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. To the obtained residue, 6 M hydrochloric acid (6 mL) was added, followed by stirring at 80° C. for 15.5 hours. To the reaction solution, a saturated aqueous sodium bicarbonate solution was added, followed by extraction with a mixed solvent of chloroform/isopropanol (4/1). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:10% aqueous ammonia-methanol solution=5:1) to individually yield an isomer U (6.1 mg, 8%), an isomer V (4.2 mg, 6%) and an isomer UV (7.1 mg, 9%) as white amorphous forms.

(Compound U)

¹H-NMR (400 MHz, CD₃OD) δ (ppm): 0.09-0.18 (m, 2H), 0.46-0.56 (m, 2H), 0.81-0.91 (m, 1H), 1.04-1.12 (m, 1H), 1.53-1.62 (m, 1H), 1.84-1.94 (m, 1H), 1.96-2.14 (m, 3H), 2.17-2.27 (m, 1H), 2.33-2.43 (m, 2H), 2.53-2.61 (m, 1H), 2.74 (dd, J=6, 18 Hz, 1H), 2.79-2.87 (m, 1H), 2.90-3.06 (m, 4H), 3.24-3.34 (m, 1H), 6.59 (s, 1H), 6.98 (s, 1H).

(Compound V)

¹H-NMR (400 MHz, CD₃OD) δ (ppm): 0.07-0.17 (m, 2H), 0.46-0.55 (m, 2H), 0.80-0.92 (m, 1H), 1.60-2.05 (m, 5H), 2.29-2.41 (m, 2H), 2.45-2.66 (m, 2H), 2.73-2.87 (m, 2H), 2.88-3.11 (m, 5H), 3.26-3.33 (m, 1H), 6.66 (d, J=8 Hz, 1H), 6.81 (d, J=8 Hz, 1H).

(Compound UV)

¹H-NMR (400 MHz, CD₃OD) δ (ppm): 0.07-0.17 (m, 2H), 0.44-0.55 (m, 2H), 0.78-0.90 (m, 1H), 1.58-1.72 (m, 2H), 1.86-2.04 (m, 2H), 2.19-2.49 (m, 4H), 2.56-2.63 (m, 1H), 2.76-2.94 (m, 5H), 3.01 (dd, J=6, 13 Hz, 1H), 3.10-3.18 (m, 1H), 3.41-3.50 (m, 1H), 6.84 (s, 1H).

Example 326
Synthesis of (5aS,6R,11bS)-9-chloro-14-(cyclopropylmethyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound U obtained in Example 325 and the compound obtained in Reference Example 33 according to the method described in Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.12 (m, 2H), 0.46-0.52 (m, 2H), 0.75-0.85 (m, 1H), 0.92-1.00 (m, 1H), 1.40-1.48 (m, 1H), 1.66-1.77 (m, 2H), 1.92-2.05 (m, 2H), 1.99 (s, 3H), 2.27-2.40 (m, 3H), 2.41-2.60 (m, 3H), 2.68-2.96 (m, 6H), 3.07-3.16 (m, 1H), 3.92-4.06 (m, 2H), 6.71 (s, 1H), 6.84 (s, 1H), 7.04 (s, 1H), 7.21 (s, 1H).

Example 327
Synthesis of 1-((5aS,6R,11bR)-11-chloro-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound V obtained in Example 325 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.12 (m, 2H), 0.47-0.54 (m, 2H), 0.74-0.86 (m, 1H), 1.49-1.55 (m, 0.3H), 1.58-1.73 (m, 1.7H), 1.76-2.06 (m, 2.7H), 2.17-2.39 (m, 2.3H), 2.48-2.75 (m, 2.7H), 2.76-2.97 (m, 3.3H), 3.16-3.26 (m, 0.7H), 3.40 (ddd, J=3, 5, 13 Hz, 0.7H), 3.48 (d, J=16 Hz, 0.7H), 3.58-3.81 (m, 3.2H), 4.18 (ddd, J=2, 5, 14 Hz, 0.7H), 4.49 (br s, 1H), 6.80-6.85 (m, 1.3H), 6.90 (d, J=8 Hz, 0.7H), 7.03-7.14 (m, 2H), 7.50-7.57 (m, 1H), 8.44-8.48 (m, 1H).

Example 328
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 290 and 2-(4-methyl-1H-pyrazol-1-yl)acetic acid according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.44-0.57 (m, 2H), 0.75-0.88 (m, 1H), 0.99-1.11 (m, 1H), 1.50-1.61 (m, 1H), 1.78-2.11 (m, 4H), 2.04 (s, 1.5H), 2.07 (s, 1.5H), 2.11-2.21 (m, 0.5H), 2.18 (s, 1.5H), 2.19 (s, 1.5H), 2.28 (dd, J=6, 13 Hz, 0.5H), 2.28-2.39 (m, 1H), 2.35 (dd, J=6, 13 Hz, 0.5H), 2.48-2.77 (m, 2.5H), 2.86 (d, J=7 Hz, 0.5H), 2.89 (d, J=19 Hz, 0.5H), 2.90 (d, J=6 Hz, 0.5H), 2.96 (d, J=18 Hz, 0.5H), 3.06 (ddd, J=3, 13, 14 Hz, 0.5H), 3.17-3.28 (m, 1H), 3.33 (ddd, J=4, 4, 13 Hz, 0.5H), 3.73 (ddd, J=5, 12, 14 Hz, 0.5H), 3.80-3.90 (m, 1H), 4.07-4.16 (m, 0.5H), 4.45 (br s, 0.5H), 4.53 (br s, 0.5H), 4.66 (s, 1H), 4.91 (d, J=16 Hz, 0.5H), 4.92 (d, J=16 Hz, 0.5H), 6.65 (s, 1H), 6.81 (s, 0.5H), 6.83 (s, 0.5H), 7.10 (s, 0.5H), 7.19 (s, 0.5H), 7.28 (s, 0.5H), 7.30 (s, 0.5H).

Example 329
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 290 and 2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid hydrochloride according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.18 (m, 2H), 0.47-0.57 (m, 2H), 0.76-0.89 (m, 1H), 1.04-1.13 (m, 1H), 1.55-1.65 (m, 1H), 1.83 (ddd, J=2, 12, 15 Hz, 0.4H), 1.88-2.24 (m, 4.2H), 2.17 (s, 1.8H), 2.19 (s, 1.2H), 2.29 (dd, J=6, 13 Hz, 0.4H), 2.35 (d, J=6 Hz, 1.2H), 2.36 (dd, J=6, 13 Hz, 0.4H), 2.49-2.59 (m, 1H), 2.61-2.80 (m, 1.4H), 2.86-2.93 (m, 1.4H), 2.96-3.03 (m, 0.6H), 2.99 (d, J=18 Hz, 0.6H), 3.30-3.40 (m, 1H), 3.44 (ddd, J=2, 6, 14 Hz, 0.4H), 3.72 (ddd, J=5, 11, 14 Hz, 0.4H), 3.81-3.91 (m, 1H), 4.17 (ddd, J=2, 5, 14 Hz, 0.6H), 4.76 (d, J=16 Hz, 0.4H), 4.81 (d, J=16 Hz, 0.4H), 4.99 (d, J=16 Hz, 0.6H), 5.04 (d, J=16 Hz, 0.6H), 6.62 (s, 0.4H), 6.65 (s, 0.6H), 6.84 (s, 0.6H), 6.85 (s, 0.4H), 7.55 (s, 0.4H), 7.66 (s, 0.4H), 7.71 (s, 0.6H), 7.80 (s, 0.6H).

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

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 51 according to the method described in Example 6.

¹H-NMR (400 MHz, CD₃OD) δ (ppm): 0.13-0.20 (m, 2H), 0.50-0.59 (m, 2H), 0.84-0.95 (m, 1H), 1.35-1.43 (m, 1H), 1.55-1.62 (m, 1H), 1.79-1.90 (m, 1H), 2.29-2.47 (m, 4H), 2.67 (dd, J=7, 19 Hz, 1H), 2.69-2.75 (m, 1H), 2.80-2.91 (m, 2H), 3.11 (d, J=7 Hz, 1H), 3.15 (d, J=5 Hz, 1H), 4.71 (s, 1H), 6.60 (d, J=8 Hz, 1H), 6.68 (d, J=8 Hz, 1H).

Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,11-dihydroxy-10-(methoxymethoxy)-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

To a solution of the compound (107 mg, 0.30 mmol) obtained in Reference Example 53 in N,N-dimethylformamide (6 mL) were added potassium carbonate (249 mg, 1.8 mmol) and chloromethyl methyl ether (91.1 μL, 1.2 mmol), followed by stirring at 40° C. for 6 hours. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in ethylenediamine (10 mL) was added Sodium silica gel Stage I (1 g) under ice cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture, tetrahydrofuran (50 mL) was added under ice cooling, and then water (100 mL) was slowly added at the same temperature, followed by stirring. The temperature of the reaction mixture was returned to room temperature, and to the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 30% methanol/chloroform) to yield the title compound (93.0 mg, 77%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.13 (m, 2H), 0.47-0.55 (m, 2H), 0.76-0.88 (m, 1H), 1.52-1.68 (m, 1H), 1.81-1.90 (m, 1H), 1.93-2.05 (m, 2H), 2.32 (dd, J=6, 12 Hz, 1H), 2.34 (dd, J=7, 13 Hz, 1H), 2.54-2.64 (m, 1H), 2.80-3.00 (m, 4H), 3.11 (dd, J=2, 14 Hz, 1H), 3.51 (s, 3H), 3.54 (d, J=14 Hz, 1H), 3.86-3.96 (m, 1H), 4.65 (br s, 1H), 5.15 (d, J=12 Hz, 1H), 5.16 (d, J=12 Hz, 1H), 5.83-5.92 (m, 1H), 6.64 (d, J=8 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 7.61 (s, 1H).

Example 331
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-11-methoxy-10-(methoxymethoxy)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol (compound W) and (5aS,6R,11bS)-14-(cyclopropylmethyl)-11-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol (compound X)

[Image Omitted]

To a solution of the compound (40.2 mg, 0.10 mmol) obtained in Example 330 in N,N-dimethylformamide (1 mL) were added methyl iodide (7.5 μL, 0.12 mmol) and potassium carbonate (69.1 mg, 0.50 mmol), followed by stirring at room temperature for 1 hour. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in tetrahydrofuran (1 mL) was added a 0.91 M borane-tetrahydrofuran complex-tetrahydrofuran solution (1.0 mL, 0.91 mmol), followed by heating under reflux for 2 hours. After allowed to cool, the reaction mixture was concentrated under reduced pressure. To the residue, a 2 M aqueous sodium hydroxide solution (2 mL) was added, followed by stirring at room temperature for 1 hours. Water was added to the reaction mixture, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 50% methanol/chloroform) to individually yield the title compound W (12.1 mg, 30%) and the crude product as colorless amorphous forms.

To the obtained crude product was added 2 M hydrochloric acid (5.0 mL, 10 mmol), followed by stirring at room temperature for 30 minutes. To the reaction mixture, a 28% aqueous ammonia solution was added under ice cooling, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=5:1) to yield the title compound X (21.0 mg, 59%) as a colorless amorphous form.

(Compound W)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.14 (m, 2H), 0.46-0.55 (m, 2H), 0.76-0.90 (m, 1H), 1.31-1.40 (m, 1H), 1.55-1.85 (m, 2H), 1.94-2.14 (m, 2H), 2.25-2.39 (m, 3H), 2.41-2.51 (m, 1H), 2.54-2.63 (m, 1H), 2.71-2.80 (m, 1H), 2.86-3.02 (m, 5H), 3.08-3.18 (m, 1H), 3.51 (s, 3H), 3.79 (s, 3H), 4.47 (br s, 1H), 5.16 (s, 2H), 6.77 (d, J=9 Hz, 1H), 6.97 (d, J=9 Hz, 1H).

(Compound X)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.13 (m, 2H), 0.47-0.54 (m, 2H), 0.77-0.88 (m, 1H), 1.29-1.38 (m, 1H), 1.55-1.70 (m, 2H), 2.02-2.14 (m, 2H), 2.20-2.63 (m, 6H), 2.75-3.02 (m, 5H), 3.06-3.16 (m, 1H), 3.71 (s, 3H), 4.53 (br s, 1H), 6.69 (d, J=8 Hz, 1H), 6.73 (d, J=8 Hz, 1H).

Example 332
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-11-methoxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To a solution of the compound W (10 mg, 0.025 mmol) obtained from Example 331 in acetonitrile (0.5 mL) were added the compound (10.2 mg, 0.050 mmol) obtained in Reference Example 33 and N,N-diisopropylethylamine (13.1 μL, 0.075 mmol), followed by stirring at 70° C. for 18 hours. After allowed to cool, to the reaction mixture was added a 28% aqueous ammonia solution, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To the obtained crude product was added 2 M hydrochloric acid (2.0 mL, 4.0 mmol), followed by stirring at room temperature for 30 minutes. To the reaction mixture, a 28% aqueous ammonia solution was added under ice cooling, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (3.5 mg, 30%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.13 (m, 2H), 0.47-0.53 (m, 2H), 0.77-0.89 (m, 1H), 1.29-1.44 (m, 2H), 1.70-1.80 (m, 1H), 2.00 (s, 3H), 2.02-2.24 (m, 3H), 2.27-2.49 (m, 4H), 2.55-2.97 (m, 8H), 3.14-3.24 (m, 1H), 3.74 (s, 3H), 3.89-4.05 (m, 2H), 6.75 (d, J=8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 6.83 (s, 1H), 7.21 (s, 1H).

Example 333
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-11-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound X obtained in Example 331 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.15 (m, 2H), 0.47-0.55 (m, 2H), 0.77-0.89 (m, 1H), 1.20-1.60 (m, 2H), 1.72-1.88 (m, 0.7H), 2.00-4.10 (m, 16.3H), 3.71 (s, 0.9H), 3.80 (s, 2.1H), 4.48 (br s, 1H), 6.65-6.70 (m, 0.3H), 6.69 (d, J=8 Hz, 0.7H), 6.76 (d, J=8 Hz, 0.7H), 6.80 (d, J=8 Hz, 0.3H), 7.04-7.16 (m, 2H), 7.51-7.60 (m, 1H), 8.42-8.46 (m, 1H).

Example 334
Synthesis of tert-butyl (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-(methylcarbamoyl)-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

To a solution of the compound (24 mg, 0.055 mmol) obtained in Example 241 in methanol (1 mL) was added 4 M aqueous sodium hydroxide solution (1 mL), followed by heating under reflux for 16 hours. The reaction solution was allowed to cool to room temperature, then neutralized with 2 M hydrochloric acid (2 mL) under ice cooling, and then concentrated under reduced pressure. The obtained residue was lyophilized. To a solution of the obtained crude product in N,N-dimethylformamide (0.5 mL) were added methylamine hydrochloride (19 mg, 0.27 mmol), N,N-diisopropylethylamine (77 μL, 0.44 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (22 mg, 0.058 mmol), followed by stirring at room temperature for 16 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (26 mg, quantitative) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.30 (m, 2H), 0.45-0.60 (m, 2H), 0.80-1.00 (m, 1H), 1.00-1.10 (m, 9H), 1.30-2.10 (m, 5H), 2.30-2.40 (m, 2H), 2.50-2.60 (m, 1H), 2.60-2.80 (m, 1H), 2.80-3.30 (m, 10H), 3.50-3.60 (m, 1H), 4.25-4.40 (m, 1H), 7.05-7.15 (m, 1H), 7.20-7.30 (m, 1H), 7.35-7.45 (m, 1H).

Example 335
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-N-methyl-3-(2-(pyridin-2-yl)acetyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carboxamide

[Image Omitted]

To the compound (26 mg, 0.055 mmol) obtained in Example 334 was added trifluoroacetic acid (0.5 mL), followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The obtained residue was roughly purified by silica gel column chromatography (amino group-supported silica gel, 0 to 20% methanol/chloroform). To a solution of half (6.5 mg) of the obtained crude product (13 mg, 64%) in N,N-dimethylformamide (1 mL) were added 2-(pyridin-2-yl) acetic acid hydrochloride (5 mg, 0.019 mmol), N,N-diisopropylethylamine (12 μL, 0.070 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (7 mg, 0.019 mmol), followed by stirring at room temperature for 16 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (1.9 mg, 22%) as a colorless oily matter.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.30 (m, 2H), 0.50-0.70 (m, 2H), 0.80-1.00 (m, 1H), 1.00-1.30 (m, 2H), 1.30-2.10 (m, 3H), 2.20-2.45 (m, 3H), 2.45-2.80 (m, 3H), 2.80-3.10 (m, 5H), 3.20-3.40 (m, 2H), 3.45-4.00 (m, 4H), 4.20-4.60 (m, 1H), 5.00-5.50 (m, 1H), 6.85 (d, J=7 Hz, 0.5H), 7.00-7.70 (m, 5.5H), 8.30-8.50 (m, 1H).

Example 336
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-((R)-3-methylpyrrolidin-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 290 and (R)-3-methylpyrrolidine hydrochloride according to the method described in Example 132.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.16 (m, 2H), 0.44-0.56 (m, 2H), 0.76-0.89 (m, 1H), 0.96-1.12 (m, 1H), 0.99 (d, J=6 Hz, 3H), 1.19-1.38 (m, 1H), 1.53-1.62 (m, 1H), 1.82 (ddd, J=2, 12, 15 Hz, 0.3H), 1.90-2.39 (m, 10.3H), 2.17 (s, 3H), 2.45-2.57 (m, 1.4H), 2.59-2.80 (m, 3H), 2.85-2.93 (m, 0.6H), 2.87 (d, J=6 Hz, 0.7H), 2.96 (d, J=18 Hz, 0.7H), 3.15 (d, J=15 Hz, 0.3H), 3.18 (d, J=14 Hz, 0.7H), 3.20 (d, J=15 Hz, 0.3H), 3.32 (d, J=14 Hz, 0.7H), 3.35-3.50 (m, 1.7H), 3.55 (ddd, J=4, 5, 14 Hz, 0.3H), 3.63 (ddd, J=4, 11, 14 Hz, 0.3H), 3.72-3.83 (m, 1H), 3.96-4.03 (m, 0.7H), 4.51 (br s, 1H), 6.61 (s, 0.3H), 6.80 (s, 0.7H), 6.81 (s, 0.3H), 6.84 (s, 0.7H).

Example 337
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-9-methoxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

To the compound (32.2 mg, 0.050 mmol) obtained in Example 292 and a copper powder (3.2 mg, 0.050 mmol) suspended in pyridine (1 mL), a 5 M sodium methoxide-methanol solution (200 μL, 1.0 mmol) was added, followed by heating under reflux for 1 hour. Thereafter, a copper powder (3.2 mg, 0.050 mmol) was added, followed by heating under reflux for 1 hour. Thereafter, a copper powder (3.2 mg, 0.050 mmol) was added, followed by heating under reflux for 1 hour. After allowed to cool, the reaction mixture was filtered through celite, and to the filtrate, a 28% aqueous ammonia solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. Although the obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 10% methanol/chloroform), it was so difficult to separate the crude product from the by-product that the crude product was used for the next reaction without further purification.

To the obtained crude product was added trifluoroacetic acid (1 mL), followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and to the concentrated reaction mixture, a 28% aqueous ammonia solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in acetonitrile (1 mL) were added the compound (20.4 mg, 0.10 mmol) obtained in Reference Example 33 and N,N-diisopropylethylamine (26.1 μL, 0.15 mmol), followed by stirring at 70° C. for 18 hours. After allowed to cool, to the reaction mixture was added a 28% aqueous ammonia solution, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in methanol (1 mL) were added 10% palladium-activated carbon (32.2 mg) and potassium formate (84.1 mg, 1.0 mmol), followed by stirring at room temperature for 30 minutes. The reaction mixture was filtered through celite, and to the filtrate, a 28% aqueous ammonia solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (3.5 mg, 13%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.14 (m, 2H), 0.46-0.54 (m, 2H), 0.77-0.90 (m, 1H), 0.96-1.04 (m, 1H), 1.38-1.48 (m, 1H), 1.76-1.88 (m, 2H), 1.94-2.10 (m, 2H), 2.00 (s, 3H), 2.27-2.41 (m, 3H), 2.48-2.59 (m, 2H), 2.64-2.72 (m, 1H), 2.77 (dd, J=6, 18 Hz, 1H), 2.85-2.99 (m, 5H), 3.18-3.26 (m, 1H), 3.86 (s, 3H), 3.98-4.18 (m, 2H), 6.57 (s, 1H), 6.66 (s, 1H), 6.90 (s, 1H), 7.23 (s, 1H).

Reference Example 54
Synthesis of (4′R,4a′S,7a′R,12b′S)-3′-(cyclopropylmethyl)-4a′-hydroxy-9′-methoxy-1′,2′,3′,4′,4a′,5′-hexahydrospiro[cyclopropane-1,6′-[4a,12]methanobenzofuro[3,2-e]isoquinolin]-7′(7a′H)-one

[Image Omitted]

To a solution of (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (synthesized by the method described in Organic Letters 2009, 11, 539) (854 mg, 3.38 mmol) in tert-butanol (28 mL) were added potassium tert-butoxide (1.20 g, 10.7 mmol) and (2-chloroethyl) dimethylsulfonium iodide (synthesized by the method described in WO 2007092681) (1.00 g, 2.81 mmol), followed by stirring at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (28 to 100% ethyl acetate/heptane) to yield the title compound (843 mg, 79%) as a pale yellow crystal.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.13-0.17 (m, 2H), 0.43-0.48 (m, 1H), 0.53-0.58 (m, 2H), 0.82-0.91 (m, 1H), 1.08-1.19 (m, 3H), 1.57-1.62 (m, 2H), 2.14 (d, J=14 Hz, 1H), 2.25 (ddd, J=3, 12, 12 Hz, 1H), 2.33-2.47 (m, 3H), 2.58 (dd, J=6, 18 Hz, 1H), 2.71 (dd, J=5, 12 Hz, 1H), 3.10 (d, J=18 Hz, 1H), 3.15 (d, J=6 Hz, 1H), 3.87 (s, 3H), 4.53 (s, 1H), 6.64 (d, J=8 Hz, 1H), 6.72 (d, J=8 Hz, 1H).

Reference Example 55
Synthesis of (4b′R,8a′S,9′R)-11′-(cyclopropylmethyl)-4′,8a′-dihydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydrospiro[cyclopropane-1,7′-[9,4b](epiminoethano)phenanthren]-6′(5′H)-one (compound Y) and (4bR,8aS,9R)-11-(cyclopropylmethyl)-7-ethyl-4,8a-dihydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one (compound Z)

[Image Omitted]

The title compounds Y and Z were individually obtained from the compound obtained in Reference Example 54 according to the method described in Reference Example 34.

(Compound Y)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.10-0.14 (m, 2H), 0.20-0.25 (m, 1H), 0.50-0.55 (m, 2H), 0.82-0.88 (m, 2H), 0.93-0.98 (m, 1H), 1.29 (d, J=14 Hz, 1H), 1.37-1.42 (m, 1H), 1.59-1.62 (m, 1H), 2.06-2.09 (m, 2H), 2.32-2.41 (m, 3H), 2.61-2.64 (m, 1H), 2.85 (dd, J=6, 19 Hz, 1H), 3.00-3.09 (m, 3H), 3.83 (s, 3H), 3.98 (d, J=16 Hz, 1H), 4.71 (br s, 1H), 6.05 (s, 1H), 6.58 (d, J=8 Hz, 1H), 6.69 (d, J=8 Hz, 1H).

(Compound Z)

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.10-0.14 (m, 2H), 0.51-0.56 (m, 2H), 0.82 (t, J=8 Hz, 3H), 0.82-0.89 (m, 2H), 0.94-1.05 (m, 1H), 1.53-1.60 (m, 1H), 1.67-1.78 (m, 1H), 1.92 (dd, J=6, 13 Hz, 1H), 1.99-2.12 (m, 2H), 2.33-2.41 (m, 2H), 2.58-2.61 (m, 1H), 2.67-2.75 (m, 1H), 2.82 (dd, J=6, 18 Hz, 1H), 2.96 (d, J=13 Hz, 1H), 2.98 (d, J=18 Hz, 1H), 3.10 (d, J=6 Hz, 1H), 3.82 (s, 3H), 3.91 (d, J=13 Hz, 1H), 4.77 (br s, 1H), 6.09 (s, 1H), 6.53 (d, J=8 Hz, 1H), 6.65 (d, J=8 Hz, 1H).

Reference Example 56
Synthesis of (4b′R,8a′S,9′R)-11′-(cyclopropylmethyl)-8a′-hydroxy-3′-methoxy-6′-oxo-5′,6′,8′,8a′,9′,10′-hexahydrospiro[cyclopropane-1,7′-[9,4b](epiminoethano)phenanthren]-4′-yl trifluoromethanesulfonate

[Image Omitted]

The title compound was obtained from the compound Y obtained in Reference Example 55 according to the method described in Reference Example 1.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.11-0.19 (m, 3H), 0.53-0.57 (m, 2H), 0.79-0.89 (m, 2H), 0.94-0.99 (m, 1H), 1.30-1.35 (m, 1H), 1.36 (d, J=14 Hz, 1H), 1.70-1.73 (m, 1H), 2.10-2.24 (m, 3H), 2.33-2.43 (m, 2H), 2.68-2.72 (m, 1H), 2.90 (dd, J=7, 18 Hz, 1H), 3.08 (d, J=18 Hz, 1H), 3.13 (d, J=7 Hz, 1H), 3.23 (d, J=16 Hz, 1H), 3.60 (d, J=16 Hz, 1H), 3.80 (s, 3H), 6.87 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H).

Reference Example 57
Synthesis of (4b′R,8a′S,9′R)-11′-(cyclopropylmethyl)-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydrospiro[cyclopropane-1,7′-[9,4b](epiminoethano)phenanthren]-6′(5′H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 56 according to the method described in Reference Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.11-0.15 (m, 2H), 0.20-0.25 (m, 1H), 0.52-0.56 (m, 2H), 0.83-0.93 (m, 3H), 1.17-1.28 (m, 2H), 1.43-1.48 (m, 1H), 2.10-2.19 (m, 2H), 2.27 (d, J=14 Hz, 1H), 2.37 (dd, J=6, 12 Hz, 1H), 2.42 (dd, J=6, 12 Hz, 1H), 2.60-2.62 (m, 1H), 2.77 (dd, J=7, 19 Hz, 1H), 2.92 (d, J=16 Hz, 1H), 3.04-3.14 (m, 3H), 3.75 (s, 3H), 6.71 (dd, J=2, 8 Hz, 1H), 6.77 (d, J=2 Hz, 1H), 7.01 (d, J=8 Hz, 1H).

Reference Example 58
Synthesis of (4b′R,8a′S,9′R)-11′-(cyclopropylmethyl)-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydrospiro[cyclopropane-1,7′-[9,4b](epiminoethano)phenanthren]-6′(5′H)-one oxime

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 57 according to the method described in Reference Example 3.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.10-0.17 (m, 3H), 0.50-0.54 (m, 2H), 0.59-0.63 (m, 1H), 0.82-0.88 (m, 2H), 0.93 (d, J=14 Hz, 1H), 1.18-1.29 (m, 2H), 2.10-2.18 (m, 3H), 2.34 (dd, J=6, 13 Hz, 1H), 2.40 (dd, J=6, 13 Hz, 1H), 2.55 (d, J=14 Hz, 1H), 2.59-2.61 (m, 1H), 2.70 (dd, J=6, 18 Hz, 1H), 3.01 (d, J=6 Hz, 1H), 3.04 (d, J=18 Hz, 1H), 3.74 (d, J=16 Hz, 1H), 3.76 (s, 3H), 6.69 (dd, J=3, 8 Hz, 1H), 6.73 (br s, 1H), 6.96 (d, J=8 Hz, 1H), 7.05 (d, J=3 Hz, 1H).

Example 338
Synthesis of (5a′S,6′R,11b′R)-14′-(cyclopropylmethyl)-5a′-hydroxy-10′-methoxy-5′,5a′,6′,7′-tetrahydro-1′H-spiro[cyclopropane-1,4′-[6,11b](epiminoethano)naphtho[1,2-d]azepin]-2′(3′H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 58 according to the method described in Example 1.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.09-0.12 (m, 2H), 0.47-0.55 (m, 4H), 0.78-0.85 (m, 1H), 0.90-0.95 (m, 1H), 0.98 (d, J=14 Hz, 1H), 1.14-1.17 (m, 1H), 1.43-1.49 (m, 1H), 2.01-2.17 (m, 2H), 2.30-2.39 (m, 2H), 2.40 (dd, J=2, 14 Hz, 1H), 2.57-2.61 (m, 2H), 2.77 (dd, J=6, 18 Hz, 1H), 2.85 (d, J=6 Hz, 1H), 3.00 (d, J=18 Hz, 1H), 3.76 (d, J=15 Hz, 1H), 3.80 (s, 3H), 4.73 (br s, 1H), 5.42 (br s, 1H), 6.71 (dd, J=2, 8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 7.16 (d, J=2 Hz, 1H).

Example 339
Synthesis of (5a′S,6′R,11b′S)-14′-(cyclopropylmethyl)-10′-methoxy-2′,3′,6′,7′-tetrahydro-1′H-spiro[cyclopropane-1,4′-[6,11b](epiminoethano)naphtho[1,2-d]azepin]-5a′(5′H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 338 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.15 (m, 3H), 0.34-0.39 (m, 1H), 0.48-0.53 (m, 2H), 0.72-0.76 (m, 2H), 0.79-0.87 (m, 1H), 1.06-1.13 (m, 2H), 2.00-2.06 (m, 3H), 2.27-2.45 (m, 4H), 2.51-2.54 (m, 1H), 2.79 (dd, J=6, 18 Hz, 1H), 2.84-3.02 (m, 4H), 3.79 (s, 3H), 4.52 (br s, 1H), 6.72 (dd, J=2, 8 Hz, 1H), 6.77 (d, J=2 Hz, 1H), 7.03 (d, J=8 Hz, 1H).

Example 340
Synthesis of 1-((5a′S,6′R,11b′R)-14′-(cyclopropylmethyl)-5a′-hydroxy-10′-methoxy-1′,2′,5′,5a′,6′,7′-hexahydro-3′H-spiro[cyclopropane-1,4′-[6,11b](epiminoethano)naphtho[1,2-d]azepin]-3′-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 339 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.10 (m, 2H), 0.46-0.53 (m, 2H), 0.66-1.18 (m, 6H), 1.48-1.54 (m, 0.7H), 1.78-1.86 (m, 1H), 1.90-1.97 (m, 1H), 2.07-2.17 (m, 1H), 2.25-2.36 (m, 2.3H), 2.48-2.60 (m, 2H), 2.72 (dd, J=6, 19 Hz, 0.7H), 2.83-2.90 (m, 3H), 2.98-3.24 (m, 1.3H), 3.54 (d, J=15 Hz, 0.3H), 3.68 (d, J=15 Hz, 0.7H), 3.78-3.86 (m, 4H), 3.95-4.03 (m, 0.3H), 4.71-4.79 (m, 0.7H), 6.55 (dd, J=3, 8 Hz, 0.7H), 6.63-6.82 (m, 3.3H), 7.03-7.09 (m, 1H), 7.42 (ddd, J=2, 8, 8 Hz, 0.7H), 7.51 (ddd, J=2, 8, 8 Hz, 0.3H), 8.37-8.40 (m, 0.7H), 8.42-8.45 (m, 0.3H).

Example 341
Synthesis of 1-((5a′S,6′R,11b′R)-14′-(cyclopropylmethyl)-5a′,10′-dihydroxy-1′,2′,5′,5a′,6′,7′-hexahydro-3′H-spiro[cyclopropane-1,4′-[6,11b](epiminoethano)naphtho[1,2-d]azepin]-3′-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 340 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.09 (m, 2H), 0.46-0.51 (m, 2H), 0.66-0.82 (m, 2H), 0.92-1.06 (m, 3H), 1.14-1.26 (m, 1H), 1.52-1.55 (m, 0.7H), 1.68-1.81 (m, 1H), 1.94-2.13 (m, 2.3H), 2.23-2.35 (m, 2H), 2.45-2.71 (m, 2.6H), 2.82-3.04 (m, 4.4H), 3.38 (d, J=Hz, 0.3H), 3.61 (d, J=15 Hz, 0.3H), 3.71 (d, J=15 Hz, 0.7H), 3.83 (d, J=15 Hz, 0.7H), 3.95-4.04 (m, 0.3H), 4.72-4.80 (m, 0.7H), 6.50 (dd, J=3, 9 Hz, 0.7H), 6.61-6.68 (m, 2.4H), 6.80 (d, J=2 Hz, 0.3H), 6.91 (d, J=8 Hz, 0.3H), 7.00-7.05 (m, 1H), 7.14-7.17 (m, 0.3H), 7.40 (ddd, J=2, 8, 8 Hz, 0.7H), 7.59 (ddd, J=2, 8, 8 Hz, 0.3H), 8.37-8.40 (m, 0.7H), 8.45-8.47 (m, 0.3H).

Example 342
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-4,4-dimethyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 268 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.13 (m, 2H), 0.48-0.54 (m, 2H), 0.80-0.87 (m, 1H), 1.02-1.05 (m, 1H), 1.14 (s, 3H), 1.38 (d, J=15 Hz, 1H), 1.91 (s, 3H), 1.95-1.98 (m, 2H), 2.11 (dd, J=10, 15 Hz, 1H), 2.27-2.40 (m, 3H), 2.58-2.60 (m, 1H), 2.73-2.90 (m, 3H), 3.00 (d, J=18 Hz, 1H), 3.72-3.78 (m, 1H), 3.78 (s, 3H), 3.88 (d, J=15 Hz, 1H), 3.99 (d, J=15 Hz, 1H), 4.46 (br s, 1H), 6.67 (d, J=3 Hz, 1H), 6.72 (dd, J=3, 8 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 7.16 (ddd, J=1, 5, 8 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.64 (ddd, J=2, 8, 8 Hz, 1H), 8.52-8.56 (m, 1H).

Example 343
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-4,4-dimethyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 342 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.13 (m, 2H), 0.47-0.53 (m, 2H), 0.78-0.87 (m, 1H), 1.00 (s, 3H), 1.05-1.08 (m, 1H), 1.34 (d, J=15 Hz, 1H), 1.89 (s, 3H), 1.90-2.08 (m, 4H), 2.29 (dd, J=6, 12 Hz, 1H), 2.36 (dd, J=6, 12 Hz, 1H), 2.42 (dd, J=7, 15 Hz, 1H), 2.57 (dd, J=4, 12 Hz, 1H), 2.71 (dd, J=6, 18 Hz, 1H), 2.78 (d, J=6 Hz, 1H), 2.86 (dd, J=10, 16 Hz, 1H), 2.97 (d, J=18 Hz, 1H), 3.82 (d, J=14 Hz, 1H), 3.85 (dd, J=7, 17 Hz, 1H), 4.12 (d, J=14 Hz, 1H), 4.49 (br s, 1H), 6.67 (d, J=2, 8 Hz, 1H), 6.80 (d, J=2 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 7.22 (ddd, J=1, 5, 8 Hz, 1H), 7.54 (d, J=8 Hz, 1H), 7.71 (ddd, J=2, 8, 8 Hz, 1H), 8.51-8.53 (m, 1H).

Reference Example 59
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-7-ethyl-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-yl trifluoromethanesulfonate

[Image Omitted]

The title compound was obtained from the compound Z obtained in Reference Example 55 according to the method described in Reference Example 1.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.12-0.15 (m, 2H), 0.53-0.58 (m, 2H), 0.80 (t, J=7 Hz, 3H), 0.83-1.00 (m, 2H), 1.39 (dd, J=13, 13 Hz, 1H), 1.60-1.71 (m, 2H), 1.92 (dd, J=6, 13 Hz, 1H), 2.08 (ddd, J=3, 12, 12 Hz, 1H), 2.21 (ddd, J=5, 13, 13 Hz, 1H), 2.38-2.40 (m, 2H), 2.68-2.75 (m, 2H), 2.86 (dd, J=7, 19 Hz, 1H), 3.04 (d, J=19 Hz, 1H), 3.13-3.17 (m, 2H), 3.50 (d, J=14 Hz, 1H), 3.79 (s, 3H), 6.83 (d, J=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H).

Reference Example 60
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-7-ethyl-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one

[Image Omitted]

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

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.11-0.18 (m, 2H), 0.51-0.59 (m, 2H), 0.79 (t, J=7 Hz, 3H), 0.84-1.04 (m, 2H), 1.17-1.21 (m, 1H), 1.48 (dd, J=13, 13 Hz, 1H), 1.64-1.74 (m, 1H), 1.91 (dd, J=6, 13 Hz, 1H), 2.06-2.21 (m, 2H), 2.41-2.42 (m, 2H), 2.58-2.63 (m, 1H), 2.68-2.78 (m, 2H), 2.81 (d, J=14 Hz, 1H), 3.05 (d, J=18 Hz, 1H), 3.09 (d, J=14 Hz, 1H), 3.16 (d, J=6 Hz, 1H), 3.77 (s, 3H), 6.68 (dd, J=2, 8 Hz, 1H), 6.82 (d, J=2 Hz, 1H), 6.97 (d, J=8 Hz, 1H).

Reference Example 61
Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-7-ethyl-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one oxime

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 60 according to the method described in Reference Example 3.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.11-0.16 (m, 2H), 0.49-0.57 (m, 2H), 0.81-0.90 (m, 1H), 0.87 (t, J=8 Hz, 3H), 0.99-1.10 (m, 1H), 1.15-1.18 (m, 1H), 1.30 (dd, J=13, 13 Hz, 1H), 1.71-1.80 (m, 2H), 2.07-2.16 (m, 2H), 2.32 (d, J=14 Hz, 1H), 2.37-2.39 (m, 2H), 2.55-2.67 (m, 2H), 2.72 (dd, J=6, 18 Hz, 1H), 3.03 (d, J=18 Hz, 1H), 3.05 (d, J=6 Hz, 1H), 3.71 (s, 3H), 3.78 (d, J=14 Hz, 1H), 6.68 (dd, J=2, 8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 7.12 (d, J=2 Hz, 1H).

Example 344
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-4-ethyl-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Reference Example 61 according to the method described in Example 1.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.10-0.13 (m, 2H), 0.50-0.55 (m, 2H), 0.80-0.86 (m, 1H), 0.94 (t, J=7 Hz, 3H), 1.12-1.14 (m, 1H), 1.34-1.46 (m, 1H), 1.49 (d, J=14 Hz, 1H), 1.57-1.66 (m, 2H), 2.02-2.11 (m, 2H), 2.34-2.36 (m, 2H), 2.56-2.63 (m, 2H), 2.75 (dd, J=6, 18 Hz, 1H), 2.89 (d, J=6 Hz, 1H), 3.01 (d, J=18 Hz, 1H), 3.49 (d, J=15 Hz, 1H), 3.81 (s, 3H), 3.82-3.89 (m, 1H), 5.22 (br s, 1H), 6.70 (dd, J=2, 8 Hz, 1H), 6.96 (d, J=8 Hz, 1H), 7.16 (d, J=2 Hz, 1H).

Example 345
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-4-ethyl-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 344 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.09-0.12 (m, 2H), 0.47-0.55 (m, 2H), 0.79-0.89 (m, 1H), 0.87 (t, J=7 Hz, 3H), 1.04-1.08 (m, 1H), 1.24-1.35 (m, 3H), 1.48-1.61 (m, 2H), 1.95-2.08 (m, 3H), 2.31-2.39 (m, 3H), 2.49-2.58 (m, 1H), 2.81 (dd, J=6, 18 Hz, 1H), 2.89-3.04 (m, 4H), 3.08-3.15 (m, 1H), 3.77 (s, 3H), 4.59 (br s, 1H), 6.70-6.73 (m, 2H), 7.02 (d, J=8 Hz, 1H).

Example 346
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-4-ethyl-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 345 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.07-0.12 (m, 2H), 0.48-0.55 (m, 2H), 0.71 (t, J=7 Hz, 1.5H), 0.80 (t, J=7 Hz, 1.5H), 0.80-0.85 (m, 1H), 1.06-1.09 (m, 1H), 1.16-1.37 (m, 2.5H), 1.55-1.76 (m, 2.5H), 1.88-2.24 (m, 3.5H), 2.32-2.37 (m, 2.5H), 2.49-2.58 (m, 1.5H), 2.74-2.92 (m, 2.5H), 3.03 (dd, J=6, 18 Hz, 1H), 3.78 (s, 1.5H), 3.79 (s, 1.5H), 3.79-3.86 (m, 0.5H), 3.91-4.16 (m, 3H), 4.58-4.66 (m, 0.5H), 6.68-6.77 (m, 2H), 7.05 (d, J=8 Hz, 1H), 7.13-7.17 (m, 1H), 7.43 (d, J=8 Hz, 0.5H), 7.47 (d, J=8 Hz, 0.5H), 7.61-7.66 (m, 1H), 8.52-8.54 (m, 1H).

Example 347
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-4-ethyl-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 346 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.08-0.12 (m, 2H), 0.48-0.52 (m, 2H), 0.63 (t, J=7 Hz, 0.9H), 0.78 (t, J=7 Hz, 2.1H), 0.82-0.91 (m, 1H), 1.07-1.34 (m, 3H), 1.50-1.77 (m, 2H), 1.85-1.98 (m, 1H), 2.03-2.17 (m, 2H), 2.29-2.40 (m, 3H), 2.47-2.51 (m, 1H), 2.63-2.86 (m, 3H), 2.95-3.02 (m, 1H), 3.83 (d, J=14 Hz, 0.3H), 3.87 (dd, J=5, 16 Hz, 0.3H), 3.98-4.27 (m, 3.1H), 4.49-4.57 (m, 0.3H), 6.59 (dd, J=2, 8 Hz, 0.3H), 6.64 (dd, J=2, 8 Hz, 0.7H), 6.70 (d, J=2 Hz, 0.3H), 6.89 (d, J=8 Hz, 0.3H), 6.94 (d, J=8 Hz, 0.7H), 7.00 (d, J=2 Hz, 0.7H), 7.15-7.18 (m, 0.7H), 7.21-7.24 (m, 0.3H), 7.43 (d, J=8 Hz, 0.7H), 7.54 (d, J=8 Hz, 0.3H), 7.66 (ddd, J=2, 8, 8 Hz, 0.7H), 7.71 (ddd, J=2, 8, 8 Hz, 0.3H), 7.85 (br s, 0.7H), 8.04 (br s, 0.3H), 8.51-8.56 (m, 1H).

Example 348
Synthesis of 1-((5aS,6R,11bR)-9,11-dichloro-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound UV obtained in Example 325 according to the method described in Example 26.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.10 (m, 2H), 0.45-0.53 (m, 2H), 0.73-0.85 (m, 1H), 1.43-1.58 (m, 1H), 1.61-1.97 (m, 3H), 2.04-2.34 (m, 4H), 2.38-2.91 (m, 5.7H), 3.07-3.20 (m, 0.3H), 3.33-3.49 (m, 2H), 3.53-3.74 (m, 1.7H), 3.79-3.94 (m, 0.3H), 4.08-4.17 (m, 0.3H), 4.44 (br s, 1H), 4.60-4.75 (m, 0.7H), 6.69 (s, 0.7H), 6.74 (s, 0.3H), 6.79-7.02 (m, 1.7H), 7.09-7.15 (m, 0.3H), 7.36-7.45 (m, 0.7H), 7.50-7.57 (m, 0.3H), 8.26-8.32 (m, 1H).

Example 349
Synthesis of (5aS,6R,11bR)-11-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-10-(methoxymethoxy)-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 330 and benzyl bromide according to the method described in Reference Example 35.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.13 (m, 2H), 0.47-0.54 (m, 2H), 0.74-0.86 (m, 1H), 1.36-1.62 (m, 3H), 1.82-2.04 (m, 3H), 2.25-2.38 (m, 2H), 2.52-2.64 (m, 1H), 2.75-2.97 (m, 3H), 3.16-3.28 (m, 2H), 3.43 (s, 3H), 3.72-3.83 (m, 1H), 4.98 (d, J=12 Hz, 1H), 4.99 (d, J=6 Hz, 1H), 5.08 (d, J=6 Hz, 1H), 5.42-5.49 (m, 1H), 5.56 (d, J=12 Hz, 1H), 6.72 (d, J=8 Hz, 1H), 6.97 (d, J=9 Hz, 1H), 7.22-7.40 (m, 3H), 7.55-7.60 (m, 2H).

Example 350
Synthesis of (5aS,6R,11bS)-11-(benzyloxy)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol

[Image Omitted]

The title compound was obtained from the compound obtained in Example 349 according to the method described in Example 2.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.12 (m, 2H), 0.46-0.53 (m, 2H), 0.74-0.86 (m, 1H), 1.23-1.32 (m, 1H), 1.45-1.55 (m, 1H), 1.57-1.69 (m, 1H), 1.95 (ddd, J=5, 12, 12 Hz, 1H), 2.04-2.22 (m, 2H), 2.26-2.38 (m, 3H), 2.54 (dd, J=3, 12 Hz, 1H), 2.67-2.95 (m, 6H), 3.04 (dd, J=12, 12 Hz, 1H), 4.69 (d, J=11 Hz, 1H), 5.05 (d, J=11 Hz, 1H), 6.68 (d, J=8 Hz, 1H), 6.72 (d, J=8 Hz, 1H), 7.32-7.44 (m, 5H).

Example 351
Synthesis of (5aS,6R,11bR)-11-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(pyridin-2-yl)acetyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-10-yl trifluoromethanesulfonate

[Image Omitted]

To the compound (43.5 mg, 0.10 mmol) obtained in Example 350, 2-(pyridin-2-yl)acetic acid hydrochloride (20.8 mg, 0.12 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (45.6 mg, 0.12 mmol) dissolved in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (52.3 μL, 0.30 mmol), followed by stirring at room temperature for 1 hour. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in N,N-dimethylformamide (1 mL) were added potassium carbonate (55.3 mg, 0.40 mmol) and N-phenylbis (trifluoromethanesulfonimide) (143 mg, 0.40 mmol), followed by stirring at room temperature for 1 hour. To the reaction mixture, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0 to 30% methanol/chloroform) to yield the title compound (56.1 mg, 82%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.15 (m, 2H), 0.46-0.56 (m, 2H), 0.75-0.90 (m, 1H), 1.20-1.30 (m, 1H), 1.45-1.68 (m, 2H), 1.90-2.23 (m, 3H), 2.25-2.42 (m, 2H), 2.43-2.55 (m, 1H), 2.56-2.70 (m, 1H), 2.71-3.46 (m, 5H), 3.50-3.90 (m, 3H), 3.92-4.02 (m, 0.3H), 4.15-4.24 (m, 0.7H), 4.65 (d, J=11 Hz, 0.7H), 4.74 (d, J=11 Hz, 0.3H), 5.26 (d, J=11 Hz, 0.3H), 5.37 (d, J=11 Hz, 0.7H), 6.90 (d, J=9 Hz, 0.3H), 6.97 (d, J=9 Hz, 0.7H), 7.06-7.20 (m, 3H), 7.30-7.44 (m, 5H), 7.53 (ddd, J=2, 8, 8 Hz, 0.3H), 7.55 (ddd, J=2, 8, 8 Hz, 0.7H), 8.44-8.51 (m, 1H).

Example 352
Synthesis of (5aS,6R,11bR)-11-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(pyridin-2-yl)acetyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carbonitrile

[Image Omitted]

The title compound was obtained from the compound obtained in Example 351 according to the method described in Example 241.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.14 (m, 2H), 0.46-0.56 (m, 2H), 0.75-0.92 (m, 1H), 1.20-4.40 (m, 19H), 5.01 (d, J=11 Hz, 0.7H), 5.12 (d, J=11 Hz, 0.3H), 5.52 (d, J=11 Hz, 0.3H), 5.54 (d, J=11 Hz, 0.7H), 6.85 (d, J=8 Hz, 0.3H), 6.93 (d, J=8 Hz, 0.7H), 7.00-7.22 (m, 2H), 7.32-7.60 (m, 7H), 8.42-8.54 (m, 1H).

Example 353
Synthesis of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,11-dihydroxy-3-(2-(pyridin-2-yl)acetyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carboxamide

[Image Omitted]

To the compound (5.0 mg, 0.0089 mmol) obtained in Example 352, palladium (2.0 mg, 0.0089 mmol) acetate, and triphenylphosphine (2.3 mg, 0.0089 mmol) dissolved in toluene (200 μL) was added acetaldoxime (1.6 μL, 0.0267 mmol), followed by stirring at 80° C. for 2 hours. After allowed to cool, to the reaction mixture was added a 28% aqueous ammonia solution, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

To a solution of the obtained crude product in methanol (0.5 mL) were added 10% palladium-activated carbon (15.0 mg) and potassium formate (15.0 mg, 0.178 mmol), followed by stirring at room temperature for 30 minutes. The reaction mixture was filtered through celite, and to the filtrate, a 28% aqueous ammonia solution was added, followed by extraction three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:2 M ammonia-methanol solution=10:1) to yield the title compound (1.7 mg, 39%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.15 (m, 2H), 0.45-0.56 (m, 2H), 0.75-0.92 (m, 1H), 1.01-2.08 (m, 6H), 2.20-3.00 (m, 8H), 3.20-4.85 (m, 5.3H), 4.10-4.61 (m, 1.7H), 6.54 (d, J=8 Hz, 0.3H), 6.60 (d, J=8 Hz, 0.7H), 6.98-7.21 (m, 3H), 7.35-7.79 (m, 2H), 8.40-8.48 (m, 1H).

Example 354
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-(trifluoromethyl)pyridin-2-yl) ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 261 and 2-(4-(trifluoromethyl)pyridin-2-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.04-0.17 (m, 2H), 0.44-0.56 (m, 2H), 0.75-0.91 (m, 1H), 1.01-1.11 (m, 1H), 1.59 (ddd, J=4, 4, 15 Hz, 0.5H), 1.60-1.67 (m, 0.5H), 1.83 (ddd, J=3, 12, 15 Hz, 0.5H), 1.89-2.11 (m, 3H), 2.15 (s, 1.5H), 2.15 (s, 1.5H), 2.17-2.25 (m, 1H), 2.26-2.40 (m, 2H), 2.50-2.60 (m, 1.5H), 2.72 (dd, J=6, 18 Hz, 0.5H), 2.77 (dd, J=6, 18 Hz, 0.5H), 2.87 (d, J=6 Hz, 0.5H), 2.90 (d, J=18 Hz, 0.5H), 2.91 (d, J=6 Hz, 0.5H), 2.97 (d, J=18 Hz, 0.5H), 3.11 (ddd, J=2, 10, 14 Hz, 0.5H), 3.46 (ddd, J=4, 4, 13 Hz, 0.5H), 3.52 (ddd, J=2, 12, 14 Hz, 0.5H), 3.62 (ddd, J=4, 4, 14 Hz, 0.5H), 3.67-3.98 (m, 1.5H), 3.73 (d, J=15 Hz, 0.5H), 3.78 (s, 1.5H), 3.80 (s, 1.5H), 3.84 (d, J=15 Hz, 0.5H), 3.93 (d, J=15 Hz, 0.5H), 3.99 (d, J=15 Hz, 0.5H), 4.20 (ddd, J=2, 6, 14 Hz, 0.5H), 6.49 (s, 0.5H), 6.55 (s, 0.5H), 6.85 (s, 1H), 7.32-7.38 (m, 1.5H), 7.56-7.59 (m, 0.5H), 8.64 (d, J=5 Hz, 0.5H), 8.68 (d, J=5 Hz, 0.5H).

Example 355
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 354 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.16 (m, 2H), 0.43-0.56 (m, 2H), 0.75-0.88 (m, 1H), 1.01-1.15 (m, 1H), 1.51-1.63 (m, 1H), 1.77-1.86 (m, 1H), 1.87-1.96 (m, 0.3H), 1.92 (ddd, J=4, 13, 13 Hz, 0.7H), 1.98-2.19 (m, 2H), 2.10 (s, 2.1H), 2.17 (s, 0.9H), 2.23-2.39 (m, 2.7H), 2.49-2.62 (m, 1.3H), 2.70 (dd, J=6, 18 Hz, 0.7H), 2.71-2.78 (m, 0.3H), 2.84 (d, J=6 Hz, 0.7H), 2.90 (d, J=6 Hz, 0.3H), 2.91 (d, J=18 Hz, 0.3H), 2.94-3.02 (m, 0.7H), 2.96 (d, J=18 Hz, 0.7H), 3.32-3.48 (m, 1.3H), 3.77-3.86 (m, 0.3H), 3.78 (d, J=15 Hz, 0.3H), 3.81 (d, J=15 Hz, 0.3H), 3.89 (ddd, J=3, 5, 14 Hz, 0.3H), 3.97 (ddd, J=4, 13, 13 Hz, 0.7H), 4.01 (d, J=15 Hz, 0.7H), 4.03 (d, J=15 Hz, 0.7H), 4.27-4.34 (m, 0.7H), 4.42 (br s, 0.7H), 4.52 (br s, 0.3H), 6.63 (s, 0.3H), 6.79 (s, 1.4H), 6.81 (s, 0.3H), 7.35-7.43 (m, 1.3H), 7.58-7.61 (m, 0.7H), 8.64 (d, J=5 Hz, 0.3H), 8.70 (d, J=5 Hz, 0.7H).

Example 356
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-indazol-3-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 261 and 2-(1H-indazol-3-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.15 (m, 2H), 0.44-0.57 (m, 2H), 0.75-0.91 (m, 1H), 0.99-1.11 (m, 1H), 1.50-1.64 (m, 1H), 1.76 (ddd, J=3, 9, 12 Hz, 0.5H), 1.80 (ddd, J=3, 8, 11 Hz, 0.5H), 1.91-2.19 (m, 3H), 2.15 (s, 1.5H), 2.16 (s, 1.5H), 2.26-2.35 (m, 1.5H), 2.28 (dd, J=6, 13 Hz, 0.5H), 2.35 (dd, J=6, 13 Hz, 0.5H), 2.45-2.56 (m, 1.5H), 2.64 (dd, J=6, 18 Hz, 0.5H), 2.73 (dd, J=6, 18 Hz, 0.5H), 2.85 (d, J=6 Hz, 0.5H), 2.88 (d, J=18 Hz, 0.5H), 2.89 (d, J=6 Hz, 0.5H), 2.92 (d, J=18 Hz, 0.5H), 3.27 (ddd, J=2, 12, 14 Hz, 0.5H), 3.44-3.56 (m, 1H), 3.60 (ddd, J=4, 4, 14 Hz, 0.5H), 3.72-3.84 (m, 0.5H), 3.77 (s, 1.5H), 3.81 (s, 1.5H), 3.85-3.98 (m, 1H), 3.85 (d, J=15 Hz, 0.5H), 3.92 (d, J=15 Hz, 0.5H), 4.03 (d, J=16 Hz, 0.5H), 4.06 (d, J=16 Hz, 0.5H), 4.07-4.14 (m, 0.5H), 4.50 (br s, 1H), 6.52 (s, 0.5H), 6.53 (s, 0.5H), 6.79 (s, 0.5H), 6.81 (s, 0.5H), 7.06 (ddd, J=1, 6, 6 Hz, 0.5H), 7.07 (ddd, J=1, 6, 6 Hz, 0.5H), 7.27-7.37 (m, 2H), 7.62-7.69 (m, 1H), 10.1 (br s, 1H).

Example 357
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(1H-indazol-3-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 356 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.40-0.56 (m, 2H), 0.73-1.00 (m, 2H), 1.47-2.06 (m, 5.5H), 2.17 (s, 1.5H), 2.21 (s, 1.5H), 2.22-2.40 (m, 1H), 2.26 (dd, J=7, 13 Hz, 0.5H), 2.31 (d, J=6 Hz, 1H), 2.33 (dd, J=7, 13 Hz, 0.5H), 2.42-2.52 (m, 1H), 2.59 (dd, J=6, 18 Hz, 0.5H), 2.68 (dd, J=6, 18 Hz, 0.5H), 2.81-2.89 (m, 1H), 2.83 (d, J=6 Hz, 0.5H), 2.90 (d, J=18 Hz, 0.5H), 2.97-3.10 (m, 0.5H), 3.13-3.27 (m, 0.5H), 3.40-3.59 (m, 1H), 3.70-4.00 (m, 3.5H), 4.54 (br s, 1H), 6.63 (s, 0.5H), 6.69 (s, 0.5H), 6.74 (s, 0.5H), 6.76 (s, 0.5H), 6.93-7.06 (m, 1H), 7.16-7.35 (m, 2H), 7.49-7.57 (m, 0.5H), 7.60-7.69 (m, 0.5H).

Example 358
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(3-fluoropyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 261 and 2-(3-fluoropyridin-2-yl)acetic acid according to the method described in Example 5.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.17 (m, 2H), 0.46-0.54 (m, 2H), 0.76-0.88 (m, 1H), 1.03-1.11 (m, 1H), 1.56-1.65 (m, 1H), 1.84 (ddd, J=2, 12, 15 Hz, 0.4H), 1.91-2.39 (m, 5.4H), 2.16 (s, 1.8H), 2.18 (s, 1.2H), 2.37 (dd, J=7, 13 Hz, 0.6H), 2.50-2.59 (m, 0.8H), 2.61 (ddd, J=4, 12, 16 Hz, 0.6H), 2.73-2.82 (m, 0.4H), 2.74 (dd, J=6, 18 Hz, 0.6H), 2.89 (d, J=6 Hz, 0.6H), 2.91 (d, J=6 Hz, 0.4H), 2.91 (d, J=18 Hz, 0.4H), 2.98 (d, J=18 Hz, 0.6H), 3.04-3.13 (m, 0.6H), 3.44 (ddd, J=4, 4, 13 Hz, 0.6H), 3.45-3.54 (m, 0.4H), 3.57 (ddd, J=4, 4, 14 Hz, 0.4H), 3.67 (dd, J=2, 16 Hz, 0.4H), 3.68-3.82 (m, 0.6H), 3.77 (s, 1.8H), 3.80 (s, 1.2H), 3.81 (dd, J=2, 16 Hz, 0.4H), 3.88-4.01 (m, 1H), 3.89 (dd, J=2, 16 Hz, 0.6H), 3.98 (dd, J=2, 16 Hz, 0.6H), 4.24 (ddd, J=2, 6, 15 Hz, 0.6H), 6.52 (s, 0.4H), 6.55 (s, 0.6H), 6.86 (s, 1H), 7.16 (ddd, J=4, 4, 9 Hz, 0.4H), 7.19 (ddd, J=4, 4, 8 Hz, 0.6H), 7.32 (ddd, J=1, 9, 10 Hz, 0.4H), 7.34 (ddd, J=1, 8, 10 Hz, 0.6H), 8.29 (ddd, J=1, 1, 4 Hz, 0.4H), 8.33 (ddd, J=1, 1, 4 Hz, 0.6H).

Example 359
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(3-fluoropyridin-2-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 358 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.44-0.57 (m, 2H), 0.76-0.90 (m, 1H), 1.01-1.11 (m, 1H), 1.52-1.64 (m, 1H), 1.79-2.07 (m, 2.7H), 2.08-2.26 (m, 2H), 2.09 (s, 2.1H), 2.19 (s, 0.9H), 2.29 (dd, J=6, 12 Hz, 0.3H), 2.32-2.39 (m, 0.3H), 2.34 (d, J=6 Hz, 1.4H), 2.48-2.56 (m, 1H), 2.59 (ddd, J=5, 11, 16 Hz, 0.3H), 2.70 (dd, J=6, 18 Hz, 0.7H), 2.74 (dd, J=6, 18 Hz, 0.3H), 2.86 (d, J=6 Hz, 0.7H), 2.90 (d, J=6 Hz, 0.3H), 2.90 (d, J=18 Hz, 0.3H), 2.94-3.03 (m, 0.7H), 2.95 (d, J=18 Hz, 0.7H), 3.30-3.47 (m, 1.3H), 3.74 (dd, J=2, 16 Hz, 0.3H), 3.78 (dd, J=2, 16 Hz, 0.3H), 3.79-3.92 (m, 1H), 3.93-3.99 (m, 0.3H), 3.94 (dd, J=2, 16 Hz, 0.7H), 4.01 (dd, J=2, 16 Hz, 0.7H), 4.30 (ddd, J=2, 6, 14 Hz, 0.7H), 4.48 (br s, 1H), 6.64 (s, 0.3H), 6.75 (s, 0.7H), 6.78 (s, 0.7H), 6.82 (s, 0.3H), 7.19 (ddd, J=4, 4, 8 Hz, 0.3H), 7.21 (ddd, J=4, 4, 8 Hz, 0.7H), 7.34 (ddd, J=1, 8, 10 Hz, 0.3H), 7.37 (ddd, J=1, 8, 10 Hz, 0.7H), 8.29 (ddd, J=1, 1, 4 Hz, 0.3H), 8.35 (ddd, J=1, 1, 4 Hz, 0.7H).

Example 360
Synthesis of (5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-N-methyl-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-10-carboxamide

[Image Omitted]

The title compound was obtained from the compound obtained in Example 334 according to the methods described in Example 243 and Example 31.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.80-1.00 (m, 2H), 1.00-1.10 (m, 1H), 1.20-1.40 (m, 1H), 1.40-1.55 (m, 1H), 1.55-2.20 (m, 7H), 2.20-2.65 (m, 5H), 2.65-2.80 (m, 1H), 2.80-3.15 (m, 7H), 3.15-3.30 (m, 1H), 3.90-4.10 (m, 2H), 6.20-6.40 (m, 1H), 6.80 (s, 1H), 7.17 (d, J=8 Hz, 1H), 7.21 (s, 1H), 7.43 (dd, J=2, 8 Hz, 1H), 7.60 (d, J=2 Hz, 1H).

Example 361
Synthesis of phenyl (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate

[Image Omitted]

To the compound E (10 mg, 0.030 mmol) obtained in Example 3 dissolved in tetrahydrofuran (2 mL) were added triethylamine (20 μL, 0.14 mmol) and phenyl chloroformate (14 μL, 0.11 mmol), followed by stirring at room temperature for 30 minutes. Thereafter, to the reaction solution, a 2 M aqueous sodium hydroxide solution (1 mL) was added, followed by further stirring at room temperature for 3 hours. To the reaction solution, a saturated ammonium chloride aqueous solution was added, followed by extraction three times with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 40 to 100% ethyl acetate/hexane) to yield the title compound (12.2 mg, 89%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.06-0.16 (m, 2H), 0.48-0.55 (m, 2H), 0.77-0.88 (m, 1H), 1.02-1.11 (m, 1H), 1.56-1.66 (m, 1H), 1.86-2.12 (m, 4H), 2.28-2.49 (m, 2.5H), 2.51-2.64 (m, 1.5H), 2.76-2.85 (m, 1H), 2.91-3.03 (m, 2H), 3.50-3.74 (m, 3H), 3.76-3.96 (m, 1H), 6.60-6.68 (m, 2H), 6.85-6.91 (m, 2H), 6.92-6.98 (m, 1H), 7.09-7.17 (m, 1H), 7.24-7.32 (m, 2H).

Example 362
Synthesis of (5aS,6R,11bR)—N-(4-chlorophenyl)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxamide

[Image Omitted]

To the compound E (30 mg, 0.091 mmol) obtained in Example 3 dissolved in chloroform (2 mL) were added triethylamine (25 μL, 0.18 mmol) and 4-chlorophenyl isocyanate (28 mg, 0.18 mmol), followed by stirring at room temperature for 1 hour. To the reaction solution, a saturated sodium bicarbonate aqueous solution was added, followed by extraction three times with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the obtained concentrated residue dissolved in tetrahydrofuran (3 mL), a 2 M aqueous sodium hydroxide solution (1 mL) was added, followed by stirring at room temperature for 16 hours. To the reaction solution, a saturated ammonium chloride aqueous solution was added, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:10% aqueous ammonia-methanol solution=12:1) to yield the title compound (36.4 mg, 83%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.14 (m, 2H), 0.46-0.55 (m, 2H), 0.75-0.87 (m, 1H), 0.97-1.05 (m, 1H), 1.53-1.62 (m, 1H), 1.85-2.07 (m, 4H), 2.16-2.40 (m, 3H), 2.47-2.57 (m, 1H), 2.69-2.79 (m, 1H), 2.85-3.00 (m, 2H), 3.11-3.31 (m, 1H), 3.38-3.55 (m, 1H), 3.60-3.92 (m, 2H), 6.49 (br s, 1H), 6.58-6.68 (m, 2H), 6.89 (d, J=8 Hz, 1H), 7.11-7.20 (m, 4H).

Example 363
Synthesis of (5aS,6R,11bR)—N-(4-chlorophenyl)-14-(cyclopropylmethyl)-5a,10-dihydroxy-N-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxamide

[Image Omitted]

To the compound (29 mg, 0.060 mmol) obtained in Example 362 dissolved in tetrahydrofuran (2 mL) were added methyl iodide (15 μL, 0.24 mmol) and sodium hydride (55% oil dispersion) (11 mg, 0.24 mmol), followed by stirring at room temperature for 17 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, followed by extraction 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 preparative thin layer chromatography (chloroform:10% aqueous ammonia-methanol solution=12:1) to yield the title compound (3.3 mg, 11%) as a colorless amorphous form.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.12 (m, 2H), 0.45-0.52 (m, 2H), 0.74-0.85 (m, 1H), 1.05-1.15 (m, 1H), 1.27-1.36 (m, 1H), 1.64-1.76 (m, 1H), 1.93-2.13 (m, 3H), 2.26-2.36 (m, 2H), 2.44-2.57 (m, 2H), 2.66 (dd, J=6, 18 Hz, 1H), 2.77-2.83 (m, 1H), 2.89-3.00 (m, 2H), 3.09 (s, 3H), 3.21-3.33 (m, 2H), 3.51-3.63 (m, 1H), 4.46 (br s, 1H), 6.66 (dd, J=2, 8 Hz, 1H), 6.79-6.88 (m, 3H), 6.94 (d, J=8 Hz, 1H), 7.16-7.22 (m, 2H).

Example 364
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-fluoro-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 261 and 4-fluoro-1H-pyrazole according to the method described in Example 132.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.05-0.18 (m, 2H), 0.45-0.59 (m, 2H), 0.76-0.90 (m, 1H), 1.03-1.12 (m, 1H), 1.55-1.65 (m, 1H), 1.80-1.91 (m, 1H), 1.92-2.09 (m, 2.4H), 2.10-2.29 (m, 1.2H), 2.17 (s, 1.8H), 2.17 (s, 1.2H), 2.30-2.40 (m, 2H), 2.49-2.61 (m, 1.4H), 2.71 (dd, J=6, 18 Hz, 0.6H), 2.77 (dd, J=6, 19 Hz, 0.4H), 2.88 (d, J=6 Hz, 0.6H), 2.91 (d, J=18 Hz, 0.4H), 2.91 (d, J=6 Hz, 0.4H), 2.97 (d, J=18 Hz, 0.6H), 3.16 (ddd, J=2, 11, 14 Hz, 0.6H), 3.34 (ddd, J=4, 4, 13 Hz, 0.6H), 3.46-3.55 (m, 0.8H), 3.64 (ddd, J=4, 12, 14 Hz, 0.4H), 3.76-3.88 (m, 1.2H), 3.79 (s, 1.8H), 3.82 (s, 1.2H), 4.10 (ddd, J=3, 6, 14 Hz, 0.4H), 4.52 (d, J=16 Hz, 0.4H), 4.77 (d, J=16 Hz, 0.4H), 4.86 (s, 1.2H), 6.51 (s, 0.4H), 6.55 (s, 0.6H), 6.87 (s, 0.6H), 6.87 (s, 0.4H), 7.16 (dd, J=1, 4 Hz, 0.4H), 7.27-7.29 (m, 0.6H), 7.31 (dd, J=1, 4 Hz, 0.4H), 7.32-7.34 (m, 0.6H).

Example 365
Synthesis of 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-fluoro-1H-pyrazol-1-yl)ethan-1-one

[Image Omitted]

The title compound was obtained from the compound obtained in Example 364 according to the method described in Example 6.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.03-0.16 (m, 2H), 0.43-0.57 (m, 2H), 0.76-0.90 (m, 1H), 1.02-1.11 (m, 1H), 1.54-1.62 (m, 1H), 1.78-2.24 (m, 4.6H), 2.18 (s, 1.8H), 2.19 (s, 1.2H), 2.29 (dd, J=6, 13 Hz, 0.4H), 2.30-2.39 (m, 1.2H), 2.39 (dd, J=6, 12 Hz, 0.4H), 2.51-2.70 (m, 1.4H), 2.70 (dd, J=6, 18 Hz, 0.6H), 2.74 (dd, J=6, 19 Hz, 0.4H), 2.89 (d, J=6 Hz, 0.6H), 2.90 (d, J=19 Hz, 0.4H), 2.91 (d, J=6 Hz, 0.4H), 2.97 (d, J=18 Hz, 0.6H), 3.08-3.17 (m, 0.6H), 3.27-3.39 (m, 1.4H), 3.71 (ddd, J=5, 12, 14 Hz, 0.4H), 3.79-3.89 (m, 1H), 4.08 (ddd, J=2, 5, 14 Hz, 0.6H), 4.46 (br s, 0.4H), 4.52 (br s, 0.6H), 4.65 (d, J=16 Hz, 0.4H), 4.67 (d, J=16 Hz, 0.4H), 4.87 (d, J=17 Hz, 0.6H), 4.87 (d, J=17 Hz, 0.6H), 6.11 (br s, 0.4H), 6.26 (br s, 0.6H), 6.62 (s, 0.4H), 6.64 (s, 0.6H), 6.83 (s, 0.4H), 6.84 (s, 0.6H), 7.19 (d, J=5 Hz, 0.4H), 7.30 (d, J=5 Hz, 0.6H), 7.31 (d, J=Hz, 0.4H), 7.34 (d, J=5 Hz, 0.6H).

Test Example 1

Opioid Receptor Function Test

The function activity of the compound of the present invention on κ opioid receptors was examined.

Method: Using a Lance Ultra cAMP kit (Perkin Elmer), the examination was performed according to a predetermined method. In evaluation of agonist activity, CHO cells expressing human κ opioid receptors (Catalog No. CT6606, accession No. NM_000912) and a test compound were reacted in an assay buffer (1×HSS, 5 mM HEPES, pH 7.4, 0.5 mM IBMX (isobutylmethyixanthine), 0.1% SA) in the presence of 10 μM forskolin for 30 minutes. Subsequently, a cAMP detection reagent in the kit was added. One hour later, time-resolved fluorescence measurement was performed using an EnVision plate reader (Perkin Elmer). The evaluation of the test compound was performed in a concentration range of 10⁻¹⁴to 10⁻⁷M for the κ opioid receptor function test.

TABLE 1

Examples
EC₅₀value (nM)

Example 3
0.83

Example 22
0.13

Example 27
0.13

Example 31
0.11

Example 32
0.13

Example 33
0.92

Example 34
0.040

Example 36
0.025

Example 37
0.051

Example 41
0.13

Example 45
0.17

Example 47
0.23

Example 49
0.089

Example 50
0.027

Example 52
0.15

Example 54
0.36

Example 56
0.97

Example 58
0.14

Example 60
0.056

Example 61
0.028

Example 66
0.14

Example 69
0.28

Example 77
0.026

Example 83
0.37

Example 84
0.47

Example 88
0.75

Example 90
0.87

Example 100
0.26

Example 102
0.13

Example 105
0.088

Example 108
0.066

Example 112
0.037

Example 113
0.56

Example 114
0.043

Example 115
0.15

Example 116
0.021

Example 117
0.40

Example 118
0.016

Example 120
0.053

Example 122
0.15

Example 123
0.064

Example 124
0.040

Example 126
0.74

Example 128
0.10

Example 130
0.36

Example 132
0.16

Example 133
0.033

Example 137
0.14

TABLE 2

Examples
EC₅₀value (nM)

Example 143
0.033

Example 144
0.019

Example 149
0.023

Example 159
0.77

Example 160
0.045

Example 162
0.39

Example 163
0.076

Example 164
0.26

Example 165
0.28

Example 166
0.31

Example 168
0.047

Example 169
0.094

Example 177
0.019

Example 179
0.024

Example 181
0.32

Example 182
0.22

Example 183
0.030

Example 184
0.095

Example 185
0.39

Example 186
0.99

Example 188
0.69

Example 189
0.39

Example 190
0.32

Example 191
0.48

Example 193
0.035

Example 195
0.023

Example 196
0.22

Example 198
0.59

Example 209
0.050

Example 210
0.72

Example 214
0.13

Example 217
0.18

Example 218
0.16

Example 219
0.23

Example 220
0.26

Example 221
0.034

Example 225
0.11

Example 226
0.017

Example 227 (I)
0.015

Example 227 (II)
0.16

Example 228
0.010

Example 229
0.025

Example 230
0.066

Example 232
0.17

Example 234
0.087

Example 236
0.012

Example 237
0.29

Example 238
0.45

Example 244
0.47

Example 246
2.6

Example 262
0.085

Example 263
0.89

Example 264
0.29

Example 265
0.12

Example 266
0.074

Example 270
0.052

Example 274
0.070

Example 281
0.14

Example 291
0.55

Example 308
0.60

Example 314
0.27

Example 323
0.18

Example 326
0.18

Example 328
0.33

Example 329
0.084

Example 332
0.64

Example 336
0.18

Example 343
0.56

Example 347
0.12

Example 355
0.11

Example 357
0.062

As shown in Table 1 and Table 2, it has been confirmed that the compound of the present invention exhibits potent agonist activity on κ opioid receptors.

Test Example 2

Metabolic Stability Test

To determine the unchanged product-residual ratio of the test compound in the reaction sample, human liver microsomes and the test compound were reacted for a predetermined time (0 to 30 minutes). The unchanged product-residual ratio at a reaction time of 0 hours was considered 100%, the residual ratio after incubation was log-linear plotted with respect to the time, a regression line (y=100 e^−kt, k=slope of the line: elimination rate constant) was determined, and the metabolic clearance CL_int(mL/min/kg) was calculated using the following formula.

CL_int*=k (−min)×45 (mg MS protein/g liver)×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 March; 39 (3): 383-393.

TABLE 3

Test compound¹⁾
CL_int(mL/min/kg)

Example 20
3.9

Example 22
7.2

Example 31
7.5

Example 45
4.5

Example 50
8.7

Example 61
26.0

Example 77
6.7

Example 90
11.6

Example 124
14.3

Example 139
29.7

Example 176
8.2

Example 177
9.5

Example 229
5.1

Example 244
7.7

Example 247
4.8

Example 262
5.8

Example 263
18.0

Example 266
4.4

Example 277
6.4

Example 281
13.7

Example 291
8.0

Example 295
17.2

Example 298
22.5

Example 308
9.0

Example 320
22.9

Example 322
6.6

Example 326
10.9

Example 332
9.2

Example 353
7.9

¹⁾A hydrochloride was used.

As shown in Table 3, the compound of the present invention exhibits excellent metabolic stability.

Test Example 3

Mouse Acetic Acid Writhing Test

The analgesic effect of the test compound was evaluated by an acetic acid writhing test. For the experiment, ICR male mice were used and acclimated to a plastic open field for 30 minutes before starting the test. After acclimation, the mice were administered with the test compound (30 to 3000 μg/kg) or water for injection subcutaneously or orally, and once returned to the open field. Thirty minutes after the administration of the test compound, a 0.6% aqueous acetic acid solution was additionally administered to the same mice by intraperitoneal administration. From 10 minutes after administration of the 0.6% aqueous acetic acid solution, the number of writhing reactions (writhing reactions in which the mouse stretches while pressing the abdominal cavity against the floor) induced in the mice was measured for 10 minutes, and the number of writhing reactions was compared with that of a control group (water for injection-administrated group) to evaluate the analgesic effect of the test compound. The results are shown in Table 4.

TABLE 4

Writhing suppressing effect

Test
Administration

Writhing
ED₅₀value

compound¹⁾
route
Dose
suppression rate²⁾
(μg/kg)

Example 22
Oral
30
+
15.2

300
++

Example 34
Subcutaneous
30
++
N.C.³⁾

Example 45
Subcutaneous
30
++
N.C.³⁾

Example 50
Oral
300
+
210

1000
+++

Example 77
Subcutaneous
30
+
12.5

300
+++

Example 308
Oral
1000
+
1420

3000
++

¹⁾A hydrochloride was used.

²⁾The writhing suppressing effect was classified as follows according to the suppression rate.

40 ≤ % <60: +,

60 ≤ % <80: ++,

80 ≤ %: +++

³⁾N.C.: not calculated

As shown in Table 4, it has been confirmed that the compound of the present invention exhibits a potent analgesic effect.

Test Example 4

Rotarod Test

The sedative effect (motor coordination disorder effect) of the test compound was evaluated by a rotarod test. For the experiment, ICR male mice that had learned a motion task in advance by rotarod training were used. Rotarod training was repeated while providing a moderate rest period until the mice acclimatized for 60 seconds on a rotating shaft rod rotating at 3 rpm (diameter 3 cm, KN-75, Natsume Seisakusho Co., Ltd.) and acquired motor learning. Thereafter, a total of three training units of 3 rpm for 180 seconds, 4 rpm for 180 seconds, and 5 rpm for 180 seconds were provided. After all training, a 90 to 120 minute rest was provided to reduce the burden on the mice. A mouse that failed to acquire motor learning by training was not used for the experiment.

In the rotarod test, the number of times of falling at 5 rpm for 300 seconds (cut-off value 300 seconds) was measured as a pre-value before administration of the test compound. After the measurement of the pre-value, the mice were treated with the test compound (3 to 500 μg/kg) or water for injection by subcutaneous administration (s.c.) or oral administration (p.o.), and the number of times of falling at 5 rpm for 300 seconds was measured at each of four points of 30 minutes, 60 minutes, 90 minutes, and 120 minutes after administration of the test compound, in the same manner as measurement of the pre-value. The total number of times of falling at the four points was defined as the total number of times of falling (total falls), and the sedative effect of the test compound was evaluated. The results are shown in FIGS. 1 to 5. As the test compound, a hydrochloride was used. In FIGS. 1 to 5, Mean±SEM ns; not significant (Welch's t test), Mean±SEM *; p<0.05, ***; p<0.001 (Bonferroni's test).

As shown in FIGS. 1 to 5, it has been confirmed that the therapeutic range is wide, since the compound of the present invention does not exhibit a sedative effect even at a dose higher than that of the comparative compound Nalfurafine, and the dose is 30 times or more higher than the ED₅₀value (Test Example 3) in the mouse acetic acid writhing test.

Although preferred examples of the present invention have been described above, the present invention is not limited to these examples. Addition, omission, substitution and other changes of the configuration can be made without departing from the spirit of the present invention. The present invention is not limited by the foregoing description, but only by the scope of the appended claims.