Azepane Derivatives

Abstract

Provided are: an azepan derivative represented by general formula (I) and a pharmaceutically acceptable salt thereof (in the formula: R1 represents a hydrogen atom, a C1-6 alkyl group which may have a substituent, etc.; R2 and R3 are the same as or different from each other, and represent a hydrogen atom, a C1-6 alkyl group which may have a substituent, etc.; R4 and R5 are the same as or different from each other, and represent a hydrogen atom, a C1-6 alkyl group which may have a substituent, etc.; R6 represents a hydrogen atom, a C1-6 alkyl group which may have a substituent, etc.; R7 and R8 are the same as or different from each other, and represent a hydrogen atom, a C1-6 alkyl group which may have a substituent, etc.; R9 and R10 are the same as or different from each other, and represent a hydrogen atom, a C1-6 alkyl group which may have a substituent, etc.; R11 represents a hydrogen atom, a C1-6 alkyl group which may have a substituent, etc.; A and B differently represent a methyl group, a carbonyl group, etc.; and X represents a nitrogen atom or an N-oxide.).

Description

[Technical field]

[0001] The present invention relates to azepane derivatives having κ opioid receptor agonistic activity. This application claims priority based on Japanese Patent Application No. 2019-179727, filed in Japan on September 30, 2019, the contents of which are incorporated herein by reference. [Background technology]

[0002] There are three types of opioid receptors: μ, δ, and κ. Morphine, which has high affinity for μ opioid receptors, has long been used as an analgesic. However, μ opioid receptor agonists, including morphine, are known to cause adverse events such as dependence and respiratory depression via the μ opioid receptor. On the other hand, kappa opioid receptor agonists also exhibit analgesic effects, but are known not to be involved in the adverse events seen with morphine. On the other hand, it is known that kappa opioid receptor agonists generally exhibit sedative and drug aversion effects. The only kappa opioid receptor agonist that is free of drug aversion is nalfurafine (Patent Document 1). However, since nalfurafine exhibits sedative effects at analgesic doses, it has been approved as an antipruritic drug but not as an analgesic drug. In other words, there is no kappa opioid receptor selective agonist approved as an analgesic drug yet. Therefore, a selective agonist for the κ-opioid receptor that does not exhibit sedative or drug aversion effects is expected to serve as an analgesic and other excellent therapeutic, ameliorative or preventive agent for diseases or symptoms associated with the κ-opioid receptor. Patent Document 2 describes the following formula (A):

[0003] [ka]

[0004] It has been disclosed that the compound represented by the formula (I) has κ opioid receptor agonist activity. However, the activity is not sufficient. In addition, Patent Document 3 describes the following formula (B):

[0005] [ka]

[0006] A compound represented by the formula (I) has been reported. It is stated that this compound has selective binding to κ opioid receptors and analgesic activity. However, its analgesic activity was not satisfactory. Furthermore, Patent Document 4 and Non-Patent Document 1 disclose a compound (C) represented by the following formula:

[0007] [ka]

[0008] However, it has been disclosed that this compound has extremely high activity, but the stability of this compound in vivo is insufficient. If a compound is unstable in vivo, it will not exert the expected medicinal effect, and its development as a pharmaceutical will be difficult due to the effects of its decomposition products on the body, etc. Therefore, in vivo stability is an important requirement in the development of pharmaceuticals. There are currently no analgesics on the market that have high kappa opioid receptor agonist activity. Therefore, in aiming at analgesics, there is a demand for compounds that exhibit selectivity and high activity for κ opioid receptors, have excellent stability in the body, and are free from sedative and drug aversion effects. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 1993 / 5081 Brochure [Patent Document 2] JP 2008-179554 A [Patent Document 3] Patent No. 2525552 [Patent Document 4] U.S. Patent No. 963460 [Non-patent literature]

[0010] [Non-Patent Document 1] JNRC2016 36th Symposium on Analgesics and Opioid Peptides, Program and Abstracts, p. 37, Society for Analgesics and Opioid Peptides Summary of the Invention [Problem to be solved by the invention]

[0011] An object of the present invention is to provide a medicine which has suppressed sedative and drug aversion effects and is effective in treating, ameliorating or preventing various diseases and symptoms associated with κ opioid receptors. [Means for solving the problem]

[0012] Under such circumstances, the present inventors conducted intensive research and found that a specific azepane derivative exhibits strong agonist activity against the κ-opioid receptor and high stability in vivo. Furthermore, it was revealed that this azepane derivative exhibits strong analgesic effect and does not exhibit sedative effect even at a higher dose than nalfurafine (Patent Document 1). As described above, the inventors have found an azepane derivative that is a highly safe κ-opioid receptor agonist aimed at analgesics, and have completed the present invention. [1] That is, the present invention provides a compound represented by the following general formula (I):

[0013] [ka] (In the formula, R 1 is a hydrogen atom, optionally substituted C 1-6 Alkyl group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3-6 Cycloalkyl C 1-6 Alkyl group, optionally substituted C 6-10An aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 represents an alkynyl group, an optionally substituted acyl group, or an amino-protecting group, R 2 and R 3 are the same or different and may have a hydrogen atom or a substituent, 1-6 Alkyl group, optionally substituted C 1-6 an alkoxy group, a halogen atom, an optionally protected hydroxy group, or R 2 and R 3 together form a carbonyl group or R 2 and R 3 C which may have a substituent 3-6 represents a saturated hydrocarbon ring or a cyclic ketal which may have a substituent, R 4 and R 5 are the same or different and may have a hydrogen atom or a substituent, 1-6 Alkyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 represents a cycloalkyl group, an optionally substituted amino group, a protected amino group, a halogen atom, an optionally protected hydroxy group, a carboxy group, a carboxylate group, or an optionally substituted carbamoyl group, R 6 is a hydrogen atom, optionally substituted C 1-6 An alkoxy group, an optionally substituted amino group, a protected amino group, a halogen atom, an optionally protected hydroxy group, an optionally substituted tetrazolyloxy group, a cyano group, a carboxy group, a carboxylate group, an optionally substituted carbamoyl group, an optionally substituted C 6-10 Aryl group, optionally substituted heteroaryl group, C 6-10 represents an aryloxy group or a saccharide, R 7 and R8 are the same or different and may have a hydrogen atom or a substituent, 1-6 Alkyl group, optionally substituted C 1-6 an alkoxy group, a halogen atom, an optionally protected hydroxy group, or R 7 and R 8 Together, they form a carbonyl or thiocarbonyl group, or R 7 and R 8 C which may have a substituent 3-6 represents a saturated hydrocarbon ring or a cyclic ketal which may have a substituent, R 9 and R 10 are the same or different and may have a hydrogen atom or a substituent, 1-6 Alkyl group, optionally substituted C 1-6 an alkoxy group, a halogen atom, an optionally protected hydroxy group, or R 9 and R 10 Together, they form a carbonyl or thiocarbonyl group, or R 9 and R 10 C which may have a substituent 3-6 represents a saturated hydrocarbon ring or a cyclic ketal which may have a substituent, R 11 is a hydrogen atom, optionally substituted C 1-6 Alkyl group, optionally substituted C 1-6 represents an alkoxy group, an aralkyloxy group which may have a substituent, an amino group which may have a substituent, a protected amino group, a halogen atom, a hydroxy group which may be protected, or a cyano group, A and B are different and NR 18 (R 18 represents a hydrogen atom or an amino protecting group; a methylene group, a carbonyl group, or a group represented by the following general formula (II): [ka] (R 12 and R 13 are the same or different and may have a hydrogen atom, a halogen atom or a substituent. 1-6 Indicates an alkyl group or R on the same carbon12 and R 13 C which may have a substituent 3-6 A saturated hydrocarbon ring, a saturated heterocyclic ring which may have a substituent, or a pair of adjacent R 12 C which may be bonded to each other and have a substituent 3-6 It is possible to form a saturated hydrocarbon ring or a saturated heterocyclic ring which may have a substituent, R 14 is a hydrogen atom, optionally substituted C 1-6 Alkyl group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1-6 An alkoxy group, an optionally substituted amino group, a protected amino group, a halogen atom, an optionally protected hydroxy group, an optionally substituted C 6-10 represents an aryl group, a heteroaryl group which may have a substituent, a saturated heterocyclic group which may have a substituent, or a cyclic amino group which may have a substituent. * represents a bond.) (wherein either A or B represents formula (II)), X represents a nitrogen atom or an N-oxide; Y represents a methylene group, a carbonyl group, or a thiocarbonyl group which may have a substituent; Z is NR 15 represents an ethenylene group or an ethynylene group which may have an oxygen atom, a bond, or a substituent (provided that when m is 0, n is 0 and Z is NR 15 ) R 15 is a hydrogen atom, optionally substituted C 1-6 Indicates an alkyl group or R 15 and R 14 represents an optionally substituted nitrogen-containing saturated heterocycle to which R 17 represents a hydrogen atom, a halogen atom, an optionally protected hydroxy group, an optionally substituted alkoxy group, or an optionally substituted tetrazolyloxy group, m represents an integer of 0 to 1; n represents an integer of 0 to 3. (However, when Z is a bond, m and n cannot simultaneously be 0.) and pharma- ceutically acceptable salts thereof. [2] The present invention also provides R 6 is a hydroxy group, optionally substituted C 1-6 The present invention relates to the azepane derivative according to the above [1], wherein the alkoxy group is an optionally substituted carbamoyl group, and a pharma- ceutically acceptable salt thereof. [3] The present invention also provides R 6 is a hydroxy group, and the azepane derivative or a pharma- ceutical acceptable salt thereof according to the above [1] or [2]. [4] The present invention also provides R 1 C may have a substituent 1-6 C which may have an alkyl group or a substituent 3-6 Cycloalkyl C 1-6 The present invention relates to the azepane derivatives according to the above [1] to [3], which are alkyl groups, and pharma- ceutically acceptable salts thereof. [5] The present invention also relates to the azepane derivatives and pharma- ceutically acceptable salts thereof according to the above [1] to [4], wherein Z is a bond. [6] The present invention also relates to the azepane derivatives according to the above [1] to [5], wherein n is 1 to 3, and pharma- ceutically acceptable salts thereof. [7] The present invention also provides R 14 is a heteroaryl group which may have a substituent, and a pharma- ceutically acceptable salt thereof according to the above [1] to [6]. [8] The present invention also relates to the azepane derivatives and pharma- ceutically acceptable salts thereof according to the above [1] to [7], wherein A represents a group represented by the general formula (II) according to claim 1 and B represents a methylene group. [9] The present invention also provides R 11 is a hydroxy group, and the azepane derivatives and pharma- ceutically acceptable salts thereof according to the above [1] to [8].

[10] The present invention also relates to a pharmaceutical composition comprising the azepane derivative or a pharma- ceutically acceptable salt thereof according to any one of the above [1] to [9] as an active ingredient.

[11] The present invention also relates to the medicament according to the above

[10] , which is an agent for treating, ameliorating or preventing a disease associated with the opioid κ receptor.

[12] The present invention also relates to the pharmaceutical composition according to the above

[10] or

[11] , which is an analgesic.

[13] The present invention also relates to the medicine according to the above

[10] or

[11] , which is an antipruritic drug. [Brief description of the drawings]

[0014] [Figure 1] FIG. 2 shows the results of a test to confirm the sedative effect of oral administration of the compound of Example 22 (500 μg / kg). [Diagram 2] FIG. 1 shows the results of a test to confirm the sedative effect of oral administration of the compound of Example 50 (7000 μg / kg). [Diagram 3] FIG. 1 shows the results of a test to confirm the sedative effect of oral administration of nalfurafine (30, 100, 300 μg / kg). [Figure 4] FIG. 1 shows the results of a test to confirm the sedative effect of the compound of Example 77 (400 μg / kg) by subcutaneous administration. [Diagram 5] FIG. 1 shows the results of a test to confirm the sedative effect of subcutaneous administration of nalfurafine (3, 10, 30 μg / kg). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The present invention will now be described in more detail. The azepane derivatives represented by the above general formula (I) and pharma- ceutically acceptable salts thereof include tautomers, stereoisomers and solvates thereof. R 1 ~R 5 , R 7 ~R 15 C which may have a substituent represented by the following formula: 1-6 C in alkyl group 1-6Examples of the alkyl group include linear or branched alkyl groups 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, and a hexyl group. Of these, a methyl group, an ethyl group, and a propyl group are preferred, and a methyl group is more preferred. Optionally substituted C 1-6 The substituents in the alkyl group include halogen atoms such as fluorine and chlorine atoms; hydroxy groups; 1-6 Alkylamino group, diC 1-6 Examples of such groups include amino groups which may have a substituent, such as alkylamino groups and acylamino groups; protected amino groups; acyl groups, such as formyl group, acetyl group, cyclopropylcarbonyl group, and benzoyl group; cyclic amino groups, such as azetidinyl group, pyrrolidinyl group, piperazinyl group, and morpholinyl group; cyclic lactam groups, such as β-lactam, γ-lactam, and δ-lactam, carboxy groups, and carboxylate groups (as described in

[0032] ).

[0016] R 1 , R 4 , R 5 and R 14 C which may have a substituent represented by the following formula: 3-6 C in cycloalkyl groups 3-6 Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and preferably a cyclopropyl group. R 1 , R 4 , R 5 and R 14 C which may have a substituent represented by the following formula: 3-6 The substituents in the cycloalkyl group include C methyl, ethyl, propyl, etc. 1-6 Alkyl groups; halogenated methyl groups such as fluoromethyl, difluoromethyl, and trifluoromethyl groups; halogen atoms such as fluorine and chlorine; hydroxy groups; C 1-6 Alkylamino group, diC 1-6Examples of the amino group include an amino group which may have a substituent, such as an alkylamino 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; and a cyclic lactam group, such as a β-lactam, a γ-lactam, or a δ-lactam.

[0017] R 2 ~R 11 , R 14 and R 17 C which may have a substituent represented by the following formula: 1-6 C in alkoxy group 1-6 Examples of the alkoxy group include linear or branched alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy groups, and preferably methoxy. Optionally substituted C 1-6 The substituents in the alkoxy group include C methoxy and ethoxy groups. 1-6 Examples of the alkyl group include an alkoxy group, a phenoxy group, and a halogen atom such as a fluorine atom or a chlorine atom, and preferably a fluorine atom. Examples of the alkyl group include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, and a 2,2,2-trifluoroethoxy group.

[0018] R 1 , R 6 and R 14 C which may have a substituent represented by the following formula: 6-10 Aryl group, R 6 C which may have a substituent represented by the following formula: 6-10 C in aryloxy group 6-10 The aryl group includes a phenyl group and a naphthyl group.

[0019] R 1 , R 6 and R 14Examples of the heteroaryl group in the heteroaryl group which may have a substituent represented by the formula (I) include 5-membered ring heteroaryl groups 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, and a tetrazolyl group; 6-membered ring heteroaryl groups such as a pyridyl group, a pyridazinyl group, a pyrazinyl group, and a pyrimidyl group; and monocyclic or bicyclic heteroaryl groups containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms, 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, and an indazolyl group. Furthermore, depending on the substituent on these heteroaryl groups, tautomers may exist. For example, when a hydroxy group is substituted on a pyridyl group, examples of the tautomer include a 6-hydroxypyridin-2-yl group and its tautomer, a 6-oxo-1,6-dihydropyridin-2-yl group, and a 4-hydroxypyridin-2-yl group and its tautomer, a 4-oxo-1,4-dihydropyridin-2-yl group. Preferred R 1 Examples of the heteroaryl group include six-membered heteroaryl groups such as a pyridyl group, a pyridazinyl group, a pyrazinyl group, and a pyrimidyl group. Preferred R 14Examples of the aryl group include 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, and an indazole group, and more preferably a furan-2-yl group, a thiazol-2-yl group, a thiazol-4-yl group, a 1H-imidazole- 4-yl group, 1H-pyrazol-3-yl group, 1H-pyrazol-1-yl group, 2H-1,2,3-triazol-2-yl group, pyridin-2-yl group, pyrimidin-2-yl group, pyrazin-2-yl group, 1H-indazol-3-yl group, imidazo[1,2-a]pyridin-2-yl group, pyrazolo[1,5-a]1H-indazol-1-yl group, quinolin-2-yl group, isoquinolin-3-yl group, indolin-1-yl group, and benzo[d]thiazol-2-yl group.

[0020] R 1 , R 6 and R 14 C which may have a substituent represented by the following formula: 6-10 The aryl group and the heteroaryl group which may have a substituent may have 1 to 3 substituents on the ring. Such substituents include linear or branched C alkyl groups such as methyl groups, ethyl groups, and propyl groups. 1-6 Alkyl groups; linear or branched halogenated alkyl groups such as fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, and trifluoromethyl groups; hydroxymethyl groups; hydroxyalkyl groups such as hydroxyethyl and 1-hydroxypropyl groups; C groups such as cyclopropyl, cyclobutyl, and cyclopentyl groups. 3-6 Cycloalkyl groups; straight or branched C groups such as methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. 1-6 Alkoxy groups; linear or branched halogenated C such as trifluoromethoxy and 2,2,2-trifluoroethoxy groups 1-6 Alkoxy group; halogen atom such as fluorine atom or chlorine atom; hydroxy group; nitro group; cyano group; C 1-6Alkylamino group, diC 1-6 Examples of the amino group include an amino group which may have a substituent, such as an alkylamino 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; and a cyclic lactam group, such as a β-lactam, a γ-lactam, or a δ-lactam.

[0021] R 1 C which may have a substituent represented by the following formula: 3-6 Cycloalkyl C 1-6 C in alkyl group 3-6 Cycloalkyl C 1-6 Examples of the alkyl group include 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, and a cyclohexylpropyl group. Of these, a cyclopropylmethyl group, a cyclopropylethyl group, a cyclobutylmethyl group, a cyclobutylethyl group, a cyclopentylmethyl group, and a cyclopentylethyl group are preferred, a cyclopropylmethyl group, a cyclobutylmethyl group, and a cyclopentylmethyl group are more preferred, and a cyclopropylmethyl group is most preferred. Optionally substituted C 3-6 Cycloalkyl C 1-6 Examples of the substituent in the alkyl group include a halogen atom such as a fluorine atom or a chlorine atom, and a hydroxy group.

[0022] R 1 and an aralkyl group represented by the following formula (I) 11 The aralkyl in the aralkyloxy group which may have a substituent represented by the following formula (1) is an aralkyl group having an aryl moiety with a carbon number of C 6-10 The number of carbon atoms in the alkylene portion is C 1-5 Examples of the alkyl group include a benzyl group, a phenylethyl group, a 1-naphthylmethyl group, and the like, and a preferred example is a benzyl group.

[0023] R 1 The heteroaryl moiety in the optionally substituted heteroarylalkyl group represented by the formula (I) includes a heteroaryl having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms, and the alkyl moiety includes a C group such as a methyl group, an ethyl group, a propyl group, etc. 1-6 Examples of the heteroarylalkyl groups include monocyclic heteroarylalkyl groups 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, a (imidazol-2-yl)methyl group, a (imidazol-4-yl)methyl group, a (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; and bicyclic heteroarylalkyl groups such as a (quinolin-3-yl)methyl group and an (indol-3-yl)methyl group.

[0024] R 11 Aryl in an aralkyloxy group optionally having a substituent represented by the formula: 1 The aryl and heteroaryl in the optionally substituted aralkyl group and the optionally substituted heteroarylalkyl group represented by the formula (I) may have a substituent, and examples of such a substituent include those described in paragraph

[0020] below. 6-10 The same substituents as those in the aryl group and the like can be mentioned.

[0025] R 1 and R 14 C which may have a substituent represented by the following formula: 2-6 C in alkenyl group 2-6 The alkenyl group is C 2-6Examples of alkenyl groups include linear or branched alkenyl groups 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, and a 5-hexenyl group.

[0026] R 1 and R 14 C which may have a substituent represented by the following formula: 2-6 C in alkynyl groups 2-6 The alkynyl group is C 2-6 and the like. Examples of the alkynyl group include an ethynyl group, a propynyl group, and a butynyl group.

[0027] Examples of groups that can be substituted for such alkenyl and alkynyl groups include C aryl groups such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl groups. 1-6 Aralkyl groups such as alkoxycarbonyl, benzyl, 2-phenylethyl, 3-phenylpropyl, and 4-phenylbutyl; C groups such as methoxy, ethoxy, propoxy, and butoxy. 1-6 Alkoxy groups; benzyloxy groups, 2-phenylethyloxy groups, and other aralkyloxy groups; C 1-6 Examples of the alkyl group include an amino group which may be substituted with a straight-chain or branched-chain alkyl group of the formula: a halogen atom such as a fluorine atom or a chlorine atom; a carboxy group and a hydroxy group.

[0028] R 1 Examples of the acyl group which may have a substituent represented by the formula (I) include a formyl group, an acetyl group, a propionyl group, a butanoyl group, a pentanoyl group, a hexanoyl group, and the like. 1-6 Alkanoyl group; cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, etc. 4―7 Examples of the alkyl group include a cycloalkanoyl group; aroyl groups such as a benzoyl group, a naphthoyl group, and the like; and 5- to 6-membered heteroaroyl groups such as a furoyl group, a thiophenecarbonyl group, a nicotinyl group, a isonicotinoyl group, and the like. Also, C 1-6Alkanoyl group, C 4―7 Examples of the substituent in the cycloalkanoyl group include the same as the substituent described in paragraph

[0015] , and examples of the substituent in the aroyl group and heteroaroyl group include the same as the substituent described in paragraph

[0020] .

[0029] R 4 ~R 6 The substituent in the optionally substituted carbamoyl group represented by the formula: 4 ~R 6 , R 11 and R 14 The substituent in the amino group which may have a substituent represented by the following formula: 6 and R 17 The substituent in the optionally substituted tetrazolyloxy group represented by the formula: 1-6 Examples of the C alkyl group include an alkyl group and an aryl group such as a phenyl group, which may have such a substituent. 1-6 The alkyl group may have one or two of the substituents described in paragraph

[0015] .

[0030] R 1 and R 18 and an amino protecting group represented by R 4 ~R 6 , R 11 , R 14Examples of the protecting group in the protected amino group represented by the formula (I) include 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 Carbamate-based protecting groups such as 4,5-trimethoxybenzyloxycarbonyl, p-biphenylisopropyloxycarbonyl, diisopropylmethyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl; sulfonamide-based protecting groups such as p-toluenesulfonyl and 2-nitrobenzenesulfonyl; imide-based protecting groups such as phthaloyl; C protecting groups such as benzyl, phenylethyl, phenylpropyl, trityl, and naphthylmethyl. 7―19 Examples of aralkyl groups include the following:

[0031] R 2 ~R 14 and R 17 Examples of the halogen atom represented by the formula (I) include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom and a chlorine atom, more preferably a fluorine atom.

[0032] R 4 ~R 6 Examples of the ester-forming group in the carboxylic acid ester group represented by the formula (I) include a straight-chain or branched C 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, a hexyl group, and the like. 1-6 Alkyl groups: vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl, etc. 2-6 Alkenyl groups; aralkyl groups such as benzyl groups; aryl groups such as phenyl and naphthyl groups; C groups such as acetoxymethyl and pivaloyloxymethyl groups 1-6 Alkanoyloxy C 1-4 Examples thereof include lower alkyl groups.

[0033] R 14 Examples of the cyclic amino group in the cyclic amino group which may have a substituent represented by the formula (I) include an azetidinyl group, a pyrrolidinyl group, an azepanyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, an oxazabicyclooctyl group, an azasilinyl group, an indolinyl group, an isoindolyl group, and the like. Preferred examples include 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, and a 1-indolinyl group. More preferred examples include a 1-pyrrolidinyl group, a 1-piperidinyl group, an azasilinan-1-yl group, and a 1-indolinyl group. The substituent may be a methyl group, an ethyl group, or the like. 1-6 Alkyl group; C which may have a substituent such as a methoxy group, an ethoxy group, or a propoxy group 1-6 Examples of the alkyl group include an alkoxy group; a halogen atom such as a fluorine atom or a chlorine atom; and a hydroxy group. Optionally substituted C 1-6 The substituent in the alkyl group may be any of those described in paragraph

[0015] . 1-6 Examples of the substituent in the alkoxy group include the substituents described in paragraph

[0017] .

[0034] R 2 and R 3 or R 7 and R 8 C which may have a substituent formed by bonding 3-6 Saturated hydrocarbon ring, R 9 and R 10 C which may have a substituent formed by bonding 3-6 Saturated hydrocarbon ring, R on the same carbon 12 and R 13 is a bond or when n is 2 to 3, a pair of adjacent R 12 C which may have a substituent formed by bonding 3-6 C in saturated hydrocarbon rings3-6 Examples of the saturated hydrocarbon ring include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring.

[0035] R on the same carbon 12 and R 13 or when n is 2 to 3, a pair of adjacent R 12 A saturated heterocycle which may have a substituent and R 14 Examples of the saturated heterocycle which may have a substituent and is represented by the following formula (I) include 3- to 6-membered saturated heterocycles, and examples of such saturated heterocycles include cyclic amines such as aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine, cyclic ethers such as epoxides, oxetane, tetrahydrofuran, tetrahydropyran, and dioxane, and cyclic thioethers such as thietane, thiolane, and thiane. Among these saturated heterocycles, when a nitrogen atom is contained as a constituent atom of the ring, it is preferable that the ring is linear or branched. 1-6 The nitrogen atom may have a substituent such as an alkyl group or an acyl group or an amino-protecting group. These substituents are as described in paragraphs

[0015] ,

[0028] and

[0030] .

[0036] R 14 and R 15 Examples of the nitrogen-containing saturated heterocycle formed by bonding with each other and which may have a substituent include 3- to 6-membered nitrogen-containing saturated heterocycles, such as cyclic amino groups such as aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine. These nitrogen-containing saturated heterocycles may be further condensed with a saturated hydrocarbon ring, a saturated heterocycle, an unsaturated hydrocarbon ring, or an unsaturated heterocycle, and examples thereof include decahydroquinoline, decahydroisoquinoline, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, benzomorpholine, and benzothiomorpholine. In these nitrogen-containing heterocycles, R 15 In the case where the ring has a nitrogen atom other than the nitrogen atom to which the ring is bonded, a straight-chain or branched C1-6 The nitrogen atom may have a substituent such as an alkyl group or an acyl group or an amino-protecting group. These substituents are as described in paragraphs

[0015] ,

[0028] and

[0030] .

[0037] R on the same carbon 12 and R 13 C which may have a substituent formed by bonding 3-6 Saturated hydrocarbon ring, R on the same carbon 12 and R 13 and when n is 2 to 3, a pair of adjacent R 12 C which may have a substituent formed by bonding 3-6 A saturated hydrocarbon ring or a saturated heterocyclic ring which may have a substituent and R 14 and R 15 Examples of the substituent in the nitrogen-containing saturated heterocycle which may have a substituent formed by bonding include the same as the substituent in the cyclic amino group described in paragraph

[0033] .

[0038] R 2 and R 3 , R 7 and R 8 and R 9 and R 10 Examples of the cyclic ketal formed by bonding with the substituted ketal include dioxolane and dioxane. Examples of such a substituent include C groups such as methyl, ethyl, and propyl groups. 1-6 Examples of such groups include alkyl groups.

[0039] R 2 ~R 11 , R 14 and R 17Examples of the hydroxy-protecting group in the optionally protected hydroxy group represented by the formula (I) include aralkyl groups which may have a substituent such as a benzyl group, a 4-methoxybenzyl group, a trityl group, etc., alkanoyl groups such as an acetyl group, etc., acetal-based protecting groups such as a methoxymethyl group, a 2-tetrahydropyranyl group, a trimethylsilyl group such as an ethoxyethyl group, a silyl group having a substituent such as a tert-butyldimethylsilyl group, etc., and sulfonyl-based protecting groups such as a methanesulfonyl group, a p-toluenesulfonyl group, a trifluoromethanesulfonyl group, etc.

[0040] R 6 Examples of the sugar represented by the formula (I) include glucuronic acid.

[0041] X represents a nitrogen atom or an N-oxide, with a nitrogen atom being preferred.

[0042] Y represents an optionally substituted methylene group, a carbonyl group or a thiocarbonyl group, preferably an optionally substituted methylene group or a carbonyl group, and particularly preferably a carbonyl group. The substituent in the optionally substituted methylene group is, for example, C 1-6 An alkyl group, an optionally protected hydroxy group (protecting groups include those of

[0039] ), a halogen atom (e.g., a fluorine atom, etc.), a C substituted with a halogen atom 1-6 Examples of the alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, and a dichloromethyl group.

[0043] Z is NR 15 , an oxygen atom, a bond, an ethenylene group, or an ethynylene group, preferably NR 15 , an oxygen atom, a bond, or an ethenylene group which may have a substituent. As the substituent in the ethenylene group which may have a substituent, those described in paragraph

[0027] can be mentioned.

[0044] m represents an integer of 0 to 1, and is preferably 1. However, when n is 2, m is preferably 0.

[0045] n represents an integer of 0 to 3, and is preferably 1 or 2.

[0046] A preferred embodiment of the compound (I) used in the present invention is R 1 C may have a substituent 1-6 Alkyl group, optionally substituted C 3-6 Cycloalkyl C 1-6 is an alkyl group, R 2 and R 3 are the same or different and may have a hydrogen atom or a substituent. 1-6 Alkyl group, optionally substituted C 1-6 Alkoxy group, halogen atom, hydroxy group, R 4 and R 5 are the same or different and may have a hydrogen atom or a substituent, 1-6 Alkyl group, optionally substituted C 1-6 R is an alkoxy group, an amino group which may have a substituent, a halogen atom, or a hydroxy group. 6 is a hydroxy group, optionally substituted C 1-6 R is an alkoxy group or an optionally substituted carbamoyl group. 7 and R 8 are the same or different and may have a hydrogen atom or a substituent, 1-6 Alkyl group, optionally substituted C 1-6 R is an alkoxy group, a halogen atom, or a hydroxy group. 9 and R 10 are the same or different and may have a hydrogen atom or a substituent, 1-6 Alkyl group, optionally substituted C 1-6 Alkoxy group, halogen atom, hydroxy group, R 11 is a hydrogen atom or a hydroxyl group, R 12 and R 13 are the same or different and may have a hydrogen atom or a substituent. 1-6 is an alkyl group, R14 C may have a substituent 6-10 an aryl group, an optionally substituted heteroaryl group, or an optionally substituted cyclic amino group; X is a nitrogen atom or an N-oxide; Y is an optionally substituted methylene group or a carbonyl group; and Z is NR 15 , an oxygen atom, a bond, an ethenylene group or an ethynylene group which may have a substituent, R 15 is a hydrogen atom, optionally substituted C 1-6 is an alkyl group, R 17 represents a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, or an alkoxy group which may have a substituent; m represents an integer of 0 or 1; and n represents an integer of 0 to 3.

[0047] A more preferred embodiment of the compound (I) used in the present invention is a compound represented by the formula: 1 C may have a substituent 1-6 C which may have an alkyl group or a substituent 3-6 Cycloalkyl C 1-6 is an alkyl group, R 2 and R 3 are the same or different and may have a hydrogen atom or a substituent. 1-6 is an alkyl group, R 4 and R 5 are the same or different and may have a hydrogen atom or a substituent. 1-6 is an alkyl group, R 6 is a hydroxy group, optionally substituted C 1-6 R is an alkoxy group or an optionally substituted carbamoyl group. 7 and R 8 are the same or different and may have a hydrogen atom or a substituent, 1-6 C which may have an alkyl group or a substituent 1-6 is an alkoxy group, R 9 and R 10 are the same or different and may have a hydrogen atom or a substituent. 1-6 is an alkyl group, R 11 is a hydrogen atom or a hydroxyl group, R 12 and R13 are the same or different and may have a hydrogen atom or a substituent. 1-6 is an alkyl group, R 14 C may have a substituent 6-10 an aryl group, an optionally substituted heteroaryl group, or an optionally substituted cyclic amino group; X is a nitrogen atom or an N-oxide; Y is an optionally substituted methylene group or a carbonyl group; and Z is NR 15 , an oxygen atom, a bond or an ethenylene group which may have a substituent, R 15 is a hydrogen atom, optionally substituted C 1-6 is an alkyl group, R 17 represents a hydrogen atom, a hydroxyl group which may be protected, or an alkoxy group which may have a substituent; m represents an integer of 0 or 1; and n represents an integer of 0 to 3.

[0048] Further, a preferred embodiment of the compound (I) used in the present invention is a compound represented by the formula: 1 C may have a substituent 1-6 Alkyl group, optionally substituted C 3-6 Cycloalkyl C 1-6 is an alkyl group, R 2 and R 3 are the same or different and may have a hydrogen atom or a substituent. 1-6 is an alkyl group, R 4 and R 5 is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group, R 6 is a hydroxy group, and R 7 and R 8 are the same or different and may have a hydrogen atom or a substituent. 1-6 is an alkyl group, R 9 and R 10 are the same or different and may have a hydrogen atom or a substituent. 1-6 is an alkyl group, R 11 is a hydrogen atom or a hydroxyl group, R 12 and R 13 are the same or different and may have a hydrogen atom or a substituent.1-6 is an alkyl group, R 14 is a heteroaryl group which may have a substituent, X is a nitrogen atom, Y is a methylene group or a carbonyl group which may have a substituent, Z is a bond, R 17 is a hydrogen atom, m is 0, and n is 1 or 2.

[0049] In the azepane derivatives represented by the above general formula (I) and pharma- ceutically acceptable salts thereof, the pharma- ceutically acceptable salts are preferably acid addition salts. Examples of the acid addition salts include (a) salts with mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.; (b) salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid, maleic acid, tartaric acid, etc.; and (c) salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid, etc.

[0050] The azepane derivatives represented by the above general formula (I) and pharma- ceutically acceptable salts thereof include tautomers and stereoisomers such as cis and trans isomers, racemates and optically active substances.

[0051] The azepane derivative represented by the above general formula (I) and its pharma- ceutically acceptable salt may also exist as a hydrate or solvate. Therefore, the compound of the present invention includes all crystal forms and hydrates or solvates thereof.

[0052] Next, a method for producing the azepane derivative represented by the above general formula (I) and a pharma- ceutical acceptable salt thereof will be described below.

[0053] (i) In the above general formula (I), X is a nitrogen atom, either A or B is NH, and the other is CH 2 Manufacturing method for the case shown in FIG. (Method A) Using compound (a) as the starting material, invention compounds (f) and (g) can be obtained by the method described below.

[0054] [ka] (In the formula, L represents a methanesulfonyl group, a p-toluenesulfonyl group, a trifluoromethanesulfonyl group, a 2-nitrobenzenesulfonyl group, or the like; R 1 ~R 11 and R 17 indicates the same as above.) (first step) The raw material (a) is reacted with 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 a mixture thereof, and a base such as potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), lithium hydride, sodium hydride, or potassium hydride; Compound (b) can be synthesized by reacting with hydroxylamine hydrochloride or hydroxylamine sulfate or the like at room temperature or under heating and reflux for 1 to 24 hours in the presence or absence of an organic base such as diphenylamine, 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. (Second process) Compound (b) is dissolved in an aprotic polar solvent such as potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), lithium hydride, sodium hydride, water, etc., in an aromatic hydrocarbon such as benzene, toluene, xylene, etc.; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, etc.; an aliphatic hydrocarbon such as pentane, hexane, heptane, ligroin, etc.; or an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc., in an aprotic polar solvent such as potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), lithium hydride, sodium hydride, water, etc. the above L-Cl or L-L in the presence of a base such as potassium chloride; 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, potassium tert-butoxide; or an inorganic base such as lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, 2 Compound (c) can be synthesized by reacting the compound (c) with a reagent represented by O at −78° C. or under reflux for 1 to 24 hours. (Third step) Compound (c) is reacted with aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; alcohols such as methanol, ethanol, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin, etc.; solvents such as water, acetic acid, etc.; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, etc., or mixed solvents thereof, or no solvent, with Brønsted acids such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.; and Lewis acids such as boron trifluoride-diethyl ether complex, aluminum chloride, iron (III) chloride, zinc chloride, titanium (IV) chloride, etc., at room temperature to under reflux for 1 to 72 hours, to synthesize compounds (d) and (e), respectively. (Fourth step) The compounds (d) and (e) can be reacted with a reducing agent such as lithium aluminum hydride, borane-tetrahydrofuran complex, or borane-dimethylsulfide complex in an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme at 0° C. or under reflux for 1 to 24 hours to synthesize the compounds (f) and (g), respectively.

[0055] (Method B) The synthetic intermediates (d) and (e) described in Method A can also be synthesized in one step from compound (b) as described below.

[0056] [ka] (In the formula, R 1 ~R 11 and R 17 indicates the same as above.) Compound (b) is reacted with aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; alcohols such as methanol, ethanol, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin, etc.; a solvent such as water, acetic acid, etc.; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, etc., or a mixture of these solvents, or in the absence of a solvent, in the presence or absence of an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, etc., a Lewis acid such as boron trifluoride-diethyl ether complex, aluminum chloride, iron chloride, zinc chloride, etc., at room temperature to under heating and reflux for 1 to 72 hours, to synthesize compounds (d) and (e), respectively.

[0057] (Method C) The synthetic intermediates (d) and (e) described in Method A can also be synthesized in one step from compound (a) by using sodium azide or trimethylsilyl azide as described below.

[0058] [ka] (In the formula, R 1 ~R 11 and R 17 indicates the same as above.) A raw material (a) is reacted with 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 dimethyl sulfoxide, or a mixture of these solvents, or in the absence of a solvent, in the presence or absence of a Brönsted acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, polyphosphoric acid, Eaton's reagent, methanesulfonic acid, or p-toluenesulfonic acid; or a Lewis acid such as boron trifluoride-diethyl ether complex, aluminum chloride, iron chloride, zinc chloride, or titanium(IV) chloride. 3 ) or trimethylsilyl azide (TMSN 3 ) at 0° C. or under reflux for 1 to 24 hours to synthesize compounds (d) and (e), respectively.

[0059] (ii) In the above general formula (I), X is a nitrogen atom, and either A or B is NR 16 (R 16 may have a substituent C 1-10 Alkyl group, aralkyl group (the number of carbon atoms in the aryl part is C 6-10 The number of carbon atoms in the alkylene portion is C 1-5 ) or a heteroarylalkyl group, and the other represents a carbonyl group. (Method D) Using compound (a) as a starting material, invention compounds (d-1) and (e-1) can be synthesized by the methods described below.

[0060] [ka] (In the formula, R 16 may have a substituent C 1-10 Alkyl group, aralkyl group (the number of carbon atoms in the aryl part is C 6-10 The number of carbon atoms in the alkylene portion is C 1-5 ) or a heteroarylalkyl group, R 1 ~R 11 and R 17 indicates the same as above.) A raw material (a) is reacted with 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 dimethyl sulfoxide, or a mixture of these solvents, or in the absence of a solvent, in the presence or absence of a Bronsted acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, polyphosphoric acid, Eaton's reagent, methanesulfonic acid, or p-toluenesulfonic acid; or a Lewis acid such as boron trifluoride-diethyl ether complex, aluminum chloride, iron chloride, zinc chloride, or titanium(IV) chloride, in R 16 -N 3 The invention compounds (d-1) and (e-1) can be synthesized by reacting the compound represented by the formula (1) with an azide represented by the following formula (1) at 0° C. or under heating under reflux for 1 to 24 hours.

[0061] (iii) A production method in which, in the above general formula (I), X is a nitrogen atom, either A or B is a carbonyl group, m is 0, and Z is a bond. (Method E) Compound (h) of the invention can be synthesized by alkylation reaction of compound (d) or (e) (collectively represented as (de)) obtained in the above (i).

[0062] [ka] (In the formula, L' represents a leaving group such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or a halogen, and R 1 ~R 14 , R 17 and n are the same as above. * indicates a bond.) The compound (d) or (e) obtained in the above (i) (collectively referred to as (de)) may be reacted with aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; alcohols such as methanol, ethanol, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin, etc.; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc.; bases such as potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), lithium hydride, sodium hydride, potassium hydride, etc.; trimethylamine The invention compound (h) can be synthesized by reacting with an alkylating agent represented by (r-1) at room temperature to under reflux for 1 to 24 hours in the presence of an organic base such as 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.

[0063] (iv) A production method in which, in the above general formula (I), X is a nitrogen atom, Y is a carbonyl group or a thiocarbonyl group, Z is an ethenylene group or an ethynylene group which may have a bond or a substituent, and m is 1. (Method F) Invention compounds (i) and (j) can be obtained by reacting invention compound (f) or (g) (collectively referred to as (fg)) obtained in the above (i) with (r-2) or (r-3).

[0064] [ka] (Wherein, either Ah or Bh is NH, and the other is CH 2 hal represents a halogen atom; Z represents an ethenylene group or an ethynylene group which may have a bond or a substituent; n and R 1 ~R 14 and R 17 indicates the same as above. * indicates a bond.) (first step) The invention compound (f) or (g) obtained in the above (i) (collectively referred to as (fg)) is reacted with aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.; alcohols such as methanol, ethanol, etc.; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin, etc.; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc.; organic bases such as N,N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, etc.; inorganic bases such as potassium carbonate, lithium carbonate, etc. In the presence of a base, a carboxylic acid represented by (r-2) or an acid halide represented by (r-3) is reacted with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), N,N'-dicyclohexylcarbodiimide (DCC), 1- The invention compound (i) can be synthesized by reacting a carboxylic acid represented by (r-2) or an acid halide represented by (r-3) in the presence or absence of a condensing agent such as 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. or under reflux for 1 to 12 hours. (Second process) Invention compound (i) can be converted to invention compound (j) by reacting with a sulfurizing agent such as diphosphorus pentasulfide, Lawesson's reagent, Davy's reagent, Japanese reagent, Belleau's reagent, etc. in aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.; or aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin, etc. at 0°C under heating to reflux for 1 to 12 hours.

[0065] (v) A production method in which, in the above general formula (I), X is a nitrogen atom, m is 0, and Z is a bond. (Method G) The invention compound (k) can be obtained by the reductive amination reaction of the invention compound (f) or (g) (collectively referred to as (fg)) obtained in the above (i) with an aldehyde (r-4).

[0066] [ka] (Wherein, either Ah or Bh is NH, and the other is CH 2 R 1 ~R 14 , R 17 and n are the same as above. * indicates a bond.) The invention compound (k) can be synthesized by reacting the invention compound (f) or (g) obtained in the above (i) (collectively referred to as (fg)) with an aldehyde represented by (r-4) in the presence of a hydride reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium tri(sec-butyl)borohydride, potassium tri(sec-butyl)borohydride, etc., at 0°C to under reflux for 1 to 12 hours in a solvent such as aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.; alcohols such as methanol, ethanol, etc.; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin, etc.; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc.; or a mixture of these solvents.

[0067] (Method H) The invention compound (f) or (g) obtained in the above (i) (collectively referred to as (fg)) is reacted with an alkylating agent (r-1) to form a S-alkylation product. N The invention compound (k) can be obtained by reaction 2.

[0068] [ka] (In the formula, either Ah or Bh represents NH, and the other represents CH; R 1 ~R 14 , R 17 , L' and n are the same as above. * represents a bond.) The invention compound (f) or (g) obtained in the above (i) (collectively referred to as (fg)) is reacted with aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; alcohols such as methanol, ethanol, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin, etc.; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc.; bases such as potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), etc.; trimethylamine, triisopropylamine, etc.; The invention compound (k) can be synthesized by reacting with an alkylating agent represented by (r-1) at room temperature to under reflux for 1 to 24 hours in the presence of an organic base such as ethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.; or an inorganic base such as sodium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc., in the presence or absence of potassium iodide or sodium iodide.

[0069] (Method I) The invention compound (k) can be obtained by reducing the amide moiety of the invention compound (i) obtained in the above (iv).

[0070] [ka] (In the formula, R 1 ~R 14 , R 17 Or n is the same as above. * represents a bond. The invention compound (i) obtained in the above (iv) can be reacted with a reducing agent such as lithium aluminum hydride, borane-tetrahydrofuran complex, or borane-dimethylsulfide complex in an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme at 0° C. or under reflux for 1 to 24 hours to synthesize the invention compound (k).

[0071] (J Law) A or B is NR 16 (R 16 may have a substituent C 1-10 Alkyl group, aralkyl group (the number of carbon atoms in the aryl part is C 6-10 The number of carbon atoms in the alkylene portion is C 1-5 ) or heteroaryl group) and the other is CH 2 In the case where the compound (d-1) or (e-1) of the invention obtained in the above (ii) (both of them are collectively referred to as (d 1 -e 1 The compound of the invention (f 1 -g 1 ) can also be synthesized.

[0072] [ka] (In the formula, R 1 ~R 11 R 16 And R 17 indicates the same as above.)

[0073] The invention compound (d-1) or (e-1) obtained in the above (ii) (together called (d 1 -e 1 )) is subjected to the same reaction as in the fourth step of (Method A) to obtain the invention compound (f 1 -g 1 ) can be synthesized.

[0074] (vi) In the above general formula (I), X is a nitrogen atom, Y is a carbonyl group, and Z is NR 15 or a method for producing an oxygen atom and m is 1 (Method K) The invention compound (n) can be obtained by the method described below using the invention compound (f) or (g) (collectively referred to as (fg)) obtained in the above (i).

[0075] [ka] (Wherein, either Ah or Bh is NH, and the other is CH 2 , Z is NR 15 or an oxygen atom, R 1 ~R 15 , R 17 , L′ and n are the same as above, L - indicates the counter anion. * indicates a bond.) (first step) The invention compound (f) or (g) obtained in the above (i) (collectively referred to as (fg)) may be reacted with aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.; alcohols such as methanol, ethanol, etc.; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin, etc.; acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc. The invention compound (l) can be synthesized by reacting carbodiimidazole in an aprotic polar solvent such as acetone, 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, procaine, or an inorganic base such as potassium carbonate or lithium carbonate at 0° C. or under reflux for 1 to 12 hours. (Second process) The compound (l) of the invention is reacted with aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.; alcohols such as methanol, ethanol, etc.; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin, etc.; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc., N,N-dimethylaminopyridine, trimethylamine, etc. The invention compound (m) can be synthesized by reacting with a methylating agent such as methyl iodide, dimethyl sulfate, trifluoromethanesulfonylmethane, Meerwein reagent, etc. in the presence or absence of an organic base such as triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, etc.; or an inorganic base such as potassium carbonate, lithium carbonate, etc., at 0°C or under reflux for 12 to 48 hours. (Third step) The invention compound (n) can be synthesized by reacting the invention compound (m) with an amine represented by (r-5) or an alcohol represented by (r-6) in the presence of 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; 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. or under reflux for 1 to 12 hours.

[0076] (vii) In the general formula (I), R 6represents a hydroxy group (Method L) Invention compound (p) can be synthesized by the dealkylation reaction of invention compound (o) obtained by the above (i) to (vi).

[0077] [ka] (In the formula, R 6a is C 1-10 R represents an alkoxy group. 1 ~R 14 , R 17 , n, m, Y and Z are the same as above. * indicates a bond.) The invention compound (o) obtained in the above (i) to (vi) can be reacted with boron tribromide, trimethylsilyl iodide, hydrogen bromide, pyridinium hydrochloride, or the like at -30 to 180°C for 30 minutes to 24 hours in a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, or a protic organic solvent such as acetic acid; or an aprotic polar solvent such as acetonitrile, ethyl acetate, or the like, or in the absence of a solvent, or with 1-propanethiol, 1-dodecanethiol, or the like in the presence of an organic base such as potassium tert-butoxide, sodium tert-butoxide, or the like, at 100°C to 180°C for 30 minutes to 24 hours in an aprotic polar solvent such as N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or the like, at 100°C to 180°C for 30 minutes to 24 hours.

[0078] (viii) A method for producing the compound of formula (I) in which X represents an N-oxide (Method M) The invention compound (s) can be synthesized by the oxidation reaction of the invention compound (q) obtained by the above (i) to (vii).

[0079] [ka] (In the formula, R 1 ~R 14 , R 17 , n, m, Y and Z are the same as above. * indicates a bond.) The invention compound (q) obtained in the above (i) to (vii) is reacted with hydrogen peroxide (H 2 O 2 The compound of the invention (s) can be synthesized by reacting with an aqueous solution of 1 to 2 equivalents of an oxidizing agent such as m-chloroperbenzoic acid (mCPBA) or the like at 0° C. to room temperature for 30 minutes to 24 hours.

[0080] The compounds obtained in each of the above steps can be purified, if necessary, by, for example, silica gel column chromatography. Furthermore, if necessary, an acid addition salt can be formed by a conventional method, for example, by dissolving Compound (I) in an organic solvent such as ethyl acetate; an alcohol such as methanol, ethanol, etc.; or a polar solvent such as water, in the presence of a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., an organic carboxylic acid such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid, maleic acid, etc., an organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid, etc., at room temperature or with appropriate heating.

[0081] The azepane derivatives represented by the above general formula (I) and pharma- ceutical acceptable salts thereof can be formulated into compositions together with pharma- ceutical acceptable carriers for parenteral administration to humans, oral administration in solid or liquid form, etc. Also, they can be used in combination with other analgesics.

[0082] Examples of solid preparations for oral administration include capsules, tablets, pills, powders, and granules. In preparing these solid preparations, excipients, disintegrants, binders, lubricants, and dyes can be used. Examples of excipients include lactose, D-mannitol, crystalline cellulose, and glucose. Examples of disintegrants include starch and carboxymethylcellulose calcium (CMC-Ca). Examples of lubricants include magnesium stearate and talc. Examples of binders include hydroxypropylcellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP). In the case of capsules, tablets, and pills, a buffering agent may be used. Tablets and pills may be coated with an enteric coating.

[0083] The form of the composition of the present invention for injection includes pharma- ceutically acceptable sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of suitable non-aqueous carriers, diluents, solvents, or vehicles include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Such compositions may also contain auxiliary agents, such as antiseptics, wetting agents, emulsifiers, soothing agents, buffers, preservatives, and dispersants. These compositions can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilant in the form of sterile solid compositions which can be dissolved in a sterilant or some other sterile injectable medium immediately before use.

[0084] Preparations for ophthalmic administration may preferably contain, in addition to the compound of the present invention, a solubilizing agent, a preservative, an isotonicity agent, a viscosity enhancer, and the like.

[0085] Liquid preparations for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, including inert diluents commonly used by those skilled in the art, such as water. In addition to such inert diluents, the compositions may also contain auxiliary agents, such as wetting agents, emulsifying and suspending agents, as well as sweeteners, seasonings, and flavoring agents.

[0086] Preparations for rectal administration may preferably contain excipients such as cocoa butter or suppository wax in addition to the compound of the present invention.

[0087] The dosage for adults is usually 0.01 μg to 1 g / day, preferably 0.0001 to 200 mg / day, for injections, and 0.1 μg to 10 g / day, preferably 0.001 to 2000 mg / day, for oral administration, of the azepane derivative represented by the above general formula (I), which is an active ingredient, or a tautomer, stereoisomer, or pharma- ceutically acceptable salt or solvate thereof, but this can be increased or decreased depending on age, symptoms, etc. If desired, this daily amount can be divided and administered 2 to 4 times.

[0088] Diseases and symptoms associated with the κ opioid receptor include, for example, cardiovascular disorders, digestive disorders, blood disorders, respiratory disorders, liver disorders, nervous disorders, urinary disorders, pain, cough, pruritus, ischemic brain disorders, etc. The compound of the present invention has selectivity for the κ opioid receptor and a strong agonist activity against the κ opioid receptor, and is therefore effective in treating, improving, and preventing these diseases and symptoms. EXAMPLES

[0089] The present invention will now be described in more detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited to these.

[0090] (Reference example 1) Synthesis of (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-4-yl trifluoromethanesulfonate

[0091] [ka] (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one (synthesized by the method described in Tetrahedron Lett., 2010,51,2359) (17.87g, 50mmol), N-phenylbis(trifluoromethanesulfonimide) (35.73g, 100mmol), potassium carbonate (20.73g, 150mmol) were dissolved in N,N-dimethylformamide (250mL) and stirred at room temperature for 18 hours. Chloroform (750mL) was added to the reaction solution, washed with 1M aqueous sodium hydroxide solution and water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was recrystallized from ethyl acetate to obtain the title compound (21.31 g) as white crystals. The recrystallized mother liquor (2.63 g) was purified by silica gel column chromatography (0-10% methanol / chloroform) and recrystallized from a mixed solvent of ethyl acetate and heptane to obtain the title compound 4 (1.245 g, total 92%) as white crystals. 1 H-NMR (400MHz, CDCl 3 )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=5,13,13Hz,1H),2.39(d,J=7Hz,2H),2.66-2.73(m, 1H),2.77(ddd,J=8,13,14Hz,1H),2.88(dd,J=7,19Hz,1H),3.01-3.18(m,3H),3.52( dd,J=2,14Hz,1H),3.80(s,3H),4.75(s,1H),6.85(d,J=8Hz,1H),7.05(d,J=8Hz,1H).

[0092] (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

[0093] [ka] The compound obtained in Reference Example 1 (22.55 g, 46 mmol), 1,3-bis(diphenylphosphino)propane (1.90 g, 4.6 mmol), and palladium acetate (1.03 g, 4.6 mmol) were dissolved in N,N-dimethylformamide (230 mL), and formic acid (5.22 mL, 138 mmol) and triethylamine (32.1 mL, 230 mmol) were added and stirred at 80° C. for 30 minutes. After adding 1M aqueous sodium hydroxide solution to the reaction solution, it was extracted three times with chloroform, and the combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-10% methanol / chloroform) to obtain the title compound (13.95 g, total 89%) as a colorless solid. 1 H-NMR (400MHz, CDCl 3 )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=7Hz,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=9Hz,1H),6.80(s,1H),6.99(d,J=9Hz,1H).

[0094] (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

[0095] [ka] Hydroxyamine hydrochloride (1.84 g, 26.4 mmol) was added 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) and the mixture was heated under reflux for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure and diluted with ethyl acetate, and then washed once with a saturated aqueous sodium bicarbonate solution and twice with saturated saline. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (2-25% methanol / ethyl acetate) to obtain the title compound (4.1 g, 87%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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=16Hz,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=3Hz,0.3H),6.92-7.02(m,2H),7.10(d,J=3Hz,0.7H).

[0096] Example 1 Synthesis of a mixture of (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphth[1,2-d]azepin-2(1H)-one (isomer A) and (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphth[1,2-c]azepin-3(4H)-one (isomer B)

[0097] [ka] Triethylamine (3.33mL, 23.9mmol) and p-toluenesulfonyl chloride (4.34g, 22.8mmol) were added to a solution of the compound (4.06g, 11.4mmol) obtained in Reference Example 3 in chloroform (120mL) under ice cooling, and the mixture was stirred at room temperature for 18 hours. p-Toluenesulfonyl chloride (2.0g, 10.5mmol) was added, and the mixture was further stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed twice with a saturated aqueous sodium bicarbonate solution, and once with saturated saline. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. 2M hydrochloric acid (40mL) was added to a solution of the obtained concentrated residue in tetrahydrofuran (80mL), and the mixture was stirred at room temperature for 2 hours. Tetrahydrofuran was distilled off under reduced pressure, and the mixture was made basic with potassium carbonate, and extracted three times with chloroform. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-5% methanol / chloroform) to give a mixture of the title isomers A and B (2.95 g, 73%) as a slightly brown amorphous solid. 1 H-NMR (400MHz, CDCl 3 )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=3Hz,0.3H),6.68-6.72(m,1H),6.96(d,J=8Hz,0.7H),7.01(d,J=8Hz,0.3H),7.14-7.16(m,0.7H).

[0098] 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)

[0099] [ka] To a tetrahydrofuran (8 mL) solution of the mixture of isomers A and B obtained in Example 1 (662 mg, 1.86 mmol), 0.91 M borane-tetrahydrofuran complex tetrahydrofuran solution (20.4 mL, 18.6 mmol) was added, and the mixture was heated to reflux for 14 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure. 6 M hydrochloric acid (12 mL) was added to the concentrated residue, and the mixture was heated to reflux for 16 hours. The reaction mixture was allowed to cool, and then potassium carbonate was added to make the mixture basic, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0-10% methanol / chloroform) to obtain the title isomer C (283 mg, 29%) and isomer D (236 mg, 24%) as colorless solids. (isomer C) 1 H-NMR (400MHz, CDCl 3 )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=4,4,14Hz,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=8Hz,1H). (isomer D) 1 H-NMR (400MHz, CDCl 3 )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=5,12,12Hz,1H),1,98(ddd,J=3,12,12Hz,1H),2.19-2.32(m,1H),2.34(dd,J=7,13Hz,1H),2.38(d d,J=6,13Hz,1H),2.53-2.61(m,1H),2.70(ddd,J=7,9,14Hz,1H),2.80(dd,J=6,18Hz,1H),2.91(d,J=6Hz,1 H),2.94-3.02(m,1H),2.98(d,J=18Hz,1H),3.14(d,J=15Hz,1H),3.18(d,J=15Hz,1H),3.78(s,3H),4.65(br s,1H),6.73(dd,J=2,8Hz,1H),6.75(d,J=2Hz,1H),7.03(d,J=8Hz,1H).

[0100] 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]azepine-3(4H)-yl)ethan-1-one (compound F)

[0101] [ka] 1-Dodecanethiol (16.6mL, 69mmol) and potassium tert-butoxide (7.80g, 69mmol) were added to a solution of isomer C (2.38g, 6.9mmol) obtained in Example 2 in N,N-dimethylacetamide (70mL), and the mixture was stirred at 160°C for 4 hours. After cooling, the reaction solution was added to 1M hydrochloric acid under ice cooling, and then washed with heptane. After that, potassium carbonate was added to make the mixture basic, and the mixture was extracted three times with a mixed solvent of chloroform / isopropanol (3 / 1). The combined extracts were 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, 0-50% methanol / chloroform) to obtain the title compound E (1.74g, 76%) and compound F (606mg, 24%), each as a colorless amorphous substance. (Compound E) 1 H-NMR (400MHz, CDCl 3 )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,1 H),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=7Hz,2H),2.48-2.59(m,1H),2.67-2.86(m,3H),2.89(d,J=6Hz,1H),2.97( d,J=18Hz,1H),3.07(ddd,J=4,4,14Hz,1H),3.18(ddd,J=3,13,13Hz,1H),4.54(br s,1H),6.56(d,J=2Hz,1H),6.63(dd,J=2,8Hz,1H),6.92(d,J=8Hz,1H). (Compound F) 1 H-NMR (400MHz, CDCl 3)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=5,15Hz,0.7H),6.4 5(dd,J=3,8Hz,0.3H),6.60(d,J=3Hz,0.3H),6.69(dd,J=3,8Hz,0.7H),6.86(d,J=8Hz,0.3H),6.95(d,J=8Hz,0.7H),7.00(d,J=2Hz,0.7H).

[0102] 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

[0103] [ka] 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) were added to a solution of isomer C (12.2 mg, 0.036 mmol) obtained in Example 2 in N,N-dimethylformamide (1 mL), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted 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), 1 M boron tribromide-dichloromethane solution (65 μL, 0.065 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 25 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform:methanol = 5:1) to obtain the title compound (4.5 mg, 28%) as a colorless solid. 1 H-NMR (400MHz, CD 3OD)δ(ppm):0.13-0.22(m,2H),0.50-0.61(m,2H),0.84-0.96(m,1H),0.9 8-1.05(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=2Hz,0.5H),6.58(dd,J=2,8Hz,0.5H),6.62(dd,J= 2,8Hz,0.5H),6.68(d,J=2Hz,0.5H),6.96(d,J=8Hz,0.5H),6.98(d,J=8H z,0.5H),7.06-7.19(m,2H),7.69(d,J=4Hz,0.5H),7.74(d,J=4Hz,0.5H).

[0104] 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

[0105] [ka] To a solution of 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), 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) were added and stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amino group-supported silica gel, 1-10% methanol / chloroform) to obtain the title compound (16 mg, 80%) as a yellow oil. 1 H-NMR (400MHz, CDCl 3 )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),3.22-3.5 2(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=2Hz ,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).

[0106] 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)(pyrimidinepyridin-2-yl)methanone

[0107] [ka] To a solution of the compound obtained in Example 5 (16 mg, 0.035 mol) in chloroform (1 mL), 1M boron tribromide-dichloromethane solution (211 μL, 0.21 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by preparative thin-layer chromatography (chloroform: 2M ammonia-methanol solution = 10:1) to obtain the title compound (11 mg, 71%) as a pale yellow oil. 1 H-NMR (400MHz, CDCl 3 )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=3Hz,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).

[0108] 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

[0109] [ka] Isomer C (13 mg, 0.038 mmol) obtained in Example 2 was dissolved in N,N-dimethylformamide (1.0 mL), and 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) were added, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was stopped by adding a saturated aqueous solution of sodium bicarbonate under ice cooling, and extracted with ethyl acetate. The extracts were combined, washed with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-10% methanol / chloroform) to give the title compound (12 mg, 74%) as a colorless oil. 1 H-NMR (400MHz, CDCl 3 )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=5,16Hz,0.4H),2.28-2.68(m,4H),2.83(ddd,J=6,12,18Hz,1H),2.91-3.05(m,2H),3.43(dd,J=12,12Hz,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=7Hz,0.6H),7.02(d,J=8Hz,0.4H),7.20(s,0.4H),7.22(s,0.6H),7.68(s,0.6H),7.71(s,0.4H).

[0110] 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

[0111] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 7. 1 H-NMR (400MHz, CDCl 3 )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),2.2 7-2.48(m,3H),2.49-2.62(m,1H),2.83(dd,J=6,9Hz,0.6H),2.78(dd,J=6,9 Hz,0.4H),2.89-3.05(m,2H),3.40(dd,J=12,15Hz,0.6H),3.72-3.81(m,0.8 H),3.98(ddd,J=4,4,14Hz,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=2Hz,0.4H),6.57(dd,J=2,8Hz,0.4H),6.7 0(dd,J=2,8Hz,0.6H),6.93(d,J=8Hz,0.4H),6.97(d,J=8Hz,0.6H),7.00(d, J=2Hz,0.6H),7.22(s,0.4H),7.24(s,0.6H),7.71(s,0.4H),7.77(s,0.6H).

[0112] 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

[0113] [ka] To a solution of isomer C (9.5 mg, 0.029 mmol) obtained in Example 2 in tetrahydrofuran (1 mL), triethylamine (12.1 μL, 0.087 mmol) and nicotinic acid chloride hydrochloride (15.4 mg, 0.087 mmol) were added and stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by preparative thin layer chromatography (chloroform:methanol=10:1) to obtain the title compound (12.8 mg, 99%) as a colorless solid. 1 H-NMR (400MHz, CDCl 3)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(d dd,J=4,,4,15Hz,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=3Hz,0.7H),6.70(dd,J=3,8Hz,0.7H),6.72-6.77(m,0.6H),7.03(d,J=8Hz,0.7H),7.05(d,J=8Hz,0.3 H),7.15-7.25(m,1.4H),7.28-7.32(m,0.3H),7.71(ddd,J=2,2,8Hz,0.3H),8.27-8.29(m,0.7H),8.58-8.61(m,1.3H).

[0114] 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

[0115] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 9. 1 H-NMR (400MHz, CDCl 3)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=3,3,15Hz,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=2Hz,0.7H),6.67(dd,J=2,8Hz,0.7H),6.68-6.70(m,0.3 H),6.85(d,J=2Hz,0.3H),6.96(d,J=8Hz,0.7H),6.97(d,J=8Hz,0.3H),7. 29-7.34(m,1H),7.41(ddd,J=2,2,8Hz,0.7H),7.73(ddd,J=2,2,8Hz,0.3H ),8.01(d,J=1Hz,0.7Hz),8.50(dd,J=1,5Hz,0.7H),8.59-8.62(m,0.6H).

[0116] 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]pyridin-3-yl)methanone

[0117] [ka] According to the method described in Example 5, the title compound was obtained from Compound E obtained in Example 3 and imidazo[1,2-a]pyridine-3-carboxylic acid. 1 H-NMR (400MHz, CDCl 3)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).

[0118] 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 Synthesis of

[0119] [ka] To a dichloromethane (0.5 mL) solution of isomer C (5 mg, 0.015 mmol) obtained in Example 2 and benzaldehyde (5 μL, 0.045 mmol), sodium triacetoxyborohydride (13 mg, 0.06 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, water, and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: 2M ammonia-methanol solution = 90:10) to obtain the title compound (5 mg, 77%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.03(d ,J=13Hz,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=5,13,13Hz,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=2Hz,1H),6.71(dd,J=2,8Hz,1H),7.00-7.10(m,3H),7.15-7.25(m,3H).

[0120] (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

[0121] [ka] According to the method described in Example 6, the title compound was obtained as a colorless amorphous free form (3.4 mg) from the compound obtained in Example 12. The obtained free form was dissolved in methanol (0.5 mL), and 1M hydrochloric acid-diethyl ether solution (50 μL) was added, followed by concentration under reduced pressure. Water (0.2 mL) was added to the obtained concentrated residue, which was then frozen and freeze-dried to obtain the title compound (4.0 mg, 54%) as a white solid. 1 H-NMR (400MHz, CD 3OD)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=8Hz,1H),7.13(d,J=8Hz,1H),7.40-7.60(m,5H).

[0122] 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

[0123] [ka] According to the method described in Example 12, the title compound was obtained from Isomer C obtained in Example 2 and picolinaldehyde. 1 H-NMR (400MHz, CDCl 3)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=2,5,14Hz,1H),1.81-1.97(m,2H),1.98-2.03(m, 1H),2.10(ddd,J=5,13,13Hz,1H),2.34(dd,J=6.13Hz,1H),2.36(dd,J=6, 13Hz,1H),2.44-2.59(m,3H),2.68(ddd,J=4,4,13Hz,1H),2.79-2.95(m,2 H),2.95(d,J=6Hz,1H),2.99(d,J=18Hz,1H),3.19(ddd,J=2,12,14Hz,1H) ,3.68(s,3H),3.70(d,J=14Hz,1H),3.74(d,J=14Hz,1H),6.62(d,J=2Hz,1 H),6.72(dd,J=2,8Hz,1H),6.92(d,J=8Hz,1H),7.02-7.06(m,1H),7.07(ddd,J=1,5,7Hz,1H),7.47(ddd,J=2,7,7Hz,1H),8.45(ddd,J=1,2,5Hz,1H).

[0124] 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

[0125] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 14. 1 H-NMR (400MHz, CDCl 3)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=2,5,14Hz,1H),1.53(ddd,J=2,5,16Hz,1H),1.85(ddd,J=3,12 ,14Hz,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=18Hz,1H),3.22(ddd,J=1,11,13Hz,1H),3.76(s,2H),4.73(br s,1H),6.25(d,J=2Hz,1H),6.56(dd,J=2,8Hz,1H),6.90(d,J=8Hz,1H),7.12(ddd,J=1 ,5,8Hz,1H),7.16-7.21(m,1H),7.57(ddd,J=2,8,8Hz,1H),8.48(ddd,J=1,2,5Hz,1H).

[0126] (Example 16) 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

[0127] [ka] According to the method described in Example 12, the title compound was obtained from Isomer C obtained in Example 2 and isonicotinaldehyde. 1 H-NMR (400MHz, CDCl 3)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=2,5,14Hz,1H),1.77-1.84(m,1H),1.88(ddd,J=3 ,12,15Hz,1H),1.99(ddd,J=2,13,13Hz,1H),2.03(ddd,J=4,13,13Hz,1H),2.35(dd,J=6,13Hz,1H),2.35(dd,J=6,13Hz,1H),2.43(ddd,J=4,4,13Hz, 1H),2.47-2.60(m,3H),2.85-2.95(m,1H),2.86(dd,J=6,18Hz,1H),2.94( d,J=6Hz,1H),3.00(d,J=18Hz,1H),3.11(ddd,J=1,11,13Hz,1H),3.51(d,J =15Hz,1H),3.56(d,J=15Hz,1H),3.69(s,3H),6.61(d,J=3Hz,1H),6.75(d d,J=3,8Hz,1H),6.86-6.91(m,2H),7.06(d,J=8Hz,1H),8.35-8.41(m,2H).

[0128] (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

[0129] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 16. 1 H-NMR (400MHz, CDCl 3)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=4,14Hz,1H),1.65(ddd,J=2,5,16Hz,1H),1.98(ddd,J=3,12,14Hz,1H),1.99-2.10(m, 2H),2.32-2.40(m,1H),2.33(dd,J=6,13Hz,1H),2.36(dd,J=6,13Hz,1H),2.45-2.61(m,3H) ,2.81-2.91(m,2H),2.94(d,J=6Hz,1H),2.97(d,J=18Hz,1H),3.19(dd,J=12,12Hz,1H),3.52 (d,J=15Hz,1H),3.66(d,J=15Hz,1H),6.48(d,J=2Hz,1H),6.70(dd,J=2,8Hz,1H),6.84-6.91(m,2H),6.96(d,J=8Hz,1H),8.30-8.42(m,2H).

[0130] (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

[0131] [ka] According to the method described in Example 12, the title compound was obtained from Isomer C obtained in Example 2 and pyrimidine-2-carbaldehyde. 1 H-NMR (400MHz, CDCl 3)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=2,5,14Hz, 1H),1.84-2.03(m,3H),2.12(ddd,J=5,13,13Hz,1H),2.33-2.44(m,3H),2.56(ddd,J=2,5,12Hz,1H),2.73-2. 84(m,2H),2.85-3.02(m,4H),3.32(ddd,J=3,11,13Hz,1H),3.75(s,3H),3.92(d,J=15Hz,1H),3.96(d,J=15Hz ,1H),6.63(d,J=3Hz,1H),6.69(dd,J=3,8Hz,1H),7.00(d,J=8Hz,1H),7.13(t,J=5Hz,1H),8.68(d,J=5Hz,2H).

[0132] (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

[0133] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 18. 1 H-NMR (400MHz, CDCl 3)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=2,5,15Hz,1H),1.75(dd,J=5,1 5Hz,1H),1.87(ddd,J=3,11,14Hz,1H),1.98(ddd,J=3,12,12Hz,1H),2.08(ddd,J=4,12,12Hz,1H),2.29-2.40(m,3H),2.5 5(dd,J=3,11Hz,1H),2.74(dd,J=5,18Hz,1H),2.80-2.98(m,5H),3.32(ddd,J=2,11,13Hz,1H),3.95(d,J=14Hz,1H),4.00 (d,J=14Hz,1H),6.44(d,J=3Hz,1H),6.57(dd,J=3,8Hz,1H),6.89(d,J=8Hz,1H),7.15(t,J=5Hz,1H),8.69(d,J=5Hz,2H).

[0134] (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

[0135] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(pyrimidin-2-yl)acetic acid according to the method described in Example 4. 1 H-NMR (400MHz, CDCl 3)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=3,12,15Hz,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=6,16,16Hz,1H),3.33-3.45(m,1.4H),3.63-3.76(m,0.4H),3.84( d,J=15Hz,0.4H),3.90-4.01(m,1H),3.96(d,J=15Hz,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=2Hz,0.6H),6.91(d,J=8Hz,1H),7.17(t,J =5Hz,0.4H),7.18(t,J=5Hz,0.6H),8.67(d,J=5Hz,0.8H),8.70(d,J=5Hz,1.2H).

[0136] Example 21 Synthesis of 1-((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)-2-(pyridin-2-yl)ethan-1-one

[0137] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(pyridin-2-yl)acetic acid hydrochloride according to the method described in Example 7. 1 H-NMR (400MHz, CDCl 3)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).

[0138] (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

[0139] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 21. 1 H-NMR (400MHz, CDCl 3) 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).

[0140] (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

[0141] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(thiophen-2-yl)acetic acid according to the method described in Example 7. 1 H-NMR (400MHz, CD 3 Cl)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,1 H),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=1,16Hz,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=3Hz,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).

[0142] (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

[0143] [ka] To a solution of the compound obtained in Example 23 (24.3 mg, 0.052 mmol) in tetrahydrofuran (3 mL), 0.9 M borane-tetrahydrofuran complex tetrahydrofuran solution (578.6 μL, 0.52 mmol) was added, and the mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure. 2 M hydrochloric acid (3 mL) was added to the concentrated residue, and the mixture was heated under reflux for 2 hours. After the reaction mixture was allowed to cool, it was poured into a saturated aqueous solution of sodium bicarbonate to make it basic, and extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0-2% methanol / ethyl acetate) to obtain the title compound (21.1 mg, 89%) as a colorless oil. 1 H-NMR (400MHz, CD 3 Cl)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).

[0144] (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

[0145] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 24. 1 H-NMR (400MHz, CD 3 Cl)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=4,15Hz,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=11,11Hz,1H),4.82(br s,1H),6.42(d,J=2Hz,1H),6.56(dd,J=2,8Hz,1H),6.77(d,J=3Hz,1H),6.87-6.91(m,2H),7.09(dd,J=1,5Hz,1H).

[0146] (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 Synthesis of

[0147] [ka] Compound E (20 mg, 0.061 mmol) obtained in Example 3, 2-(1H-pyrazol-3-yl)acetic acid (12 mg, 0.17 mmol) and N,N-diisopropylethylamine (31 μL, 0.18 mmol) were added to a solution of N,N-dimethylformamide (0.5 mL) under ice cooling, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24 mg, 0.064 mmol) was added and stirred at room temperature for 16 hours. Potassium carbonate (83 mg, 0.61 mmol) and methanol (1 mL) were added to the reaction mixture, and the mixture was further stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the title compound (27 mg, 100%) as a white solid. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.75-0.90(m,1H),1.01(d,J=10Hz,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=4,12,12Hz,1H),2.80-3.00(m,2H),3. 28(t,J=12Hz,1H),3.37(t,J=12Hz,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=8Hz,0.5H),6.91(d,J=8Hz,0.5H),7.44(s,0.5H),7.49(s,0.5H).

[0148] 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

[0149] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 26. 1 H-NMR (400MHz, CDCl 3 )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=14Hz,1H),1.80-2.00(m,1H),2.00-2.10(m,3 H),2.20-2.40(m,3H),2.40-3.10(m,9H),3.16(ddd,J=7,19,19Hz,1H),5.9 8(s,1H),6.67(d,J=8Hz,1H),6.73(s,1H),6.97(d,J=8Hz,1H),7.43(s,1H).

[0150] (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

[0151] [ka] According to the method described in Example 4, the title compound was obtained from Isomer C obtained in Example 2 and (E)-3-(furan-3-yl)acrylic acid. 1 H-NMR (400MHz, 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=4,12Hz,1H),2.79( dd,J=6,18Hz,1H),2.88-2.96(m,1.2H),2.99-3.10(m,1.6H),3.48(ddd,J=3,3,12Hz,0.8 H),3.52-3.68(m,0.4H),3.76-3.85(m,0.2H),3.91(ddd,J=3,3,14Hz,0.2H),4.11(ddd,J =3,12,12Hz,0.8H),4.51(dd,J=6,14Hz,0.8H),6.51(d,J=16Hz,0.2H),6.55(dd,J=3,8Hz ,0.2H),6.57(s,0.8H),6.64(d,J=15Hz,0.8H),6.65-6.68(m,0.2H),6.71(dd,J=2,8Hz,0 .8H),6.89(d,J=8Hz,0.2H),6.97(d,J=8Hz,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=15Hz,0.8H),7.55(s,0.2H),7.65(s,0.8H).

[0152] (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

[0153] [ka] A solution of isomer C (14 mg, 0.040 mmol) obtained in Example 2 in dichloromethane (1.0 mL) was cooled to 0°C, triethylamine (17 μL, 0.12 mmol) and benzoic anhydride (18 mg, 0.079 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture to terminate the reaction, and the mixture was extracted 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 (0-10% methanol / chloroform) to obtain the title compound (17 mg, 96%) as a colorless oil. 1 H-NMR (400MHz, CDCl 3 )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=3,3,14Hz,0.3H),1.71(dd,J =4,14Hz,0.7H),1.74-2.14(m,3.7H),2.21(dd,J=5,15Hz,0.3H),2.27-2.61 (m,3.3H),2.69(ddd,J=6,12,17Hz,0.7H),2.76(dd,J=6,18Hz,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=2,4,14Hz,0.7H),4.17(ddd, J=1,5,14Hz,0.3H),6.20(d,J=2Hz,0.7H),6.66-6.78(m,1.3H),6.92-6.98( m,1.3H),7.02(d,J=8Hz,0.7H),7.04(d,J=8Hz,0.3H),7.24-7.40(m,3.7H).

[0154] (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

[0155] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 29. 1 H-NMR (400MHz, CDCl 3 )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=4,4,15Hz,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=6,18Hz,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=4,13,13Hz,0.6H),3.93-4.01(m,0.4H),4.29-4.38(m,0.6H),6.20(d,J=2Hz,0.4H),6.61(dd,J=2,8Hz,0.4H ),6.65(dd,J=2,8Hz,0.6H),6.94(d,J=8Hz,0.6H),6.95(d,J=8Hz,0.4H),6.97-7.02(m,0.6H),7.06(d,J=2Hz,0.6H),7.29-7.45(m,4.4H).

[0156] (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

[0157] [ka] Compound E (30 mg, 0.091 mmol) obtained in Example 3 and 2-(thiazol-2-yl)ethyl methanesulfonate (synthesized by the method described in WO2010105179) (23 mg, 0.11 mmol) were dissolved in acetonitrile (1 mL), N,N-diisopropylethylamine (47 μL, 0.27 mmol) was added, and the mixture was stirred at 80 ° C. for 12 hours, and then stirred at room temperature for 4 days. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. 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: 2M ammonia-methanol solution = 85:15) to obtain the title compound (26 mg, 65%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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),1.17-1.7 3(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=3,8Hz,1H),6.93(d,J=8Hz,1H),7.09(d,J=3Hz,1H),7.61(d,J=4Hz,1H).

[0158] 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

[0159] [ka] Triethylamine (18 μL, 0.12 mmol) was added to a solution of 2-(furan-2-yl)ethan-1-ol (7 mg, 0.06 mmol) in dichloromethane (1 mL), and then mesylic anhydride (11 mg, 0.066 mmol) was added under ice cooling, and the mixture was stirred for 1 hour under ice cooling. Under ice cooling, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, extracted three times with chloroform, and the combined extracts were dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product of 2-(furan-2-yl)ethyl methanesulfonate. A solution of the crude product obtained in N,N-dimethylformamide (0.25 mL) was added dropwise to a solution of 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, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (chloroform: 2M ammonia-methanol solution = 90:10) to give the title compound (2.1 mg, 17%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.00-0.15(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.04(d,J=11H z,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=3Hz,1H), 6.20-6.25(m,1H),6.50-6.55(m,1H),6.58(dd,J=3,8Hz,1H),6.90(d,J=8Hz,1H)

[0160] (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

[0161] [ka] The title compound was obtained from Compound E obtained in Example 3 and 2-(thiazol-4-yl)acetic acid according to the method described in Example 7. 1 H-NMR (400MHz, CDCl 3 )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=6,18Hz,0. 6H),2.77(dd,J=6,18Hz,0.4H),2.86(d,J=6Hz,0.6H),2.91(d,J=6Hz,0.4H),2.92(d,J= 18Hz,0.4H),2.97(d,J=18Hz,0.6H),3.12-3.30(m,1.4H),3.37-3.46(m,0.6H),3.49(ddd ,J=4,4,13Hz,0.6H),3.67(d,J=16Hz,0.4H),3.72-3.83(m,0.4H),3.84(d,J=16Hz,0.4H ),3.85-3.99(m,1H),3.90(d,J=16Hz,0.6H),4.00(d,J=16Hz,0.6H),4.11-4.19(m,0.6H) ,6.61(dd,J=3,8Hz,0.4H),6.63-6.68(m,1H),6.85(d,J=3Hz,0.6H),6.90(d,J=8Hz,0.4H ),6.92(d,J=8Hz,0.6H),7.07-7.11(m,1H),8.73(d,J=2Hz,0.6H),8.74(d,J=2Hz,0.4H).

[0162] (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

[0163] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 33. 1 H-NMR (400MHz, CDCl 3 )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=5,14Hz,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=6,18Hz,1H),2.85-3.05(m,7H),3.16(dd,J=12,12Hz,1H),4.72(br s,1H),6.46(s,1H),6.59(d,J=8Hz,1H),6.84(s,1H),6.89(d,J=8Hz,1H),8.68(s,1H).

[0164] 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

[0165] [ka] The title compound was obtained from 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. 1 H-NMR (400MHz, CDCl 3 )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).

[0166] (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

[0167] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 35. 1 H-NMR (400MHz, CDCl 3)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),3.3 5-3.59(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=2Hz,0.6H),6.88-6.97(m,1H).

[0168] (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

[0169] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 36. 1 H-NMR (400MHz, CDCl 3 )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=2Hz,1H),6.55(dd,J=2,8Hz,1H),6.89(d,J=8Hz,1H).

[0170] (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

[0171] [ka] According to the method described in Example 5, the title compound was obtained from Isomer C obtained in Example 2 and 2-(1H-imidazol-4-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3 )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).

[0172] (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

[0173] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 38. 1 H-NMR (400MHz, CDCl 3)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=8Hz,0.6H),6.97(d,J=8Hz,0.4H),7.37(s,0.6H),7.40(s,0.4H).

[0174] (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

[0175] [ka] According to the method described in Example 5, the title compound was obtained from Compound E obtained in Example 3 and 2-(1-methyl-1H-imidazol-4-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3 )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,1 H),1.71-2.60(m,8H),2.73(ddd,J=2,8,8Hz,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=3,8Hz,0.6H),6.67(dd,J=3,8Hz,0.4H),6.70-6.77(m,1.6 H),6.82(d,J=3Hz,0.4H),6.87(d,J=8Hz,0.6H),6.91(d,J=8Hz,0.4H),7.31(s,0.4H),7.36(s,0.6H).

[0176] (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

[0177] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 40. 1 H-NMR (400MHz, CDCl 3 )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),2.6 6-3.02(m,10H),3.17-3.30(m,1H),3.58(s,3H),6.51(s,1H),6.54(s,1H),6.60(d,J=8Hz,1H),6.87(d,J=8Hz,1H),7.29(s,1H).

[0178] (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

[0179] [ka] According to the method described in Example 5, the title compound was obtained from Isomer C obtained in Example 2 and 2-(1H-pyrazol-1-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3)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,3 H),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=16Hz,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).

[0180] (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

[0181] [ka] To a solution of compound E (7.6 mg, 0.023 mmol) obtained in Example 3 in N,N-dimethylformamide (1.0 mL), 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) were added and stirred at room temperature for 2 hours. A 2M aqueous sodium hydroxide solution (1 mL) was added to the reaction mixture and stirred at room temperature for 17 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. 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:2M ammonia-methanol=10:1) to obtain the title compound (9.9 mg, 98%) as a colorless oil. 1 H-NMR (400MHz, CDCl 3)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=18Hz,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=16Hz,0.5H),4.81(d,J=16Hz,0.5H),4.95(d,J=16Hz,0.5H),4.99(d,J=16Hz,0.5H),6.26-6.29(m ,1H),6.62-6.68(m,2H),6.90-6.95(m,1H),7.33(dd,J=2,2Hz,0.5H),7.41(d,J=2Hz,0.5H),7.55(dd,J=2,4Hz,1H).

[0182] (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

[0183] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 42. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.75-0.90(m,1H),1.03(d,J=13Hz,1H),1.40- 1.50(m,1H),1.75(ddd,J=3,11,14Hz,1H),1.86(ddd,J=4,4,12Hz,1H),1.90-2.10(m,2H),2.3 4(d,J=6Hz,2H),2.40-2.50(m,2H),2.50-2.60(m,1H),2.64(dt,J=13,4Hz,1H),2.70-2.90(m, 3H),2.90-3.00(m,3H),3.14(ddd,J=1,11,12Hz,1H),3.76(s,3H),4.00-4.10(m,2H),4.59(br s,1H),6.04(t,J=2Hz,1H),6.68(d,J=2Hz,1H),6.72(dd,J=2,8Hz,1H),6.91(d,J=2Hz,1H),7.03(d,J=8Hz,1H),7.40(d,J=2Hz,1H).

[0184] (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

[0185] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 44. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.75-0.85(m,1H),1.00(d,J=11Hz,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=13,4Hz,1 H),2.75(dd,J=6,18Hz,1H),2.80-3.00(m,4H),3.10-3.20(m,1H),4.05-4.15(m,2H),6.09(t,J=2Hz,1H) ,6.55(d,J=2Hz,1H),6.61(dd,J=2,8Hz,1H),6.93(d,J=8Hz,1H),7.05(d,J=2Hz,1H),7.41(d,J=2Hz,1H).

[0186] (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

[0187] [ka] According to the method described in Example 5, the title compound was obtained from Compound E obtained in Example 3 and 2-(4-methyl-1H-pyrazol-1-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.07(d,J=12Hz,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=16Hz,0.6H),4.70(d,J=16Hz,0.6H),4.85(d,J=16Hz,0.4H),4.90(d ,J=16Hz,0.4H),6.05(s,1H),6.60-6.70(m,2H),6.85-7.00(m,1H),7.20-7.35(m,1H).

[0188] (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

[0189] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 46. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.03(d,J=11Hz,1H),1 .48(dd,J=8.14Hz,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=2Hz,1H),6.55(d,J=2Hz,1H),6.62(dd,J=2,8Hz,1H),6.93(d,J=8Hz,1H),6.99(s,1H).

[0190] (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

[0191] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(4-methyl-1H-pyrazol-1-yl)acetic acid according to the method described in Example 5. 1 H-NMR (400MHz, CDCl 3)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,3.5 H),3.02-3.10(m,0.5H),3.35(ddd,J=4,4,13Hz,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=16Hz,0.5H),4.83(d,J=16Hz,0.5H),4.87(d,J= 16Hz,0.5H),4.93(d,J=16Hz,0.5H),6.67(d,J=6Hz,0.5H),6.68(d,J=6Hz,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).

[0192] (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

[0193] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 48. 1 H-NMR (400MHz, CDCl 3)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),2.50-2.6 5(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=16Hz,0.5H),4.74(d,J=16Hz,0.5H),4.86(d ,J=16Hz,0.5H),4.91(d,J=16Hz,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).

[0194] (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

[0195] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 49. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.75-0.90(m,1H),1.02(d,J=11Hz,1H),1 .45(dd,J=3,14Hz,1H),1.70-1.85(m,2H),1.90-2.10(m,2H),2.00(s,3H),2.30-2.40(m,3 H),2.50-2.70(m,3H),2.75(dd,J=6,18Hz,1H),2.80-3.00(m,5H),3.13-3.25(m,1H),4.00 -4.15(m,2H),6.54(d,J=3Hz,1H),6.61(dd,J=3,8Hz,1H),6.85-6.95(m,2H),7.24(s,1H).

[0196] (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

[0197] [ka] According to the method described in Example 5, the title compound was obtained from Compound E obtained in Example 3 and 2-(5-methyl-1H-pyrazol-1-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.80-0.90(m,1H),1.06(d,J=11Hz,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),3.15-3.5 0(m,1.4H),3.60-4.00(m,2H),4.53(d,J=16Hz,0.6H),4.72(d,J=16Hz,0.6H),4.85(d,J=16Hz,0.4H),4.90(d,J= 16Hz,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).

[0198] (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

[0199] [ka] The title compound was obtained from the compound obtained in Example 51 according to the method described in Example 24. obtained. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.75-0.90(m,1H),1.02(d,J=10Hz, 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=8Hz, 2H),5.95(s,1H),6.54(s,1H),6.60-6.65(m,1H),6.91(d,J=8Hz,1H),7.36(s,1H).

[0200] (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

[0201] [ka] According to the method described in Example 5, the title compound was obtained from Compound E obtained in Example 3 and 2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3)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),4.0 0-4.15(m,0.5H),4.72(d,J=16Hz,0.5H),4.89(d,J=16Hz,0.5H),5.01(d,J=16Hz,0.5H),5.02(d,J=16Hz,0.5H),,6.51(d,J=2H) z,0.5H),6.54(d,J=2Hz,0.5H),6.60-6.70(m,2H),6.95(s,0.5H),6.97(s,0.5H),7.37(d,J=1Hz,0.5H),7.50(d,J=1Hz,0.5H).

[0202] (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

[0203] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 53. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.70-1.00(m,1H),1.02 (d,J=13Hz,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=8Hz,1H).

[0204] (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

[0205] [ka] According to the method described in Example 5, the title compound was obtained from Compound E obtained in Example 3 and 2-(3,5-dimethyl-1H-pyrazol-1-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3)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=16Hz,0.6H),4.62(d,J=16Hz,0.6H),4.75(d ,J=16Hz,0.4H),4.82(d,J=16Hz,0.4H),5.77(s,0.4H),5.80(s,0.6H),6.60-6.70(m,2H),6.85-6.95(m,1H).

[0206] (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

[0207] [ka] The title compound was obtained from the compound obtained in Example 55 according to the method described in Example 24. obtained. 1 H-NMR (400MHz, CDCl 3)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,3 H),2.20-2.40(m,3H),2.50-2.60(m,1H),2.60-3.00(m,8H),3.20-3.30(m,1H),4.0 0(t,J=7Hz,2H),5.74(s,1H),6.53(s,1H),6.61(d,J=8Hz,1H),6.90(d,J=8Hz,1H).

[0208] (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

[0209] [ka] According to the method described in Example 5, the title compound was obtained from Compound E obtained in Example 3 and 2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.10(d,J=12Hz,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),3.6 5-3.75(m,0.5H),3.80-3.90(m,1H),3.95-4.05(m,0.5H),4.72(d,J=16Hz,0.5H),4.98(d,J=16 Hz,0.5H),5.00(d,J=16Hz,0.5H),5.15(d,J=16Hz,0.5H),6.40-6.80(m,5H),6.90-7.00(m,1H).

[0210] (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

[0211] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 57. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.00(d,J=10Hz,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(d dd,J=4,5,13Hz,1H),2.75(dd,J=6,8Hz,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=6Hz,2H),6.50-6.90(m,5H),6.93(d,J=8Hz,1H).

[0212] (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-(ethano)naphtho[1,2-d]azepin-3(4H)-yl)ethan-1-one

[0213] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(4-bromo-1H-pyrazol-1-yl)acetic acid according to the method described in Example 5. 1 H-NMR (400MHz, CDCl 3)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=16Hz,0.5H),4.84(d,J=16Hz,0.5H),4.94(d,J=16Hz,0.5H),4.94(d,J=16Hz,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).

[0214] (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

[0215] [ka] According to the method described in Example 5, the title compound was obtained from Compound E obtained in Example 3 and 2-(4-bromo-1H-pyrazol-1-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3)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=16Hz,0.5H),4.79(d,J=16Hz, 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).

[0216] (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

[0217] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 60. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.00-0.15(m,2H),0.45-0.65(m,2H),0.75-0.90(m,1H),1.02(d,J =10Hz,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=8Hz,1H),7.35(s,1H).

[0218] (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

[0219] [ka] According to the method described in Example 5, the title compound was obtained from Compound E obtained in Example 3 and 2-(1H-imidazol-1-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3 )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= 8,14Hz,0.8H),3.70-3.80(m,0.2H),3.85-4.05(m,1.8H),4.43(d,J=16Hz,0.8H),4.67(d,J=16Hz,0.2H),4.75-4.90(m,1H),6.57(d, J=2Hz,0.2H),6.65-6.75(m,1H),6.81(dd,J=2,8Hz,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).

[0220] (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

[0221] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 62. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.70-0.90(m,1H),1.04(d,J=10Hz,1H),1.51(dd,J= 5,14Hz,1H),1.65-1.75(m,1H),1.82(ddd,J=3,11,14Hz,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=6Hz,2H),6.6 0(s,1H),6.64(d,J=3Hz,1H),6.73(dd,J=3,8Hz,1H),6.91(s,1H),6.97(d,J=8Hz,1H),7.08(s,1H).

[0222] (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

[0223] [ka] According to the method described in Example 5, the title compound was obtained from Isomer C obtained in Example 2 and 2-(2H-1,2,3-triazol-2-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3 )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),2.50-2.7 0(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=16Hz,0.4H),5.19(d,J=16Hz,0.4H),5.28(d,J=16Hz,0.6H),5.38(d ,J=16Hz,0.6H),6.60-6.80(m,2H),7.00-7.10(m,1H),7.61(s,0.8H),7.66(s,1.2H).

[0224] (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

[0225] [ka] The title compound was obtained from the compound obtained in Example 64 according to the method described in Example 24. obtained. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.75-0.90(m,1H),1.02(d,J= 11Hz,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=2Hz,1H),6.68(dd,J=2,8Hz,1H),6.98(d,J=8Hz,1H),7.52(s,2H).

[0226] (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

[0227] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 65. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.75-0.90(m,1H),1.03(d ,J=11Hz,1H),1.20-1.30(m,1H),1.40-1.50(m,1H),1.70-1.90(m,2H),1.9 0-2.10(m,3H),2.20-2.40(m,4H),2.50-3.25(m,7H),4.40-4.60(m,2H),6. 51(d,J=2Hz,1H),6.59(dd,J=2,8Hz,1H),6.91(d,J=8Hz,1H),7.54(s,2H).

[0228] (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

[0229] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 3-(pyridin-2-yl)propanoic acid according to the method described in Example 7. 1 H-NMR (400MHz, CDCl 3 )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= 2,12,15Hz,0.5H),1.87(ddd,J=4,12,16Hz,0.5H),1.91-2.23(m,3.5H),2.29(dd,J=6,12Hz,0.5H),2.30-2.40(m,1.5 H),2.41-2.60(m,2H),2.66-3.18(m,7H),3.34(ddd,J=4,4,14Hz,0.5H),3.39-3.49(m,0.5H),3.50(ddd,J=4,4,14Hz, 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=3,5,15Hz,0.5H),4.48(br s,1H),6.63(d,J=2Hz,0.5H),6.64-6.73(m,1.5H),7.00(d,J=8Hz,0.5H),7.01(d,J=8Hz,0.5H),7. 04-7.10(m,1H),7.13(d,J=8Hz,0.5H),7.20(d,J=8Hz,0.5H),7.51-7.59(m,1H),8.46-8.51(m,1H).

[0230] (Example 68) (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(3-pyridine Synthesis of (2-yl)propyl-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol

[0231] [ka] A solution of the compound obtained in Example 67 (14 mg, 0.030 mmol) in tetrahydrofuran (1.0 mL) was cooled to -20°C, lithium aluminum hydride (3.1 mg, 0.082 mmol) was added, and the mixture was stirred at -20°C for 2 hours, then heated to 0°C and stirred for 1 hour. Lithium aluminum hydride (3.1 mg, 0.082 mmol) was then added, and the mixture was stirred at 0°C for 25 hours, after which lithium aluminum hydride (3.1 mg, 0.082 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and a saturated Rochelle salt solution was added to stop the reaction. The mixture was warmed to room temperature, stirred overnight, and extracted three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (18-60% 2M ammonia-methanol solution / ethyl acetate) to obtain the title compound (3.0 mg, 22%) as a colorless oil. 1 H-NMR (400MHz, CDCl 3)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=3,5,15Hz,1H),1.7 4-2.03(m,5H),2.09(ddd,J=5,13,13Hz,1H),2.29-2.52(m,6H),2.55(ddd,J=2,6,11Hz,1H),2.59-2.69(m,3H),2.75-2 .86(m,2H),2.95(d,J=6Hz,1H),2.98(d,J=18Hz,1H),3.09(ddd,J=2,10,13Hz,1H),3.76(s,3H),6.64-6.71(m,2H),6. 97-7.01(m,1H),7.00(d,J=8Hz,1H),7.06(ddd,J=1,5,7Hz,1H),7.54(ddd,J=2,7,7Hz,1H),8.49(ddd,J=1,2,5Hz,1H).

[0232] (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

[0233] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 68. 1 H-NMR (400MHz, CDCl 3)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=1,6,14Hz,1H),1.73-1.90(m,4H),1.9 5-2.09(m,3H),2.32-2.68(m,9H),2.76(dd,J=6,18Hz,1H),2.90(d,J=6Hz,1H),2.94-3.08(m,2H),2.95(d,J=18Hz,1H),4.73(br s,1H),6.59(dd,J=2,8Hz,1H),6.62(d,J=2Hz,1H),6.89(d,J=8Hz,1H),7.07-7. 12(m,1H),7.11(dd,J=5,8Hz,1H),7.58(ddd,J=2,8,8Hz,1H),8.48-8.51(m,1H).

[0234] (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

[0235] [ka] According to the method described in Example 7, the title compound was obtained from Isomer C obtained in Example 2 and 3-(pyridin-3-yl)propanoic acid. 1 H-NMR (400MHz, CDCl 3)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=3,3,14Hz,0.5H),1.63(ddd,J=2,5,15Hz,0.5H),1.78(ddd,J=2, 12,14Hz,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=4,4,13Hz,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=3,13,13Hz,0.5H),3.91(ddd,J=3,4,14Hz,0.5H), 4.22(ddd,J=2,5,14Hz,0.5H),6.62(d,J=2Hz,0.5H),6.67(dd,J=2,8Hz,0.5H),6. 69-6.74(m,1H),7.01(d,J=8Hz,0.5H),7.03(d,J=8Hz,0.5H),7.18(dd,J=5,8Hz,1 H),7.45(ddd,J=2,2,8Hz,0.5H),7.53(ddd,J=2,2,8Hz,0.5H),8.38-8.49(m,2H).

[0236] (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

[0237] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 70. 1 H-NMR (400MHz, CDCl 3)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=3,4,14Hz,1H),1.59-1.72(m,2H),1. 84(ddd,J=4,11,14Hz,1H),1.90(ddd,J=4,4,16Hz,1H),1.98(ddd,J=3,11,12Hz,1H),2.09(ddd,J=4,12,12Hz,1H),2.32-2.46(m,8H),2. 52-2.62(m,2H),2.78-2.90(m,2H),2.96(d,J=6Hz,1H),2.99(d,J=18Hz,1H),3.06(ddd,J=2,12,13Hz,1H),3.75(s,3H),6.67(dd,J=2,8H z,1H),6.71(d,J=2Hz,1H),7.01(d,J=8Hz,1H),7.16(dd,J=5,8Hz,1H),7.35(ddd,J=2,2,8Hz,1H),8.29-8.31(m,1H),8.38-8.41(m,1H).

[0238] (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

[0239] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 71. 1 H-NMR (400MHz, CDCl 3)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=5,14Hz,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=6,18Hz,1H),2.84-2. 95(m,1H),2.90(d,J=6Hz,1H),2.95(d,J=18Hz,1H),2.98-3.07(m,1H),4.72(br s,1H),6.56-6.61(m,2H),6.91(d,J=8Hz,1H),7.18(dd,J=5,7Hz,1H),7.41(d,J=7Hz,1H),8.18(s,1H),8.38(d,J=5Hz,1H).

[0240] (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

[0241] [ka] According to the method described in Example 7, the title compound was obtained from Isomer C obtained in Example 2 and 3-(pyridin-4-yl)propanoic acid. 1 H-NMR (400MHz, CDCl 3)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=4,4,14Hz,0.5H),1.63(ddd,J=2,5,15Hz,0.5H ),1.77(ddd,J=3,12,15Hz,0.5H),1.84-2.23(m,4H),2.25-3.06(m,11H),3.25(ddd,J=4,4,13Hz,0.5H),3.36(ddd,J=1,12,14Hz,0.5H),3.41(ddd ,J=3,6,14Hz,0.5H),3.66-3.80(m,0.5H),3.69(s,1.5H),3.78(s,1.5H) ,3.83(ddd,J=3,13,13Hz,0.5H),3.91(ddd,J=3,5,14Hz,0.5H),4.22(ddd ,J=3,5,14Hz,0.5H),6.63(d,J=3Hz,0.5H),6.67(dd,J=3,8Hz,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).

[0242] (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

[0243] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 73. 1 H-NMR (400MHz, CDCl 3)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=3,5,14Hz,1H),1.55-1.72(m,2 H),1.84(ddd,J=4,11,14Hz,1H),1.89(ddd,J=4,4,16Hz,1H),1.98(ddd,J=3,11,11Hz,1H),2.09(ddd,J=5,13,13Hz,1H),2.29-2. 46(m,8H),2.52-2.61(m,2H),2.82(dd,J=6,18Hz,1H),2.82-2.91(m,1H),2.95(d,J=6Hz,1H),2.99(d,J=18Hz,1H),3.04(ddd,J=2 ,12,14Hz,1H),3.75(s,3H),6.66(dd,J=2,8Hz,1H),6.71(d,J=2Hz,1H),6.94-6.98(m,2H),7.01(d,J=8Hz,1H),8.41-8.45(m,2H).

[0244] (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

[0245] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 74. 1 H-NMR (400MHz, CDCl 3) 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),1.5 1(dd,J=5,14Hz,1H),1.63-1.81(m,3H),1.83(ddd,J=3,12,14Hz,1H),1.95-2.0 8(m,2H),2.29-2.50(m,7H),2.51-2.62(m,3H),2.77(dd,J=6,18Hz,1H),2.85-2 .94(m,1H),2.90(d,J=6Hz,1H),2.94(d,J=18Hz,1H),2.99-3.08(m,1H),4.74(br s,1H),6.53(d,J=2Hz,1H),6.56(dd,J=2,8Hz,1H),6.88(d,J=8Hz,1H),6.97-7.00(m,2H),8.41-8.44(m,2H).

[0246] (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

[0247] [ka] (Method 1) According to the method described in Example 31, 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). (Method 2) Acetic acid (430.1 μL, 7.52 mmol) and 2-vinylpyridine (807.3 μL, 7.52 mmol) were added to a solution of isomer C (257.7 mg, 0.75 mmol) obtained in Example 2 in ethanol (10 mL), and the mixture was heated under reflux for 3.5 hours. The reaction solution was allowed to cool and then concentrated under reduced pressure. The concentrated residue obtained was purified by silica gel column chromatography (amino group-supported silica gel, 0-3% methanol / chloroform) to obtain the title compound (357.3 mg, quantitative) as a pale yellow oil. 1 H-NMR (400MHz, CDCl 3 )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(d dd,J=3,4,14Hz,1H),1.81(ddd,J=4,11,15Hz,1H),1.91-2.02(m,2H),2.08(ddd,J= 4,12,12Hz,1H),2.28-2.40(m,3H),2.50-2.61(m,2H),2.71-2.91(m,7H),2.94(d,J =6Hz,1H),2.97(d,J=18Hz,1H),3.20(ddd,J=3,10,13Hz,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=5,8Hz,1H),7.50(ddd,J=2,8,8Hz,1H),8.45-8.49(m,1H).

[0248] (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

[0249] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 76. 1 H-NMR (400MHz, CDCl 3 )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=2,6,15Hz,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=6,18Hz,1H),2.86-3.00(m,7H),3.21(ddd,J=2,11,11Hz,1H),4.73(br s,1H),6.48(d,J=2Hz,1H),6.57(dd,J=2,8Hz,1H),6.87(d,J=8Hz,1H),7.08-7.13(m,2H),7.56(ddd,J=2,8,8Hz,1H),8.46-8.49(m,1H).

[0250] (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

[0251] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(pyridin-3-yl)acetic acid according to the method described in Example 5. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.75-0.90(m,1H),1.03(d,J =13Hz,1H),1.45-1.55(m,1H),1.80-1.90(m,2H),1.99(ddd,J=4,11,11Hz,1H ),2.10(ddd,J=3,13,13Hz,1H),2.30-2.70(m,6H),2.70-2.90(m,2H),2.90- 3.00(m,2H),3.07(ddd,J=3,11,13Hz,1H),3.54(s,2H),3.68(s,3H),4.78(br s,1H),6.62(d,J=2Hz,1H),6.71(dd,J=2,8Hz,1H),7.00-7.10(m,3H),7.10-7.25(m,2H).

[0252] (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

[0253] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 78. 1 H-NMR (400MHz, CDCl 3)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),6.5 5-6.65(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).

[0254] (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

[0255] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 79. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.80-0.90(m,1H),1.04(d,J=11Hz,1H),1.50(dd,J=5 ,14Hz,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=2Hz,1H),6.63(dd,J=2,8Hz,1H),6.93(d,J=8H z,1H),7.16(dd,J=6,8Hz,1H),7.42(ddd,J=2,2,6Hz,1H),8.35(d,J=2Hz,1H),8.40(dd,J=2,6Hz,1H).

[0256] (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

[0257] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(pyridin-4-yl)acetic acid according to the method described in Example 5. 1 H-NMR (400MHz, CDCl 3)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,1 H),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=3Hz,0.5H),6.65-6.75(m,1.5H),6.90-7.00(m,1H),7.03(d,J=8Hz,1H),7.08(d,J=6Hz,1H),8.40-8.50(m,2H).

[0258] (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

[0259] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 81. 1 H-NMR (400MHz, CDCl 3)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=8Hz,1H),6.98(d,J=8Hz,2H),8.37(d,J=5Hz,2H).

[0260] (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

[0261] [ka] According to the method described in Example 32, the title compound was obtained from Compound E obtained in Example 3 and 2-(pyrimidin-2-yl)ethan-1-ol. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.00-0.15(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.05(d,J=10Hz,1H), 1.51(dd,J=6,15Hz,1H),1.80-2.10(m,4H),2.25-2.40(m,3H),2.54(d,J=7Hz,1H),2.73( dd,J=6,17Hz,1H),2.80-3.00(m,5H),3.10-3.25(m,4H),3.25-3.40(t,J=11Hz,1H),6.52 (s,1H),6.55(d,J=8Hz,1H),6.86(d,J=8Hz,1H),7.10(t,J=5Hz,1H),8.62(d,J=5Hz,2H).

[0262] (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

[0263] [ka] According to the method described in Example 31, the title compound was obtained from compound E obtained in Example 3 and 2-(pyrazin-2-yl)ethyl methanesulfonate (synthesized by the method described in WO2017223239). 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.00-0.15(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.02(d,J=9Hz,1H), 1.50(dd,J=4,14Hz,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=12Hz,1H),6.49(d,J=2Hz ,1H),6.57(dd,J=2,8Hz,1H),6.89(d,J=8Hz,1H),8.30-8.40(m,2H),8.40-8.50(m,1H).

[0264] (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

[0265] [ka] 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-hydroxybenzotriazole 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) were stirred overnight at room temperature, and then a suspension of potassium carbonate (50 mg, 0.36 mmol) in methanol (1 mL) was added and stirred at room temperature for 4 hours. The reaction mixture was extracted four times with ethyl acetate, and the combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (3-15% methanol / chloroform) to obtain the title compound (11 mg, 97%) as a white powder. 1 H-NMR (400MHz, CDCl 3 )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).

[0266] (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

[0267] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 85. 1 H-NMR (400MHz, CDCl 3 )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=2,8Hz,1H)6.65(d,J=7Hz,1H),6.89(d,J=8Hz,1H),7.37-7.45(m,1H).

[0268] (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

[0269] [ka] The title compound was obtained from Compound E obtained in Example 3 and 2-(6-(trifluoromethyl)pyridin-2-yl)acetic acid according to the method described in Example 85. 1 H-NMR (400MHz, CDCl 3)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,1 H),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=2Hz,0.6H),6.87-6.97(m,1H),7.37-7.45(m,1H),7.49-7.56(m,1H),7.75(dd,J=8,8Hz,1H).

[0270] (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

[0271] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 87. 1 H-NMR (400MHz, CDCl 3)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=3,5,13Hz,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=8Hz,1H),7.20(d,J=8Hz,1H),7.44(d,J=8Hz,1H),7.65(dd,J=8,8Hz,1H).

[0272] (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

[0273] [ka] According to the method described in Example 31, the title compound was obtained from 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). 1 H-NMR (400MHz, CDCl 3)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 ,5,15Hz,1H),1.84(ddd,J=4,12,15Hz,1H),1.92-2.03(m,2H),2.09(ddd,J=5,13,13Hz,1H ),2.29-2.38(m,3H),2.52-2.60(m,2H),2.62-2.83(m,6H),2.87(ddd,J=2,11,13Hz,1H),2 .94(d,J=6Hz,1H),2.98(d,J=18Hz,1H),3.21(ddd,J=3,12,13Hz,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).

[0274] (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

[0275] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 89. 1 H-NMR (400MHz, CDCl 3)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=8Hz,1H),6.84(d,J=8Hz,1H),7.10-7.19(m,3H),7.23(d,J=8Hz,2H).

[0276] (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

[0277] [ka] According to the method described in Example 7, the title compound was obtained from Isomer C obtained in Example 2 and 3-phenylpropanoic acid. 1 H-NMR (400MHz, CDCl 3)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=3,3,15Hz,0.5H),1.63(ddd,J=2,5,15Hz,0.5H),1.79(ddd,J=3, 12,15Hz,0.5H),1.83-2.03(m,2H),2.08(ddd,J=5,13,13Hz,0.5H),2.15-2.20(m ,1H),2.26-2.66(m,5.5H),2.68(ddd,J=4,6,10Hz,0.5H),2.73-3.05(m,5.5H),3. 25(ddd,J=4,4,13Hz,0.5H),3.34-3.45(m,1H),3.64-3.74(m,0.5H),3.69(s,1.5 H),3.79(s,1.5H),3.83(ddd,J=3,12,12Hz,0.5H),3.91(ddd,J=2,4,14Hz,0.5H), 4.21(ddd,J=3,5,14Hz,0.5H),6.62(d,J=3Hz,0.5H),6.68(dd,J=3,8Hz,0.5H),6 .70-6.74(m,1H),7.01(d,J=8Hz,0.5H),7.02(d,J=8Hz,0.5H),7.12-7.32(m,5H).

[0278] (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

[0279] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 91. 1 H-NMR (400MHz, CDCl 3)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=3,4,15H z,1H),1.62-1.72(m,2H),1.84(ddd,J=4,12,15Hz,1H),1.89-2.02(m,2H),2.10(ddd,J=5,13,13H z,1H),2.29-2.48(m,8H),2.55(ddd,J=2,5,11Hz,1H),2.62(ddd,J=4,4,13Hz,1H),2.76-2.85(m, 2H),2.96(d,J=6Hz,1H),2.98(d,J=18Hz,1H),3.07(ddd,J=3,11,13Hz,1H),3.76(s,3H),4.79(br s,1H),6.67(dd,J=3,8Hz,1H),6.70(d,J=3Hz,1H),7.00(d,J=8Hz,1H),7.06-7.10(m,2H),7.14(tt,J=2,7Hz,1H),7.21-7.27(m,2H).

[0280] (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

[0281] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 92. 1 H-NMR (400MHz, CDCl 3)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=2,6,15Hz,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=6Hz,1H),2.93(d,J=18Hz,1H),3.05-3.15(m,1H), 4.80(br s,1H),6.42(d,J=3Hz,1H),6.53(dd,J=3,8Hz,1H),6.87(d,J=8Hz,1H),7.11-7.18(m,3H),7.21-7.28(m,2H).

[0282] (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

[0283] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(2-fluorophenyl)ethan-1-ol according to the method described in Example 32. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.04(d,J=14Hz,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).

[0284] (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

[0285] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 94. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.00-0.15(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.04(d,J=11Hz,1H),1.52(dd,J=4,15Hz,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=3Hz,1H),6.57(dd,J=3,8Hz,1H),6.89(d,J=8Hz,1H),6.95-7.05(m,2H),7.10-7.20(m,2H).

[0286] (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

[0287] [ka] According to the method described in Example 31, the title compound was obtained from compound E obtained in Example 3 and 2-methoxyphenethyl 4-methylbenzenesulfonate (synthesized by the method described in WO2010021149). 1 H-NMR (400MHz, CDCl 3 )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=2,6,14Hz,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=12,12Hz,1H),3.78(s,3H),4.79(br s,1H),6.47(d,J=2Hz,1H),6.56(dd,J=2,8Hz,1H),6.79-6.90(m,3H),7.10(dd,J=1,7Hz,1H),7.16(ddd,J=1,8,8Hz,1H).

[0288] (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

[0289] [ka] The title compound was obtained from Compound E obtained in Example 3 and 2-(3-methoxypyridin-2-yl)acetic acid according to the method described in Example 7. 1 H-NMR (400MHz, CDCl 3 )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=4,4,15Hz,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=6,18Hz,0.6H),2 .76(dd,J=6,18Hz,0.4H),2.84(d,J=6Hz,0.6H),2.88-2.95(m,0.8H),2.96(d,J=18Hz,0.6 H),3.08-3.23(m,0.6H),3.27-3.45(m,1.4H),3.64(d,J=16Hz,0.4H),3.64-3.76(m,0.4H) ,3.73(s,3H),3.80(d,J=16Hz,0.4H),3.85-3.98(m,2.2H),4.22(ddd,J=2,5,14Hz,0.6H), 6.59(dd,J=2,8Hz,0.6H),6.61(dd,J=2,8Hz,0.4H),6.66(d,J=2Hz,0.4H),6.80(d,J=2Hz, 0.6H),6.88(d,J=8Hz,0.4H),6.89(d,J=8Hz,0.6H),7.07-7.17(m,2H),8.06-8.10(m,1H).

[0290] (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

[0291] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 97. 1 H-NMR (400MHz, CDCl 3 )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=2,5,14Hz,1H),1.80-1.92(m,2H),1.9 6-2.09(m,2H),2.26-2.39(m,3H),2.50-2.55(m,1H),2.72(dd,J=6,18Hz,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=2Hz,1H),6.55(dd,J=2,8Hz,1H),6.85(d,J=8Hz,1H),7.08(dd,J=2,8Hz,1H),7.10(dd,J=4,8Hz,1H),8.07(dd,J=2,4Hz,1H).

[0292] (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

[0293] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(3-fluoropyridin-2-yl)ethyl 4-methylbenzenesulfonate according to the method described in Example 31. 1 H-NMR (400MHz, CDCl 3)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=3,4,15Hz,1H),1.82(ddd,J=4,12,15Hz,1H),1.92-2.01(m,2H),2.08( ddd,J=5,13,13Hz,1H),2.25-2.40(m,3H),2.54(ddd,J=2,4,11Hz,1H),2.61(ddd,J= 4,4,13Hz,1H),2.72-3.02(m,9H),3.20(ddd,J=3,12,13Hz,1H),3.77(s,3H),4.67(br s,1H),6.65-6.69(m,2H),6.98(d,J=9Hz,1H),7.09(ddd,J=4,4,8Hz,1H),7.26(ddd,J=1,8,10Hz,1H),8.29(ddd,J=1,1,4Hz,1H).

[0294] (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

[0295] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 99. 1 H-NMR (400MHz, CDCl 3)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=2,5,15Hz,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=6,18Hz,1H),2. 82(ddd,J=3,6,13Hz,1H),2.85-3.09(m,8H),3.19-3.28(m,1H),4.73(br s,1H),6.45(d,J=3Hz,1H),6.54(dd,J=3,8Hz,1H),6.86(d,J=8Hz,1H),7.12( ddd,J=4,4,8Hz,1H),7.29(ddd,J=1,8,10Hz,1H),8.29(ddd,J=1,1,4Hz,1H).

[0296] (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

[0297] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(3-methylpyridin-2-yl)ethan-1-ol according to the method described in Example 32. 1 H-NMR (400MHz, CDCl 3)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=3,5,15Hz,1H),1.84(ddd,J=4,12,15Hz,1H),1.93-2.03(m,2H),2.10(dd d,J=5,13,13Hz,1H),2.27(s,3H),2.29-2.39(m,3H),2.52-2.59(m,1H),2.64(ddd,J= 4,4,13Hz,1H),2.73-3.04(m,9H),3.28(ddd,J=3,12,13Hz,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=1,5Hz,1H).

[0298] (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

[0299] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 101. 1 H-NMR (400MHz, CDCl 3)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=2,5,15Hz,1H),1.80-1.93(m,2H),1.9 5-2.11(m,2H),2.23(s,3H),2.26-2.40(m,3H),2.48-2.59(m,1H),2.73(dd,J=6,18Hz,1H),2.83-3.04(m,9H),3.23-3.32(m,1H),4.76(br s,1H),6.49(d,J=2Hz,1H),6.58(dd,J=2,8Hz,1H),6.77(d,J=8Hz,1H),7.05(dd,J=5,8Hz,1H),7.38-7.43(m,1H),8.33(dd,J=1,5Hz,1H).

[0300] (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

[0301] [ka] According to the method described in Example 31, the title compound was obtained from Isomer C obtained in Example 2 and 2-(6-methylpyridin-2-yl)ethyl 4-methylbenzenesulfonate (synthesized by the method described in WO9905095). 1 H-NMR (400MHz, CDCl 3)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=3,4,15Hz,1H),1.82(ddd,J=4,11,15Hz,1H),1.90-2.03(m,2H),2.09(ddd,J=5 ,13,13Hz,1H),2.28-2.40(m,3H),2.49(s,3H),2.51-2.61(m,2H),2.71-2.90(m,7H),2.9 4(d,J=6Hz,1H),2.97(d,J=18Hz,1H),3.18(ddd,J=3,11,13Hz,1H),3.76(s,3H),4.69(br s,1H),6.67-6.71(m,2H),6.82(d,J=8Hz,1H),6.91(d,J=8Hz,1H),6.98-7.02(m,1H),7.38(dd,J=8,8Hz,1H).

[0302] (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

[0303] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 103. 1 H-NMR (400MHz, CDCl 3)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=2,5,14Hz,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=2Hz,1H),6.56(dd,J=2,8Hz,1H),6.86(d,J=8Hz,1H),6.90(d,J=8Hz,1H),6.96(d,J=8Hz,1H),7.45(dd,J=8,8Hz,1H).

[0304] (Reference example 4) Synthesis of (E)-2-(2-methoxyvinyl)-4-methylpyridine (isomer G) and (Z)-2-(2-methoxyvinyl)-4-methylpyridine (isomer H)

[0305] [ka] 4-Methylpicolinaldehyde (363.4 mg, 3.0 mmol) and (methoxymethyl)triphenylphosphonium chloride (3.09 g, 9.0 mmol) were dissolved in tetrahydrofuran (60 mL), and sodium hydride (55% oil dispersion) (600 mg, 13.8 mmol) was added at -20°C, and the mixture was stirred at -20°C for 30 minutes and at room temperature for 18 hours. The reaction mixture was poured into ice water and extracted three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10-100% ethyl acetate / heptane) to obtain the title isomers G (70.2 mg, 16%) and H (73.9 mg, 17%), respectively. (Isomer G) 1 H-NMR (400MHz, CDCl 3)δ(ppm):2.29(s,3H),3.73(s,3H),5.83(d,J=13Hz,1H),6.84(dd,J=1,5Hz,1H),6.90(d,J=1Hz,1H),7.56(d,J=13Hz,1H),8.29(d,J=5Hz,1H). (isomer H) 1 H-NMR (400MHz, CDCl 3 )δ(ppm):2.33(s,3H),3.84(s,3H),5.47(d,J=7Hz,1H),6.32(d,J=7Hz,1H),6.85(dd,J=1,5Hz,1H),7.70(d,J=1Hz,1H),8.36(d,J=5Hz,1H).

[0306] (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

[0307] [ka] 2M hydrochloric acid (1mL) was added to a methanol (1mL) solution of isomer G (14.9mg, 0.10mmol) obtained in Reference Example 4, and the mixture was heated under reflux for 8 hours. After cooling, the reaction solution was made basic by adding a saturated aqueous solution of sodium bicarbonate, and extracted three times with chloroform. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product of 2-(4-methylpyridin-2-yl)acetaldehyde. The title compound was obtained from compound E obtained in Example 3 and a crude product of 2-(4-methylpyridin-2-yl)acetaldehyde according to the method described in Example 12. 1 H-NMR (400MHz, CDCl 3)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=2Hz,1H),6.57(dd,J=2,8Hz,1H),6.87(d,J=8Hz,1H),6.90-6.97(m,2H),8.33(d,J=5Hz,1H).

[0308] (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

[0309] [ka] According to the method described in Example 31, the title compound was obtained from Isomer C obtained in Example 2 and 2,2-difluoro-2-(pyridin-2-yl)ethyl trifluoromethanesulfonate (synthesized by the method described in WO2011045383). 1 H-NMR (400MHz, CDCl 3)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=3,11,15Hz,1H),1.71(ddd,J=3,3,16Hz,1H),1.90-2.02(m,2H),2.23-2 .33(m,3H),2.46-2.52(m,1H),2.56(ddd,J=4,4,13Hz,1H),2.62(dd,J=6,18Hz,1H),2.76-2.83 (m,2H),2.90(d,J=18Hz,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=2Hz,1H),6.60(dd,J=2,8Hz,1H),6.89(d,J=8Hz,1H),7.24-7.30(m,2H),7.63(ddd,J=2,8,8Hz,1H),8.57-8.62(m,1H).

[0310] (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

[0311] [ka] According to the method described in Example 85, the title compound was obtained from Compound E obtained in Example 3 and 1-(pyridin-2-yl)cyclopropane-1-carboxylic acid. 1 H-NMR (400MHz, CDCl 3)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=3,3,15Hz,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=6,18Hz,0.6H),2.76(dd,J=6,18Hz,0.4H),2.78(d,J =6Hz,0.6H),2.87(d,J=6Hz,0.4H),2.90(d,J=18Hz,0.4H),2.94-3.04(m,0.4H),2.96(d,J=18Hz,0.6H),3.08(ddd,J=4,4,14Hz,0.6H),3 .21(dd,J=12,14Hz,0.6H),3.40(ddd,J=2,12,14Hz,0.4H),3.78(ddd,J=4,14,14Hz,0.4H),3.90-4.01(m,1H),4.25-4.38(m,1H),4.51(br s,1H),6.55(d,J=3Hz,0.4H),6.63(dd,J=3,8Hz,0.4H),6.69(d,J=2,8Hz,0.6H),6.8 9(d,J=8Hz,0.4H),6.93(d,J=8Hz,0.6H),7.01-7.09(m,1.2H),7.10(d,J=2Hz,0.6H), 7.13(ddd,J=1,5,7Hz,0.4H),7.19-7.23(m,0.4H),7.48(ddd,J=2,8,8Hz,0.6H),7.6 0(ddd,J=2,8,8Hz,0.4H),8.44(ddd,J=1,2,5Hz,0.6H),8.45(ddd,J=1,2,5Hz,0.4H).

[0312] (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

[0313] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 107. 1 H-NMR (400MHz, CDCl 3 )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=7Hz,2H),2.46-2.53(m,1H),2.62-2.73(m,3H),2.78(d,J=13Hz,1H),2.78-2. 84(m,1H),2.85(d,J=5Hz,1H),2.88(d,J=18Hz,1H),2.91(d,J=13Hz,1H),2.95-3.04(m,1H),3.67-3.74(m,2H),6.33(d,J=3Hz,1H),6. 50(dd,J=3,8Hz,1H),6.83(d,J=8Hz,1H),6.93(ddd,J=1,5,8Hz,1H),7.23-7.28(m,1H),7.38(ddd,J=2,8,8Hz,1H),8.35-8.38(m,1H).

[0314] (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

[0315] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(1H-indol-2-yl)acetic acid according to the method described in Example 7. 1 H-NMR (400MHz, 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=6,18Hz,0.6H),2.81(dd,J=7,19Hz,0.4H) ,2.88-2.96(m,1.6H),2.97-3.00(m,0.4H),3.20(ddd,J=3,11,14Hz,0.6H),3.49 (ddd,J=4,4,13Hz,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=3,12,1 2Hz,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) =8Hz,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).

[0316] (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

[0317] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 109. 1 H-NMR (400MHz, CDCl 3)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),1.5 6-1.67(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(d d,J=5,18Hz,0.8H),2.77(dd,J=6,18Hz,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=8Hz,0.2H),6.60-6.72(m,1H),6.73-6.81(m,0.8H),6.8 6-6.92(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).

[0318] (Reference example 5) Synthesis of tert-butyl 3-(2-hydroxyethyl)-1H-indazole-1-carboxylate

[0319] [ka] To a solution of 2-(1H-indazol-3-yl)ethan-1-ol (13 mg, 0.077 mmol) in chloroform (2 mL), triethylamine (32 μL, 0.23 mmol), di-tert-butyl dicarbonate (20 mg, 0.093 mmol) and N,N-dimethylaminopyridine (1 mg, 0.0077 mmol) were added and stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (60-80% ethyl acetate / heptane) to obtain the title compound (16 mg, 80%) as a colorless oil. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):1.72(s,9H),2.63(t,J=6Hz,1H),3.23(t,J=6Hz,2H),4.13(dt,J=6,6Hz,2 H),7.32(t,J=8Hz,1H),7.51-7.56(m,1H),7.70(d,J=8Hz,1H),8.12(d,J=9Hz,1H).

[0320] (Reference example 6) Synthesis of tert-butyl 3-(2-(tosyloxy)ethyl)-1H-indazole-1-carboxylate

[0321] [ka] Triethylamine (25 μL, 0.18 mmol) and p-toluenesulfonyl chloride (14 mg, 0.072 mmol) were added to a solution of the compound obtained in Reference Example 5 (16 mg, 0.060 mmol) in chloroform (1 mL) under ice cooling, and the mixture was stirred at room temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture under ice cooling, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (15-35% ethyl acetate / heptane) to obtain the title compound (25 mg, 99%) as a pale yellow oil. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):1.72(s,9H),2.41(s.3H),3.56(t,J=7Hz,2H),4.47(t,J=7Hz,2H),7.17 -7.34(m,3H),7.52(ddd,J=1,7,9Hz,1H),7.61-7.68(m,3H),8.05(d,J=9Hz,1H).

[0322] (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

[0323] [ka] According to the method described in Example 5, the title compound was obtained from Isomer C obtained in Example 2 and the compound obtained in Reference Example 6. 1 H-NMR (400MHz, CDCl 3 )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=9Hz ,1H),7.21-7.31(m,1H),7.48(ddd,J=1,7,8Hz,1H),7.63(d,J=8Hz,1H),8.05(d,J=8Hz,1H).

[0324] (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

[0325] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 111. 1 H-NMR (400MHz, CDCl 3 )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=9Hz,1H),7.07-7.14(m,1H),7.30-7.38(m,1H),7.43-7.52(m,1H),7.66(d,J=8Hz,1H).

[0326] (Reference example 7) Synthesis of 2-(1-methyl-1H-indazol-3-yl)ethyl methanesulfonate

[0327] [ka] To a solution of 2-(1-methyl-1H-indazol-3-yl)ethan-1-ol (6.9 mg, 0.039 mmol) in chloroform (1 mL), triethylamine (16 μL, 0.12 mmol) and methanesulfonic anhydride (10 mg, 0.059 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture under ice cooling, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude title compound (8.9 mg, 89%) as a pale yellow oil. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):2.92(s,3H),3.43(t,J=7Hz,2H),4.03(s,3H),4.63(t,J=7Hz,2H),7.16(ddd,J=1,6,8Hz,1H),7.33-7.44(m,2H),7.70(d,J=8Hz,1H).

[0328] (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

[0329] [ka] According to the method described in Example 31, the title compound was obtained from compound E obtained in Example 3 and the compound obtained in Reference Example 7. 1 H-NMR (400MHz, CDCl 3 )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=6,18Hz,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=8Hz,1H),7.03-7.12(m,1H),7.27-7.39(m,2H),7.63(d,J=8Hz,1H).

[0330] (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

[0331] [ka] The title compound was obtained from Compound E obtained in Example 3 and 2-(1H-indazol-3-yl)acetic acid according to the method described in Example 85. 1 H-NMR (400MHz, CDCl 3 )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=8Hz,1H),7.02-7 ,13(m,1H),7.24-7.45(m,2H),7.63(d,J=8Hz,0.4H),7.72(d,J=8Hz,0.6H).

[0332] (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

[0333] [ka] The title compound was obtained from 2-(imidazo[1,2-a]pyridin-2-yl)acetic acid according to the method described in Example 5. 1 H-NMR (400MHz, CDCl 3)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=2,8Hz,0.6H),6.64(dd,J=3,8Hz,0.4H),6.68-6.82(m,2.4H),6.86(d,J=8Hz,0.6H),7.07 -7.19(m,1H),7.38(s,0.4H),7.43(s,0.6H),7.48(d,J=9Hz,0.4H),7.52(d,J=9Hz,0.6H),7.94-8.04(m,1H).

[0334] (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

[0335] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 115. 1 H-NMR (400MHz, CDCl 3)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=2Hz,1H),6.65(dd,J=2,8Hz,1H),6.70(ddd,J=1,1,7Hz,1H),6.89(d,J= 8Hz,1H),7.09(ddd,J=1,7,9Hz,1H),7.19(s,1H),7.47(d,J=8Hz,1H),7.98-8.04(m,1H).

[0336] (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

[0337] [ka] The title compound was obtained from 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. 1 H-NMR (400MHz, CDCl 3)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),6.5 0-6.75(m,2.5H),6.80-6.95(m,1.5H),7.00-7.10(m,1H),7.40(d,J=3Hz,1H),8.30-8.40(m,1H).

[0338] (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

[0339] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 117. 1 H-NMR (400MHz, CDCl 3)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=3Hz,1H),6.57(dd,J=3,8Hz,1H),6.65(ddd,J=1,6,6Hz ,1H),6.89(d,J=8Hz,1H),7.00-7.10(m,1H),7.39(d,J=8Hz,1H),8.33(d,J=6Hz,1H).

[0340] (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

[0341] [ka] The title compound was obtained from Compound E obtained in Example 3 and 2-(2H-indazol-2-yl)acetic acid according to the method described in Example 26. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.75-0.90(m,1H),1.04(d,J=10Hz,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=4,4,12Hz ,0.4H),3.77(ddd,J=5,12,12Hz,0.6H),3.80-4.00(m,2.4H),4.80(d,J=16Hz,0.6H),5.02(d,J=16Hz,0.6H),5.19 (s,0.8H),6.50-6.75(m,2H),6.88(d,J=8Hz,0.4H),6.97(d,J=8Hz,0.6H),7.10-7.35(m,4H),7.68(d,J=8Hz,1H).

[0342] (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

[0343] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 119. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.80-0.90(m,1H),1.01(d,J=9Hz,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, 18Hz,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=8Hz,1H),7.63(d,J=8Hz,1H).

[0344] (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

[0345] [ka] The title compound was obtained from Compound E obtained in Example 3 and 2-(1H-indazol-1-yl)acetic acid according to the method described in Example 26. 1 H-NMR (400MHz, CDCl 3)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,0.6 H),3.90-4.00(m,0.4H),4.87(d,J=16Hz,0.6H),5.03(d,J=16Hz,0.6H),5.20(d,J=16Hz,0.4H),5.26(d,J=16Hz,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).

[0346] (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

[0347] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 121. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.00-0.15(m,2H),0.45-0.55(m,2H),0.75-0.90(m,1H),1.01(d,J=9Hz,1 H),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=6,6Hz,1H),7.20-7.40(m,2H),7.69(d,J=8Hz,1H),7.96(s,1H).

[0348] (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

[0349] [ka] According to the methods described in Reference Example 4 and Example 105, the title compound was obtained from 2-(isoquinolin-3-yl)acetaldehyde and Compound E obtained in Example 3. 1 H-NMR (400MHz, CDCl 3)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=3,15Hz,1H),1.80-2. 10(m,4H),2.26-2.40(m,3H),2.44-2.56(m,1H),2.72(dd,J=2,18Hz,1H),2.81-3.17(m,9H),3.22-3.33(m,1H),4.75(br s,1H),6.48(d,J=3Hz,1H),6.55(dd,J=3,8Hz,1H),6.84(d,J=8Hz,1H),7.47(s,1H),7.4 8-7.56(m,1H),7.60-7.68(m,1H),7.72(d,J=8Hz,1H),7.90(d,J=8Hz,1H),9.15(s,1H).

[0350] (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

[0351] [ka] According to the methods described in Reference Example 4 and Example 105, the title compound was obtained from 2-(quinolin-2-yl)acetaldehyde and Compound E obtained in Example 3. 1 H-NMR (400MHz, CDCl 3)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=6,18Hz,1H) ,2.77-3.18(m,9H),3.22-3.33(m,1H),6.51(d,J=2Hz,1H),6.59(dd,J=3,8Hz,1H),6.86(d,J=8Hz,1H) ,7.22(d,J=8Hz,1H),7.45-7.53(m,1H),7.62-7.70(m,1H),7.77(dd,J=1,8Hz,1H),8.03(d,J=8Hz,2H).

[0352] (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

[0353] [ka] The title compound was obtained from Compound E obtained in Example 3 and 2-(1H-indol-1-yl)acetic acid according to the method described in Example 26. 1 H-NMR (400MHz, CDCl 3)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 =6,13,13Hz,0.4H),3.84(ddd,J=3,13,13Hz,0.4H),3.90-4.00(m,1H),4 .51(d,J=16Hz,0.6H),4.64(d,J=16Hz,0.6H),4.82(d,J=16Hz,0.4H),4. 90(d,J=16Hz,0.4H),6.48(d,J=8Hz,0.4H),6.50(d,J=8Hz,0.6H),6.54( d,J=2Hz,0.4H),6.59(d,J=2Hz,0.6H),6.65(ddd,J=3,8,8Hz,1H),6.88( d,J=3Hz,1H),6.90-7.00(m,2H),7.00-7.20(m,2H),7.59(t,J=8Hz,1H).

[0354] (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

[0355] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 125. 1 H-NMR (400MHz, CDCl 3)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=8Hz,1H),6.50(d,J=3Hz,1H),6.56(dd,J=3,8Hz,1H),6.61(dd,J=8,8Hz,1H),6.89(d,J=8Hz,1H),7.00-7.05(m,2H).

[0356] (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

[0357] [ka] The title compound was obtained from Isomer C obtained in Example 2 and 2-(benzo[d]thiazol-2-yl)ethan-1-ol according to the method described in Example 32. 1 H-NMR (400MHz, CDCl 3)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=2,5,14Hz,1H),1.86-2.03(m,3H),2. 09(ddd,J=5,13,13Hz,1H),2.35(dd,J=6,13Hz,1H),2.367(dd,J=6,13Hz,1H),2.45-2.58(m,2H),2.61(ddd,J=3,5,13Hz,1H),2.72(ddd ,J=4,4,13Hz,1H),2.78-2.91(m,3H),2.95(d,J=6Hz,1H),2.98(d,J=18Hz,1H),3.04(ddd,J=3,12,12Hz,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=1,7,8Hz,1H),7.40(ddd,J=1,7,8Hz,1H),7.75-7.79(m,1H),7.88-7.92(m,1H).

[0358] (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

[0359] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 127. 1 H-NMR (400MHz, CDCl 3)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=4,14Hz,1H),1.71-1.80(m,1H),1.89(ddd,J=3,12,14Hz,1H),1.95-2.09(m,2H),2.34 (dd,J=6,12Hz,1H),2.34(dd,J=6,12Hz,1H),2.42(ddd,J=4,12,16Hz,1H),2.48-2.58(m,1H) ),2.59-2.70(m,2H),2.76(dd,J=6,18Hz,1H),2.83-2.98(m,5H),3.10-3.22(m,3H),4.70(br s,1H),6.55(d,J=2Hz,1H),6.62(dd,J=2,8Hz,1H),6.91(d,J=8Hz,1H),7.30(dd ,J=8,8Hz,1H),7.39(dd,J=8,8Hz,1H),7.78(d,J=8Hz,1H),7.91(d,J=8Hz,1H).

[0360] (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

[0361] [ka] According to the method described in Example 31, the title compound was obtained from Isomer C obtained in Example 2 and 1-(2-chloroethyl)piperidine hydrochloride. 1 H-NMR (400MHz, CDCl 3)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,10Hz),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=8Hz,1H).

[0362] (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

[0363] [ka] To a solution of the compound obtained in Example 129 (5.3 mg, 0.0117 mmol) in chloroform (1 mL), 1M boron tribromide-dichloromethane solution (70 μL, 0.070 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture under ice cooling, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The concentrated residue obtained was dissolved in methanol (1 mL), and 10% palladium-activated carbon (55% wet) (3.4 mg) was added, followed by stirring at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative thin layer chromatography (chloroform: 2M ammonia-methanol solution = 4:1) to obtain the title compound (4.0 mg, 78%) as a pale yellow solid substance. 1 H-NMR (400MHz, CDCl 3)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=2Hz,1H),6.55(dd,J=2,8Hz,1H),6.89(d,J=8Hz,1H).

[0364] (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

[0365] [ka] According to the method described in Example 31, the title compound was obtained from compound E obtained in Example 3 and 2-chloro-1-(piperidin-1-yl)ethan-1-one (synthesized by the method described in WO2018148576). 1 H-NMR (400MHz, CDCl 3 )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=6Hz,1H), 2.42-2.61(m,4H),2.72-2.84(m,1H),2.85-3.20(m,6H),3.15(d,J=13Hz,1H),3.23(d,J=13Hz,1H),3.33-3.51(m,2H),4.63(br s,1H),6.57-6.70(m,2H),6.91(d,J=8Hz,1H).

[0366] (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

[0367] [ka] To a solution of compound E (10 mg, 0.030 mmol) obtained in Example 3 in chloroform (1 mL), N,N-diisopropylethylamine (21 μL, 0.12 mmol) and chloroacetyl chloride (4.8 μL, 0.061 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Next, 4,4-dimethyl-1,4-azasilinane (16 mg, 0.12 mmol), sodium iodide (10 mg, 0.061 mmol) and acetonitrile (1 mL) were added to the reaction mixture, and the mixture was stirred at 60° C. for 6 hours. Then, a suspension of potassium carbonate (28 mg, 0.204 mmol) in methanol (1 mL) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0-5% methanol / chloroform) to obtain the title compound (14 mg, 95%) as a pale yellow solid. 1 H-NMR (400MHz, CDCl 3)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).

[0368] (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

[0369] [ka] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 132. 1 H-NMR (400MHz, CDCl 3 )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=2Hz,1H),6.56(dd,J=2,8Hz,1H),6.89(d,J=8Hz,1H).

[0370] (Example 134) Synthesis of a mixture of (5aR,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphth[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)naphth[1,2-d]azepin-2(1H)-one (isomer H)

[0371] [ka] According to the method described in Reference Example 3 and Example 1, (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) was used to obtain a mixture of the title isomers G and H as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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=5,12,12Hz,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=3Hz,0.5H),6.68(dd,J=3,8Hz,1H),6.94(d,J=8Hz,0.5H),6.99(d,J=8Hz,0.5H),7.10(d,J=3Hz,0.5H).

[0372] (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

[0373] [ka] According to the method described in Example 2, the title compound was obtained as a colorless amorphous substance from isomers G and H described in Example 134. 1 H-NMR (400MHz, CDCl 3 )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=7,12Hz,1H),2.55(dd,J=6,13Hz,1H),2.60-2.70(m,2H),2.70-2.90(m,3H),3.04(dd,J=5,13Hz,1H),3.18(br s,1H),3.45(d,J=14Hz,1H),3.78(s,3H),6.50-6.70(m,2H),7.02(d,J=8Hz,1H).

[0374] (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

[0375] [ka] The title compound was obtained from Isomer D obtained in Example 2 and 2-(pyridin-2-yl)ethyl 4-methylbenzenesulfonate according to the method described in Example 31. 1 H-NMR (400MHz, 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,6 H),3.73(s,3H),6.67(dd,J=3,8Hz,1H),6.78(d,J=3Hz,1H),6.96(d,J=8Hz,1H),7.08(dd ,J=5,8Hz,1H),7.14-7.18(m,1H),7.54(ddd,J=2,8,8Hz,1H),8.52(ddd,J=1,2,5Hz,1H).

[0376] (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

[0377] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 136. 1 H-NMR (400MHz, CDCl 3)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=2,12,13Hz,1H),1.88(ddd,J=6,13,13Hz,1H),2.14(ddd,J=4,12,12Hz,1H),2.23-2.42(m,3H),2 .54-2.81(m,6H),2.84-3.09(m,5H),3.44(d,J=15Hz,1H),6.72(dd,J=2,8Hz,1H),6.88(d,J=2Hz,1H),6.93 (d,J=8Hz,1H),7.08-7.13(m,1H),7.18(ddd,J=1,5,8Hz,1H),7.63(ddd,J=2,8,8Hz,1H),8.53-8.58(m,1H).

[0378] (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

[0379] [ka] According to the method described in Example 7, the title compound was obtained from Isomer D obtained in Example 2 and 2-(pyrimidin-2-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3)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=6,13Hz,1H),1.92-2.10(m,2H),2.23-2.42(m,3H),2.55-2.63(m,1H),2.79(dd,J=6,18Hz,1H),2.90-3.06(m, 3H),3.64(d,J=15Hz,1H),3.69-3.81(m,1H),3.71(s,3H),3.95(d,J=15Hz,1H),4.09(d,J=15Hz,1H),4.79(d,J=1 5Hz,1H),6.69(dd,J=3,8Hz,1H),6.89(d,J=3Hz,1H),6.94(d,J=8Hz,1H),7.15(t,J=5Hz,1H),8.65(d,J=5Hz,2H).

[0380] (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

[0381] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 138. 1 H-NMR (400MHz, CDCl 3)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,1 H),1.52-1.63(m,1H),1.65-1.74(m,1H),1.78(dd,J=6,13Hz,1H),2.02(d dd,J=4,12,12Hz,1H),2.11(ddd,J=3,12,12Hz,1H),2.19-2.32(m,1H),2. 35(dd,J=6,13Hz,1H),2.36(dd,J=7,13Hz,1H),2.55-2.63(m,1H),2.65-2 .74(m,1H),2.78(dd,J=7,18Hz,1H),2.98(d,J=7Hz,1H),3.00(d,J=18Hz,1H),3.54(dd,J=4,12Hz,1H),3.78(d,J=15Hz,1H),3.89(d,J=16Hz,1H), 3.96(d,J=16Hz,1H),4.62(d,J=15Hz,1H),6.65(d,J=3Hz,1H),6.74(dd,J =3,8Hz,1H),6.97(d,J=8Hz,1H),7.29(t,J=5Hz,1H),8.76(d,J=5Hz,2H).

[0382] (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 (single isomer A)

[0383] [ka] To a solution of the compound (14 g, 39.3 mmol) obtained in Reference Example 3 in chloroform (400 mL), triethylamine (16.4 mL, 117.8 mmol) and p-toluenesulfonyl chloride (22.5 g, 117.8 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and 2M hydrochloric acid (160 mL) was added to a solution of the concentrated residue in tetrahydrofuran (250 mL), and the mixture was stirred at room temperature for 71 hours. The reaction solution was washed three times with a mixture of ethyl acetate / heptane (2 / 1), and the aqueous layer was made basic with potassium carbonate, and then extracted twice with ethyl acetate and 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) and stirred for one hour, and then insoluble matter was filtered off, and the title compound 4-methylbenzenesulfonate (5.15 g, 25%) was obtained as a colorless solid. Subsequently, the 4-methylbenzenesulfonate salt of the title compound was subjected to a reaction similar to that described in Example 24 to obtain the title compound (509.3 mg, recovery rate 10%) as a colorless amorphous substance as the unreacted recovered raw material. 1 H-NMR (400MHz, CDCl 3 )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=2,11,14Hz,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=18Hz,1H),3.51(d,J=15Hz,1H),3.80(s,3H),3.87(ddd,J= 3,11,15Hz,1H),5.62-5.71(m,1H),6.71(dd,J=3,8Hz,1H),6.97(d,J=8Hz,1H),7.15(d,J=3Hz,1H).

[0384] (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)naphth[1,2-d]azepin-2(1H)-one

[0385] [ka] To a solution of the compound obtained in Example 140 (14.3 mg, 0.04 mmol) in N,N-dimethylformamide (1 mL), sodium hydride (55% oil dispersion, 16 mg, 0.37 mmol) was added and stirred at room temperature for 10 minutes. Then, benzyl bromide (47.5 μL, 0.4 mmol) was added and stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-10% methanol / chloroform) to obtain the title compound (14.4 mg, 79%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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),2.3 3(d,J=7Hz,2H),2.52-2.66(m,2H),2.77(d,J=15Hz,1H),2.78-2.92(m,2H),2.94(d,J=18Hz,1H),3.62(d,J= 15Hz,1H),3.82(d,J=15Hz,1H),3.85(s,3H),4.06(dd,J=11,15Hz,1H),5.05(d,J=15Hz,1H),6.62(d,J=8Hz, 2H),6.79(dd,J=3,8Hz,1H),6.97(d,J=9Hz,1H),7.01(t,J=8Hz,2H),7.09(t,J=7Hz,1H),7.32(d,J=3Hz,1H).

[0386] (Example 142) Synthesis of (5aS,6R,11bR)-3-benzyl-14-(cyclopropylmethyl)-5a,10-dihydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphth[1,2-d]azepin-2(1H)-one

[0387] [ka] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 141. 1 H-NMR (400MHz, CDCl 3 )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=6Hz,2H),2.50-2.64(m,2H),2.71(d,J=15Hz,1H),2.78-2.98(m,3H),3.60(d,J=15Hz ,1H),3.84(d,J=15Hz,1H),4.07(dd,J=11,15Hz,1H),5.03(d,J=14Hz,1H),6.65(d,J=8Hz,2H),6.78 (dd,J=3,8Hz,1H),6.95(d,J=8Hz,1H),7.03(t,J=7Hz,2H),7.11(t,J=7Hz,1H),7.18(d,J=2Hz,1H).

[0388] (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

[0389] [ka]

[0390] According to the method described in Example 26, the title compound was obtained from compound E obtained in Example 3. 1 H-NMR (400MHz, CDCl 3 )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=16Hz,0.5H),4.86(d,J=16Hz,0.5H),4.94(d,J=16Hz,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).

[0391] (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

[0392] [ka]

[0393] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 143. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.05-0.20(m,2H),0.45-0.60(m,2H),0.75-1.00(m,1H),1.0 0-1.10(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=8Hz,1H),7.17(s,1H),7.62(s,1H).

[0394] (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)naphth[1,2-d]azepin-2(1H)-one

[0395] [ka]

[0396] The title compound was obtained from the compound obtained in Example 140 and (2-bromoethyl)cyclohexane according to the method described in Example 141. 1 H-NMR (400MHz, CDCl 3 )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),2.3 5(dd,J=7,13Hz,1H),2.36(dd,J=7,13Hz,1H),2.53-2.61(m,1H),2.66(d,J=15Hz,1H),2.74 (dd,J=6,18Hz,1H),2.83-2.97(m,3H),3.01(d,J=18Hz,1H),3.46-3.64(m,2H),3.81(s,3H) ,4.06(dd,J=11,15Hz,1H),6.68(dd,J=3,8Hz,1H),6.94(d,J=8Hz,1H),7.20(d,J=3Hz,1H).

[0397] (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)naphth[1,2-d]azepin-2(1H)-one

[0398] [ka]

[0399] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 145. 1 H-NMR (400MHz, CDCl 3 )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,1 H),1.47-1.65(m,5H),1.67-1.79(m,1H),1.96-2.12(m,2H),2.35(dd,J=7,13Hz,1H),2.36(dd,J=7,1 3Hz,1H),2.51-2.61(m,1H),2.66(d,J=15Hz,1H),2.73(dd,J=6,18Hz,1H),2.84-3.04(m,4H),3.44-3 .58(m,2H),4.07(dd,J=11,15Hz,1H),6.68(dd,J=2,8Hz,1H),6.91(d,J=8Hz,1H),7.16(d,J=2Hz,1H).

[0400] (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

[0401] [ka]

[0402] Compound E (40 mg, 0.12 mmol) obtained in Example 3 and N,N-diisopropylethylamine (125 μL, 0.73 mmol) were dissolved in tetrahydrofuran (1.5 mL), and chloroacetyl chloride (32 μL, 0.40 mmol) was added under ice cooling, and the mixture was stirred for 1 hour under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, and the resulting organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amino group-supported silica gel, 1-20% methanol / chloroform) to obtain the title compound (40 mg, 81%) as a yellow oil. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.05-0.20(m,2H),0.45-0.60(m,2H),0.75-1.00(m,1H),1.08(d,J=12Hz,0.3H),1 .16(d,J=12Hz,0.7H),1.40-2.50(m,8H),2.55-2.70(m,1.3H),2.75-2.85(m,1H),2.90-3.1 5(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=3,8Hz,0.7H),6.90(d,J=3Hz,0.7H),6.94(d,J=8Hz,0.3H),6.98(d,J=8Hz,0.7H).

[0403] (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

[0404] [ka]

[0405] The compound obtained in Example 147 (20 mg, 0.049 mmol), 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) and stirred at 60° C. for 16 hours under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, and the obtained 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, 1-20% methanol / chloroform) to obtain the title compound (10 mg, 41%) as a yellow oil. 1 H-NMR (400MHz, CDCl 3 )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=16Hz,0.7H),4.69(d,J=16Hz,0.7H),4.88(s,0.6H),6. 60-6.70(m,2H),6.94(d,J=8Hz,0.7H),6.98(d,J=8Hz,0.3H),7.16(s,0.7H),7.24(s,0.3H),7.36(s,0.7H),7.37(s,0.3H).

[0406] (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

[0407] [ka]

[0408] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 148. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.05-0.20(m,2H),0.45-0.60(m,2H),0.75-1.00(m,1H),1.03(d,J=11Hz ,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(d d,J=6,18Hz,1H),2.80-3.00(m,5H),3.10-3.30(m,1H),4.00-4.10(m,2H),6.54(d ,J=3Hz,1H),6.60(dd,J=3,8Hz,1H),6.91(d,J=8Hz,1H),7.10(s,1H),7.25(s,1H).

[0409] (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

[0410] [ka]

[0411] To a solution of isomer C (342 mg, 1.0 mmol) obtained in Example 2 in tetrahydrofuran (10 mL), N,N-diisopropylethylamine (348 μL, 2.0 mmol) and 2,2,2-trichloroethyl chloroformate (165 μL, 1.2 mmol) were added and stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted three times with chloroform. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-20% methanol / chloroform) to obtain the title compound (481 mg, 93%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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=12Hz,0.5H),4.52(br s,1H),4.62(s,1H),4.79(d,J=12Hz,0.5H),6.64-6.71(m,2H),6.95-7.02(m,1H).

[0412] (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

[0413] [ka]

[0414] Acetic anhydride (10 mL) was added to the compound obtained in Example 150 (481 mg, 0.93 mmol), and the mixture was heated to reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with chloroform three times. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-20% methanol / chloroform) to obtain the title compound (410 mg, 79%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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,1 5H),2.09(s,1.5H),2.13(s,1.5H),3.79(s,3H),3.86-3.99(m,1H),4.22(d,J=6Hz) ,0.5H),4.27(d,J=6Hz,0.5H),4.62(d,J=12Hz,0.5H),4.69(d,J=12Hz,0.5H),4.7 1(d,J=12Hz,0.5H),4.90(d,J=12Hz,0.5H),6.69-6.76(m,2H),6.97-7.07(m,1H).

[0415] (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

[0416] [ka]

[0417] A solution of the compound obtained in Example 151 (410 mg, 0.73 mmol) in toluene (7 mL) was added with diisopropyl azodicarboxylate (40% toluene solution, about 1.9 mol / L, 768 μL, 1.46 mmol) and stirred at 100 ° C for 90 minutes. The reaction mixture was concentrated under reduced pressure, and ethanol (14 mL) and pyridine hydrochloride (888 mg, 7.7 mmol) were added and stirred at 40 ° C for 18 hours. Water and potassium carbonate were added to the reaction mixture to adjust the pH to 11, and the mixture was extracted three times with chloroform. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (50-100% ethyl acetate / heptane) to obtain the title compound (346 mg, 93%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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).

[0418] (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

[0419] [ka]

[0420] Zinc powder (895 mg, 13.7 mmol) was added to a solution of the compound obtained in Example 152 (346 mg, 0.68 mmol) in acetic acid (30 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through Celite to remove zinc, and the mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the obtained crude product, and the mixture was extracted 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, 0-50% methanol / chloroform) to obtain the title compound (187 mg, 83%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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=7Hz,0.5H),4.33-4.40(m,0.5H),4.87(d,J=6Hz,0.5H),6.76( dd,J=2,8Hz,1H),6.80-6.83(m,1H),7.05(d,J=8Hz,0.5H),7.06(d,J=8Hz,0.5H).

[0421] (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

[0422] [ka]

[0423] The title compound was obtained from the compound obtained in Example 153 according to the method described in Example 76 (Method 1). 1 H-NMR (400MHz, CDCl 3 )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=6Hz ,0.5H),4.31-4.38(m,0.5H),4.87(d,J=6Hz,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).

[0424] (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

[0425] [ka]

[0426] A 2M aqueous sodium hydroxide solution (5mL, 10mmol) was added to a solution of the compound obtained in Example 154 (87.0mg, 0.20mmol) in ethanol (5mL), and the mixture was heated under reflux for 40 hours. After cooling, water was added and the mixture was extracted three times with chloroform. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0-50% methanol / chloroform) to obtain the title compound (69.3mg, 88%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.92-1.00(m,1H),1.48(dd,J=7,14Hz,1H),1.72-1.93(m,3H),2.28(dd,J=4,15H z,1H),2.40-2.71(m,5H),2.82-3.00(m,7H),3.19(dd,J=7,18Hz,1H),3.79(s,3H),4.81(br s,1H),6.72(dd,J=3,8Hz,1H),6.75(d,J=3Hz,1H),7.06(d,J=8Hz,1H),7.12-7.20(m,2H),7.63(ddd,J=2,7,7Hz,1H),8.54-8.57(m,1H).

[0427] (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)

[0428] [ka]

[0429] According to the method described in Example 6, the title compounds I and J were obtained from the compound obtained in Example 155.

[0430] (Compound I) 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.93-1.03(m,1H),1.47(dd,J=7,15Hz,1H),1.60-1.71(m,1H),1.77 -1.92(m,2H),2.19(dd,J=4,15Hz,1H),2.32-2.63(m,5H),2.75-3.01(m,7H), 3.18(dd,J=7,18Hz,1H),6.64(dd,J=2,8Hz,1H),6.69(d,J=2Hz,1H),6.96(d, J=8Hz,1H),7.14-7.22(m,2H),7.66(ddd,J=2,8,8Hz,1H),8.53-8.58(m,1H).

[0431] (Compound J) 1 H-NMR (400MHz, CDCl 3 )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=6Hz,1H),2.63-2.96(m,8H),3.03(d,J=18Hz,1H),3.11-3.23(m,1H),4.58(br s,1H),6.53(d,J=2Hz,1H),6.59(dd,J=2,8Hz,1H),6.91(d,J=8Hz,1H),7.07-7.14(m,2H),7.56(ddd,J=2,7,7Hz,1H),8.46-8.51(m,1H).

[0432] (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

[0433] [ka]

[0434] According to the method described in Example 26, the title compound was obtained from Compound E obtained in Example 3 and 3-(1H-pyrazol-1-yl)propanoic acid hydrochloride. 1 H-NMR (400MHz, CDCl 3 )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),3.00-3.2 2(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).

[0435] (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

[0436] [ka]

[0437] According to the method described in Example 5, the title compound was obtained from Compound E obtained in Example 3 and 2-(thiazol-2-yl)acetic acid. 1 H-NMR (400MHz, CDCl 3 )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=2,8Hz,0.6H),6.65(dd,J=2,8Hz,0.4H) ,6.69(d,J=2Hz,0.6H),6.72(d,J=2Hz,0.4H),6.88-6.92(m,1H),7.25-7.28(m,1H),7.67-7.69(m,1H).

[0438] (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

[0439] [ka]

[0440] 1-Bromopropane (4.6 μL, 0.051 mmol) and N,N-diisopropylethylamine (13.2 μL, 0.076 mmol) were added to a solution of compound I (10 mg, 0.026 mmol) obtained in Example 156 in N,N-dimethylformamide (1 mL), and the mixture was stirred at room temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The crude product obtained was used in the next reaction without purification. To a solution of the obtained crude product in chloroform (2 mL), 1M boron tribromide-dichloromethane solution (500 μL, 0.50 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, 28% aqueous ammonia solution was added under ice-cooling, and the mixture was extracted three times with chloroform. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin-layer chromatography (chloroform: 2M ammonia-methanol solution = 10:1) to obtain the title compound (4.9 mg, 45%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.90(t,J=7Hz,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=6Hz,1H),2.75(dd,J=6,18Hz,1H),2.80-3.02( m,8H),3.32(dd,J=11,11Hz,1H),6.49(d,J=3Hz,1H),6.58(dd,J=3,8Hz,1H),6.8 9(d,J=8Hz,1H),7.07-7.14(m,2H),7.55(ddd,J=2,8,8Hz,1H),8.45-8.48(m,1H).

[0441] (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

[0442] [ka]

[0443] The title compound was obtained from Compound E obtained in Example 3 and 2-(4-cyclopropyl-1H-pyrazol-1-yl)acetic acid according to the method described in Example 26. 1 H-NMR (400MHz, CDCl 3 )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=16Hz,0.6H),4.70(d,J=16Hz,0.6H),4.85(d,J=16Hz,0.4H) ,4.89(d,J=16Hz,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).

[0444] (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

[0445] [ka]

[0446] To a solution of the compound obtained in Example 155 (10 mg, 0.025 mmol) in N,N-dimethylformamide (1.0 mL), (bromomethyl)cyclobutane (4.6 μL, 0.042 mmol) and N,N-diisopropylethylamine (13.2 μL, 0.076 mmol) were added, and the mixture was stirred at room temperature for 18 hours, and then stirred at 80° C. for 6 hours. After cooling, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: 2M ammonia-methanol solution = 10:1) to obtain the title compound (7.1 mg, 62%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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=18Hz,1H),3.14-3.26(m,1H),3.76(s,3H),4.63(br s,1H),6.66(d,J=2Hz,1H),6.69(dd,J=3,8Hz,1H),6.98-7.08(m,3H),7.49(ddd,J=2,8,8Hz,1H),8.44-8.47(m,1H).

[0447] (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

[0448] [ka]

[0449] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 161. 1 H-NMR (400MHz, CDCl 3 )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=6Hz,1H),2.73(dd,J=6,18Hz,1H),2. 80-3.04(m,7H),3.31(dd,J=12,12Hz,1H),6.47(d,J=2Hz,1H),6.58(dd,J=2,8Hz,1H) ,6.88(d,J=8Hz,1H),7.07-7.15(m,2H),7.56(ddd,J=2,8,8Hz,1H),8.44-8.47(m,1H).

[0450] (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

[0451] [ka]

[0452] The title compound was obtained from Compound E obtained in Example 3 and 2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid according to the method described in Example 26. 1 H-NMR (400MHz, CDCl 3)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=6,19,19Hz,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=16Hz,0.5H),4.79(d,J=16Hz,0.5H),4.90(d,J=16Hz,0.5H),4.95(d,J=16Hz,0.5H),5.90(br s,0.5H),6.62-6.67(m,2H),6.95(dd,J=2,8Hz,1H),7.16(s,0.5H).

[0453] (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

[0454] [ka]

[0455] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 163. 1 H-NMR (400MHz, CDCl 3)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=4,14Hz,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=12,12Hz,1H),3.99-4 .13(m,2H),6.60(s,1H),6.62(d,J=8Hz,1H),6.83(s,1H),6.97(d,J=8Hz,1H).

[0456] (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

[0457] [ka]

[0458] According to the method described in Example 26, the title compound was obtained from 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). 1 H-NMR (400MHz, CDCl 3)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=16Hz,0.6H),5.12(d,J=16Hz,0.4H),5.25(d,J=16Hz,0.4H),5.29(d,J=16Hz ,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).

[0459] (Reference example 8) Synthesis of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1H-pyrrole

[0460] [ka] 3-Methyl-1H-pyrrole (97 mg, 1.20 mmol) was dissolved in N,N-dimethylformamide (3 mL), and sodium hydride (55% oil dispersion) (156.5 mg, 3.59 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (765.6 μL, 3.59 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (2-12% ethyl acetate / heptane) to obtain the title compound (314 mg, quantitative) as a yellow liquid. 1 H-NMR (400MHz, CDCl 3)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).

[0461] (Reference example 9) Synthesis of 2-(3-methyl-1H-pyrrol-1-yl)ethan-1-ol

[0462] [ka]

[0463] The compound obtained in Reference Example 8 (304.9 mg, 1.27 mmol) was dissolved in tetrahydrofuran (1 mL), and 1M tetrabutylammonium fluoride-tetrahydrofuran solution (3.82 mL, 3.82 mmol) was added, followed by stirring at room temperature for 10 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed once with a saturated aqueous solution of sodium bicarbonate, 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 (34-54% ethyl acetate / heptane) to obtain the title compound (69.5 mg, 44%) as a pale yellow oil. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):2.10(s,3H),3.83(t,J=5Hz,2H),3.95(t,J=5Hz,2H),5.98-6.02(m,1H),6.46-6.49(m,1H),6.58-6.61(m,1H).

[0464] (Reference example 10) Synthesis of 2-(3-methyl-1H-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate

[0465] [ka]

[0466] According to the method described in Reference Example 6, the title compound was obtained from the compound obtained in Reference Example 9. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):2.04(s,3H),2.44(s,3H),4.05(t,J=6Hz,2H),4.20(t,J=6Hz,2H),5.90-5.94 (m,1H),6.30-6.33(m,1H),6.44-6.48(m,1H),7.29(d,J=8Hz,2H),7.66(d,J=8Hz,2H).

[0467] (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

[0468] [ka]

[0469] According to the method described in Example 31, the title compound was obtained from compound E obtained in Example 3 and the compound obtained in Reference Example 10. 1 H-NMR (400MHz, CDCl 3)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=7Hz,2H),4.72(br s,1H),5.89(dd,J=2,2Hz,1H),6.30-6.34(m,1H),6.42-6.45(m,1H),6.45-6.48(m,1H),6.58(dd,J=2,8Hz,1H),6.92(d,J=8Hz,1H).

[0470] (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

[0471] [ka]

[0472] To a solution of compound E (20 mg, 0.061 mmol) obtained in Example 3 in chloroform (1 mL), N,N-diisopropylethylamine (49 μL, 0.29 mmol) and trifluoroacetic anhydride (16 μL, 0.12 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 23 hours. Potassium carbonate (60 mg, 0.43 mmol) and methanol (1 mL) were added to the reaction mixture, and the mixture was further stirred for 1 hour. Water was added to the reaction mixture under ice cooling, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (1-10% methanol / chloroform) to obtain the title compound (14 mg, 54%) as a pale yellow gum. 1 H-NMR (400MHz, CDCl 3 )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=2Hz,0.5H),6.60-6.70(m,1.5H),6.91-7.02(m,1H).

[0473] (Reference example 11) Synthesis of 3-(chloromethyl)-5-methylisothiazole

[0474] [ka]

[0475] To a solution of (5-methylisothiazol-3-yl)methanol (103 mg, 0.797 mmol) in toluene (3 mL), thionyl chloride (0.12 mL, 1.7 mmol) was added and stirred at 80° C. for 5 hours. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (4-25% ethyl acetate / heptane) to give the title compound (69.7 mg, 59%) as a light brown oil. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):2.58(s,3H),4.62(s,2H),7.05(s,1H).

[0476] (Reference example 12) Synthesis of 2-(5-methylisothiazol-3-yl)acetonitrile

[0477] [ka]

[0478] Sodium cyanide (69.4 mg, 1.42 mmol) was added to a solution of the compound (69.7 mg, 0.472 mmol) obtained in Reference Example 11 in dimethyl sulfoxide (1.5 mL), and the mixture was stirred at room temperature for 1.5 hours and at 50° C. for 17 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted three times with tert-butyl methyl ether. The combined extracts were washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (19-40% ethyl acetate / heptane) to obtain the title compound (42.9 mg, 66%) as a colorless oil. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):2.59(s,3H),3.86(s,2H),7.01(s,1H).

[0479] (Reference example 13) Synthesis of 2-(5-methylisothiazol-3-yl)acetic acid

[0480] [ka]

[0481] 6M hydrochloric acid (0.5mL) was added to a solution of the compound (42.9mg, 0.310mmol) obtained in Reference Example 12 in acetic acid (1mL), and the mixture was stirred at 90°C for 4.5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. Water was added to the resulting residue, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (42.9mg, 88%) as pale brown crystals. 1 H-NMR (400MHz, CDCl3 )δ(ppm):2.59(s,3H),3.88(s,2H),6.91(s,1H).

[0482] (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

[0483] [ka]

[0484] According to the method described in Example 26, the title compound was obtained from compound E obtained in Example 3 and the compound obtained in Reference Example 13. 1 H-NMR (400MHz, CDCl 3 )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=6,18Hz,0.6H),2.77(dd,J=6,18Hz,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=15Hz,0.4H),3.72(d,J=15Hz,0.4H),3.73-3.78(m,0.4H),3.78(d,J=15Hz,0.6H),3.85-3.88(m,1H) ),3.89(d,J=15Hz,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).

[0485] (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

[0486] [ka]

[0487] According to the method described in Example 85, the title compound was obtained from Compound E obtained in Example 3 and 3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propanoic acid. 1 H-NMR (400MHz, CDCl 3 )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=3,12,14Hz,0.5H),1.87-2 .25(m,3.5H),2.29(dd,J=6,13Hz,0.5H),2.32-2.39(m,1.5H),2.51-3. 09(m,7H),3.24(ddd,J=4,4,13Hz,0.5H),3.26-3.34(m,0.5H),3.36(ddd ,J=2,6,14Hz,0.5H),3.63-3.90(m,1.5H),4.03-4.18(m,1.5H),4.32(ddd,J=7,7,14Hz,0.5H),4.47(t,J=7Hz,1H),6.61(dd,J=2,8Hz,0.5H),6. 64-6.69(m,1H),6.75-6.80(m,0.5H),6.91(d,J=8Hz,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).

[0488] (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

[0489] [ka]

[0490] To a xylene (10 mL) solution of the compound (270 mg, 0.52 mmol) obtained in Example 150, 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, and the mixture was stirred at 140 ° C for 18 hours. Then, 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, and the mixture was stirred at 140 ° C for 42 hours. After cooling, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (25-100% ethyl acetate / heptane) to obtain the title compound (213 mg, 66%) as a white amorphous product. 1 H-NMR (400MHz, CDCl 3)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=12Hz,0.6H),4.63(d,J=12Hz,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).

[0491] (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

[0492] [ka]

[0493] The title compound was obtained from the compound obtained in Example 170 according to the method described in Example 152. 1 H-NMR (400MHz, CDCl 3 )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).

[0494] (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

[0495] [ka]

[0496] The title compound was obtained from the compound obtained in Example 171 according to the method described in Example 153. 1 H-NMR (400MHz, CDCl 3 )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=8Hz,0.5H),7.11(d,J=8Hz,0.5H),7.32-7.61(m,5H).

[0497] (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

[0498] [ka]

[0499] 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. 1 H-NMR (400MHz, 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).

[0500] (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

[0501] [ka]

[0502] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 173. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.96-1.06(m,1H),1.34-1.43(m,1H),1.73(ddd,J=3,11,11Hz,1H),1.84(dd d,J=4,4,16Hz,1H),1.95-2.10(m,2H),1.99(s,3H),2.31-2.48(m,3H),2.64(ddd,J=4, 4,13Hz,1H),2.73(d,J=6Hz,1H),2.76-2.88(m,3H),2.94-3.04(m,1H),3.09-3.20(m,2 H),3.59(d,J=13Hz,1H),3.64(d,J=13Hz,1H),3.77(s,3H),3.86-4.05(m,2H),4.51(br s,1H),6.69(d,J=2Hz,1H),6.70-6.76(m,2H),7.09(d,J=8Hz,1H),7.17-7.35(m,6H).

[0503] (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

[0504] [ka]

[0505] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 174. 1 H-NMR (400MHz, CDCl 3 )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=6Hz,1H),2.79(dd,J=6,18Hz,1H),2.83-2 .99(m,3H),3.05-3.23(m,2H),3.58(d,J=13Hz,1H),3.64(d,J=13Hz,1H),3.99-4.11(m,2H),6 .53(d,J=2Hz,1H),6.63(dd,J=2,8Hz,1H),6.90(s,1H),6.97(d,J=8Hz,1H),7.20-7.38(m,6H).

[0506] (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

[0507] [ka]

[0508] 10% palladium-activated carbon (4.7 mg) and methanol (500 μL) were added to the compound obtained in Example 175 (4.7 mg, 0.010 mmol), and the mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through Celite to remove palladium, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: 2M ammonia-methanol solution = 5:1) to obtain the title compound (2.2 mg, 58%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.92-1.00(m,1H),1.47(dd,J=7,15Hz,1H),1.63-2.05(m,3H),2.09(s,3H),2.16(dd,J=5,15Hz,1H),2.31-2.64(m,5H) ,2.82-2.98(m,5H),3.17(dd,J=7,18Hz,1H),4.08-4.15(m,2H),6.62-6.68(m,2H),6.98(d,J=8Hz,1H),7.15(s,1H),7.35(s,1H).

[0509] (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

[0510] [ka]

[0511] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 168. 1 H-NMR (400MHz, CDCl 3)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=2,8Hz,1H),6.71(s,1H),6.89(d,J=8Hz,1H).

[0512] (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

[0513] [ka]

[0514] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 167. 1 H-NMR (400MHz, CDCl 3 )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=8Hz, 1H).

[0515] (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

[0516] [ka]

[0517] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 169. 1 H-NMR (400MHz, CDCl 3 )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=6,18Hz,1H),2.91-3.04(m,4H),3.76(ddd,J=7,7,14Hz,1H),3.82(ddd,J=7,7,14Hz,1H),4.65(br s,1H),6.58(dd,J=2,8Hz,1H),6.72(d,J=2Hz,1H),6.97(d,J=8Hz,1H),7.19(s,1H),7.64(s,1H).

[0518] (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

[0519] [ka]

[0520] To a solution of compound E (50 mg, 0.15 mmol) obtained in Example 3 in chloroform (1 mL), N,N-diisopropylethylamine (77 μL, 0.45 mmol) and chloroacetyl chloride (18 μL, 0.23 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 15 hours. Then, potassium carbonate (207 mg, 1.5 mmol) and methanol (1 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture under ice cooling, and the mixture was extracted three times with ethyl acetate. The 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, 1-100% methanol / chloroform) to obtain the title compound (30 mg, 50%) as a pale yellow amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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).

[0521] (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

[0522] [ka]

[0523] To a solution of the compound obtained in Example 180 (15.3 mg, 0.038 mmol) in acetonitrile (1 mL), N,N-diisopropylethylamine (65 μL, 0.38 mmol) and 3,3-difluoropyrrolidine (16 mg, 0.11 mmol) were added, and the mixture was stirred at room temperature for 42 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0-5% methanol / chloroform) to obtain the title compound (16.6 mg, 92%) as a pale yellow gum. 1 H-NMR (400MHz, CDCl 3 )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).

[0524] (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

[0525] [ka]

[0526] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 181. 1 H-NMR (400MHz, CDCl 3)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=2Hz,1H),6.56(dd,J=2,8Hz,1H),6.90(d,J=8Hz,1H).

[0527] (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

[0528] [ka]

[0529] According to the method described in Example 68, the title compound was obtained from the compound obtained in Example 160. 1 H-NMR (400MHz, CDCl 3 )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),6.5 6(d,J=3Hz,1H),6.63(dd,J=3,8Hz,1H),6.94(d,J=8Hz,1H),7.00(s,1H),7.22(s,1H).

[0530] (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

[0531] [ka]

[0532] According to the methods described in Examples 181 and 182, the title compound was obtained from the compound obtained in Example 180 and 4-fluoro-1H-pyrazole. 1 H-NMR (400MHz, CDCl 3 )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,6 H),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=8Hz,1H),7.19(d,J=4Hz,1H).

[0533] (Reference example 14) Synthesis of 2-(5-methylisoxazol-3-yl)acetic acid

[0534] [ka]

[0535] According to the method described in Reference Example 13, the title compound was obtained from 2-(5-methylisoxazol-3-yl)acetonitrile. 1 H-NMR (400MHz, CDCl 3)δ(ppm):2.43(s,3H),3.76(s,2H),6.06(s,1H).

[0536] (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

[0537] [ka]

[0538] According to the method described in Example 26, the title compound was obtained from compound E obtained in Example 3 and the compound obtained in Reference Example 14. 1 H-NMR (400MHz, CDCl 3 )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),1.5 5-1.64(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=7,19Hz,0.6H),2.77(dd,J=6,20Hz,0.4H),2.87-3.01(m,2H),3.16-3.22(m,0.6H),3.3 6-3.48(m,2H),3.59(d,J=15Hz,0.4H),3.67(d,J=15Hz,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).

[0539] (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

[0540] [ka]

[0541] According to the method described in Example 85, the title compound was obtained from Compound E obtained in Example 3 and 3-(dimethylamino)propanoic acid. 1 H-NMR (400MHz, CDCl 3 )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(d dd,J=2,12,14Hz,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=6Hz,0.5H),2.92(d,J=19Hz,0.5H),2.92(d,J=6Hz,0.5H),3.00(d,J=18Hz,0.5H),3.12-3.27(m,1H),3 .37(ddd,J=3,3,14Hz,0.5H),3.40(ddd,J=2,6,14Hz,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=2,8Hz,0.5H),6.68-6.71(m,0 .5H),6.81(d,J=2Hz,0.5H),6.90(d,J=8Hz,0.5H),6.94(d,J=8Hz,0.5H).

[0542] (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

[0543] [ka]

[0544] According to the method described in Example 85, the title compound was obtained from Compound E obtained in Example 3 and 3-methoxypropanoic acid. 1 H-NMR (400MHz, CDCl 3 )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=6,18Hz,1H),2.83-2.92(m,1.3H),2.98(d, J=18Hz,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=2,8Hz,0.3H),6.65(d,J=2Hz,0.3H),6.69(dd,J=2,8Hz ,0.7H),6.77-6.82(m,0.7H),6.86(d,J=8Hz,0.3H),6.89(d,J=8Hz,0.7H).

[0545] (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

[0546] [ka]

[0547] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 185. 1 H-NMR (400MHz, CDCl 3 )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=4,14Hz,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=8Hz,1H).

[0548] (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

[0549] [ka]

[0550] According to the methods described in Reference Example 6 and Example 31, the title compound was obtained from 1-(2-hydroxyethyl)-1H-pyrazole-4-carbonitrile and Compound E obtained in Example 3. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.05-0.20(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.03(d,J=12Hz, 1H),1.15-1.25(m,1H),1.77(dd,J=5,15Hz,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=8Hz,1H),7.63(s,1H).

[0551] (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

[0552] [ka]

[0553] According to the method described in Example 85, the title compound was obtained from Compound E obtained in Example 3 and 3-(pyridin-2-yl)propanoic acid. 1 H-NMR (400MHz, CDCl 3)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=3,13,13Hz,0.3H),3.94-4.07(m,1.4H),4.22(dd,J=4,15Hz,0.3H),4.43(br s,0.3H),4.55(br s,0.7H),6.69(dd,J=2,8Hz,0.3H),6.71-6.76(m,0.7H),6.83(dd,J=2,2Hz,0.7H),6.88-6.97(m,1.3H),7.09(dd,J =5,8Hz,0.3H),7.16-7.23(m,1.7H),7.56(ddd,J=2,8,8Hz,0.3H),7.65(ddd,J=2,8,8Hz,0.7H),8.47-8.53(m,1H).

[0554] (Reference example 15) Synthesis of (5-ethylisoxazol-3-yl)methanol

[0555] [ka]

[0556] To a solution of ethyl 5-ethylisoxazole-3-carboxylate (synthesized by the method described in WO2016040515) (410 mg, 2.42 mmol) in tetrahydrofuran (4.8 mL), 4M lithium borohydride-tetrahydrofuran solution (1.21 mL, 4.84 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 24.5 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (195 mg, 63%) as a pale yellow oil. 1 H-NMR (400MHz, CDCl 3)δ(ppm):1.30(t,J=8Hz,3H),2.77(q,J=8Hz,2H),4.73(s,2H),6.03(s,1H).

[0557] (Reference example 16) Synthesis of 3-(chloromethyl)-5-ethylisoxazole

[0558] [ka]

[0559] According to the method described in Reference Example 11, the title compound was obtained from the compound obtained in Reference Example 15. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):1.31(t,J=8Hz,3H),2.77(q,J=8Hz,2H),4.56(s,2H),6.10(s,1H).

[0560] (Reference example 17) Synthesis of 2-(5-ethylisoxazol-3-yl)acetonitrile

[0561] [ka]

[0562] According to the method described in Reference Example 12, the title compound was obtained from the compound obtained in Reference Example 16. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):1.31(t,J=8Hz,3H),2.79(q,J=8Hz,2H),3.78(s,2H),6.10(s,1H).

[0563] (Reference example 18) Synthesis of 2-(5-ethylisoxazol-3-yl)acetic acid

[0564] [ka]

[0565] According to the method described in Reference Example 13, the title compound was obtained from the compound obtained in Reference Example 17. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):1.30(t,J=8Hz,3H),2.77(q,J=8Hz,2H),3.77(s,2H),6.05(s,1H).

[0566] (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

[0567] [ka]

[0568] According to the method described in Example 26, the title compound was obtained from compound E obtained in Example 3 and the compound obtained in Reference Example 18. 1 H-NMR (400MHz, CDCl 3)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=15Hz,0.4H),3.68(d,J=15Hz,0.6H),3.71-3.80(m,1H),3.83-3.88(m,0.4H),3.93(ddd,J=3 ,12,12Hz,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).

[0569] (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

[0570] [ka]

[0571] According to the method described in Example 181, the title compound was obtained from the compound obtained in Example 180 and 4-ethyl-1H-pyrazole. 1 H-NMR (400MHz, CDCl 3)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=16Hz,0.6H),4.73(d,J=16Hz,0.6H),4.88(d,J=16Hz,0.4H),4.93(d,J=16Hz,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).

[0572] (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

[0573] [ka]

[0574] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 192. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.05-0.20(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.03(d,J=10Hz,1H),1.15( t,J=8Hz,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=8Hz,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),4.0 0-4.15(m,2H),6.55(s,1H),6.61(d,J=8Hz,1H),6.92(d,J=8Hz,1H),6.96(s,1H),7.28(s,1H).

[0575] (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

[0576] [ka]

[0577] According to the method described in Example 181, the title compound was obtained from the compound obtained in Example 180 and 4-isopropyl-1H-pyrazole. 1 H-NMR (400MHz, CDCl 3)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=7Hz,3.6H),1.18(d,J=7Hz,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=16Hz,0.6H),4.74(d,J=16Hz,0.6H),4.78(d,J=16Hz,0.4H),4.86(d,J=16Hz,0.4H),6.60-6.70( m,2H),6.90(d,J=8Hz,0.6H),6.93(d,J=8Hz,0.4H),7.15(s,0.4H),7.16(s,0.6H),7.34(s,0.4H),7.36(s,0.6H).

[0578] (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

[0579] [ka]

[0580] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 194. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.05-0.20(m,2H),0.45-0.60(m,2H),0.75-0.90(m,1H),1.03(d,J=10Hz,1H),1.16( d,J=7Hz,3H),1.17(d,J=7Hz,3H),1.44(dd,J=2,15Hz,1H),1.70-1.85(m,2H),1.95-2.05(m,2 H),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=2Hz,1H),6.60(dd,J=2,8Hz,1H),6.90(d,J=8Hz,1H),7.05(s,1H),7.31(s,1H).

[0581] (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

[0582] [ka]

[0583] According to the method described in Example 161, the title compound was obtained from the compound obtained in Example 176 and allyl bromide. 1 H-NMR (400MHz, CDCl 3)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 =2Hz,1H),6.62(dd,J=2,8Hz,1H),6.86(s,1H),6.95(d,J=8Hz,1H),7.23(s,1H).

[0584] (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

[0585] [ka]

[0586] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 191. 1 H-NMR (400MHz, CDCl 3 )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=8Hz,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=2Hz,1H),6.58(dd,J=2,8Hz,1H),6.91(d,J=8Hz,1H).

[0587] (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

[0588] [ka]

[0589] According to the method described in Example 85, the title compound was obtained from Compound E obtained in Example 3 and dimethylglycine. 1 H-NMR (400MHz, CDCl 3 )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=6,18Hz,0.7H),2.77(dd,J=6,18Hz,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=4,12,14Hz,0.3H),3.81-3.91(m,1H),4.09-4.17(m,0.7H),4.52(br s,1H),6.54(dd.J=3,8Hz,0.3H),6.65-6.70(m,1H),6.87(d,J=8Hz,0.3H),6.92(d,J=8Hz,0.7H),6.95(d,J=2Hz,0.7H).

[0590] (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)naphth[1,2-d]azepin-2(1H)-one

[0591] [ka]

[0592] 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. 1 H-NMR (400MHz, CDCl 3 )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),2.6 4(d,J=15Hz,1H),2.73(dd,J=6,18Hz,1H),2.88-2.99(m,2H),3.00(d,J=18Hz,1H),3 .06-3.21(m,2H),3.33-3.56(m,3H),3.81(s,3H),4.10(dd,J=11,15Hz,1H),4.72(br s,1H),6.68(dd,J=2,8Hz,1H),6.93(d,J=9Hz,1H),7.19(d,J=2Hz,1H).

[0593] (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)naphth[1,2-d]azepin-2(1H)-one

[0594] [ka]

[0595] To a solution of the compound obtained in Example 199 (138 mg, 0.26 mmol) in tetrahydrofuran (30 mL), 1 M tetrabutylammonium fluoride tetrahydrofuran solution (2.6 mL, 2.6 mmol) was added and stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted 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, 0-50% methanol / chloroform) to obtain the title compound (99.5 mg, 92%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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=6,12Hz,1H),2.37(dd,J=6,12Hz,1H),2.53-2.67(m,2H),2.71(d,J=15Hz,1H),2.74(d d,J=7,18Hz,1H),2.84-2.96(m,2H),3.00(d,J=18Hz,1H),3.01-3.18(m,2H),3.56(d,J=15Hz,1H),3.68-3.88( m,2H),3.83(s,3H),4.17(dd,J=10,15Hz,1H),6.72(dd,J=2,8Hz,1H),6.95(d,J=9Hz,1H),7.19(d,J=2Hz,1H).

[0596] (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

[0597] [ka]

[0598] According to the method described in Reference Example 7, the title compound was obtained from the compound obtained in Example 200. 1 H-NMR (400MHz, CDCl 3 )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=11,15Hz,1H),6.69(dd,J=2,8Hz,1H),6.97(d,J=9Hz,1H),7.16(d,J=2Hz,1H).

[0599] (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)naphth[1,2-d]azepin-2(1H)-one

[0600] [ka]

[0601] 4-Methylpyrazole (16.5 μL, 0.20 mmol) and sodium hydride (55% oil dispersion, 7.0 mg, 0.16 mmol) were added to a solution of the compound obtained in Example 201 (9.8 mg, 0.020 mmol) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0-20% methanol / chloroform) to obtain the title compound (8.0 mg, 84%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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=7,12Hz,1H),2.36(dd,J=7,12Hz,1H),2.5 3-2.62(m,1H),2.68(d,J=15Hz,1H),2.76(dd,J=6,18Hz,1H),2.83-2.95(m,3H),3.01(d,J=18Hz,1H),3. 44(t,J=7Hz,2H),3.55(d,J=15Hz,1H),3.58-3.69(m,1H),3.78(s,3H),4.09(dd,J=11,15Hz,1H),4.68(br s,1H),6.63(dd,J=3,8Hz,1H),6.94(d,J=9Hz,1H),6.99(s,1H),7.22(s,1H),7.24(d,J=3Hz,1H).

[0602] (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)naphth[1,2-d]azepin-2(1H)-one

[0603] [ka]

[0604] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 202. 1 H-NMR(400MHz,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=15Hz,1H),3.61-3.72(m,1H),4.09(dd ,J=11,15Hz,1H),6.52(dd,J=2,8Hz,1H),6.93(d,J=9Hz,1H),6.97(d,J=3Hz,1H),7.16(s,1H),7.20(s,1H).

[0605] (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)naphth[1,2-d]azepin-2(1H)-one

[0606] [ka]

[0607] Pyrrolidine (16.4 μL, 0.20 mmol) was added to a solution of the compound obtained in Example 201 (9.8 mg, 0.020 mmol) in tetrahydrofuran (1 mL), and the mixture was stirred at 60° C. for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0-20% methanol / chloroform) to obtain the title compound (5.0 mg, 53%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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=15Hz,1H),3.60-3.75(m,1H),3.81(s,3H),4.10(dd,J=11,15Hz,1H),4.70(br s,1H),6.66(dd,J=2,8Hz,1H),6.93(d,J=8Hz,1H),7.21(d,J=2Hz,1H).

[0608] (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)naphth[1,2-d]azepin-2(1H)-one

[0609] [ka]

[0610] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 204. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):0.03-0.17(m,2H),0.47-0.55(m,2H),0.72-0.96(m,1H),1.0 3-1.90(m,10H),1.97-2.20(m,3H),2.22-2.41(m,6H),2.52-2.59(m,1H ),2.64(d,J=15Hz,1H),2.71(dd,J=6,18Hz,1H),2.86-3.03(m,4H),3.51(d,J=15Hz,1H),3.64-3.75(m,1H),4.09(dd,J=11,15Hz,1H),4.72(br s,1H),6.64(dd,J=2,8Hz,1H),6.90(d,J=8Hz,1H),7.12(d,J=2Hz,1H).

[0611] (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)naphth[1,2-d]azepin-2(1H)-one

[0612] [ka]

[0613] According to the method described in Example 202, the title compound was obtained from the compound obtained in Example 201 and 4-(tert-butyl)-1H-pyrazole. 1 H-NMR (400MHz, CDCl 3)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=7,13Hz,1H),2.36(dd,J=7,13Hz,1H),2.52-2.61(m ,1H),2.70(d,J=15Hz,1H),2.76(dd,J=6,19Hz,1H),2.83-2.97(m,3H),3.01(d,J=18Hz,1H),3.34-3 .53(m,2H),3.55(d,J=15Hz,1H),3.61-3.72(m,1H),3.78(s,3H),4.10(dd,J=11,15Hz,1H),4.74(br s,1H),6.65(dd,J=2,8Hz,1H),6.94(d,J=8Hz,1H),6.98(s,1H),7.25(d,J=2Hz,1H),7.30(s,1H).

[0614] (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)naphth[1,2-d]azepin-2(1H)-one

[0615] [ka]

[0616] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 206. 1 H-NMR (400MHz, CDCl 3)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=15 Hz,1H),2.74(dd,J=6,18Hz,1H),2.84-3.04(m,4H),3.38-3.72(m,4H),4.10(dd,J=11,15Hz,1 H),6.64(dd,J=1,8Hz,1H),6.90(d,J=8Hz,1H),6.98(s,1H),7.22(d,J=1Hz,1H),7.31(s,1H).

[0617] (Reference example 19) Synthesis of isothiazol-3-ylmethyl methanesulfonate

[0618] [ka]

[0619] Methanesulfonic anhydride (141 mg, 0.809 mmol) and N,N-diisopropylethylamine (183 μL, 1.06 mmol) were added to a solution of isothiazol-3-ylmethanol (synthesized by the method described in WO2018160878) (61.4 mg, 0.533 mmol) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was 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 (49-70% ethyl acetate / heptane) to obtain the title compound (71.0 mg, 69%) as a light brown oil. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):3.06(s,3H),5.40(s,2H),7.39(d,J=5Hz,1H),8.73(d,J=5Hz,1H).

[0620] (Reference example 20) Synthesis of 2-(isothiazol-3-yl)acetonitrile

[0621] [ka]

[0622] Sodium cyanide (53.4 mg, 1.09 mmol) was added to a solution of the compound obtained in Reference Example 19 (71.0 mg, 0.367 mmol) in dimethyl sulfoxide (2 mL), and the mixture was stirred at 70° C. for 18.5 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted three times with tert-butyl methyl ether. The combined extracts were washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (30.0 mg, 66%) as a brown oil. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):3.98(s,2H),7.32(d,J=5Hz,1H),8.74(d,J=5Hz,1H).

[0623] (Reference example 21) Synthesis of 2-(isothiazol-3-yl)acetic acid

[0624] [ka]

[0625] According to the method described in Reference Example 13, the title compound was obtained from the compound obtained in Reference Example 20. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):4.00(s,2H),7.22(d,J=5Hz,1H),8.71(d,J=5Hz,1H).

[0626] (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 Synthesis of

[0627] [ka]

[0628] According to the method described in Example 5, the title compound was obtained from Compound E obtained in Example 3 and the compound obtained in Reference Example 21. 1 H-NMR (400MHz, CDCl 3 )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=6,18Hz,0.6H),2.78(dd,J=6,18Hz,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=16Hz,0.4H),3.83-3.95(m,2H),4.02(d,J=16Hz, 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).

[0629] (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

[0630] [ka]

[0631] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 208. 1 H-NMR (400MHz, CDCl 3 )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,2 H),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=4Hz,1H),8.42(d,J=4Hz,1H).

[0632] (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

[0633] [ka]

[0634] According to the method described in Example 26, the title compound was obtained from Compound E obtained in Example 3 and 3-(thiazol-2-yl)propanoic acid. 1 H-NMR (400MHz, CDCl 3)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=3Hz,0.3H),7.21(d,J=3Hz,0.7H),7.65(d,J=3Hz,0.3H),7.72(d,J=3Hz,0.7H).

[0635] (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

[0636] [ka]

[0637] According to the method described in Example 24, the title compound was obtained from the compound obtained in Example 157. 1 H-NMR (400MHz, CDCl 3 )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=6,18Hz,1H),2.87-3.02(m,4H),3.77-3.94(m,2H),4.69(br s,1H),6.18(dd,J=1,2Hz,1H),6.57(dd,J=2,8Hz,1H),6.61(d,J=2Hz,1H),6.90(d,J=8Hz,1H),7.15(d,J=2Hz,1H),7.48(d,J=1Hz,1H).

[0638] (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)naphth[1,2-d]azepin-2(1H)-one

[0639] [ka]

[0640] According to the method described in Example 202, the title compound was obtained from the compound obtained in Example 201 and pyrazole. 1 H-NMR (400MHz, CDCl 3 )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=6,13Hz,1H),2.36(dd,J=6,13Hz,1H),2.53-2.63(m,1H),2.69(d,J=15Hz,1H),2.77 (dd,J=6,18Hz,1H),2.83-2.96(m,3H),3.01(d,J=18Hz,1H),3.43-3.60(m,3H),3.62-3.72(m,1H),3.77(s,3H),4.11(d d,J=11,15Hz,1H),6.13-6.17(m,1H),6.63(dd,J=2,9Hz,1H),6.94(d,J=8Hz,1H),7.20-7.26(m,2H),7.42-7.46(m,1H).

[0641] (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)naphth[1,2-d]azepin-2(1H)-one

[0642] [ka]

[0643] According to the method described in Example 6, the title compound was obtained from the compound obtained in Example 212. 1 H-NMR (400MHz, CDCl 3 )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=6,14Hz,1H),1 .66-1.82(m,2H),1.90-2.16(m,3H),2.35(dd,J=6,13Hz,1H),2.36(dd,J=6,13Hz,1H),2.52-2.62(m,1H),2.67(d ,J=15Hz,1H),2.76(dd,J=6,18Hz,1H),2.85-2.95(m,3H),3.00(d,J=18Hz,1H),3.48-3.70(m,4H),4.10(dd,J=11 ,15Hz,1H),6.11-6.15(m,1H),6.62(dd,J=2,8Hz,1H),6.90(d,J=8Hz,1H),7.23-7.28(m,2H),7.42-7.46(m,1H).

[0644] (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

[0645] [ka]

[0646] According to the method described in Example 132, the title compound was obtained from Compound E obtained in Example 3 and 2,4-dihydro-3H-pyrazol-3-one. 1 H-NMR (400MHz, CDCl 3 )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).

[0647] (Reference example 22) Synthesis of ethyl (E)-3-(5-methylisothiazol-3-yl)acrylate

[0648] [ka]

[0649] To a suspension of potassium tert-butoxide (106 mg, 0.94 mmol) in tetrahydrofuran (1 mL), triethyl phosphonoacetate (189 μL, 0.94 mmol) was added dropwise under ice cooling, and the mixture was stirred at 0° C. for 30 minutes. Then, a solution of 5-methylisothiazole-3-carbaldehyde (100 mg, 0.79 mmol) in THF (1 mL) was added dropwise, and the mixture was stirred at room temperature for 5 hours. Under ice cooling, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (1-10% ethyl acetate / heptane) to obtain the title compound (143 mg, 92%) as a colorless oil. 1 H-NMR (400MHz, CDCl 3 )δ(ppm):1.33(t,J=7Hz,3H),2.59(s,3H),4.27(q,J=7Hz,2H),6.56(d,J=16Hz,1H),7.15(s,1H),7.65(d,J=16Hz,1H).

[0650] (Reference example 23) Synthesis of (E)-3-(5-methylisothiazol-3-yl)acrylic acid

[0651] [ka] A 2M aqueous sodium hydroxide solution (0.73mL, 1.45mmol) was added to a solution of the compound (143mg, 0.73mmol) obtained in Reference Example 22 in tetrahydrofuran (1mL) and stirred at room temperature for 5 hours. 2M hydrochloric acid (0.73mL, 1.45mmol) was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (122mg, 99%) as a white powder. 1 H-NMR (400MHz, DMSO-d 6 )δ(ppm):2.57(s,3H),6.61(d,J=16Hz,1H),7.42(d,J=16Hz,1H),7,58(s,1H),12.71(br s,1H).

[0652] (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

[0653] [ka]

[0654] According to the method described in Example 26, the title compound was obtained from compound E obtained in Example 3 and the compound obtained in Reference Example 23. 1 H-NMR (400MHz, CDCl 3)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=2,8Hz,0. 4H),6.65-6.73(m,1H),6.84-7.12(m,3H),7.13-7.24(m,1H),7.55(d,J=16Hz,0.6H).

[0655] (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

[0656] [ka]

[0657] According to the methods described in Examples 5 and 24, the title compound was obtained from Compound E obtained in Example 3 and 3,3,3-trifluoro-2-phenylpropanoic acid. 1 H-NMR (400MHz, CDCl 3)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=4,11,14H z,1H),1.73(ddd,J=4,4,15Hz,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=6Hz, 1H),2.86-2.97(m,1H),2.90(d,J=18Hz,1H),2.96(dd,J=9,13Hz,1H),3.09(ddd,J=2,11,13Hz,1H),3.15(dd,J=5,13Hz,1H),3. 26(ddq,J=5,9,9Hz,1H),6.52(d,J=2Hz,1H),6.60(dd,J=2,8Hz,1H),6.93(d,J=8Hz,1H),7.02-7.08(m,2H),7.21-7.31(m,3H).

[0658] (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

[0659] [ka]

[0660] To a solution of the compound obtained in Example 215 (14 mg, 0.029 mmol) in methanol (1 mL), 10% palladium-activated carbon (55% wet, 8.5 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 10 days. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative thin-layer chromatography (chloroform: 2M ammonia-methanol solution = 10:1), and the title compound and the raw material compound (compound described in Example 215) (6.6 mg) were obtained as a colorless gummy substance. The product obtained was dissolved in a methanol (1 mL) solution, and 10% palladium-activated carbon (55% wet, 13.2 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 19 hours. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amino group-supported silica gel, 0-5% methanol / chloroform) to obtain the title compound (5.4 mg, 39%) as a white solid. 1 H-NMR (400MHz, CDCl 3 )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).

[0661] (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

[0662] [ka]

[0663] 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. 1 H-NMR (400MHz, CDCl 3 )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=3Hz,1H),6.63(dd,J=2,8Hz,1H),6.86-6.88(m,1H),6.94(d,J=8Hz,0.5H),6.95(d,J=8Hz,0.5H),7.24(s,1H).

[0664] (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

[0665] [ka]

[0666] (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (5.0mg,0.048mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (18.3mg,0.048mmol), N,N-dimethylformamide (1mL) and N,N-diisopropylethylamine (17μL,0.10mmol) were added to the compound obtained in Example 176 (15.3mg,0.040mmol) and stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted three times with chloroform. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was used in the next reaction without purification. To a solution of the obtained crude product in tetrahydrofuran (0.5 mL), 0.91 M borane-tetrahydrofuran complex tetrahydrofuran solution (0.44 mL, 0.40 mmol) was added, and the mixture was heated to reflux for 6 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure. 6 M hydrochloric acid (2 mL) was added to the concentrated residue, and the mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool, and then water and potassium carbonate were added to make the mixture basic, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (chloroform: 2 M ammonia-methanol solution = 10:1) to obtain the title compound (9.0 mg, 49%) as a colorless amorphous substance. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.60(dddd,J=3,7,7,23Hz,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= 6,13Hz,1H),2.75-3.04(m,6H),3.16(dd,J=11,11Hz,1H),3.95-4.09(m,2H),4.55(dddd,J=3,6,6,6 5Hz,1H),6.53(d,J=3Hz,1H),6.61(dd,J=3,8Hz,1H),6.87(s,1H),6.93(d,J=8Hz,1H),7.24(s,1H).

[0667] (Example 220) Synthesis of 1-((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)-3-(4-methyl-1H-pyrazol-1-yl)propan-1-one

[0668] [ka]

[0669] According to the method described in Example 26, the title compound was obtained from the compound obtained in Example 3 and 3-(4-methyl-1H-pyrazol-1-yl)propanoic acid hydrochloride. 1 H-NMR (400MHz, CDCl 3)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=3,8Hz,0.3H),6.72(dd,J=3,8Hz,0.7H),6.75(d,J=3Hz,0.3H),6.79(d,J=3Hz,0.7H),6. 92(d,J=8Hz,0.7H),6.93(d,J=8Hz,0.3H),7.15(s,0.7H),7.19(s,0.3H),7.25-7.28(m,0.3H),7.34(s,0.7H).

[0670] (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

[0671] [ka]

[0672] According to the method described in Example 219, the title compound was obtained from the compound obtained in Example 176 and 1-methylcyclopropane-1-carboxylic acid. 1 H-NMR (400MHz, CDCl 3)δ(ppm):0.02-0.32(m,4H),0.99-1.10(m,1H),1.07(s,3H),1.39-1.49(m,1H),1.70-1.8 1(m,2H),1.90-2.08(m,2H),1.99(s,3H),2.21(d,J=12Hz,1H),2.35-2.45(m,1H),2.38(d, J=12Hz,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=3Hz,1H),6.61(dd,J=3,8Hz,1H),6.85(s,1H),6.92(d,J=8Hz,1H),7.23(s,1H).

[0673] (Example 222) Synthesis of a diastereomeric mixture (1:1) of (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 (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

[0674] [ka]

[0675] To a solution of compound C (98.2 mg, 0.287 mmol) obtained in Example 2 in acetonitrile (3.0 mL), (E)-4,4,4-ethyl trifluorocrotonate (210 μL, 1.46 mmol) and cesium carbonate (467 mg, 1.43 mmol) were added, and the mixture was stirred at 85° C. for 2 hours. Water (10 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted three times with ethyl acetate. The combined organic layers 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 (5-20% methanol / ethyl acetate) to obtain the title compound (154 mg, quantitative) as a yellow amorphous substance. 1 H-NMR (400MHz, CDCl 3 )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),1.7 3(ddd,J=3,11,14Hz,0.5H),1.79(ddd,J=3,10,14Hz,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=11,11Hz,0.5H),3.34(dd,J=12,12Hz,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=3,8Hz,0.5H),6.68(dd,J=2,8Hz,0.5H),6.98(d,J=8Hz,0.5H),6.99(d,J=8Hz,0.5H).

[0676] (Example 223) (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 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 II)

[0677] [ka]

[0678] Lithium borohydride (4M tetrahydrofuran solution, 380μL, 1.52mmol) was added to a solution of the compound obtained in Example 222 (154mg, 0.301mmol) in tetrahydrofuran (3.0mL) and stirred at room temperature for 5 hours. Then, lithium borohydride (4M tetrahydrofuran solution, 380μL, 1.52mmol) was added and stirred at room temperature for 2 hours. Water (10mL) was added to the reaction mixture under ice cooling, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. Lithium borohydride (4M tetrahydrofuran solution, 800μL, 3.20mmol) was added to a solution of the obtained crude product in tetrahydrofuran (3.0mL) and stirred at room temperature for 18 hours. Water (3mL) and saturated aqueous ammonium chloride solution (10mL) were added to the reaction mixture under ice cooling, and the mixture was extracted 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), N,N-diisopropylethylamine (31.2 μL, 179 μmol) and methanesulfonic anhydride (16.0 mg, 91.9 μmol) were added at 0° C., and the mixture was stirred at 0° C. for 2.5 hours. Then, methanesulfonic anhydride (6.0 mg, 34.4 μmol) was added, and the mixture was stirred at 0° C. for 40 minutes. A saturated aqueous solution of sodium bicarbonate (3 mL) and water (2 mL) were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. To a solution of the obtained crude product in acetonitrile (1.0 mL), N,N-diisopropylethylamine (15.6 μL, 89.6 μmol) and 4-methyl-1H-pyrazole (5.6 μL, 67.7 μmol) were added and stirred at room temperature for 18 hours. Then, N,N-diisopropylethylamine (15.6 μL, 89.6 μmol) and 4-methylpyrazole (6.0 μL, 72.6 μmol) were added and stirred at 70° C. for 6.5 hours. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate (3 mL) was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. According to the method described in Example 6, the title compound (Diastereomer I (4.3 mg, 16% over four steps) and Diastereomer II (1.8 mg, 7% over four steps) were obtained from the obtained crude product.

[0679] (Diastereomer I) 1 H-NMR (400MHz, CDCl 3) 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).

[0680] (Diastereomer II) 1 1H - NMR (400 MHz, CDCl 3 ) 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).

[0681] (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

[0682] [ka]

[0683] 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. 1 H-NMR (400MHz, CDCl 3 )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=3Hz,1H),6.61(dd,J=3,8Hz,1H),6.85(s,1H),6.92(d,J=8Hz,1H),7.23(s,1H).

[0684] (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

[0685] [ka]

[0686] According to the method described in Example 219, the title compound was obtained from the compound obtained in Example 176 and 1-hydroxycyclopropane-1-carboxylic acid. 1 H-NMR (400MHz, CDCl 3 )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=4,12,12Hz,1H),4.00-4.09(m,2H),6.58-6.66(m,2H),6.94(d,J=8Hz,1H),6.96(s,1H),7.25-7.28(m,1H).

[0687] (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

[0688] [ka]

[0689] According to the method described in Example 219, the title compound was obtained from the compound obtained in Example 176 and 1-fluorocyclopropane-1-carboxylic acid. 1 H-NMR (400MHz, CDCl 3)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=5,13,13Hz,1H),2.17(d dd,J=3,12,12Hz,1H),2.37(ddd,J=4,11,11Hz,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=2Hz,1H),6.62(dd,J=2,8Hz,1H),6.87(s,1H),6.95(d,J=8Hz,1H),7.24(s,1H).

[0690] (Reference example 24) Synthesis of 3-(4-methyl-1H-pyrazol-1-yl)cyclobutan-1-one

[0691] [ka]

[0692] Sodium hydride (55% oil dispersion, 43.8 mg, 1.00 mmol) was added to a solution of 4-methylpyrazole (81.9 mg, 0.997 mmol) in N,N-dimethylformamide (2.5 mL) and stirred at 70°C for 1 hour. After cooling to room temperature, a solution of 3-bromocyclobutan-1-one (175 mg, 1.17 mmol) in N,N-dimethylformamide (1.0 mL) was added and stirred at room temperature for 20 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined extracts were washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The crude product obtained was used in the next reaction without purification. 1 H-NMR (400MHz, CDCl 3 )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...

Claims

1. The following general formula (I): 【Chemistry 1】 (In the formula, R １ is a hydrogen atom, or C １－６ Alkyl group, optionally substituted C ３－６ Cycloalkyl group, optionally substituted C ３－６ Cycloalkyl C １－６ Alkyl group, optionally substituted C ６－１０ an aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted C ２－６ Alkenyl group, optionally substituted C ２－６ represents an alkynyl group, an optionally substituted acyl group, or an amino-protecting group, R ２ and R ３ are the same or different, a hydrogen atom, or C １－６ Alkyl group, optionally substituted C １－６ an alkoxy group, a halogen atom, an optionally protected hydroxy group, or R ２ and R ３ together form a carbonyl group or R ２ and R ３ C which may have a substituent ３－６ represents a saturated hydrocarbon ring or a cyclic ketal which may have a substituent, R ４ and R ５ are the same or different, a hydrogen atom, or C １－６ Alkyl group, optionally substituted C １－６ Alkoxy group, optionally substituted C ３－６ represents a cycloalkyl group, an optionally substituted amino group, a protected amino group, a halogen atom, an optionally protected hydroxy group, a carboxy group, a carboxylate group, or an optionally substituted carbamoyl group, R ６ is a hydrogen atom, or C １－６ An alkoxy group, an optionally substituted amino group, a protected amino group, a halogen atom, an optionally protected hydroxy group, an optionally substituted tetrazolyloxy group, a cyano group, a carboxy group, a carboxylate group, an optionally substituted carbamoyl group, an optionally substituted C ６－１０ an aryl group, an optionally substituted heteroaryl group, C ６－１０ represents an aryloxy group or a saccharide, R ７ and R ８ are the same or different, a hydrogen atom, or C １－６ Alkyl group, optionally substituted C １－６ an alkoxy group, a halogen atom, an optionally protected hydroxy group, or R ７ and R ８ Together, they form a carbonyl or thiocarbonyl group, or R ７ and R ８ C which may have a substituent ３－６ represents a saturated hydrocarbon ring or a cyclic ketal which may have a substituent, R ９ and R １０ are the same or different, a hydrogen atom, or C １－６ Alkyl group, optionally substituted C １－６ an alkoxy group, a halogen atom, an optionally protected hydroxy group, or R ９ and R １０ Together, they form a carbonyl or thiocarbonyl group, or R ９ and R １０ C which may have a substituent ３－６ represents a saturated hydrocarbon ring or a cyclic ketal which may have a substituent, R １１ is a hydrogen atom, or C １－６ Alkyl group, optionally substituted C １－６ represents an alkoxy group, an aralkyloxy group which may have a substituent, an amino group which may have a substituent, a protected amino group, a halogen atom, a hydroxy group which may be protected, or a cyano group, A and B are different NR １８ (R １８ represents a hydrogen atom or an amino-protecting group; a methylene group, a carbonyl group, or a group represented by the following general formula (II): 【Chemistry 2】 (R １２ and R １３ are the same or different and may have a hydrogen atom, a halogen atom or a substituent. １－６ Indicates an alkyl group or R on the same carbon １２ and R １３ C which may have a substituent ３－６ represents a saturated hydrocarbon ring, a saturated heterocyclic ring which may have a substituent, or when n is 2 or 3, a pair of adjacent R １２ C which may have a substituent and are bonded to each other ３－６ It is possible to form a saturated hydrocarbon ring or a saturated heterocyclic ring which may have a substituent, R １４ is a hydrogen atom, or C １－６ Alkyl group, optionally substituted C ３－６ Cycloalkyl group, optionally substituted C ２－６ Alkenyl group, optionally substituted C ２－６ Alkynyl group, optionally substituted C １－６ An alkoxy group, an optionally substituted amino group, a protected amino group, a halogen atom, an optionally protected hydroxy group, an optionally substituted C ６－１０ an aryl group, a heteroaryl group which may have a substituent, a saturated heterocyclic group which may have a substituent, or a cyclic amino group which may have a substituent; * represents a bond; (provided that either A or B represents formula (II)), X represents a nitrogen atom or an N-oxide; Y represents a methylene group, a carbonyl group, or a thiocarbonyl group which may have a substituent; Z is NR １５ represents an ethenylene group or an ethynylene group which may have an oxygen atom, a bond, or a substituent (provided that when m is 0, n is 0 and Z is NR １５ (Does not indicate.) R １５ is a hydrogen atom, or C １－６ Indicates an alkyl group or R １５ and R １４ represents an optionally substituted nitrogen-containing saturated heterocycle to which R １７ represents a hydrogen atom, a halogen atom, an optionally protected hydroxy group, an optionally substituted alkoxy group or an optionally substituted tetrazolyloxy group, m represents an integer of 0 to 1, n represents an integer of 0 to 3; (However, when Z is a bond, m and n cannot simultaneously represent 0.) The amino-protecting groups represented by R 1 and R 18 , and the amino-protecting groups represented by R 4 to R 6 , R 11 , and R 14 is 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, a 9-fluorenylmethyloxycarbonyl group, a p-toluenesulfonyl group, a 2-nitrobenzenesulfonyl group, a phthaloyl group or a C 7-19 aralkyl group; The hydroxy-protecting group in the optionally protected hydroxy group represented by R 2 to R 11 , R 14 and R 17 is an aralkyl group optionally having a substituent, an alkanoyl group, a silyl group having a substituent, a methanesulfonyl group, a p-toluenesulfonyl group, or a trifluoromethanesulfonyl group, The saccharide represented by R 6 is glucuronic acid. and pharma- ceutically acceptable salts thereof.

2. R ６ is a hydroxy group, optionally substituted C １－６ 2. The azepane derivative according to claim 1, wherein the aryl group is an alkoxy group or an optionally substituted carbamoyl group, and a pharma- ceutically acceptable salt thereof.

3. R ６ The azepane derivative or the pharma- ceutically acceptable salt thereof according to claim 1 or 2, wherein is a hydroxy group.

4. R １ C which may have a substituent １－６ C which may have an alkyl group or a substituent ３－６ Cycloalkyl C １－６ The azepane derivative or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the azepane derivative is an alkyl group.

5. The azepane derivative or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Z is a bond.

6. The azepane derivative or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 5, wherein n is 1 to 3.

7. R １４ The azepane derivative or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 6, wherein is an optionally substituted heteroaryl group.

8. The azepane derivative or pharma- ceutically acceptable salt thereof according to any one of claims 1 to 7, wherein A represents a group represented by the general formula (II) and B represents a methylene group.

9. R １１ The azepane derivative or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 8, wherein is a hydroxy group.

10. (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, (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepin-3(4H)-one, (5aS,6R,11bS)-14-(cyclopropyl methyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a(1H)-ol, (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, (5aS,6R,11bS)-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepin-5a(1H)-ol [1,2-d]azepine-5a,10(1H)-diol, 1-((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)-yl)ethan-1-one, ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4 H)-yl)(3-hydroxypyridin-2-yl)methanone, ((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, ((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)(pyrimidinepyridin-2-yl)methanone, ((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, ((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, ((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, ((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, ((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]pyridin-3-yl)methanone, ((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, ((5aS,6R,11bS)-3-benzyl-14-(cyclopropylmethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a,10(1H)-diol dihydrochloride, (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, (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, (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]azepine-5a(1H)-ol, (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, (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]azepine-5a(1H)-ol, (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, 1-((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)-yl)-2-(pyrimidin-2-yl)ethan-1-one, 1-((5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-yl)-2-(pyrimidin-2-yl)ethan-1-one, 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, 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, (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, (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, 1-((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)-yl)-2-(1H-pyrazol-3-yl)ethan-1-one, (5aS,6R,11bS)-3-(2-(1H-pyrazol-3-yl)ethyl)-14-(cyclopropylmethyl) (E)-1-((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)-yl)-3-(furan-3-yl)prop-2-en-1-one, ((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-meth 1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)(phenyl)methanone, ((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, (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, (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, 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, (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]azepin-5a,10(1H)-diol, 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, 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 Tan-1-one, (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, 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, 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, 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, (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]azepin-5a,10(1H)-diol, 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, 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, (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]azepine-5a(1H)-ol, (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, 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)- propylmethyl)-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, (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]azepin-5a,10(1H)-diol, 1-((5aS,6R,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, -pyrazol-1-yl)ethan-1-one, (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, 1-((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)- (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, 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, (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]azepin-5a,10(1H)-diol, 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, (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]azepin-5a,10(1H)-diol, 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]azepine-3(4H)-yl)ethan-1-one, (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, 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-(ethano)naphtho[1,2-d]azepin-3(4H)-yl)ethan-1-one, 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-(epiminoeta (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)-yl)ethan-1-one, (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, 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, (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]azepin-5a,10(1H)-diol, 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-5a,10(1H)-diol, (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, (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, 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, (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(3-(pyridin 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-3-(3-(pyridin-2-yl)propyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a(1H)-diol; 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, (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, (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, 1-((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)-yl)-3-(pyridin-4-yl)propan-1-one, (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-(3-(pyridin-4 (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(1H)-ol, (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]azepine-5a(1H)-ol, (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, 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, (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]azepine, -5a(1H)-ol, (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, 1-((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)-yl) -2-(pyridin-4-yl)ethan-1-one, (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, (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 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, (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, 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, (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]azepin-5a,10(1H)-diol, (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-3-phenethyl-2,3,4,5,6,7-hexahydro 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a(1H)-ol, (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, 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, (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, (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(3-phenylpropyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a,1 0(1H)-diol, (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-fluorophenethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a(1H)-ol, (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, (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, 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, (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, (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]azepine-5a(1H)-ol, (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, (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]azepine-5a(1H)-ol, (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, (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]azepine-5a(1H)-ol, (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, (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, (5aS,6R,11b S)-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, ((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, ((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, 1-((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)-yl)-2-(1H-yne 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, 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]azepine-3(4H)-yl)ethyl)-1H-indazole-1-carboxylate tert-butyl, (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, (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(1-methyl-1H-indazol-3-yl)ethyl)-2,3,4,5,6,7-hexahydro 1-((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)-yl)-2-(1H-indazol-3-yl)ethan-1-one; 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,1 1b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(imidazo[1,2-a]pyridin-2-yl)ethan-1-one, (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]azepin-5a,10(1H)-diol, 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, (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]azepin-5a,10(1H)-diol, 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, (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]azepin-5a,10(1H)-diol, 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-di, Hydroxy-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, (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]azepin-5a,10(1H)-diol, (5aS,6R,11bS)-14-(cyclopropyl (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, (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, 1-((5aS,6R,11bR)-14-(cyclopropylmethyl) (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; (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]azepine-5a(1H)-ol, (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, (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]azepine-5a(1H)-ol, (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, 2-((5aS,6R,11bS)-14-( 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)-1-(piperidin-1-yl)ethan-1-one, 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 5aR,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, (5aR,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepine-3(4H)-one, (5aR,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-c]azepine-3(4H)-one, (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, (5aR,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-1,2,3,4,5,5a,6,7-octahydro-6,11b-(epiminoethano)naphtho[1,2-c]azepine, (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]azepine-5a(1H)-ol, (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, 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, 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, (5aS,6R,11bR)-3-benzyl-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b- (epiminoethano)naphth[1,2-d]azepin-2(1H)-one, (5aS,6R,11bR)-3-benzyl-14-(cyclopropylmethyl)-5a,10-dihydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphth[1,2-d]azepin-2(1H)-one, 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphth[1,2-d]azepin-3(4H)-yl)- 2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one, (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, (5aS,6R,11bR)-3-(2-cyclohexylethyl)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-Hexahydro-6,11b-(epiminoethano)naphth[1,2-d]azepin-2(1H)-one, (5aS,6R,11bR)-3-(2-cyclohexylethyl)-14-(cyclopropylmethyl)-5a,10-dihydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphth[1,2-d]azepin-2(1H)-one, 2-chloro-1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-( 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, (5aS,6R,11bS)-3-(2-(4-(tert-butyl)-1H-pyrazol-1-yl)ethyl)-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, 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; 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 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 2,2,2-trichloroethyl, 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, 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, (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]azepine-5a(1H)-ol, (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, (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, 1-((5aS,6R,11bR)-14-(cyano) 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, 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, (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, 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]azepine-3(4H)-yl)ethan-1-one, (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, (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]azepin-5a(1H)-ol, Zepine-5a,10(1H)-diol, 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, (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, 1-((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)-yl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)ethan-1-one, (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, 1-((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)-yl)-2,2,2-trifluoroethan-1-one, 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy hydroxy-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, 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, (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 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 2,2,2-trichloroethyl, ((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, 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, (5aS,6R,11bS)-14-benzyl-10-meth 1,2-d]azepine-5a(1H)-ol, (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, (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, )ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol, (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, (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, (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, 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, 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, (5aS,6R,11bS)-14-(cyclopropylmethyl)-3-(2-(3,3-difluoropyrrolidine-1 1-(4-cyclopropyl-1H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol, (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, (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 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; 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, 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, (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, 1-(2-((5aS,6R,11bS)-14-(cyclopropylmethyl)-5a,10-dihydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-yl)ethyl)-1H-pyrazole-4-carbonitrile, 1-((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)-yl)ethyl)-1H-pyrazole-4-carbonitrile, 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, 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, 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, (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]azepin-5a,10(1H)-diol, 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, (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]azepin-3(4H)-yl)-2-(4-isopropyl-1H-pyrazol-1-yl)ethan-1-one (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, (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, 1-((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)-yl)-2-(dimethylamino)ethan-1-one, (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, (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, methanesulfonic acid 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, (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-6,1, 1b-(epiminoethano)naphth[1,2-d]azepin-2(1H)-one, (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)naphth[1,2-d]azepin-2(1H)-one, (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)naphth[1,2-d]azepin-2(1H)-one, (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-3-(3-(pyrrolidin-1-yl)propyl)-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphth[1,2-d]azepin-2(1H)-one, (5aS,6R,11bR)-3-(3-(4-(tert-butyl)-1H-pyrazol-1-yl)propyl)-14-(cyclopropylmethyl)-5a-hydroxy hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one, (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, 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, (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]azepin-5a,10(1H)-diol, 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, (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]azepin-5a,10(1H)-diol, (5aS,6R,11bR)-3-(3-(1H-pyrazole (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, 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, (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, (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, 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, (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]azepin-5a,10(1H)-diol, (5aS,6R,11bS)-14-(((1S,2S)-2-fluorocyclopropyl)methyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl) 1-((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)-3-(4-methyl-1H-pyrazol-1-yl)propan-1-one; (5aS,6R,11bS)-3-(2-(4-methyl-1H-pyrazolyl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-5a,10(1H)-diol; (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-trifluorobutanoic acid ethyl ester; (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-trifluorobutanoic acid ethyl ester; 11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-yl)-4,4,4-trifluorobutanoic acid ethyl, (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, (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, (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-hexa Hydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol, (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, (5aS,6R,11bS)-14-((1-fluorocyclopropyl)methyl)-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl) 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, (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 (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, (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, (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, (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, (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, (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, (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, (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, (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(1H)-ol, (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, (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]azepi, azepine-5a,10(1H)-diol, (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, (5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-1,2,3,4,5,5a,6,7-octane pivalate tert-butyl 5a,10-dihydroxy-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate; (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; noethano)naphtho[1,2-d]azepine-3(4H)-carboxylate 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 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 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 tert-butyl, (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, (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, triacetic acid (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, (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-acetic acid, (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, (5aS,6R,11bR)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-11-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-( epiminoethano)naphth[1,2-d]azepin-2(1H)-one, (5aS,6R,11bS)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-11-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphth[1,2-c]azepin-3(4H)-one, (5aS,6R,11aR)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-11-methoxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphth[1,2-d]azepine-3(4H)-carboxylate 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 tert-butyl, (5aS,6R,11bR)-10-cyano-14-(cyclopropylmethyl)-5a-hydroxy-11-methoxy-1,2,5,5a,6,7-hexahydro tert-butyl hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate, (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)-tert-butyl, (5aS,6R,11bS)-14-(cyclopropylmethyl)-5a-hydroxy-11-methoxy-3-(2-(4-methyl-1H-pyrazo (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, (5a'S,6'R,11b'R)-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, a'-Hydroxy-10'-methoxy-5',5a',6',7'-tetrahydro-1'H-spiro[cyclopentane-1,4'-[6,11b](epiminoethano)naphtho[1,2-d]azepine]-2'(3'H)-one, (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]azepine]-5a'(5'H)-ol, 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]azepine]-3'-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one, (5a'S,6'R,11b'R)-14'-(cyclopropylmethyl)-10'-methoxy-3'-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-2',3',6'7'-tetrahydro- Hydro-1'H-spiro[cyclopentan-1,4'-[6,11b](epiminoethano)naphth[1,2-d]azepine]-5a'(5'H)-ol, (5aS,6R,11bR)-9-bromo-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphth[1,2-d]azepine-2(1H)-one, (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-9-methyl-3,4,5,5a,6,7-hexa 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]azepin-2(1H)-one, (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]azepin-5a(1H)-ol, naphtho[1,2-d]azepine-5a,10(1H)-diol, (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, (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, (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, (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-3-(2-(4-(trifluoromethyl)-1H-pyra (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]azepine-2(1H)-one; (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, 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, (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, (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]azepine-2(1H)-one, (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-4-methyl-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphth[1,2-d]azepin-5a(1H)-ol, (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)naphth, 1,2-d]azepine-5a(1H)-ol, (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, (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,11-dihydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine 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, trifluoromethanesulfonic acid (5a S,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, 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-(pyridinyl 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, 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, (5aR,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, (5aS,6R,11bS)-14-(cyclopropylmethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin- 5a,11(1H)-diol, (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, (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, (5aS,6R,11bR)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-2(1H)-one, (5aS,6R,11bS)-10-(benzyloxy)-14-(cyclopropylmethyl)-5a-hydroxy-1,2,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-2(1H)-one (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, (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, (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 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 tert-butyl, (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, 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]azepine-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one, (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 tert-butyl, (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 3-(tert-butyl) 9-(2 , 4,6-trichlorophenyl), (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 tert-butyl, (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, (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-iodo-3,4,5,5a,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-2(1H)-one, (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, (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, (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 tert-Butyl pin-3(4H)-carboxylate, 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, (5aS,6R,11bR)-10-(benzyloxy)-9-cyclopropyl-14-(cyclopropylmethyl)-5a-hydroxy-1,2,5,5a,6,7-hexahydro-6,11 b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)carboxylate tert-butyl, (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, 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, (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]azepin-5a,10(1H)-diol, (5aS,6R,11bR)-9-chloro-14-(cyclopropylmethyl)-5a-hydroxy-10-methoxy-3,4,5,5a,6,7-hexa Hydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one, (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, (5aS,6R,11bS)-9-chloro-14-(cyclopropylmethyl)-10-methoxy-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-2(1H)-one pin-5a(1H)-ol, 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, 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, 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, (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, (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, (5aS,6R,11bS)-9,11-dibromo-14-(cyclopropylmethyl)-3-(2-(4-methyl-1, H-pyrazol-1-yl)ethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a,10(1H)-diol, (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, 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, 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)ethane-1- one, (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)-tert-butyl carboxylate, (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) -tert-butyl carboxylate, (5aS,6R,11bS)-10-(benzyloxy)-14-(cyclopropylmethyl)-9-(trifluoromethyl)-2,3,4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a(1H)-ol, (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, 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, (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, 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]azepine-3(4H)-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)ethan-1-one, 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,11 b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(5-methylisothiazol-3-yl)ethan-1-one, 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, (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, (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, (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, (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, 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]azepine-3( 4H)-yl)-2-(pyridin-2-yl)ethan-1-one, 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, 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5a,6,7-hexahydro-6,1 1b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one, (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, (5aS,6R,11bS)-14-(cyclopropylmethyl)-11-methoxy-10-(methoxymethoxy)-2,3 , 4,5,6,7-hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepine-5a(1H)-ol, (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, (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, 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]azepine-3(4H)-yl)-2-(pyridin-2-yl)ethan-1-one, (5aS,6R,11bR)-14-(cyclopropylmethyl)-5a-hydroxy-10-(methylcarbamoyl)-1,2,5,5a,6,7-hexahydro tert-Butyl 6,11b-(epiminoethano)naphtho[1,2-d]azepine-3(4H)-carboxylate, (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, 1-((5aS,6R,11bR)-14-(cyclopropylmethyl)-5a,10-dihydroxy-9-methyl-1,2,5,5 a,6,7-Hexahydro-6,11b-(epiminoethano)naphtho[1,2-d]azepin-3(4H)-yl)-2-((R)-3-methylpyrrolidin-1-yl)ethan-1-one, (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]azepin-5a,10(1H)-diol, (5a'S,6'R,11b'R)-14'-(cyclopropylmethyl) methyl)-5a'-hydroxy-10'-methoxy-5',5a',6',7'-tetrahydro-1'H-spiro[cyclopropane-1,4'-[6,11b](epiminoethano)naphtho[1,2-d]azepine]-2'(3'H)-one, (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]azepine]-5a'(5'H)-ol, 1-((5a'S,6'R,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]azepine]-3'-yl)-2-(pyridin-2-yl)ethan-1-one, 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, 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, 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, (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, (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, 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, 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, 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, (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, (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, (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-yl trifluoromethanesulfonate, (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-yl trifluoromethanesulfonate, (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-carbonitrile, (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, 1-((5 aS,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, 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, 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, 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, 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, 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, (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]azepin -10-carboxamide, (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)-phenyl carboxylate, (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, (5aS,6R,1-((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, 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]azepine-3(4H)-carboxamide azepane derivatives selected from 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, and ...pharma- ceutically acceptable salts thereof.

11. A pharmaceutical composition comprising the azepane derivative or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 10 as an active ingredient.

12. The pharmaceutical composition according to claim 11, which is an agent for treating, ameliorating or preventing a disease associated with the κ opioid receptor.

13. 13. The pharmaceutical composition according to claim 11 or 12, which is an analgesic.

14. 13. The pharmaceutical composition according to claim 11 or 12, which is an antipruritic drug.

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