Spirocyclic morphinane derivatives

Abstract

To provide a spirocyclic morphine derivative having κ-opioid receptor agonist activity. 【Solution means】 A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: TIFF2026086955000362.tif5071 (In the formula, R 1 ~R 5 , R 7 ~R 1 3 represents a hydrogen atom, a C 1-6 alkyl group, etc., R 6 represents a hydrogen atom, a hydroxy group, etc., A represents a heterocycle which may contain at least one heteroatom selected from N, O and S as ring-constituting atoms, etc., W represents a C 1-6 alkylene group, etc., X represents a C 1-6 alkylene group, etc., Y represents a C 1-6 alkylene, etc., Z represents a C 3-7 saturated hydrocarbon ring, etc.).

Description

[Technical Field]

[0001] The present invention relates to a spirocyclic morphinan derivative having κ-opioid receptor agonist activity. [Background technology]

[0002] Three types of opioid receptors are known: μ, δ, and κ (MOR, DOR, and KOR). Morphine, which shows a strong affinity for MOR receptors, has long been used as an analgesic. However, morphine is problematic because it can cause adverse events such as dependence, respiratory depression, and constipation via MOR receptors. KOR agonists hold potential for the treatment, improvement, or prevention of drug addiction (Patent Document 1, Non-Patent Document 1). Currently, drug therapy is used for addictions to alcohol and nicotine, but there are no treatments for cocaine or cannabis. Similarly, there are no treatments for stimulants, and psychosocial treatment, mainly cognitive behavioral therapy, is the focus for stimulant addiction. Furthermore, while opioid receptor antagonists such as naltrexone are on the market as treatments for opioid addiction, they have not reached the point of being an essential treatment for narcotic addiction (Non-Patent Document 2). Therefore, research and development of treatments for opioid addiction, such as opioid crisis, is urgently needed. In addition, there is a desire for the development of drug addiction preventative drugs that prevent drug addiction even with repeated use of opioid analgesics such as morphine and oxycodone. Patent Document 2 describes a morphinane derivative represented by general formula (I):

[0003] [ka] but, Patent Document 3 describes a morphinane derivative represented by general formula (I):

[0004] [ka]

[0005] However, it has been disclosed that these compounds possess κ-opioid receptor agonist activity. Nevertheless, the compounds represented in Patent Documents 2 and 3 do not describe or suggest the presence of a spiro ring. General formula (I) as shown in Patent Document 4:

[0006] [ka] , General formula (I), as shown in Patent Document 5:

[0007] [ka] , General formula (I), as shown in Patent Document 6 and Non-Patent Document 3:

[0008] [ka]

[0009] While the compounds are disclosed in their respective publications as possessing κ-opioid receptor agonist activity, none of them are described or suggested to have a spiro ring. Patent Document 7 contains formula (I):

[0010] [ka] Compounds having a spiro ring represented by are disclosed as modulators of μ, δ, κ, and / or ORL-1 opioid receptors, but the results of the examples show that the disclosure is limited to partial agonists of the μ receptor, and even that agonist activity is very weak. Furthermore, the compounds described in the examples are limited to imidazolidinedione as the ring constituting the spiro ring. Patent Document 8 contains formula (I):

[0011] [ka] , Patent Document 9 discloses a compound having a spiro ring represented by the formula (I'-A):

[0012] [Chemical Formula] and the formula (I-A): TIFF2026086955000009.tif3956,

[0013] as a compound having KOR agonist activity, but its activity and κ receptor selectivity are not sufficient. Also, the compounds described in the examples are limited in that the rings constituting the spiro ring are imidazolidinedione or imidazolidinone. [Prior Art Documents] [Patent Documents]

[0014] [Patent Document 1] Japanese Patent No. 4359711 [Patent Document 2] International Publication No. 93 / 15081 [Patent Document 3] International Publication No. 99 / 11289 [Patent Document 4] Japanese Unexamined Patent Application Publication No. 2008-179554 [Patent Document 5] Japanese Unexamined Patent Application Publication No. 2009-196933 [Patent Document 6] Japanese Unexamined Patent Application Publication No. 2018-127432 [Patent Document 7] International Publication No. 2015 / 183780 [Patent Document 8] International Publication No. 2015 / 097547 [Patent Document 9] International Publication No. 2014 / 091297 [Non-Patent Documents]

[0015] [Non-Patent Document 1] Handb Exp Pharmacol. 2020; 258: 147-165. [Non-Patent Document 2] The Addiction Subcommittee of the Clinical Medicine Committee and the Neuroscience Subcommittee of the Basic Medicine Committee of the Brain and Mind Subcommittee of the Science Council of Japan made recommendations on the ideal approach to academic activities aimed at overcoming addiction problems, on April 15, 2020. [Non-Patent Document 3] JNRC2016 36th Symposium on Analgesics and Opioid Peptides Program and Abstracts, p. 37, Research Group on Analgesics and Opioid Peptides [Overview of the project] [Problems that the invention aims to solve]

[0016] The object of the present invention is to provide a pharmaceutical agent that has high agonist activity to κ-opioid receptors and is effective in treating, improving, or preventing various diseases and symptoms related to κ-opioid receptors. [Means for solving the problem]

[0017] As a result of diligent research to solve the above problems, the inventors have found that the spirocyclic morphinane derivative represented by the following formula (I) has potent agonist activity against KOR, high κ receptor selectivity, or high metabolic stability. [1] That is, the present invention relates to a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 1 C is a hydrogen atom. 1-6 Alkyl alkyl group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyl C 1-6 Alkyl alkyl group, C 6-10An aryl group, a heteroaryl group having 2 to 9 carbon atoms, an aralkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, a heteroarylalkyl group having 2 to 9 carbon atoms in the heteroaryl moiety and 1 to 6 carbon atoms in the alkyl moiety, C 2-6 An alkenyl group, C 2-6 An alkynyl group, an acyl group or a protected amino group, R 2 and R 3 are the same or different and represent a hydrogen atom, C 1-6 An alkyl group, C 1-6 An alkoxy group, a halogen atom, a hydroxy group or R 2 and R 3 together represent a carbonyl group or a thiocarbonyl group or R 2 and R 3 are bonded to form C 3-7 A saturated hydrocarbon ring or a cyclic ketal of C 1-6 is represented, R 4 and R 5 are the same or different and represent a hydrogen atom, C 1-6 An alkyl group, C 1-6 An alkoxy group, an amino group, a protected amino group, a halogen atom or a hydroxy group, R 6 is a hydrogen atom, C 1-6 An alkoxy group, an amino group, an amide group, a protected amino group, a halogen atom, a hydroxy group, a cyano group, a carboxy group, a carboxylic acid ester group or a carbamoyl group, R 7 and R 8 are the same or different and represent a hydrogen atom, C 1-6 An alkyl group, C 1-6 An alkoxy group, a halogen atom, an optionally protected hydroxy group or or R 7 and R 8 together represent one oxygen atom and form an epoxy ring by ether bonding as shown in the following general formula (II),

Chemical formula

[0018] Furthermore, the present invention relates to a pharmaceutical product comprising a compound represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof. Furthermore, the present invention relates to a pharmaceutical composition containing a compound represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient. [Modes for carrying out the invention]

[0019] Next, the present invention will be described in more detail. In this specification, the "alkylene group" in substituent W refers to a carbon atom that is directly bonded to ring A but has lost one hydrogen atom, when a double line consisting of a solid and a dashed line indicates a double bond. C in this specification 1-6 Examples of alkyl groups include linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups. C in this specification 1-6 Examples of halogenated alkyl groups include linear or branched halogenated alkyl groups such as fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, and trifluoromethyl groups. C in this specification 1-6Examples of alkoxy groups include linear or branched alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, or isobutoxy groups. In this specification, halogenated C 1-6 Examples of alkoxy groups include linear or branched halogenated carbon atoms such as trifluoromethoxy or 2,2,2-trifluoroethoxy groups. 1-6 An example is an alkoxy group. C in this specification 1-6 Examples of alkoxycarbonyl groups include methoxycarbonyl groups, ethoxycarbonyl groups, and propoxycarbonyl groups.

[0020] C in this specification 1-6 As for alkylene groups, C 1-6 Examples of linear or branched alkylene groups include methylene, ethylene, propylene, butylene, pentylene, hexylene, 1,1-dimethylethylene, or 1,1-dimethylpropylene groups. C in this specification 2-6 As for the alkenylene group, C 2-6 Examples of linear or branched alkenylene groups include vinylene, propenylene, butenylene, pentenylene, or hexenylene groups, such as 1-methylvinylene, 1-propenylene, 1-methyl-1-propenylene, 2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 3-butenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, or 5-hexenylene.

[0021] C in this specification 2-6 As for alkenyl groups, C 2-6Examples of linear or branched alkenyl groups include vinyl groups, propenyl groups, butenyl groups, pentenyl groups, or hexenyl groups, such as 1-propenyl group, allyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, or 5-hexenyl group. C in this specification 2-6 As for the alkynyl group, C 2-6 Examples include linear or branched alkynyl groups, such as ethynyl, propynyl, or butynyl groups.

[0022] Examples of halogen atoms used herein include fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms. C in this specification 1-6 Examples of alkyl halides include linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl groups, which are substituted with one to three halogen atoms: fluorine, chlorine, bromine, or iodine. In this specification, the amino group may have substituents, for example, an acylamino group, and further, the substituent is C 1-6 It may also be a linear or branched alkyl group, for example C 1-6 Alkylamino group or diC 1-6 Examples include alkylamino groups. In this specification, acyl groups include C groups such as formyl, acetyl, propionyl, butanoyl, pentanoyl, or hexanoyl. 1-6 Alkanoyl group; C such as cyclopropanecarbonyl group, cyclobutanecarbonyl group or cyclopentanecarbonyl group. 4―7 Examples include cycloalkanoyl groups; alloyl groups such as benzoyl groups and naphthoyl groups; and heteroaloyl groups of 5-6 membered rings such as froyl groups, thiophenecarbonyl groups, nicotinyl groups, or isonicotinoyl groups.

[0023] C in this specification 3-6Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. C in this specification 6-10 Examples of aryl groups include phenyl groups and naphthyl groups. Examples of heteroaryl groups having 2 to 9 carbon atoms as used herein include five-membered heteroaryl groups such as furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, or tetrazolyl groups; six-membered heteroaryl groups such as pyridyl, pyridadinyl, pyrazinyl, or pyrimidinyl groups; and bicyclic heteroaryl groups such as quinolyl, isoquinolyl, quinazolyl, quinoxalyl, indolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, imidazopyridinyl, or pyrazolopyridinyl groups, which contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms as ring constituent atoms. Furthermore, tautomers may exist depending on the substituents on these heteroaryl groups. For example, when a hydroxyl group is substituted on the pyridyl group, examples include the 6-hydroxypyridine-2-yl group and its tautomer, the 6-oxo-1,6-dihydropyridine-2-yl group, and the 4-hydroxypyridine-2-yl group and its tautomer, the 4-oxo-1,4-dihydropyridine-2-yl group.

[0024] C in this specification 3-6 Cycloalkyl C 1-6 Examples of alkyl groups include cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpropyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclobutylpropyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclopentylpropyl group, cyclohexylmethyl group, cyclohexylethyl group, or cyclohexylpropyl group. Examples of aralkyl groups in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms, and aralkyloxy groups in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms, include benzyl group, phenylethyl group, phenylpropyl group, or 1-naphthylmethyl group. Examples of aralkyloxy groups used herein include benzyloxy groups and 2-phenylethyloxy groups.

[0025] In this specification, in heteroarylalkyl groups where the heteroaryl moiety has 2 to 9 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, the heteroaryl moiety includes a heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms as ring constituent atoms, and the alkyl moiety includes a methyl group, an ethyl group, a propyl group, etc. 1-6 Examples of alkyl groups include monocyclic heteroarylalkyl groups such as (pyridine-2-yl)methyl group, (pyridine-3-yl)methyl group, (pyridine-4-yl)methyl group, 2-(pyridine-2-yl)ethyl group, (furan-2-yl)methyl group, (furan-3-yl)methyl group, (imidazole-2-yl)methyl group, (imidazole-4-yl)methyl group, (imidazole-5-yl)methyl group, (thiazole-2-yl)methyl group, (thiazole-4-yl)methyl group, (thiazole-5-yl)methyl group, (thiophene-2-yl)methyl group or 2-(thiophene-2-yl)ethyl group, and bicyclic heteroarylalkyl groups such as (quinoline-3-yl)methyl group or (indole-3-yl)methyl group.

[0026] Examples of cyclic amino groups in this specification include azilidinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, azepanyl group, oxazepanyl group, oxazabicyclooctyl group, azasilinyl group, indolinyl group, or isoindolinyl group, and may have substituents. In this specification, lactams have a ring-forming atom count of any number from 4 to 8, and examples include β-lactams, γ-lactams, or δ-lactams.

[0027] In this specification, the ester-forming group in a carboxylic acid ester group is C 1-6 Alkyl alkyl group; C 2-6 Alkenyl group; an aralkyl group in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; or C 6-10 Examples include aryl groups.

[0028] C in this specification 3-7 Examples of saturated hydrocarbon rings include cyclopropane rings, cyclobutane rings, cyclopentane rings, or cyclohexane rings. In this specification, saturated heterocycles include saturated heterocycles with 3 to 7 members, such as cyclic amines like aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine; cyclic ethers like epoxides, oxetanes, tetrahydrofuran, tetrahydropyran, and dioxane; and cyclic thioethers like thiethane, thiolane, or thian. Among these saturated heterocycles, if a nitrogen atom is present as a constituent atom of the ring, then C is also included. 1-6 It may have substituents such as alkyl groups or acyl groups, or an amino protecting group on the nitrogen atom. In this specification, a saturated heterocycle includes a saturated heterocycle that is further fused or bridged with a saturated hydrocarbon, saturated heterocycle, unsaturated hydrocarbon, or unsaturated heterocycle, and also includes those that constitute a spiro ring. Examples of condensed heterocycles include decahydroquinoline, decahydroisoquinoline, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, benzomorpholine, benzothiomorpholine, etc. Examples of bridged heterocycles include 2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 2-azabi Examples include cyclo[2.2.2]octane, 8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, and 3-oxa-7-azabicyclo[3.3.1]nonane. Examples of compounds forming a spiro ring include 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, or hexahydro-1H-fl[3,4-c]pyrrole. C in this specification 1-6 Examples of cyclic ketals include dioxirane, dioxetane, dioxolane, or dioxane.

[0029] The substituents mentioned above may have substituents. Examples of the substituents are given below, but are not limited to those specified herein.

[0030] C in this specification 1-6 Alkyl alkyl group, C 1-6 The alkanoyl group may have substituents, such as halogen atoms; hydroxyl groups; and C. 1-6 Examples include alkoxycarbonyl groups, cyano groups, amino groups, protected amino groups, acyl groups, cyclic amino groups, or lactams. C in this specification 1-6 The alkoxy group may have substituents, for example, C 1-6Examples include alkoxy groups, phenoxy groups, and halogen atoms. For example, fluoromethoxy groups, difluoromethoxy groups, trifluoromethoxy groups, or 2,2,2-trifluoroethoxy groups.

[0031] C in this specification 2-6 Alkenyl group and C 2-6 The alkynyl group may have substituents, for example, C 1-6 Alkoxycarbonyl group; an aralkyl group in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; C 1-6 Alkoxy group; Aralkyloxy group in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; C 1-6 Examples include amino groups which may be substituted with linear or branched alkyl groups; halogen atoms; carboxyl groups; or hydroxyl groups. C in this specification 2-6 Alkylene group and C 2-6 The alkenylene group may have substituents, such as halogen atoms; hydroxyl groups; and C. 1-6 Alkoxy group; C 1-6 Alkoxycarbonyl group; cyano group; C 1-6 Examples include amino groups which may be substituted with linear or branched alkyl groups; or acyl groups, etc. The carbamoyl group and amino group in this specification may have substituents, for example, C 1-6 C may have an alkyl group or one or two substituents. 1-6 Alkyl alkyl group, C 6-10 Examples include aryl groups, heteroaryl groups with 2 to 9 carbon atoms, acyl groups, aralkyl groups with 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, or heteroarylalkyl groups with 2 to 9 carbon atoms in the heteroaryl portion and 1 to 6 carbon atoms in the alkyl portion. Protecting groups for protected amino groups in this specification include, for example, carbamate protecting groups such as methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, tert-amyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, 2-(trimethylsilyl)ethoxycarbonyl group, and 9-fluorenylmethyloxycarbonyl group; sulfonamide protecting groups such as p-toluenesulfonyl group and 2-nitrobenzenesulfonyl group; imide protecting groups such as phthaloyl group; or C2 groups such as benzyl group, trityl group, and naphthylmethyl group. 7―19 Examples include the aralkyl group. Protecting groups for protected hydroxyl groups in this specification include, for example, acetal protecting groups such as methoxymethyl, 2-methoxyethoxymethyl, 2-tetrahydropyranyl, and benzyloxymethyl; silyl protecting groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl; acyl protecting groups such as acetyl, pivaloyl, and benzoyl; or C2 groups such as benzyl, naphthylmethyl, and trityl. 7ー19 Examples include the aralkyl group. C in this specification 3-6 Cycloalkyl groups, C 4―7 Cycloalkanoyl group and C 3-6 Cycloalkyl C 1-6 The alkyl group may have 1 to 4 substituents on the ring, for example, C 1-6 Examples include alkyl groups; alkyl halides; halogen atoms; hydroxyl groups; amino groups; protected amino groups; acyl groups; cyclic amino groups; or lactams. C in this specification 6-10 The aryl group and the heteroaryl group having 2 to 9 carbon atoms may have 1 to 4 substituents on the ring, for example, C 1-6Alkyl alkyl group; halogenated alkyl group; hydroxyalkyl group; C 3-6 Cycloalkyl group; C 1-6 Alkoxy group; halogenated C 1-6 Examples include alkoxy groups; halogen atoms; hydroxyl groups; nitro groups; cyano groups; carbamoyl groups; optionally substituted amino groups; protected amino groups; acyl groups; cyclic amino groups; or lactams. The substituents of an amino group which may have substituents in this specification include at least one C 1-6 Alkyl alkyl group, C 6-10 Examples include arylamino groups, heteroarylamino groups with 2 to 9 carbon atoms, acylamino groups, aralkylamino groups with 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, or heteroarylalkylamino groups with 2 to 9 carbon atoms in the heteroaryl portion and 1 to 6 carbon atoms in the alkyl portion.

[0032] In this specification, the aryl portion of an aralkyl group having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, or the aralkyloxy group having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, the heteroaryl portion of a heteroarylalkyl group having 2 to 9 carbon atoms in the heteroaryl portion and 1 to 6 carbon atoms in the alkyl portion, the alloyl group, and the heteroaloyl group may have 1 to 4 substituents on the ring, for example, C 1-6 Alkyl group; halogenated alkyl group; hydroxymethyl group; hydroxyalkyl group; C 3-6 Cycloalkyl group; C 1-6 Alkoxy group; halogenated C 1-6 Examples include alkoxy groups; halogen atoms; hydroxyl groups; nitro groups; cyano groups; optionally substituted amino groups; protected amino groups; acyl groups; cyclic amino groups; or lactams. In this specification, cyclic amino groups, C 3-7 A saturated hydrocarbon ring or saturated heterocycle may have 1 to 4 substituents on the ring, for example, C 1-6 Alkyl alkyl group; C1-6 Alkoxy group; C 1-6 Examples include alkyl halides, halogen atoms, hydroxyl groups, or cyano groups. The lactams in this specification may have 1 to 4 substituents on the ring, C 1-6 Alkyl alkyl group; C 1-6 Alkoxy group; C 1-6 Examples include alkyl halides, halogen atoms, hydroxyl groups, or cyano groups. C in this specification 1-6 A cyclic ketal may have 1 to 4 substituents on the ring, for example, C 1-6 Alkyl groups are examples.

[0033] Among the compounds represented by the general formula (I) in (1) above, or pharmaceutically acceptable salts thereof, the following are preferred: [2] The compound described in [1] or a pharmaceutically acceptable salt thereof, wherein the heterocycle of A comprises 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring constituent atoms, and is a 3 to 7-membered saturated heterocycle or a 5 to 10-membered bicyclic saturated heterocycle. [3] The compound described in [1] or [2] or a pharmaceutically acceptable salt thereof, wherein the heterocycle of A is a 3- to 7-membered saturated heterocycle containing 1 to 4 N atoms and at least 1 carbon atom as ring constituent atoms. [4] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein the heterocycle of A is a five-membered saturated heterocycle containing one or two N atoms and at least one carbon atom as ring constituent atoms. [5] A compound according to any one of [1] to [4], wherein the heterocycle of A is pyrrolidine, or a pharmaceutically acceptable salt thereof. [6] The compound described in [1] or a pharmaceutically acceptable salt thereof, wherein the saturated hydrocarbon ring of A is a 3- to 7-membered saturated carbon ring. [7] The compounds described in [1] or [6] or pharmaceutically acceptable salts thereof, wherein the saturated hydrocarbon ring of A is a 4- to 6-membered saturated carbon ring. [8] The compounds described in [1], [6] or [7] or pharmaceutically acceptable salts thereof, wherein the saturated hydrocarbon ring of A is cyclobutane.

[0034] [9]W is C 1-6 Alkylene group, carbonyl group, or 1 to 4 identical or different hydrogen atoms or C12. 1-6 A compound described in any one of [1] to [8] or a pharmaceutically acceptable salt thereof, wherein N may be substituted with an alkyl group.

[10] A compound according to any one of [1] to [9], wherein W is a carbonyl group, or a pharmaceutically acceptable salt thereof.

[11] W is C 1-6 A compound described in any one of [1] to

[10] or a pharmaceutically acceptable salt thereof, wherein N may be substituted with an alkyl group.

[0035]

[12] X is C 1-6 Alkylene group, C 2-6 An alkenylene group, a carbonyl group, an amide group, N, O, or a bond, wherein the substituent or atom is 1 to 4 identical or different C atoms. 1-6 A compound described in any one of [1] to

[11] , or a pharmaceutically acceptable salt thereof, which may be substituted with an alkyl group.

[13] X is one to four identical or different C 1-6 C may be substituted with an alkyl group. 1-6 A compound described in any one of [1] to

[12] , which is an alkylene group, or a pharmaceutically acceptable salt thereof.

[0036]

[14] Y is C 1-6 A compound according to any one of [1] to

[13] , comprising an alkylene group, N, O, or a bond, or a pharmaceutically acceptable salt thereof.

[15] A compound or pharmaceutically acceptable salt thereof, wherein Y is a bonding compound, one of any one of [1] to

[14] .

[0037]

[16] Z's C 6-10 A compound or a pharmaceutically acceptable salt thereof described in any one of [1] to

[15] , wherein the aryl is benzene.

[17] A compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof, wherein the C3-7 saturated hydrocarbon ring of Z is cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[18] A compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof, wherein the heteroaryl group of Z is isoxazole, oxazole, imidazole, pyrazole, isothiazole, thiazole, furan, thiophene, pyrrole, pyridine, pyrazine, pyrimidine, pyridazine, or 2-pyridone.

[19] The saturated heterocycle of Z is found in azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperazine, piperidine, tetrahydropyran, morpholine, azepan, oxazepam, indole, benzofuran, benzothiophene, benzimidazole, indazole, benzoxazole, benzothiazole, quinoline, isoquinoline, 2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2 The compounds described in [1] to

[15] , or pharmaceutically acceptable salts thereof, are octane, 2-azabicyclo[2.2.2]octane, 8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-7-azabicyclo[3.3.1]nonane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, and hexahydro-1H-fl[3,4-c]pyrrole.

[20] A compound according to any one of [1] to

[15] , wherein the lactam of Z is a β-lactam, γ-lactam, or δ-lactam, or a pharmaceutically acceptable salt thereof.

[0038]

[21] Z may consist of 1 to 4 identical or different C 1-6 Alkyl groups; may be substituted with halogen atoms: benzene ring, pyridine ring, thiazole ring, imidazole ring, tetrahydropyran ring, piperidine ring, pyrimidine ring, pyrazine ring, pyridazine ring, isothiazole ring, pyrazole ring, pyran ring, pyrrolidine ring, morpholine ring, oxazepam ring, cyclobutyl, cyclopropyl, C 1-6A compound described in any one of [1] to

[15] , which is an alkoxy group, an amino group, or an oxygen atom, or a pharmaceutically acceptable salt thereof.

[22] A compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof, wherein Z is one to four identical or different benzene rings, pyridine rings, thiazole rings, or tetrahydropyran rings.

[23] A compound according to any one of [1] to

[15] , wherein Z is one to four identical or different tetrahydropyran rings, or a pharmaceutically acceptable salt thereof.

[0039]

[24] Z may consist of 1 to 4 identical or different C 1-6 Alkyl alkyl group; C 1-6 Alkyl halogenated compounds; C 1-6 Benzene rings, pyrazole rings, pyridine rings, thiazole rings, isothiazole rings, isoxazole rings, furan rings, morpholine rings, pyrrolidine rings, pyran rings, piperidine rings, cyclopropane, cyclobutane, cyclohexane, γ-lactam, C 1-6 A compound described in any one of [1] to

[15] , which is an alkoxy group, a cyano group, an amino group, or a carbamoyl group, or a pharmaceutically acceptable salt thereof.

[25] Z may consist of 1 to 4 identical or different C 1-6 A compound according to any one of [1]-

[15] and

[21] -

[24] or a pharmaceutically acceptable salt thereof, which is a pyrazole ring, morpholine ring, pyrrolidine ring, piperidine ring, cyclopropane, cyano group, or γ-lactam, which may be substituted with substituents selected from alkyl groups; halogen atoms; or cyano groups.

[26] A compound according to any one of [1] to

[15] , wherein Z is a γ-lactam, or a pharmaceutically acceptable salt thereof.

[0040]

[27] Z may consist of 1 to 4 identical or different C 1-6A compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof, which is a benzene ring, pyrazole ring, pyridine ring, isothiazole ring, morpholine ring, cyclopropane, or carboxyl group, which may be substituted with substituents selected from alkyl groups; halogen atoms; cyano groups; or carbamoyl groups.

[28] Z may consist of 1 to 4 identical or different C 1-6 A compound described in any one of [1] to

[15] or a pharmaceutically acceptable salt thereof, which is a benzene ring, pyrazole ring, pyridine ring, isothiazole ring, cyclopropane, or carboxyl group, which may be substituted with substituents selected from alkyl groups; halogen atoms; cyano groups; or carbamoyl groups.

[29] Z may consist of 1 to 4 identical or different C 1-6 A compound described in any one of [1] to

[15] or a pharmaceutically acceptable salt thereof, which is a pyrazole ring or a pyridine ring that may be substituted with an alkyl group.

[0041]

[30] Z may consist of 1 to 4 identical or different C 1-6 Alkyl alkyl group; halogen atom; C 1-6 A piperidine ring, a tetrahydropyran ring, and C may be substituted with substituents selected from alkoxy groups. 1-6 Alkoxy groups, pyrrolidine rings, morpholine rings, oxazepam rings, piperazine rings, azepane rings, azetidine rings, bridging rings or spiro rings consisting of a 4-7 member saturated heterocycle and a 4-7 member saturated hydrocarbon ring, 5-10 member bicyclic saturated heterocycles, oxazole rings, thiazole rings, benzene rings, pyridine rings, cyclopentane, C 1-6 A compound described in any one of [1] to

[15] , which is an alkoxy group or a hydroxyl group, or a pharmaceutically acceptable salt thereof.

[31] Z may consist of 1 to 4 identical or different C 1-6 Alkyl alkyl group; halogen atom; C 1-6 A piperidine ring; a tetrahydropyran ring; C, which may be substituted with substituents selected from alkoxy groups. 1-6A compound or pharmaceutically acceptable salt thereof described in any one of [1] to

[15] , which is an alkoxy group; pyrrolidine ring; morpholine ring; oxazepam ring; piperazine ring; azepane ring; azetidine ring; a bridging ring or spiro ring consisting of a 4-7 member saturated heterocycle and a 4-7 member saturated hydrocarbon ring; a 5-10 member bicyclic saturated heterocycle; cyclopentane; or a hydroxyl group.

[32] The compound according to

[30] or

[31] or a pharmaceutically acceptable salt thereof, wherein the bridging ring consisting of a 4- to 7-membered saturated heterocycle and a 4- to 7-membered saturated hydrocarbon ring is 2-oxa-5-azabicyclo[2.2.2]octane or 3-oxa-8-azabicyclo[3.2.1]octane.

[33] The compound according to

[30] or

[31] or a pharmaceutically acceptable salt thereof, wherein the spiro ring consisting of a 4- to 7-membered saturated heterocycle and a 4- to 7-membered saturated hydrocarbon ring is 2-azaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, or 8-oxa-2-azaspiro[4.5]decane.

[34] The compound described in

[30] or

[31] or a pharmaceutically acceptable salt thereof, wherein the 5-10 membered bicyclic saturated heterocycle is hexahydro-1H-fl[3,4-c]pyrrole, octahydrofl[3,4-c]pyridine, octahydro-6H-fl[3,4-d]azepine, or hexahydro-5H-fl[2,3-c]pyrrole.

[35] A compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof, wherein Z is a pyrrolidine ring, a piperidine ring, or hexahydro-1H-fl[3,4-c]pyrrole, which may be substituted with 1 to 4 identical or different halogen atoms.

[0042]

[36] R 1 C 1-6 Alkyl alkyl group, C 3-6 Cycloalkyl C 1-6 A compound according to any one of [1] to

[35] above, or a pharmaceutically acceptable salt thereof, which is an aralkyl group having 6 to 10 carbon atoms in the alkyl or aryl portion and 1 to 5 carbon atoms in the alkylene portion.

[37] R 1 C is substituted with a hydroxyl group 2-6Alkyl groups, C substituted with 1 to 6 halogen atoms 1-6 Alkyl alkyl group or C 1-6 C substituted with an alkoxy group 2-6 A compound according to any one of the above [1] to

[36] , which is an alkyl group, or a pharmaceutically acceptable salt thereof.

[38] R 1 A compound according to any one of the above [1] to

[37] , wherein is a C3-6 cycloalkyl C1-6 alkyl group, or a pharmaceutically acceptable salt thereof.

[39] R 1 A compound according to any one of the above [1] to

[38] , wherein is an amino protecting group, or a pharmaceutically acceptable salt thereof.

[40] R 2 and R 3 They are the same or different hydrogen atoms, C 1-6 Alkyl alkyl group, C 1-6 A compound according to any one of the above [1] to

[39] , which is an alkoxy group, a halogen atom, or a hydroxyl group, or a pharmaceutically acceptable salt thereof.

[41] R 2 and R 3 They are the same or different, hydrogen atoms or C 1-6 A compound according to any one of the above [1] to

[40] , which is an alkyl group, or a pharmaceutically acceptable salt thereof.

[42] R 2 and R 3 The compound described in any one of [1] to

[41] above, or a pharmaceutically acceptable salt thereof, wherein the compound is a hydrogen atom.

[43] R 4 and R 5 They are the same or different hydrogen atoms, C 1-6 Alkyl alkyl group, C 1-6 A compound according to any one of the above [1] to

[42] , which is an alkoxy group, an amino group, a halogen atom, or a hydroxyl group, or a pharmaceutically acceptable salt thereof.

[44] R 4 and R 5 They are the same or different, hydrogen atoms or C 1-6 A compound according to any one of the above [1] to

[43] , which is an alkyl group, or a pharmaceutically acceptable salt thereof.

[45] R 4 and R5 The compound described in any one of the above [1] to

[44] , or a pharmaceutically acceptable salt thereof, wherein the compound is a hydrogen atom.

[46] R 6 is C 1-6 A compound according to any one of the above [1] to

[45] , which is an alkoxy group or a hydroxyl group, or a pharmaceutically acceptable salt thereof.

[47] R 6 The compound described in any one of the above [1] to

[46] , wherein is a hydroxyl group, or a pharmaceutically acceptable salt thereof.

[0043]

[48] R 7 and R 8 The compound described in any one of [1] to

[47] above, or a pharmaceutically acceptable salt thereof, wherein is the same or different hydrogen atom, halogen atom, optionally protected hydroxyl group, or alkoxy group.

[49] R 7 and R 8 The compound described in any one of [1] to

[48] above, or a pharmaceutically acceptable salt thereof, wherein is the same or different hydrogen atom, a protected hydroxyl group, or an alkoxy group.

[50] R 7 and R 8 is a hydrogen atom, which is one of the compounds described in any one of [1] to

[49] above or a pharmaceutically acceptable salt thereof.

[51] R 7 and R 8 The two atoms together represent one oxygen atom, and by forming an ether bond as shown in the general formula (II) below, an epoxy ring is formed: [ka] The compound described in any one of [1] to

[50] above, or a pharmaceutically acceptable salt thereof.

[52] R 9 and R 10 They are the same or different hydrogen atoms, C 1-6 Alkyl alkyl group, C 1-6 A compound according to any one of the above [1] to

[51] , which is an alkoxy group, a halogen atom, or a hydroxyl group, or a pharmaceutically acceptable salt thereof.

[53] R9 and R 10 They are the same or different hydrogen atoms, C 1-6 Alkyl alkyl group or C 1-6 A compound according to any one of the above [1] to

[52] , which is an alkoxy group, or a pharmaceutically acceptable salt thereof.

[54] R 9 and R 10 They are the same or different, hydrogen atoms or C 1-6 A compound according to any one of the above [1] to

[53] , which is an alkyl group, or a pharmaceutically acceptable salt thereof.

[55] R 9 and R 10 The compound described in any one of [1] to

[54] above, or a pharmaceutically acceptable salt thereof, wherein the compound is a hydrogen atom.

[56] R 11 and R 12 They are the same or different, hydrogen atom, hydroxyl group, C 1-6 Alkyl alkyl group, C 1-6 A compound according to any one of the above [1] to

[55] , which is an alkoxy group or a halogen atom, or a pharmaceutically acceptable salt thereof.

[57] R 11 and R 12 They are the same or different hydrogen atoms, hydroxyl groups, or C 1-6 A compound according to any one of the above [1] to

[56] , which is an alkyl group, or a pharmaceutically acceptable salt thereof.

[58] R 11 and R 12 The compound described in any one of [1] to

[57] above, or a pharmaceutically acceptable salt thereof, wherein is the same or different hydrogen atom or hydroxyl group.

[59] R 13 is a hydrogen atom, a hydroxyl group, or C 1-6 Alkoxy C 1-6 A compound according to any one of the above [1] to

[58] , which is an alkyl group, or a pharmaceutically acceptable salt thereof.

[60] R 13 The compound described in any one of [1] to

[59] above, which is a hydroxyl group, or a pharmaceutically acceptable salt thereof.

[61] A compound or mixture of compounds selected from the group consisting of (1) to (224) below, or a pharmaceutically acceptable salt of the said compound or a mixture of pharmaceutically acceptable salts of the said compound: (1) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (2) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one; (3) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one; (4) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(4-methyl-1H-pyrazole-1-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (5) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(4-methyl-1H-pyrazole-1-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (6) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-(pyridine-2-yl)ethane-1-one; (7) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-2-yl)ethane-1-one; (8) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridine-2-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (9) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one; (10) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one; (11) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-(4-methyl-1H-pyrazole-1-yl)propyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (12) (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(furan-3-yl)prop-2-en-1-one; (13) (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(furan-3-yl)prop-2-en-1-one; (14) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)propan-1-one; (15) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)propan-1-one; (16) (1S,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-one; (17) (2S,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-5-one; (18) (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-9'-methoxy-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a'-ol; (19) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one; (20) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one; (21) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-(pyridine-3-yl)ethane-1-one; (22) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-3-yl)ethane-1-one; (23) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-(pyridine-4-yl)ethane-1-one; (24) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-4-yl)ethane-1-one; (25) (E)-1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one; (26) (E)-1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one; (27) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one; (28) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one; (29) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyrrolidine-1-yl)propan-1-one; (30) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyrrolidine-1-yl)propan-1-one; (31) ((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)(pyridine-2-yl)methanone; (32) ((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)(pyridine-2-yl)methanone; (33) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinopropan-1-one; (34) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinopropan-1-one; (35) (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one; (36) (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one; (37) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-3-(pyridine-2-yl)propan-1-one; (38) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-2-(pyridine-2-yl)ethane-1-one; (39) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-2-(pyridine-2-yl)ethane-1-one; (40) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-(pyridine-2-yl)propyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (41) (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-9'-methoxy-1-(2-(pyridine-2-yl)ethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a'-ol; (42) (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1-(2-(pyridine-2-yl)ethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (43) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(thiazole-4-yl)propan-1-one; (44) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(thiazole-4-yl)propan-1-one; (45) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(pyridine-4-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (46) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridine-4-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (47) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(pyridine-3-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol; (48) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridine-3-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (49) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(2-fluorophenyl)propan-1-one; (50) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(2-fluorophenyl)propan-1-one; (51) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (52) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (53) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-(pyridine-3-yloxy)ethane-1-one; (54) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-3-yloxy)ethane-1-one; (55) ((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1-((E)-3-(pyridine-2-yl)aryl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (56) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(piperidine-1-yl)propan-1-one; (57) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(piperidine-1-yl)propan-1-one; (58) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-(pyridine-2-yl)butan-1-one; (59) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-(pyridine-2-yl)butan-1-one; (60) 3-Cyclobutyl-1-((2R,4b'R,8a'S,9'R)-11'-(Cyclopropylmethyl)-8a'-Hydroxy-3'-Methoxy-8',8a',9',10'-Tetrahydro-5'H,7'H-Spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propan-1-one; (61) 3-Cyclobutyl-1-((2R,4b'R,8a'S,9'R)-11'-(Cyclopropylmethyl)-3',8a'-Dihydroxy-8',8a',9',10'-Tetrahydro-5'H,7'H-Spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propan-1-one; (62) 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2,2-dimethyl-5-oxopentannitrile; (63) 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2,2-dimethyl-5-oxopentannitrile; (64) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-morpholinopropan-1-one; (65) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-3-morpholinopropan-1-one; (66) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((R)-3-fluoropyrrolidine-1-yl)propan-1-one; (67) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((R)-3-fluoropyrrolidine-1-yl)propan-1-one; (68) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(pyridine-2-ylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (69) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(pyridine-2-ylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (70) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-(pyridine-2-yloxy)ethane-1-one; (71) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-2-yloxy)ethane-1-one; (72) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (73) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (74) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(4-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (75) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(4-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (76) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)prop-2-en-1-one; (77) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-3-(piperidine-1-yl)propan-1-one; (78) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(3-fluoropiperidine-1-yl)propan-1-one; (79) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(3-fluoropiperidine-1-yl)propan-1-one; (80) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (81) 1-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxopropyl)cyclopropane-1-carbonitride; (82) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(isothiazol-3-yl)ethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (83) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(isothiazol-3-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (84) (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylisothiazol-3-yl)prop-2-en-1-one; (85) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylisothiazol-3-yl)propan-1-one; (86) 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl) tert-butyl acetate; (87) 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-1-morpholinoethane-1-one; (88) 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-1-morpholinoethane-1-one; (89) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-(4-methylpiperazine-1-yl)propan-1-one; (90) 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl) tert-butyl propanoate; (91) 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-1-morpholinopropan-1-one; (92) 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-1-morpholinopropan-1-one; (93) 4-(3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-oxopropyl)piperazine-2-one; (94) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-(5-fluoropyridine-2-yl)ethane-1-one; (95) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(5-fluoropyridine-2-yl)ethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (96) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(5-fluoropyridine-2-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (97) 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)ethyl)benzonitrile; (98) 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzonitrile; (99) 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)ethyl)benzamide; (100) 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzamide; (101) (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (102) 4-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-N,N-dimethyl-4-oxobutanamide; (103) 1-(3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-3-oxopropyl)cyclopropane-1-carbonitride; (104) 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)ethyl)benzonitrile; (105) 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)ethyl)benzonitrile; (106) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-one; (107) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-one; (108) 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-5-oxopentannitrile; (109) 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-5-oxopentannitrile; (110) (S)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinbutan-1-one and (R)-1 -((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinbutan-1-one diastereomer mixture; (111) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinbutan-1-one; (112) 1-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-oxoethyl)cyclopropane-1-carbonitride; (113) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propan-1-one; (114) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(isoxazole-3-yl)propan-1-one; (115) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(isoxazole-3-yl)propan-1-one; (116) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-(1,4-oxazepan-4-yl)propan-1-one; (117) 4-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-oxobutannitrile; (118) 4-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-oxobutanamide; (119) 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzamide; (120) 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzamide; (121) 4-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-oxobutannitrile; (122) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl) tert-butyl propanoate; (123) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propanoic acid; (124) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-1-(piperidine-1-yl)propan-1-one; (125) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-1-(piperidine-1-yl)propan-1-one; (126) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((S)-3-fluoropyrrolidine-1-yl)propan-1-one; (127) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((S)-3-fluoropyrrolidine-1-yl)propan-1-one; (128) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylisoxazole-3-yl)propan-1-one; (129) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylisoxazole-3-yl)propan-1-one; (130) 1-((E)-3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxoprop-1-en-1-yl)cyclopropane-1-carbonitrile; (131) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-methoxycyclopropyl)propan-1-one; (132) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-fluorocyclobutyl)propan-1-one; (133) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-(difluoromethyl)cyclopropyl)propan-1-one; (134) (R)-5-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxopropyl)pyrrolidine-2-one; (135) (S)-5-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxopropyl)pyrrolidine-2-one; (136) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(dimethylamino)propan-1-one; (137) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((S)-3-methylpyrrolidine-1-yl)propan-1-one; (138) 3-Cyclohexyl-1-((2R,4b'R,8a'S,9'R)-11'-(Cyclopropylmethyl)-3',8a'-Dihydroxy-8',8a',9',10'-Tetrahydro-5'H,7'H-Spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propan-1-one; (139) 1-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxopropyl)cyclobutan-1-carbonitriel; (140) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propanoic acid; (141) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-N,N-dimethylpropanamide; (142) 3-Cyclopropyl-1-((2R,4b'R,8a'S,9'R)-11'-(Cyclopropylmethyl)-3',8a'-Dihydroxy-8',8a',9',10'-Tetrahydro-5'H,7'H-Spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propan-1-one; (143) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylfuran-2-yl)propan-1-one; (144) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-carboxylic acid (1-cyanocyclopropyl)methyl; (145) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-cyclopropylpropyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (146) 1-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxopropyl)pyrrolidine-2-one; (147) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-cyclopropylmethyl carboxylate; (148) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)methyl propanoate; (149) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-1-(pyrrolidine-1-yl)propan-1-one; (150) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-methoxypropan-1-one; (151) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((S)-2-methylpyrrolidine-1-yl)propan-1-one; (152) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)methyl acetate; (153) (1S,4'R,4a'S,7a'S,12b'S,E)-3'-(cyclopropylmethyl)-9'-methoxy-2-(2-(pyrrolidine-1-yl)ethylidene)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a'-ol; (154) (1S,4'R,4a'S,7a'S,12b'S,E)-3'-(cyclopropylmethyl)-2-(2-(pyrrolidine-1-yl)ethylidene)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (155) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)-1-(pyrrolidine-1-yl)ethane-1-one; (156) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)-1-(pyrrolidine-1-yl)ethane-1-one; (157) (E)-N-cyclopentyl-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)acetamide; (158) (E)-N-cyclopentyl-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)acetamide; (159) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)acetic acid; (160) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)-1-morpholinoethane-1-one; (161) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)-1-morpholinoethane-1-one; (162) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(piperidine-1-yl)ethane-1-one; (163) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)-1-(piperidine-1-yl)ethane-1-one; (164) (1S,4'R,4a'S,7a'S,12b'S,E)-3'-(cyclopropylmethyl)-2-(2-hydroxyethylidene)-9'-(methoxymethoxy)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a'-ol (compound 164A) and (E) A mixture of -2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-bis(methoxymethoxy)-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-ol (compound 164B); (165) (1S,4'R,4a'S,7a'S,12b'S,E)-3'-(cyclopropylmethyl)-2-(2-(pyridine-2-ylmethoxy)ethylidene)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (166) (1S,4'R,4a'S,7a'S,12b'S,E)-3'-(cyclopropylmethyl)-2-(2-(methyl(pyridine-2-ylmethyl)amino)ethylidene)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (167) (E)-1-(azetidine-1-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (168) (E)-1-(azetidine-1-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (169) (E)-1-(azepan-1-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (170) (E)-1-(azepan-1-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (171) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)-1-(2-azaspiro[3,3]heptan-2-yl)ethane-1-one; (172) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)-1-(2-azaspiro[3,3]heptan-2-yl)ethane-1-one; (173) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethyl acetate; (174) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(3-fluoropiperidine-1-yl)ethane-1-one; (175) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(4-methylpiperazine-1-yl)ethane-1-one; (176) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(4-methylpiperazine-1-yl)ethane-1-one; (177) 2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-yl)-1-(piperidine-1-yl)ethane-1-one; (178) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)acetic acid; (179) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(1,4-oxazepan-4-yl)ethane-1-one; (180) (1S,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-one; (181) (1S,4'R,4a'S,7a'S,12b'S,E)-1'H,7a'H-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-one O-pyridine-2-ylmethyloxime; (182) (E)-1-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (183) (E)-1-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (184) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-((2R,6S)-2,6-dimethylmorpholino)ethane-1-one; (185) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-((2R,6S)-2,6-dimethylmorpholino)ethane-1-one; (186) (E)-1-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (187) (E)-1-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (188) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)-1-(tetrahydro-1H-floflo[3,4-c]pyrrol-5(3H)-yl)ethane-1-one; (189) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(4-methoxypiperidine-1-yl)ethane-1-one; (190) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(3-methoxypyrrolidine-1-yl)ethane-1-one diastereomer mixture (1:1); (191) (1S,4'R,4a'S,7a'S,12b'S,E)-1'H,7a'H-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-one O-cyclohexyloxime; (192) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)-N-(2-methoxyethyl)-N-methylacetamide; (193) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((2-methoxyethyl)(methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (194) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-2-ylidene)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide; (195) (1S,4'R,4a'S,7a'S,12b'S,E)-1'H,7a'H-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-one O-tetrahydro-2H-pyran-4-yloxime; (196) (1S,2S,4'R,4a'S,7a'S,12b'S)-2-(benzylamino)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (197) (1S,2S,4'R,4a'S,7a'S,12b'S)-2-(benzylamino)-3'-(cyclopropylmethyl)-9'-methoxy-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a'-ol; (198) (1S,2S,4'R,4a'S,7a'S,12b'S)-2-(benzyl(methyl)amino)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (199) (1S,2R,4'R,4a'S,7a'S,12b'S)-2-(benzyl(methyl)amino)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (200) N-((1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-yl)-N-methylbenzamide; (201) N-((1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-yl)-N-methylbenzamide; (202) N-((1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-yl)benzamide; (203) N-((1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-yl)benzamide; (204) N-((1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-yl)benzamide; (205) N-((1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-yl)benzamide; (206) (1S,2S,4'R,4a'S,7a'S,12b'S)-2-amino-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (207) (1S,2R,4'R,4a'S,7a'S,12b'S)-2-amino-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (208) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((pyridine-2-ylmethyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (209) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((pyridine-2-ylmethyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (210) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (211) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (212) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(3,3-difluoropiperidine-1-yl)ethane-1-one; (213) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(4,4-difluoropiperidine-1-yl)ethane-1-one; (214) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((thiazole-2-ylmethyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (215) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((thiazole-2-ylmethyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (216) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((3-fluoropyridine-2-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (217) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((3-fluoropyridine-2-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (218) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((1-methyl-1H-imidazole-2-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (219) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((1-methyl-1H-imidazole-2-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (220) (1S,2S,4'R,4a'S,7a'S,12b'S)-2-(((5-chloropyridine-2-yl)methyl)amino)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (221) (1S,2R,4'R,4a'S,7a'S,12b'S)-2-(((5-chloropyridine-2-yl)methyl)amino)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol; (222) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((2-fluorobenzyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-4a',9'-diol; (223) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((2-fluorobenzyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-4a',9'-diol; and (224) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((1-(pyridine-2-yl)ethyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol. A κ-opioid receptor agonist containing one of the compounds described in any one of

[62] [1] to

[61] or a pharmacopositically acceptable salt thereof as an active ingredient. A preventive or therapeutic agent for diseases or symptoms related to κ-opioid receptors, comprising as an active ingredient any compound described in any one of

[63] [1] to

[62] or a pharmacoposityal salt thereof.

[0044] Preferred embodiments of compound (I) used in the present invention include: R 1 is C 1-6Alkyl alkyl group, C 3-6 Cycloalkyl C 1-6 It is an alkyl group, R 2 and R 3 are the same or different hydrogen atoms or C 1-6 Alkyl alkyl group, C 1-6 These are alkoxy groups, halogen atoms, and hydroxyl groups. R 4 and R 5 The hydrogen atoms are the same or different C 1-6 Alkyl alkyl group, C 1-6 It is an alkoxy group, an amino group, a halogen atom, or a hydroxyl group. R 6 is C 1-6 It is an alkoxy group or a hydroxyl group, R 7 and R 8 Both indicate a hydrogen atom or R 7 and R 8 The two represent one oxygen atom, and the epoxy ring represents... R 9 and R 10 The hydrogen atoms are the same or different C 1-6 Alkyl alkyl group, C 1-6 It is an alkoxy group, a halogen atom, or a hydroxyl group. R 11 and R 12 The hydrogen atoms are the same or different C 1-6 Alkyl alkyl group, C 1-6 These are alkoxy groups, halogen atoms, and hydroxyl groups. R 13 is a hydroxyl group or C 1-6 Alkoxy C 1-6 It is an alkyl group, A is a 5- or 6-membered saturated heterocycle or a 4- or 5-membered saturated hydrocarbon ring containing at least one N atom in its ring constituent atoms. A double line consisting of a solid and a dashed line represents a single or double bond. W is a carbonyl group, C 1-6 Alkylene group or hydrogen atom or C 1-6 The alkyl group is a nitrogen atom that may be substituted. X is a carbonyl group, C 1-6Alkylene group, C 2-6 Alkenylene group, hydrogen atom or C 1-6 The alkyl group may be substituted with N, O, or a bond. Y is C 1-6 The alkylene group may be substituted with 1 to 3 halogen atoms. 1-6 Alkyl group, carbonyl group, hydrogen atom or C 1-6 The alkyl group may be substituted with N, O, or a bond. Z may consist of 1 to 4 identical or different halogen atoms; cyano groups; carbamoyl groups; oxo groups; and C. 1-6 Alkyl alkyl group; C 1-6 Alkyl halogenated compounds; C 1-6 C may be substituted with an alkoxy group. 1-6 Alkoxy group, carbamoyl group, cyano group, C 2-8 Examples include a dialkylamino group, benzene, isoxazole, imidazole, isothiazole, thiazole, pyrazole, pyridine, furan, cyclohexane, cyclobutane, cyclopropane, azetidine, azepane, oxazepam, piperazine, piperidine, tetrahydropyran, pyrrolidine, morpholine, γ-lactam, a 7 or 8-membered spiro ring containing 1 to 4 heteroatoms selected from N and O, a 2-oxa-5-azabicyclo[2.2.2]octan-5-yl group, or a 3-oxa-8-azabicyclo[3.2.1]octan-8-yl group.

[0045] A more preferred embodiment of compound (I) used in the present invention is: If A is a 5-membered saturated heterocycle containing 1 or 2 N atoms and at least 1 carbon atom as ring constituent atoms, R 1 is C 1-6 Alkyl alkyl group or C 3-6 Cycloalkyl C 1-6 It is an alkyl group, R 2 and R 3 are the same or different hydrogen atoms or C 1-6 It is an alkyl group, R 4 and R 5are the same or different hydrogen atoms or C 1-6 It is an alkyl group, R 6 is C 1-6 It is an alkoxy group or a hydroxyl group, R 7 and R 8 Both represent hydrogen atoms. R 9 and R 10 The hydrogen atoms are the same or different C 1-6 Alkyl alkyl group or C 1-6 It is an alkoxy group, R 11 and R 12 are the same or different hydrogen atoms or C 1-6 It is an alkyl group, R 13 is a hydroxyl group or a methoxymethyl group, A double line consisting of a solid and a dashed line is a single connection. W is a carbonyl group, C 1-6 Alkylene group or hydrogen atom or C 1-6 The alkyl group is a nitrogen atom that may be substituted. X is a carbonyl group or C 1-6 It is an alkylene group, Y is a joint, Z may consist of 1 to 4 identical or different elements, C 1-6 Alkyl alkyl group; C 1-6 Alkyl halogenated compounds; C 1-6 Benzene rings, pyrazole rings, pyridine rings, thiazole rings, isoxazole rings, furan rings, morpholine rings, pyrrolidine rings, tetrahydropyran rings, piperidine rings, cyclopropane, cyclobutane, cyclohexane, γ-lactam, C 1-6 Alkoxy group, cyano group, or carbamoyl group One example is when this happens. If A is a saturated carbon ring with 4 to 6 members, R 1 is C 1-6 Alkyl alkyl group or C 3-6 Cycloalkyl C 1-6 It is an alkyl group, R 2 and R 3 are the same or different hydrogen atoms or C 1-6 It is an alkyl group, R 4 and R 5 are the same or different hydrogen atoms or C 1-6 It is an alkyl group, R 6 is C 1-6 It is an alkoxy group or a hydroxyl group, R 7 and R 8 The two represent one oxygen atom, and the epoxy ring represents... R 9 and R 10 The hydrogen atoms are the same or different C 1-6 Alkyl alkyl group or C 1-6 It is an alkoxy group, R 11 and R 12 are the same or different hydrogen atoms or C 1-6 It is an alkyl group, R 13 is a hydroxyl group or a methoxymethyl group, A double line consisting of a solid and a dashed line is a single connection. W is C 1-6 The alkyl group is an N or bond that may be substituted, X is a carbonyl group, C 1-6 It is an alkylene group or bond. Y is a joint, Z may consist of 1 to 4 identical or different elements, C 1-6 Alkyl groups; may be substituted with halogen atoms, such as benzene rings, pyridine rings, thiazole rings, imidazole rings, tetrahydropyran rings, and C 1-6 Alkoxy group, amino group, or oxygen atom One example is the case where...

[0046] Furthermore, preferred embodiments of compound (I) used in the present invention include: If A is a pyrrolidine ring, R 1 is C 3-6 Cycloalkyl C1-6 It is an alkyl group, R 2 , R 3 , R 4 and R 5 It is a hydrogen atom, R 6 It is a hydroxyl group, R 7 and R 8 Both represent hydrogen atoms. R 9 , R 10 , R 11 and R 12 It is a hydrogen atom, R 13 It is a hydroxyl group, A double line consisting of a solid and a dashed line is a single connection. W is a carbonyl group, X is C 1-6 It is an alkylene group, Y is a joint, Z may consist of 1 to 4 identical or different elements, C 1-6 Pyrazole ring, morpholine ring, pyrrolidine ring, piperidine ring, cyclopropane, cyano group or γ-lactam, which may be substituted with substituents selected from alkyl groups, halogen atoms, or cyano groups. One example is when this happens. If A is cyclobutane, R 1 is C 3-6 Cycloalkyl C 1-6 It is an alkyl group, R 2 , R 3 , R 4 and R 5 It is a hydrogen atom, R 6 It is a hydroxyl group, R 7 and R 8 Both indicate a hydrogen atom or R 7 and R 8 The two represent one oxygen atom, and the epoxy ring represents... R 9 , R 10 , R 11 and R 12It is a hydrogen atom, R 13 It is a hydroxyl group, A double line consisting of a solid and a dashed line is a single connection. W is C 1-6 The alkyl group is an N or bond that may be substituted, X is C 1-6 It is an alkylene group, Y is a joint, Z may consist of 1 to 4 identical or different elements, C 1-6 A benzene ring, pyridine ring, thiazole ring, or tetrahydropyran ring may be substituted with substituents selected from alkyl groups, halogen atoms, or cyano groups. One example is the case where...

[0047] In the spirocyclic morphinan derivative represented by the above general formula (I) and its pharmaceutically acceptable salts, pharmaceutically acceptable salts are preferably acid addition salts, and examples of acid addition salts include (a) salts with mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; (b) salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid, maleic acid, and tartaric acid; and (c) salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.

[0048] The spirocyclic morphinane derivatives represented by the above general formula (I) and their pharmaceutically acceptable salts include tautomers and stereoisomers such as cis, trans isomers, racemates, and optically active compounds.

[0049] The spirocyclic morphinane derivatives represented by the above general formula (I) and their pharmaceutically acceptable salts can also exist as hydrates or solvates. Therefore, the compounds of the present invention include all crystalline forms and hydrates or solvates thereof.

[0050] Next, the synthesis method of the compound of the present invention represented by the above general formula (I) is shown below. Furthermore, among the compounds of the present invention represented by the above general formula (I), the following general formula (III) or general formula (IV) is used as one embodiment for the synthesis method. [ka] [ka] The abbreviations used herein are as follows: Abbreviations Ar: Aryl group Bn: benzyl group Bz: Benzoyl group Boc:tert-butoxycarbonyl group t-Bu:tert-butyl group CD3OD: Heavy methanol CF3: Trifluoromethyl group CN: cyano group DBU:1,8-Diazabicyclo[5.4.0]-7-Undecene DCC: N,N'-Dicyclohexylcarbodiimide DMSO-d6: Deuterated Dimethyl Sulfoxide DMT-MM:4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride n hydrate Et: Ethyl group KHMDS: Potassium bis(trimethylsilyl)amide LDA: Lithium diisopropylamide M: Molar concentration Me: Methyl group MOM: Methoxymethyl group Ms: Methanesulfonyl group N: Regulation HATU:O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU:O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 11H NMR: Proton Nuclear Magnetic Resonance Ph: Phenyl group Tf: Trifluoromethanesulfonyl group TFA: Trifluoroacetic acid WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride For the record, in general formula (III), w in (w)m is small w, and in general formula (IV), x in (x)m is small x, and (w)m and (x)m correspond to W (large W) and X (large) in general formula (I), respectively.

[0051] (1) General formula (III) (i) In the above general formula (III), D is a nitrogen atom, R 8 Manufacturing method when represents a hydrogen atom (Method A) Compound (a-7) can be obtained using compound (a-1) as a starting material by the method described below. [ka] (In the formula, Ar represents a phenyl group or a 5-chloro-2-pyridyl group, etc., R 1 ~R 7 , R 13 (This refers to the same thing as above.)

[0052] (first step) The raw material (a-1) is mixed with an inorganic base such as lithium hydride, sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, sodium ethoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium ethoxide, sodium ethoxide, potassium methoxide, sodium ethoxide, sodium ethoxide, potassium tert-butoxide, sodium ethoxide, sodium ethoxide, sodium ethoxide, potassium tert-butoxide, sodium ethoxide, sodium ethoxide, sodium ethoxide, potassium tert-butoxide, sodium ethoxide, sodium ethoxide, sodium ethoxide, potassium methoxide, sodium ethoxide, sodium ethoxide, potassium tert-butoxide, sodium ethoxide, sodium ethoxide, sodium ethoxide, potassium methoxide, sodium ethoxide, sodium ethoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium methoxide, potassium ethoxide, potassium ethoxide, potassium methoxide, sodium ethoxide, sodium ethoxide, potassium ethoxide, potassium methoxide, potassium eth Compound (a-2) can be synthesized by reacting Comins' reagent (N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide)) or trifluoromethanesulfonic anhydride, etc., with organic bases such as toxide, KHMDS, LDA, trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, and procaine for 30 minutes to 24 hours at -78°C to room temperature.

[0053] (Second process) Compound (a-2) is subjected to an aprotic polar solvent such as ethyl acetate, acetonitrile, N,N-dimethylformamide, or dimethyl sulfoxide, in which an occlusive palladium catalyst such as tetrakistriphenylphosphine palladium or (dichlorobis(t)) is used. Compound (a-3) can be synthesized by reacting propargyl alcohol with a divalent palladium catalyst such as liphenylphosphine palladium, a copper(I) salt such as copper(I) iodide or copper(I) bromide, and an organic base such as trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine at room temperature or under reflux for 1 to 24 hours.

[0054] (Third step) Compound (a-4) can be synthesized by reacting compound (a-3) under a hydrogen atmosphere or in the presence of potassium formate, etc., in a solvent such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; alcohols such as methanol, ethanol, or 2-propanol; or a mixture thereof, in a metal catalyst, such as a nickel catalyst such as Raney nickel; a palladium catalyst such as palladium-activated carbon (Pd / C) and Pearlman's catalyst (Pd(OH)2); or a platinum catalyst such as Adams' catalyst (PtO2), at room temperature or under reflux for 1 to 24 hours.

[0055] (Fourth step) Compound (a-5) can be synthesized by reacting compound (a-4) with azodicarboxylic acid diesters such as diethyl azodicarboxylic acid and diisopropyl azodicarboxylic acid, in the presence of phosphines such as triphenylphosphine and tri-n-butylphosphine, in a non-protic polar solvent or a mixture thereof, in a room temperature to reflux, for 1 to 24 hours, using tert-butyl (benzoyloxy)carbamate.

[0056] (Fifth step) Compound (a-6) can be synthesized by reacting compound (a-5) with aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol and ethanol; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; solvents such as water and acetic acid; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, or a mixture thereof, or in no solvent, with Brønsted acids such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid for 1 to 24 hours at room temperature under reflux.

[0057] (Sixth step) By referring to the reaction conditions described in general public literature (Organic Letters 2020, 22, 8769), compound (a-6) can be reacted in 1,1,1,3,3,3-hexafluoro-2-propanol in the presence of a rhodium catalyst such as bis[rhodium(α,α,α',α'-tetramethyl-1,3-benzenedipropionic acid)] for 1 to 24 hours at 0°C to room temperature to synthesize the inventive compound (a-7).

[0058] (ii) In the above general formula (III), D is a nitrogen atom, R 7 and R 8 A manufacturing method in which the two atoms become one oxygen atom and show -O- (Method B) Compound (b-1) can be used as a starting material, and the inventive compounds (b-4) to (b-8) can be obtained by the method described below. [ka] (In the formula, L represents a methanesulfonyl group, a trifluoromethanesulfonyl group, a p-toluenesulfonyl group, a 2-nitrobenzenesulfonyl group, a 2-mesitylenesulfonyl group, etc., R 1 ~R 6 , R 13 (This refers to the same thing as above.)

[0059] (first step) Compound (b-2) can be synthesized by reacting raw material (b-1) with (cyclopropylmethyl)triphenylphosphonium bromide at -78°C under reflux for 1 to 24 hours in an aprotic polar solvent or a mixture thereof, such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; an inorganic base such as lithium hydride, sodium hydride, and potassium hydride; and organic bases such as n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, phenyllithium, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, KHMDS, and LDA.

[0060] (Second process) Compound (b-3) can be synthesized by reacting compound (b-2) with osmium tetroxide at 0°C to room temperature for 1 to 24 hours in an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, or carbon tetrachloride; alcohols such as methanol, ethanol, 2-propanol, or tert-butanol; solvents such as water or acetic acid; or aprotic polar solvents or mixed solvents such as acetone, acetonitrile, N,N-dimethylformamide, or dimethyl sulfoxide, in the presence of a reoxidizing agent such as N-methylmorpholine, trimethylamine oxide, tert-butyl hydroperoxide, or potassium hexacyanoferrate(III) and a Brønsted acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid.

[0061] (Third step) The inventive compound (b-4) can be synthesized by reacting compound (b-3) with aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; solvents such as water and acetic acid; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, or mixed solvents thereof, or without a solvent, with Brønsted acids such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid; Lewis acids such as boron trifluoride-diethyl ether complex, aluminum chloride, iron(III) chloride, zinc chloride, and titanium(IV) chloride for 1 to 24 hours at room temperature under reflux.

[0062] (Fourth step) The inventive compound (b-4) is used in aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; solvents such as water and acetic acid; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, or in mixed solvents thereof, along with sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, KHMDS, and LD50. The inventive compound (b-5) can be synthesized by reacting organic bases such as A, trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, and procaine, with hydroxylamine hydrochloride or hydroxylamine sulfate, etc., in the presence or absence of inorganic bases such as lithium hydride, sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and sodium acetate, at room temperature or under reflux for 1 to 24 hours.

[0063] (Fifth step) The inventive compound (b-5) is used in aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; and in aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, with lithium hydride, sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, etc. The inventive compound (b-6) can be synthesized by reacting an inorganic base; an organic base such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, KHMDS, LDA, trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine with a reagent represented by L-Cl or L2O under reflux at -78°C for 1 to 24 hours.

[0064] (Sixth step) The inventive compound (b-7) can be synthesized by reacting the inventive compound (b-6) with aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; solvents such as water and acetic acid; Brønsted acids such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid in a non-protic polar solvent such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, or in a mixture thereof, or in no solvent, with Lewis acids such as boron trifluoride-diethyl ether complex, aluminum chloride, iron(III) chloride, zinc chloride, and titanium(IV) chloride for 1 to 24 hours at room temperature under reflux.

[0065] (Seventh step) The inventive compound (b-8) can be synthesized by reacting the inventive compound (b-7) with a reducing agent such as lithium aluminum hydride, borane-tetrahydrofuran complex, or borane-dimethyl sulfide complex in an ether solvent such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme at 0°C under reflux for 1 to 24 hours.

[0066] (iii) A method of production in which, in the above general formula (III), D is a nitrogen atom, w is a carbonyl group or a thiocarbonyl group, X is an ethenylene group or ethynylene group which may have a bond or substituent, and m is 1. (C method) The inventive compound (c-1) can be obtained by the reaction (first step) of the inventive compound (a-7) or (b-8) obtained in (i) to (ii) above with (r-1) or (r-2), and the inventive compound (c-2) can be obtained by further reaction with a sulfurizing agent (second step). [ka] (In the formula, hal is a halogen atom, R 1 ~R 8 , R 13 ~R 16 (And n are the same as above.)

[0067] (first step) The inventive compound (a-7) or (b-8) obtained in (i) to (ii) above is mixed with aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; inorganic bases such as lithium carbonate, sodium carbonate, and potassium carbonate in aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide; and trimethylamine. The inventive compound (c-1) can be synthesized by reacting an acid halide represented by (r-1) with an organic base such as triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine at 0°C under reflux for 1 to 12 hours, or by reacting a carboxylic acid represented by (r-2) with a condensing agent such as HATU, HBTU, DCC, WSC, or DMT-MM, with or without such a condensing agent, at 0°C under reflux for 1 to 96 hours.

[0068] (Second process) The inventive compound (c-1) can be converted to the inventive compound (c-2) by reacting it with an aromatic hydrocarbon such as benzene, toluene, and xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglime, and diglyme; a halogenated hydrocarbon such as dichloromethane, chloroform, and carbon tetrachloride; or an aliphatic hydrocarbon solvent such as pentane, hexane, heptane, and ligroin, with a sulfidating agent such as phosphorus pentasulfide, Lawson's reagent, Davy's reagent, Japanese reagent, or Belleau's reagent, under heating and reflux at 0°C for 1 to 12 hours.

[0069] (iv) A method of manufacturing in which, in the above general formula (III), D is a nitrogen atom, X is a bond, and m is 0. (D method) The S of the inventive compound (a-7) or (b-8) obtained in (i) to (ii) above and the alkylating agent (r-3)N The inventive compound (c-3) can be obtained through two reactions. [ka] (In the formula, L represents a leaving group such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or a halogen, R 1 ~R 8 , R 13 ~R 16 (And n are the same as above.)

[0070] The inventive compounds (a-7) or (b-8) obtained in (i) to (ii) above are mixed in aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglime, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; and in aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, lithium hydride, sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, vinegar. The inventive compound (c-3) can be synthesized by reacting an alkylating agent represented by (r-3) with an organic base such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, KHMDS, LDA, trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine, in the presence or absence of sodium iodide or potassium iodide, at room temperature or under reflux for 1 to 24 hours.

[0071] (Law E) By reducing the amide portion of the inventive compound (c-1) obtained in (iii) above, the inventive compound (c-3') can be obtained. [ka] (In the formula, R 1 ~R 8 , R 13 ~R 16 (And n are the same as above.)

[0072] The inventive compound (c-1) obtained in (iii) above can be reacted with an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme, along with a reducing agent such as lithium aluminum hydride, a borane-tetrahydrofuran complex, or a borane-dimethyl sulfide complex, under heating and reflux at 0°C for 1 to 24 hours to synthesize the inventive compound (c-3').

[0073] (F method) The inventive compound (c-3') can be obtained by a reductive amination reaction between the inventive compound (a-7) or (b-8) obtained in (i) to (ii) above and the aldehyde (r-4). [ka] (In the formula, R 1 ~R 8 , R 13 ~R 16 (And n are the same as above.)

[0074] The inventive compound (a-7) or (b-8) obtained in (i) to (ii) above can be synthesized by reacting it 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)boron hydride, or potassium tri(sec-butyl)boron hydride, 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 alcohol such as methanol or ethanol; an aliphatic hydrocarbon such as pentane, hexane, heptane, or ligroin; an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethyl sulfoxide; or a solvent or a mixture thereof, such as acetic acid, with an aldehyde represented by (r-4) for 1 to 12 hours under heating at 0°C or reflux.

[0075] (v) In the above general formula (III), D is a nitrogen atom, w is a carbonyl group, and X is NR 17 Alternatively, a manufacturing method in which the oxygen atom and m are 1. (G method) Using the inventive compounds (a-7) or (b-8) obtained in (i) to (ii) above, the inventive compound (c-6) or (c-7) can be obtained by the method described below. [ka] (In the formula, R 1 ~R 8 , R 13 ~R 17 And n are the same as above, L - (This indicates the counter anion.)

[0076] (first step) The inventive compound (a-7) or (b-8) obtained in (i) to (ii) above is used as an aromatic hydrocarbon such as benzene, toluene, and xylene; an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglime, and diglyme; a halogenated hydrocarbon such as dichloromethane, chloroform, and carbon tetrachloride; an alcohol such as methanol and ethanol; an aliphatic hydrocarbon such as pentane, hexane, heptane, and ligroin; and a non-protohydrocarbon such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide. The inventive compound (c-4) can be synthesized by reacting carbodiimidazole with an inorganic base such as lithium carbonate, sodium carbonate, or potassium carbonate in a polar solvent, and an organic base such as trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine, under heating at 0°C under reflux for 1 to 12 hours.

[0077] (Second process) The inventive compound (c-4) is mixed with aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglime, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; and inorganic bases such as lithium carbonate, sodium carbonate, and potassium carbonate in a protic polar solvent such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide. The inventive compound (c-5) can be synthesized by reacting a methylating agent such as methyl iodide, dimethyl sulfate, methyl trifluoromethanesulfonate, or Meerwein's reagent with an organic base such as trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine, in the presence or absence of such an organic base, with the reaction taking place at 0°C under reflux for 12 to 48 hours.

[0078] (Third step) The inventive compound (c-5) can be reacted with an amine represented by (r-5) or an alcohol represented by (r-6) at 0°C under reflux for 1 to 12 hours in an aprotic polar solvent such as benzene, toluene, or xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglime, or diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, or carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane, or ligroin; an inorganic base such as lithium carbonate, sodium carbonate, or potassium carbonate in an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, or dimethyl sulfoxide; and an organic base such as trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine to synthesize the inventive compound (c-5) with an alcohol represented by (r-6) at 0°C under reflux.

[0079] (H method) The inventive compound (c) can be obtained by reacting the inventive compound (a-7) or (b-8) obtained in (i) to (ii) above with the formic halogen ester (r-7). [ka] (In the formula, hal represents a halogen atom, R 1 ~R 8 , R 13 ~R 16 (And n are the same as above.)

[0080] The inventive compound (a-7) or (b-8) obtained in (i) to (ii) above is mixed with aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; and aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide. The inventive compound (c-7) can be synthesized by reacting a formic acid halogen represented by (r-7) with an inorganic base such as lithium carbonate, sodium carbonate, or potassium carbonate in a medium; or with an organic base such as trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine, under heating at 0°C under reflux for 1 to 12 hours.

[0081] (vi) In the above general formula (III), D is a nitrogen atom, R 6 Manufacturing method when the group shows a hydroxyl group (Method I) By dealkylation of the inventive compounds (c-8) obtained in (i) to (v) above, inventive compound (c-9) can be synthesized. [ka] (In the formula, R 6a is C 1-6 It shows an alkoxy group, R 1 ~R 5 , R 7 , R 8 , R 13 ~R 16 (n, m, w, and X are the same as above.)

[0082] The inventive compound (c-8) obtained in (i) to (v) above can be reacted with boron tribromide, trimethylsilyl iodide, hydrogen bromide, pyridine hydrochloride, etc., in a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; a solvent such as acetic acid; an aprotic polar solvent such as acetonitrile, or in no solvent, at -30 to 180°C for 30 minutes to 24 hours, or the inventive compound (c-9) can be synthesized by reacting it with 1-propanethol, 1-dodecanethiol, etc., in an aprotic polar solvent such as N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide, in the presence of an organic base such as potassium tert-butoxide or sodium tert-butoxide, at 100 to 180°C for 30 minutes to 24 hours.

[0083] (vii) Method of production when D represents N-oxide in the above general formula (III) (J method) By the oxidation reaction of the inventive compound (c-10) obtained in (i) to (vi) above, the inventive compound (c-11) can be synthesized. [ka] (In the formula, R 1 ~R 8 , R 13 ~R 16 (n, m, w, and X are the same as above.) The inventive compound (c-11) can be synthesized by reacting the inventive compound (c-10) obtained in (i) to (vi) above with an oxidizing agent (1 to 2 equivalents) such as an aqueous solution of hydrogen peroxide (H2O2) or m-chloroperbenzoic acid (mCPBA) in a halogenated hydrocarbon solvent such as dichloromethane, chloroform, or carbon tetrachloride for 30 minutes to 24 hours at 0°C to room temperature.

[0084] (2) General formula (IV) (viii) In the above general formula (IV), W is CH, D is a nitrogen atom, x is a carbonyl group, and Y is NR 17 The double line, consisting of a solid line and a dashed line, represents a double bond and the manufacturing method when m is 1. (K method) Using the inventive compound (b-4) obtained in (ii) above, inventive compounds (d-1) to (d-3) can be obtained by the method described below. [ka] (In the formula, R 1 ~R 6 , R 13 ~R 17 (And n are the same as above.)

[0085] (first step) The inventive compound (d-1) can be synthesized by reacting methyl dimethylphosphonoacetate with the inventive compound (b-4) at -78°C under reflux for 1 to 24 hours in an aprotic polar solvent or a mixture thereof, such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglime, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; inorganic bases such as lithium hydride, sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and sodium acetate; and organic bases such as n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, phenyllithium, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, KHMDS, and LDA.

[0086] (Second process) The inventive compound (d-2) can be synthesized by reacting the inventive compound (d-1) with an alcohol such as methanol, ethanol, or 2-propanol; an ether such as tetrahydrofuran or dioxane; a ketone such as acetone or methyl ethyl ketone; a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate; a mineral acid such as hydrochloric acid, sulfuric acid, or hydrobromic acid; or an organic acid such as p-toluenesulfonic acid, at room temperature to 120°C for 1 to 24 hours.

[0087] (Third step) The inventive compound (d-2) is subjected to the following processes in aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglime, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; and aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, as well as atypical solvents such as lithium carbonate, sodium carbonate, and potassium carbonate. The inventive compound (d-3) can be synthesized by reacting an amine represented by (r-5) with an organic base such as trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine, in the presence or absence of a condensing agent such as HATU, HBTU, DCC, WSC, or DMT-MM, under heating under reflux at 0°C for 1 to 24 hours.

[0088] (ix) A manufacturing method in which, in the above general formula (IV), W is NH or NH2, D is a nitrogen atom, Y is a bond, and the double line consisting of a solid and a dashed line indicates a single bond and m is 0. (L method) Using the inventive compound (b-4) obtained in (ii) above, inventive compounds (d-4) to (d-9) can be obtained by the method described below. [ka] (In the formula, R 1 ~R 6 , R 13 ~R 16 (And n are the same as above.)

[0089] (first step) The inventive compound (b-4) obtained in (ii) above can be reacted with benzylamine in the presence of a hydride reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium tri(sec-butyl)boron hydride, or potassium tri(sec-butyl)boron hydride for 1 to 12 hours at 0°C under reflux to synthesize the inventive compounds (d-4) and (d-5). This reaction is carried out in a solvent or a mixture thereof, in the presence of a hydride reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium tri(sec-butyl)boron hydride, or potassium tri(sec-butyl)boron hydride.

[0090] (Second process) The inventive compound (d-4) or (d-5) can be synthesized by reacting it under a hydrogen atmosphere or in the presence of potassium formate, etc., in a solvent such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; an alcohol such as methanol, ethanol, or 2-propanol; or a mixture thereof, in the presence of a metal catalyst, such as a nickel catalyst such as Raney nickel, a palladium catalyst such as Pd / C and Pd(OH)2, or a platinum catalyst such as PtO2, at room temperature or under reflux for 1 to 24 hours.

[0091] (Third step) The inventive compound (d-8) or (d-9) can be synthesized by reacting the inventive compound (d-6) or (d-7) with an aldehyde represented by (r-4) at 0°C under reflux for 1 to 12 hours in the presence of a hydride reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium tri(sec-butyl)boron hydride, or potassium tri(sec-butyl)boron hydride, in a solvent or a mixture thereof, such as aromatic hydrocarbons like benzene, toluene, or xylene; ethers like diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; halogenated hydrocarbons like dichloromethane, chloroform, or carbon tetrachloride; alcohols like methanol or ethanol; aliphatic hydrocarbons like pentane, hexane, heptane, or ligroin; aprotic polar solvents like acetonitrile, N,N-dimethylformamide, or dimethyl sulfoxide; or acetic acid.

[0092] (x) The manufacturing method in the above general formula (IV), where W is NH, D is a nitrogen atom, x is a carbonyl group, Y is an ethenylene group or etynylene group which may have a bond or substituent, and the double line consisting of a solid line and a dashed line indicates a single bond and m is 1. (M method) By reacting the inventive compound (d-6) or (d-7) obtained in (ix) above with (r-1) or (r-2), the inventive compound (d-10) or (d-11) can be obtained. [ka] (In the formula, hal is a halogen atom, R 1 ~R 6 , R 13 ~R 16 (And n are the same as above.)

[0093] The inventive compound (d-6) or (d-7) obtained in (ix) above is mixed with aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; inorganic bases such as lithium carbonate, sodium carbonate, and potassium carbonate in a protic polar solvent such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide; trimethylamine, triethyl The inventive compound (d-10) or (d-11) can be synthesized by reacting an acid halide represented by (r-1) with an organic base such as an amine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, or procaine at 0°C under reflux for 1 to 24 hours, or by reacting a carboxylic acid represented by (r-2) with a condensing agent such as HATU, HBTU, DCC, WSC, or DMT-MM, with or without such a condensing agent, at 0°C under reflux for 1 to 24 hours.

[0094] (xi) The manufacturing method in the above general formula (IV), where W is a nitrogen atom, D is a nitrogen atom, Y is an oxygen atom, the double line consisting of a solid and a dashed line represents a double bond, and m is 0. (N method) The inventive compound (d-12) can be obtained by the reaction of the inventive compound (b-4) obtained in (ii) above with hydroxylamine (r-8). [ka] (In the formula, R 1 ~R 6 , R 13 ~R 16 (And n are the same as above.) The inventive compound (b-4) obtained in (ii) above is mixed with: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; alcohols such as methanol and ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; solvents such as water and acetic acid; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, or a mixture thereof, and lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate The inventive compound (d-12) can be synthesized by reacting an inorganic base such as potassium; sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, KHMDS, LDA, trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, or other organic bases with hydroxylamine represented by (r-8) or its hydrochloride salt, etc., at room temperature or under reflux for 1 to 24 hours.

[0095] (xii) In the above general formula (IV), D is a nitrogen atom, R 6 Manufacturing method when the group shows a hydroxyl group (O method) By dealkylation of the inventive compound (d-13) obtained in (viii) to (xi) above, the inventive compound (d-14) can be synthesized. [ka] (In the formula, R 6a is C 1-6 It shows an alkoxy group, R 1 ~R 5 , R 13 ~R 16 (where n, m, W, x, and Y are the same as above.) The inventive compound (d-14) obtained in (viii) to (xi) above can be synthesized by reacting the inventive compound (d-13) with a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; a solvent such as acetic acid; an aprotic polar solvent such as acetonitrile, or in no solvent, with boron tribromide, trimethylsilyl iodide, hydrogen bromide, pyridine hydrochloride, etc., at -30 to 180°C for 30 minutes to 24 hours; or by reacting the inventive compound (d-14) with a propanethol, 1-dodecanethiol, etc., at 100 to 180°C for 30 minutes to 24 hours in an aprotic polar solvent such as N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide, in the presence of an organic base such as potassium tert-butoxide or sodium tert-butoxide.

[0096] (xiii) Method of manufacture when D represents N-oxide in the above general formula (IV) (P method) By the oxidation reaction of the inventive compound (d-15) obtained in (viii) to (xii) above, the inventive compound (d-16) can be synthesized. [ka] (In the formula, R 1 ~R 6 , R 13 ~R 16 (where n, m, W, x, and Y are the same as above.)

[0097] The inventive compound (d-16) can be synthesized by reacting the inventive compound (d-15) obtained in (viii) to (xii) above with an oxidizing agent (1 to 2 equivalents) such as an aqueous solution of H2O2 or mCPBA in a halogenated hydrocarbon solvent such as dichloromethane, chloroform, or carbon tetrachloride at 0°C to room temperature for 30 minutes to 24 hours.

[0098] The compounds obtained by each of the above steps can be purified as necessary, for example, by silica gel column chromatography. Furthermore, if necessary, an acid addition salt can be formed by a conventional method, for example, by heating compound (I) or (II) of the present invention at room temperature or appropriately in the presence of an organic solvent such as ethyl acetate; alcohols such as methanol or ethanol; or a polar solvent such as water, mineral acids such as hydrochloric acid, sulfuric acid, or phosphoric acid; organic carboxylic acids such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid, or maleic acid; or organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, or naphthalenesulfonic acid.

[0099] Representative compounds of the present invention obtained by the synthesis method described above are shown below. Representative compounds 1 to 13 are shown, but representative compounds 1, 2, 5, 7, 9, 10, or 12 are preferred, and representative compound 5 or 12 are particularly preferred. In the representative compounds 1-13, m represents an integer greater than or equal to 1. (Representative compound 1)

[0100] [ka] (In the formulas, m and Z are as shown in Tables 1 and 2.)

[0101] [Table 1] [Table 2] (Representative compound 2)

[0102] [ka] (In the formula, m and Z are as shown in Table 3)

[0103] [Table 3] (Representative compound 3)

[0104] [ka] (In the formula, Y and Z are as shown in Tables 4 and 5.)

[0105] [Table 4] [Table 5] (Representative compound 4)

[0106] [ka] (In the formula, Z is as shown in Table 6)

[0107] [Table 6] (Representative compound 5)

[0108] [ka] (In the formula, -(C n H 2n )- and Z are as shown in Tables 7 to 10.

[0109] [Table 7] [Table 8] [Table 9] [Table 10] (Representative compound 6)

[0110] [ka] (In the formula, whether (CH=CH) is the E-form or the Z-form, and the value of Z, are as shown in Table 11.)

[0111] [Table 11] (Representative compound 7)

[0112] [ka] (In the formula, X, m, and Z are as shown in Table 12)

[0113] [Table 12] (Representative compound 8)

[0114] [ka] (In the formula, m, X, and Z are as shown in Table 13)

[0115] [Table 13] (Representative compound 9)

[0116] [ka] (In the formula, X, Y, and Z are as shown in Tables 14 and 15.)

[0117] [Table 14] [Table 15] (Representative compound 10)

[0118] [ka] (In the formula, Y and Z are as shown in Tables 16 to 18)

[0119] [Table 16]

[0120] [Table 17]

[0121] [Table 18] (Representative compound 11)

[0122] [ka] (In the formula, X, Y, and Z are as shown in Table 19)

[0123] [Table 19] (Representative compound 12)

[0124] [ka] (In the formula, W, X, and Z are as shown in Tables 20 to 26)

[0125] [Table 20]

[0126] [Table 21]

[0127] [Table 22]

[0128] [Table 23]

[0129] [Table 24]

[0130] [Table 25]

[0131] [Table 26] (Representative compound 13)

[0132] [ka] (In the formula, a, W, and the double line consisting of a solid and a dashed line, Y and Z are as shown in Table 27.)

[0133] [Table 27]

[0134] Spirocyclic morphinan derivatives represented by the above general formula (I) and pharmaceutically acceptable salts thereof can be formulated in combination with pharmaceutically acceptable carriers for parenteral administration, oral administration in solid or liquid form, etc., to humans. They can also be used in combination with other analgesics. Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Excipients, disintegrants, binders, lubricants, and dyes can be used in the preparation of these solid dosage forms. 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; and examples of binders include hydroxypropylcellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP). In the case of capsules, tablets, and pills, buffers may also be used. Tablets and pills may also be coated with an enteric coating.

[0135] Forms of the present invention's compositions for injection include pharmaceutically acceptable sterile water or non-aqueous solutions, suspensions, or emulsions. Examples of suitable non-aqueous carriers, diluents, solvents, or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Such compositions may also contain auxiliary agents, such as preservatives, wetting agents, emulsifiers, analgesics, buffers, preservatives, and dispersants. These compositions can be sterilized, for example, by filtration using a bacterial-retaining filter, or by mixing in a sterilizing agent in the form of a sterile solid composition that can dissolve in a sterilizing agent or some other injectable sterilizing medium immediately before use.

[0136] Formulations for ophthalmic administration may preferably contain, in addition to the compound of the present invention, solubilizers, preservatives, isotonic agents, and thickeners.

[0137] Liquid formulations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used by those skilled in the art, such as water. In addition to such inert diluents, the composition may also contain auxiliary agents such as wetting agents, emulsifiers, suspending agents, and sweeteners, flavorings, and aromas.

[0138] Formulations for rectal administration may preferably contain, in addition to the compound of the present invention, an excipient such as cocoa butter or suppository wax.

[0139] The usual dosage for adults is 0.01 μg to 1 g / day, preferably 0.0001 to 200 mg / day, of the active ingredient, a spirocyclic morphinan derivative represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof, for injection, and 0.1 μg to 10 g / day, preferably 0.001 to 2000 mg / day, for oral administration. However, the dosage may be increased or decreased depending on age, symptoms, etc. Furthermore, this daily dose can be divided into 2 to 4 doses if desired.

[0140] Diseases and symptoms associated with κ-opioid receptors include, for example, cardiovascular disorders, digestive disorders, hematological disorders, respiratory disorders, liver diseases, nervous system disorders, urinary tract disorders, pain, cough, itching, ischemic brain disease, and drug dependence. The compound of the present invention has high selectivity for κ-opioid receptors and potent agonist activity against κ-opioid receptors, making it effective in treating, improving, and preventing these diseases and symptoms. [Examples]

[0141] Next, the present invention will be described in more detail with reference examples, examples, and test examples, but the present invention is not limited to these.

[0142] The names of the example compounds and reference example compounds were derived by first plotting the structural formulas using CambridgeSoft's ChemDraw ver. 14, then converting them to English names using the software's naming algorithm, and finally translating them into Japanese.

[0143] (Reference example 1) Synthesis of trifluoromethanesulfonic acid (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl

[0144] [ka] (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl trifluoromethanesulfonate

[0145] A tetrahydrofuran (16 mL) solution of (4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthrene-6(7H)-one (synthesized by the method described in WO2021065898, 1.46 g, 4.28 mmol) was cooled to -78°C, and a 1.08 M lithium bis(trimethylsilyl)amide-tetrahydrofuran solution (8.70 mL, 9.40 mmol) was added and the mixture was stirred for 1 hour. A tetrahydrofuran (5 mL) solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (2.06 g, 5.25 mmol) was added to the reaction mixture and the mixture was stirred at -78°C for 1 hour and at room temperature for 2.5 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted three times with ethyl acetate. The combined extract was washed with saturated brine, 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, 15-100% ethyl acetate / heptane) to obtain the title compound (812 mg, 40%) as white crystals. 1H-NMR(400MHz,CDCl3)δ(ppm):0.09-0.16(m,2H),0.49-0.58(m,2H),0.80-0.90(m,1H),1.24-1.32(m,1H),2.05-2.16(m,3H),2.25-2.32(m,1H), 2.37-2.38(m,2H),2.57-2.65(m,1H),2.84(dd,J=6,18Hz,1H),2.87-2.8 9(m,2H),3.08(d,J=18Hz,1H),3.12(d,J=6Hz,1H),3.79(s,3H),4.68(br s,1H),5.52-5.54(m,1H),6.74(dd,J=3,8Hz,1H),6.86(d,J=3Hz,1H),7.01(d,J=8Hz,1H).

[0146] (Reference example 2) Synthesis of (4bS,8aS,9R)-11-(cyclopropylmethyl)-6-(3-hydroxyprop-1-in-1-yl)-3-methoxy-5,8,9,10-tetrahydro-8aH-9,4b-(epiminoethano)phenanthrene-8a-ol

[0147] [ka] (4bS,8aS,9R)-11-(cyclopropylmethyl)-6-(3-hydroxyprop-1-yn-1-yl)-3-methoxy-5,8,9,10-tetrahydro-8aH-9,4b-(epiminoethano)phenanthren-8a-ol

[0148] To a solution of the compound obtained in Reference Example 1 (812 mg, 1.71 mmol) in tetrahydrofuran (17 mL), propargyl alcohol (0.30 mL, 5.2 mmol), N,N-diisopropylethylamine (1.45 mL, 8.32 mmol), copper(I) iodide (66.7 mg, 0.350 mmol), and bis(triphenylphosphine)palladium(II) dichloride (120 mg, 0.171 mmol) were added, and the mixture was stirred at room temperature for 40 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and it was extracted three times with ethyl acetate. The combined extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (25-100% ethyl acetate / heptane) to obtain the title compound (543 mg, 83%) as a light brown amorphous material. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.08-0.15(m,2H),0.48-0.58(m,2H),0.80-0.90(m,1H),1.18-1.22(m,1H),2.00-2.22(m,4H),2.35- 2.37(m,2H),2.59-2.64(m,3H),2.84(dd,J=7,18Hz,1H),3.06(d,J=18Hz,1H),3.08(d,J=7Hz,1H),3.78(s,3H),4.38(s,2H),4.68(br s,1H),5.84-5.86(m,1H),6.70(dd,J=2,8Hz,1H),6.83(d,J=2Hz,1H),6.99(d,J=8Hz,1H).

[0149] (Reference example 3) Synthesis of a diastereomer mixture (1.8:1.0) of (4bS,6S,8aS,9R)-11-(cyclopropylmethyl)-6-(3-hydroxypropyl)-3-methoxy-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoetano)phenanthrene-8a-ol and (4bS,6R,8aS,9R)-11-(cyclopropylmethyl)-6-(3-hydroxypropyl)-3-methoxy-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoetano)phenanthrene-8a-ol

[0150] [ka] (4bS,6S,8aS,9R)-11-(cyclopropylmethyl)-6-(3-hydroxypropyl)-3-methoxy-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoethano)phenanthren-8a-ol

[0151] [ka] (4bS,6R,8aS,9R)-11-(cyclopropylmethyl)-6-(3-hydroxypropyl)-3-methoxy-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoethano)phenanthren-8a-ol

[0152] To a methanol (9.5 mL) solution of the compound obtained in Reference Example 2 (543 mg, 1.43 mmol), 20% palladium hydroxide-activated carbon (50% wet, 808 mg, 0.575 mmol) was added, and the mixture was stirred at 60°C for 22 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To the resulting residue, methanol (9.5 mL) and 20% palladium hydroxide-activated carbon (50% wet, 808 mg, 0.575 mmol) were added again, and the mixture was stirred at 60°C for 21 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the resulting residue, and the mixture was extracted three times with ethyl acetate. The combined extract was washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (25-100% ethyl acetate / heptane) to obtain the title compound (diastereomer ratio 1.8:1.0, 263 mg, 48%) as a colorless oil. 1H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.14(m,2H),0.45-0.54(m,2H),0.74 -0.93(m,2H),1.01-1.36(m,3.6H),1.42-1.71(m,5.4H),1.78-1.84(m,0. 6H),1.90-2.22(m,4.4H),2.27-2.39(m,2H),2.50-2.57(m,1H),2.68-3.0 3(m,3H),3.39-3.51(m,1.2H),3.60-3.65(m,0.8H),3.78(s,3H),4.69(br s,1H),6.68(dd,J=2,8Hz,0.6H),6.70(dd,J=2,8Hz,0.4H),6.80(d,J=2Hz, 0.4H),6.91(d,J=2Hz,0.6H),6.97(d,J=8Hz,0.6H),7.00(d,J=8Hz,0.4H).

[0153] (Reference example 4) Synthesis of a diastereomer mixture (1.6:1.0) of (benzoyloxy)(3-((4bS,6S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)propyl) tert-butyl carbamate and (benzoyloxy)(3-((4bS,6R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)propyl) tert-butyl carbamate

[0154] [ka] tert-butyl (benzoyloxy)(3-((4bS,6S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)propyl)carbamate

[0155] [ka] tert-butyl (benzoyloxy)(3-((4bS,6R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)propyl)carbamate

[0156] To a tetrahydrofuran:toluene = 1:1 (v / v, 3.4 mL) mixed solution of the compound obtained in Reference Example 3 (263 mg, 0.682 mmol) was mixed with tert-butyl (benzoyloxy)carbamate (196 mg, 0.826 mmol), triphenylphosphine (212 mg, 0.808 mmol), and a 1.9 M azodicarboxylic acid diisopropyl-toluene solution (0.43 mL, 0.82 mmol). The mixture was stirred at room temperature for 16.5 hours. The reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (20-100% ethyl acetate / heptane) to obtain the title compound (diastereomer ratio 1.6:1.0, 242 mg, 59%) as a colorless amorphous material. 1H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.15(m,2H),0.45-0.53(m,2H),0.74-0.95(m,2H),1.01-1.15(m,1.6H),1.27-1.71 (m,16.4H),1.82-2.17(m,5H),2.26-2.39(m,2H),2.49-2.57(m,1H),2.67-3.01(m,3H),3.45-3.49(m,1.2H),3.65-3.69 (m,0.8H),3.72(s,1.8H),3.74(s,1.2H),6.64(dd,J=2,8Hz,0.6H),6.68(dd,J=2,8Hz,0.4H),6.75(d,J=2Hz,0.4H),6.8 7(d,J=2Hz,0.6H),6.93(d,J=8Hz,0.6H),6.98(d,J=8Hz,0.4H),7.44-7.49(m,2H),7.59-7.63(m,1H),8.04-8.08(m,2H).

[0157] (Reference example 5) Synthesis of a diastereomer mixture (1.7:1.0) of (4bS,6S,8aS,9R)-6-(3-((benzoyloxy)amino)propyl)-11-(cyclopropylmethyl)-3-methoxy-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoetano)phenanthrene-8a-ol and (4bS,6R,8aS,9R)-6-(3-((benzoyloxy)amino)propyl)-11-(cyclopropylmethyl)-3-methoxy-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoetano)phenanthrene-8a-ol

[0158] [ka] (4bS,6S,8aS,9R)-6-(3-((benzoyloxy)amino)propyl)-11-(cyclopropylmethyl)-3-methoxy-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoethano)phenanthren-8a-ol

[0159] [ka] (4bS,6R,8aS,9R)-6-(3-((benzoyloxy)amino)propyl)-11-(cyclopropylmethyl)-3-methoxy-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoethano)phenanthren-8a-ol

[0160] To a chloroform (1 mL) solution of the compound obtained in Reference Example 4 (242 mg, 0.400 mmol), trifluoroacetic acid (1 mL) was added under ice cooling and stirred at room temperature for 1.5 hours. The reaction mixture was added to saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate. The combined extract was washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (20-100% ethyl acetate / heptane) to obtain the title compound (diastereomer ratio 1.7:1.0, 195 mg, 97%) as a colorless oil. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.14(m,2H),0.45-0.54(m,2H),0.74-0.98(m,2H),1.03-1.18(m,1.6H),1.26-1.71(m,7. 6H),1.82-2.21(m,4.8H),2.26-2.39(m,2H),2.50-2.56(m,1H),2.72-3.02(m,4.4H),3.10-3.15(m,0.6H),3.74(s,1.2H),3.76 (s,1.8H),6.66(dd,J=2,8Hz,0.6H),6.69(dd,J=2,8Hz,0.4H),6.77(d,J=2Hz,0.4H),6.91(d,J=2Hz,0.6H),6.95(d,J=8Hz,0. 6H),6.99(d,J=8Hz,0.4H),7.43-7.49(m,2H),7.52-7.60(m,1H),7.75-7.78(m,0.6H),7.86-7.90(m,0.4H),7.99-8.03(m,2H).

[0161] (Example 1) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol

[0162] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-8a'-ol

[0163] To a solution of the compound obtained in Reference Example 5 (195 mg, 0.386 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (4 mL), bis[rhodium(α,α,α',α'-tetramethyl-1,3-benzenedipropionic acid)] (14.6 mg, 0.0192 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was added to 1N sodium hydroxide aqueous solution and extracted four times with ethyl acetate. The combined extract was washed with saturated saline solution, 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, 10-100% methanol / ethyl acetate) to obtain the title compound (78.3 mg, 53%) as a light brown oily substance. 1H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.12(m,2H),0.46-0.53(m,2H),0.77-0.87(m,1H), 1.02(ddd,J=5,8,12Hz,1H),1.08-1.12(m,1H),1.36(ddd,J=8,8,12Hz,1H),1.47-1.50(m ,2H),1.54-1.95(m,5H),2.04-2.12(m,3H),2.30(dd,J=7,12Hz,1H),2.37(dd,J=7,12Hz, 1H),2.51-2.55(m,1H),2.80(dd,J=6,18Hz,1H),2.92-2.98(m,4H),3.77(s,3H),4.64(br s,1H),6.69(dd,J=2,8Hz,1H),6.88(d,J=2Hz,1H),6.98(d,J=8Hz,1H).

[0164] (Example 2) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one

[0165] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H- spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

[0166] To a solution of the compound obtained in Example 1 (9.3 mg, 0.024 mmol) and 2-(4-methyl-1H-pyrazole-1-yl)acetic acid (10.1 mg, 0.0721 mmol) in N,N-dimethylformamide (0.8 mL), N,N-diisopropylethylamine (24.5 μL, 0.141 mmol) and HATU (18.5 mg, 0.0487 mmol) were added, and the mixture was stirred at room temperature for 88 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and it was extracted three times with ethyl acetate. The combined extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (chloroform:2M ammonia-methanol solution = 96:4, twice) to obtain the title compound (6.5 mg, 53%) as a colorless oil. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.11(m,2H),0.42-0.52(m,2H),0.74-0.84(m,1H),1.01-1.28(m,3H),1.39-1.95(m,7H) ),2.08(s,3H),2.13-2.38(m,3H),2.50-3.01(m,4H),3.26(ddd,J=5,13,13Hz,1H),3.42-3.65(m,3H),3.78(s,3H),4.52(br s,1H),4.78(d,J=16Hz,0.9H),4.84(d,J=16Hz,0.9H),5.21(d,J=16Hz,0.1H ),5.43(d,J=16Hz,0.1H),6.69(dd,J=2,8Hz,0.9H),6.72(dd,J=2,8Hz,0.1H) ,6.86(d,J=2Hz,0.9H),6.87(d,J=2Hz,0.1H),6.98(d,J=8Hz,0.9H),7.01(d ,J=8Hz,0.1H),7.31(s,0.9H),7.35(s,0.1H),7.38(s,0.9H),7.44(s,0.1H).

[0167] (Example 3) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one

[0168] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spi ro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

[0169] To a solution of the compound obtained in Example 2 (6.5 mg, 0.013 mmol) in dichloromethane (1 mL), 0.080 mL, 0.080 mmol, 1 M boron tribromide-dichloromethane solution was added under ice cooling, and the mixture was stirred at room temperature for 16.5 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and it was extracted three times with ethyl acetate. The combined extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (chloroform:2 M ammonia-methanol solution = 95:5, 3 times) to obtain the title compound (3.6 mg, 57%) as a colorless oil. 1H-NMR(400MHz,CDCl3)δ(ppm):0.02-0.12(m,2H),0.42-0.51(m,2H),0.72-0.82(m,1H),1.00-1.28(m,3H),1.43-1.97(m,7H), 2.07-2.15(m,4H),2.23-2.39(m,2H),2.47-2.53(m,1H),2.65-2.98(m,3.2H),3.15-3.20(m,0.8H),3.39-3.70(m,3H),4.54(br s,0.8H),4.70(br s,0.2H),4.78(d,J=16Hz,0.8H),4.85(d,J=16Hz,0.8H),5.20(d,J=16Hz,0.2 H),5.45(d,J=16Hz,0.2H),6.62(dd,J=2,8Hz,0.8H),6.66(dd,J=2,8Hz,0.2H ),6.81(d,J=2Hz,0.8H),6.84(d,J=2Hz,0.2H),6.89(d,J=8Hz,0.8H),6.92(d ,J=8Hz,0.2H),7.25(s,0.2H),7.31(s,0.8H),7.38(s,0.8H),7.41(s,0.2H).

[0170] (Example 4) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(4-methyl-1H-pyrazole-1-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol

[0171] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-7' ,8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-8a'-ol

[0172] To a solution of the compound obtained in Example 1 (10.3 mg, 0.0269 mmol) and 2-(4-methyl-1H-pyrazole-1-yl)ethyl methanesulfonic acid (synthesized by the method described in WO2021065898, 16.6 mg, 0.0813 mmol) in acetonitrile (1 mL), N,N-diisopropylethylamine (27.4 μL, 0.157 mmol) was added and the mixture was stirred at 75°C for 19.5 hours. After cooling to room temperature, saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted three times with ethyl acetate. The combined extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (chloroform:2M ammonia-methanol solution = 95:5, twice) to obtain the title compound (4.5 mg, 34%) as a colorless oil. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.13(m,2H),0.44-0.53(m,2H),0.76-0.86(m,1H), 1.05-1.12(m,3H),1.41-1.48(m,2H),1.53-1.79(m,4H),1.85-2.08(m,7H),2.27(dd,J= 6,13Hz,1H),2.37(dd,J=6,13Hz,1H),2.50-2.53(m,1H),2.62(ddd,J=6,10,10Hz,1H),2 .76-2.98(m,5H),3.17(ddd,J=8,8,12Hz,1H),3.77(s,3H),4.16(t,J=8Hz,2H),4.55(br s,1H),6.68(dd,J=2,8Hz,1H),6.87(d,J=2Hz,1H),6.96(d,J=8Hz,1H),7.25(s,1H),7.30(s,1H).

[0173] (Example 5) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(4-methyl-1H-pyrazole-1-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0174] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-7',8',9',1 0'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0175] The title compound was obtained from the compound obtained in Example 4 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.13(m,2H),0.45-0.52(m,2H),0.76-0.85 (m,1H),1.03-1.12(m,3H),1.41-1.67(m,6H),1.81-1.94(m,2H),1.99-2.05(m,2 H),2.09(s,3H),2.27(dd,J=6,13Hz,1H),2.37(dd,J=6,13Hz,1H),2.50-2.58(m, 2H),2.74-2.99(m,5H),3.24(ddd,J=8,8,12Hz,1H),4.20(t,J=8Hz,2H),4.55(br s,1H),6.61(dd,J=3,8Hz,1H),6.88(d,J=3Hz,1H),6.90(d,J=8Hz,1H),7.26(s,1H),7.31(s,1H).

[0176] (Example 6) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-(pyridine-2-yl)ethane-1-one

[0177] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5' H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(pyridin-2-yl)ethan-1-one

[0178] The title compound was obtained from the compound obtained in Example 1 and 2-(pyridine-2-yl) acetate hydrochloride according to the method described in Example 2. 1H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.10(m,2H),0.43-0.50(m,2H),0.75-0.85(m,1H),1.02 -1.25(m,3H),1.47-1.72(m,5H),1.81-1.91(m,2H),2.08-2.39(m,3H),2.51-2.55(m,1H),2. 76-2.84(m,1H),2.91-2.99(m,2H),3.32(ddd,J=5,13,13Hz,1H),3.46-3.68(m,3H),3.77(s, 2.7H),3.79(s,0.3H),3.84(s,1.8H),4.33(d,J=15Hz,0.1H),4.39(d,J=15Hz,0.1H),4.55(br s,0.9H),4.68(br s,0.1H),6.68(dd,J=2,8Hz,0.9H),6.71(dd,J=2,8Hz,0.1H),6.86(d,J=2Hz,0.9H),6.88(d,J=2Hz,0.1H),6.98(d,J=8Hz,0.9H),7.00(d, J=8Hz,0.1H),7.12-7.17(m,1H),7.40-7.42(m,0.1H),7.46-7.48(m,0.9H),7.61-7.67(m,1H),8.51-8.53(m,0.9H),8.56-8.58(m,0.1H).

[0179] (Example 7) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-2-yl)ethane-1-one

[0180] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7 'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(pyridin-2-yl)ethan-1-one

[0181] The method described in Example 3 was obtained, and the compound was obtained in Example 6. The title compound was obtained. 1 H-NMR (400MHz, CDCl3) δ (ppm): 0.04-0.10 (m, 2H), 0.42-0.51 (m, 2H), 0.75-0.84 (m, 1H ),1.07-1.30(m,3H),1.46-1.78(m,7H),1.84-2.55(m,5H),2.73-2.98(m,3.4H),3.18 (ddd,J=4,13,13Hz,0.8H),3.43-3.49(m,0.8H),3.58-3.70(m,2H),3.82(d,J=15Hz,0 .8H),3.87(d,J=15Hz,0.8H),4.32(d,J=15Hz,0.2H),4.42(d,J=15Hz,0.2H),4.55(br s,0.8H),4.71(br s,0.2H),6.60(dd,J=2,8Hz,0.8H),6.68(dd,J=2,8Hz,0.2H),6.77(d,J=2Hz,0. 8H),6.89(d,J=8Hz,0.8H),6.93-6.95(m,0.4H),7.01-7.04(m,0.2H),7.15-7.1 8(m,0.8H),7.37(d,J=8Hz,0.2H),7.47(d,J=8Hz,0.8H),7.56(ddd,J=2,7,7Hz, 0.2H),7.65(ddd,J=2,7,7Hz,0.8H),8.26-8.27(m,0.2H),8.50-8.51(m,0.8H).

[0182] (Example 8) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridine-2-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0183] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridin-2-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0184] To a solution of the compound obtained in Example 6 (12.7 mg, 0.0253 mmol) in tetrahydrofuran (2 mL), 0.9 M boranetetrahydrofuran complex-tetrahydrofuran solution (0.28 mL, 0.25 mmol) was added and the mixture was heated under reflux for 21 hours. After cooling to room temperature, 2 M hydrochloric acid (1 mL) was added and the mixture was stirred at 85°C for 30 minutes. After cooling to room temperature, the reaction mixture was added to saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate. The combined extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To a solution of the resulting colorless oily substance (9.2 mg) in dichloromethane (1.2 mL), 1 M boron tribrominated-dichloromethane solution (0.10 mL, 0.10 mmol) was added under ice cooling and the mixture was stirred at room temperature for 4.5 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted three times with ethyl acetate. The combined extracts were washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (chloroform:2M ammonia-methanol solution = 94:6, twice) to obtain the title compound (3.4 mg, 28%) as a colorless oil. 1H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.11(m,2H),0.44-0.52(m,2H),0.75-0.84 (m,1H),1.02-1.15(m,3H),1.37-1.63(m,5H),1.86-1.96(m,2H),2.04-2.17(m,3 H),2.27(dd,J=6,12Hz,1H),2.36(dd,J=6,12Hz,1H),2.50-2.58(m,2H),2.72-2 .80(m,2H),2.89(d,J=5Hz,1H),2.92(d,J=17Hz,1H),3.10-3.27(m,4H),4.58(br s,1H),6.64(dd,J=2,8Hz,1H),6.87(d,J=8Hz,1H),7.01(d,J=2Hz,1H),7.12- 7.15(m,1H),7.26-7.28(m,1H),7.63(ddd,J=2,8,8Hz,1H),8.55-8.56(m,1H).

[0185] (Reference example 6) Synthesis of tert-butyl 3-(4-methyl-1H-pyrazole-1-yl)propanoate

[0186] [ka] tert-butyl 3-(4-methyl-1H-pyrazol-1-yl)propanoate

[0187] To a solution of 4-methylpyrazole (211 mg, 2.57 mmol) in acetonitrile (2 mL), tert-butyl acrylate (0.56 mL, 3.8 mmol) and DBU (192 μL, 1.27 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (12-45% ethyl acetate / heptane) to obtain the title compound (472 mg, 87%) as a colorless liquid. 1H-NMR(400MHz,CDCl3)δ(ppm):1.42(s,9H),2.05(s,3H),2.77(t,J=7Hz,2H),4.31(t,J=7Hz,2H),7.19(s,1H),7.29(s,1H).

[0188] (Reference example 7) Synthesis of 3-(4-methyl-1H-pyrazole-1-yl)propanoic acid

[0189] [ka] 3-(4-methyl-1H-pyrazol-1-yl)propanoic acid

[0190] The compound obtained in Reference Example 6 (472 mg, 2.24 mmol) was dissolved in chloroform (4 mL), cooled to 0°C, and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 17.5 hours, and the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the resulting residue, and 1N hydrochloric acid was added to adjust the pH to 4. The mixture was then extracted three times with a chloroform:2-propanol = 4:1 (v / v) mixed solution. The combined extract was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (218 mg, 63%) as pale yellow crystals. 1 H-NMR(400MHz,CDCl3)δ(ppm):2.06(s,3H),2.93(t,J=6Hz,2H),4.36(t,J=6Hz,2H),7.22(s,1H),7.34(s,1H).

[0191] (Example 9) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one

[0192] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H- spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(4-methyl-1H-pyrazol-1-yl)propan-1-one

[0193] The title compound was obtained from the compound obtained in Example 1 and the compound obtained in Reference Example 7, according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.12(m,2H),0.45-0.51(m,2H),0.77-0.87(m,1H),1.03-1.08 (m,2H),1.17-1.32(m,1H),1.48-1.71(m,5H),1.83-1.90(m,2H),2.05(s,3H),2.21(ddd,J=5,12,1 2Hz,1H),2.28(dd,J=6,12Hz,1H),2.38(dd,J=6,12Hz,1H),2.52-2.56(m,1H),2.71-2.83(m,3H),2 .92-2.97(m,2H),3.22-3.33(m,3H),3.41(d,J=14Hz,1H),3.77(s,3H),4.37-4.51(m,2H),4.66(br s,1H),6.68(dd,J=3,8Hz,1H),6.85(d,J=3Hz,1H),6.98(d,J=8Hz,1H),7.29(s,1H),7.32(s,1H).

[0194] (Example 10) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one

[0195] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spi ro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(4-methyl-1H-pyrazol-1-yl)propan-1-one

[0196] The title compound was obtained from the compound obtained in Example 9 according to the method described in Example 3. 1H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.12(m,2H),0.45-0.51(m,2H),0.76-0.86(m,1H),1.03-1 .09(m,2H),1.20-1.28(m,1H),1.47-1.69(m,5H),1.79-1.96(m,2H),2.05(s,3H),2.20(ddd,J= 5,13,13Hz,1H),2.28(dd,J=6,13Hz,1H),2.37(dd,J=6,13Hz,1H),2.52-2.56(m,1H),2.71-2.8 4(m,3H),2.91-2.95(m,2H),3.20-3.27(m,3H),3.46(d,J=14Hz,1H),4.37-4.50(m,2H),4.65(br s,1H),5.11(br s,1H),6.60(dd,J=2,8Hz,0.9H),6.63(dd,J=2,8Hz,0.1H),6.75(d,J=2Hz, 0.1H), 6.79(d,J=2Hz,0.9H),6.92(d,J=8Hz,1H),7.29(s,1H),7.31(s,1H).

[0197] (Example 11) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-(4-methyl-1H-pyrazole-1-yl)propyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol

[0198] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-(4-methyl-1H-pyrazol-1-yl)propyl)-7',8',9',1 0'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0199] The title compound was obtained from the compound obtained in Example 9 according to the method described in Example 8. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.13(m,2H),0.47-0.51(m,2H),0.76- 0.86(m,1H),0.99-1.07(m,2H),1.13-1.16(m,1H),1.30-1.62(m,6H),1.81 -2.23(m,9H),2.28(dd,J=6,13Hz,1H),2.34-2.40(m,3H),2.51-2.55(m,1H ),2.74-2.95(m,4H),3.05(ddd,J=4,9,9Hz,1H),4.14-4.26(m,2H),4.61(br s,1H),6.62(dd,J=2,8Hz,1H),6.87(d,J=8Hz,1H),7.00(d,J=2Hz,1H),7.23(s,1H),7.32(s,1H).

[0200] (Example 12) Synthesis of (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(furan-3-yl)prop-2-en-1-one

[0201] [ka] (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5 'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(furan-3-yl)prop-2-en-1-one

[0202] The title compound was obtained from the compound obtained in Example 1 and (E)-3-(furan-3-yl)acrylic acid according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.07-0.16(m,2H),0.47-0.57(m,2H),0.80-0.90(m,1 H),1.03-1.33(m,2H),1.37-1.47(m,1H),1.57-1.79(m,4.6H),1.83-1.95(m,1.7H), 2.10(ddd,J=5,13,13Hz,1H),2.20-2.45(m,3H),2.54-2.58(m,1H),2.68(d,J=14Hz, 0.7H),2.76-2.89(m,2H),2.93-3.06(m,2H),3.39-3.74(m,2H),3.79(s,3H),4.59(br s,0.3H),4.77(br s,0.7H),6.47(d,J=15Hz,0.3H),6.56-6.57(m,0.3H),6.68-6.73(m,1H),6.8 7-6.89(m,1.7H),6.98-7.03(m,1H),7.41-7.44(m,1.7H),7.56-7.66(m,2H).

[0203] (Example 13) Synthesis of (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(furan-3-yl)prop-2-en-1-one

[0204] [ka] (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H, 7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(furan-3-yl)prop-2-en-1-one

[0205] The title compound was obtained from the compound obtained in Example 12 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.14(m,2H),0.44-0.56(m,2H),0.77-0.90(m,1 H),0.95-1.08(m,1H),1.35-1.80(m,7H),1.83-1.97(m,2H),2.18-2.29(m,2.6H),2. 33-2.41(m,1H),2.46-2.49(m,0.2H),2.58(d,J=14Hz,0.8H),2.73-2.81(m,2H),2.9 0-3.01(m,2H),3.16-3.24(m,0.2H),3.47-3.52(m,0.2H),3.62-3.84(m,2H),4.61(br s,0.2H),4.69(br s,0.8H),6.42(d,J=15Hz,0.2H),6.54-6.55(m,0.2H),6.63-6.77(m,2.6H),6.92(d,J=8Hz,1H),7.35-7.62(m,4H).

[0206] (Example 14) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)propan-1-one

[0207] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5' H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(pyridin-2-yl)propan-1-one

[0208] The title compound was obtained from the compound obtained in Example 1 and 3-(pyridine-2-yl)propanoic acid according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.17(m,2H),0.45-0.51(m,2H),0.76-0.86(m,1H),1.02-1.09(m, 2H),1.18-1.34(m,2H),1.47-1.72(m,5H),1.82-1.89(m,2H),2.21(ddd,J=5,13,13Hz,1H),2.28(dd,J= 6,12Hz,1H),2.37(dd,J=6,12Hz,1H),2.44-2.56(m,1H),2.69-2.82(m,3H),2.92-2.97(m,2H),3.10-3 .24(m,2H),3.31(ddd,J=5,13,13Hz,1H),3.37-3.40(m,1H),3.47(d,J=14Hz,1H),3.77(s,3H),4.60(br s,1H),6.68(dd,J=2,8Hz,1H),6.80(d,J=2Hz,0.1H),6.87(d,J=2Hz,0.9H),6.98(d,J=8Hz ,1H),7.08-7.11(m,1H),7.26-7.28(m,1H),7.57(ddd,J=2,8,8Hz,1H),8.51(d,J=4Hz,1H).

[0209] (Example 15) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)propan-1-one

[0210] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7 'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(pyridin-2-yl)propan-1-one

[0211] The title compound was obtained from the compound obtained in Example 14 according to the method described in Example 3. 1H-NMR (400MHz, CDCl3) δ (ppm): 0.04-0.11 (m, 2H), 0.44-0.50 (m, 2H), 0.76-0.86 (m, 1H),1.03-1.09(m,2H),1.21-1.33(m,2H),1.38-1.69(m,4H),1.81-1.95(m,2H),2. 11-2.31(m,2H),2.37(dd,J=6,12Hz,1H),2.49-2.55(m,1H),2.61-2.80(m,3H),2.9 0-2.96(m,2H),3.09-3.27(m,3H),3.31-3.42(m,2H),3.54(d,J=13Hz,1H),4.57(br s,0.1H),4.59(br s,0.9H),6.61(dd,J=2,8Hz,0.9H),6.67(dd,J=2,8Hz,0.1H),6.81(d,J=2Hz,0.9H),6.82(d,J=2Hz,0.1H),6.91(d ,J=8Hz,0.9H),6.93(d,J=8Hz,0.1H),7.06-7.12(m,1H),7.26-7.28(m,1H),7.53-7.61(m,1H),8.50-8.52(m,1H).

[0212] (Refer to Example 8) (4R,4aS,7aS,12bS)-7-シクロプロピリデン-3-(シクロプロピルメチル)-9-メトキシ-1,2,3, 4,5,6,7,7a-オクタヒドロ-4aH-4,12-メタノベンゾフロ[3,2-e]イソキノリン-4a-オールの synthesis

[0213]

change

[0214] To a 30 mL solution of cyclopropyltriphenylphosphonium bromide (5.21 g, 13.6 mmol) in tetrahydrofuran, sodium hydride (55% oil dispersion, 595 mg, 13.6 mmol) was added under ice cooling and stirred at room temperature for 30 minutes. Then, a 10 mL solution of (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzoflo[3,2-e]isoquinoline-7(7aH)-one (synthesized by the method described in Organic Letters 2009, 11, 539, 3.85 g, 10.8 mmol) in tetrahydrofuran was added and heated under reflux for 20 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (amino group-supported silica gel, 10-40% ethyl acetate / heptane) to obtain the title compound (2.70 g, 66%) as a colorless oil.

[0215] 1 H-NMR(400MHz,CDCl3)δ(ppm):0.08-0.17(m,2H),0.49-0.57(m,2H),0.75-0 .91(m,3H),1.19-1.30(m,2H),1.37(ddd,J=5,13,13Hz,1H),1.52-1.66(m,2H ),2.17(ddd,J=4,12,12Hz,1H),2.24-2.34(m,2H),2.37(d,J=7Hz,2H),2.54 -2.70(m,3H),3.03(d,J=18Hz,1H),3.07(d,J=6Hz,1H),3.86(s,3H),5.09(br s,1H),5.17(s,1H),6.56(d,J=8Hz,1H),6.68(d,J=8Hz,1H).

[0216] (Reference example 9) Synthesis of (4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-7-(1-hydroxycyclopropyl)-9-methoxy-1,2,3,4,5,6,7,7a-octahydro-4aH-4,12-methanobenzoflo[3,2-e]isoquinoline-4a,7-diol

[0217] [ka] (4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-7-(1-hydroxycyclopropyl)-9-methoxy-1,2,3,4,5,6,7,7a-octahydro-4aH-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diol

[0218] To a 70 mL solution of the compound obtained in Reference Example 8 (2.70 g, 7.11 mmol) in acetone, water (24 mL), acetic acid (1.00 mL, 17.5 mmol), N-methylmorpholine N-oxide (1.67 g, 14.2 mmol), and osmium tetroxide (4% aqueous solution, 1.81 g, 285 μmol) were added and the mixture was stirred at room temperature for 16 hours. Saturated sodium thiosulfate aqueous solution (20 mL) was added to the reaction mixture and stirred at room temperature for 30 minutes, then saturated sodium bicarbonate aqueous solution was added and the mixture was extracted three times with chloroform. The combined extract 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, 30-60% ethyl acetate / heptane) to obtain the title compound (1.88 g, 64%) as a white solid. 1H-NMR(400MHz,CDCl3)δ(ppm):0.08-0.17(m,2H),0.51-0.58(m,2H),0.59-0.73(m,2H ),0.75-0.94(m,3H),1.46-1.56(m,2H),1.58-1.72(m,2H),1.74-1.88(m,1H),2.19-2 .43(m,4H),2.64-2.73(m,2H),3.07(d,J=18Hz,1H),3.19(d,J=6Hz,1H),3.56(s,1H), 3.83(s,3H),4.62(d,J=2Hz,1H),5.38(s,1H),6.63(d,J=8Hz,1H),6.73(d,J=8Hz,1H).

[0219] (Example 16) Synthesis of (1S,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-2-one

[0220] [ka] (1S,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6' -hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-2-one

[0221] To a chloroform (30 mL) solution of the compound obtained in Reference Example 9 (1.88 g, 4.55 mmol), boron trifluoride diethyl ether complex (4.03 mL, 31.8 mmol) was added and the mixture was stirred at room temperature for 17 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted three times with chloroform. The combined extract was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was recrystallized in a mixed solvent of heptane / diethyl ether / ethyl acetate (1 / 1 / 1) to obtain the title compound (1.25 g, 69%) as a white solid. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.07-0.17(m,2H),0.49-0.56(m,2H),0.78-0.89(m, 1H),1.28-1.45(m,3H),1.48-1.64(m,2H),1.87-1.97(m,1H),2.09(ddd,J=4.12,12 ,1H),2.17-2.28(m,2H),2.30-2.42(m,2H),2.56-2.68(m,2H),2.84-2.95(m,1H),3 .00-3.12(m,3H),3.89(s,3H),4.88(s,1H),6.63(d,J=8Hz,1H),6.73(d,J=8Hz,1H).

[0222] (Example 17) Synthesis of (2S,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-5-one

[0223] [ka] (2S,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6' -hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-5-one

[0224] To a solution of the compound obtained in Example 16 (123 mg, 0.311 mmol) in tetrahydrofuran (4 mL), water (0.8 mL), ethanol (4 mL), and hydroxylamine hydrochloride (108 mg, 1.55 mmol) were added and the mixture was stirred at 50°C for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted three times with chloroform. The combined extract was dried over sodium sulfate and concentrated under reduced pressure. The resulting concentrated residue was dissolved in tetrahydrofuran (4 mL), and triethylamine (100 μL, 0.717 mmol), 2-mesitylene sulfonyl chloride (81 mg, 0.37 mmol), and sodium hydride (55% oil dispersion, 20 mg, 0.46 mmol) were added and the mixture was stirred at room temperature for 10 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted three times with chloroform. The combined extract was dried over sodium sulfate and concentrated under reduced pressure. The concentrated residue was mixed with chloroform (6 mL) and 2 M hydrochloric acid (6 mL) and stirred at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted three times with chloroform. The combined extract 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, 50-85% ethyl acetate / heptane) to obtain the title compound (50.0 mg, 39%) as a colorless amorphous material. 1H-NMR(400MHz,CDCl3)δ(ppm):0.08-0.17(m,2H),0.51-0.59(m,2H),0.78-0.91(m,1H ),1.08-1.19(m,1H),1.42-1.62(m,3H),1.70-1.87(m,2H),2.15-2.29(m,2H),2.30-2. 41(m,4H),2.44-2.54(m,1H),2.60-2.71(m,2H),3.05(d,J=18Hz,1H),3.14(d,J=6Hz, 1H),3.87(s,3H),4.32(d,J=2Hz,1H),6.59(d,J=8Hz,1H),6.73(d,J=8Hz,1H),7.86(br s,1H).

[0225] (Example 18) Synthesis of (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-9'-methoxy-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a'-ol

[0226] [ka] (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-9'-methoxy-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-4a'-ol

[0227] To a solution of the compound obtained in Example 17 (67 mg, 0.16 mmol) in tetrahydrofuran (3 mL), a 0.9 M borane-tetrahydrofuran complex tetrahydrofuran solution (2.90 mL, 2.61 mmol) was added and the mixture was heated under reflux for 3 hours. After the reaction mixture cooled to room temperature, it was concentrated under reduced pressure. 2 M hydrochloric acid (2.0 mL) was added to the concentrated residue and the mixture was stirred at 70°C for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted three times with chloroform. The combined extract 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, 0-2% methanol / ethyl acetate) to obtain the title compound (44.8 mg, 69%) as a colorless oil. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.08-0.16(m,2H),0.49-0.57(m,2H),0.79-0.91(m, 1H),1.08-1.19(m,1H),1.23-1.35(m,1H),1.41-1.56(m,3H),1.69-1.91(m,3H),2. 03-2.12(m,1H),2.15-2.43(m,4H),2.58-2.69(m,2H),2.98-3.08(m,3H),3.14(d,J =6Hz,1H),3.87(s,3H),4.35(d,J=2Hz,1H),6.56(d,J=8Hz,1H),6.71(d,J=8Hz,1H).

[0228] (Example 19) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one

[0229] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H -spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-3-(4-methyl-1H-pyrazol-1-yl)propan-1-one

[0230] The title compound was obtained from the compound obtained in Example 18 and 3-(4-methyl-1H-pyrazole-1-yl)propanoate salt according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.17(m,2H),0.45-0.58(m,2H),0.78-0.90(m,1H),1.03-1.14(m,2H),1.23-1 .43(m,2H),1.50-1.67(m,2H),1.72-1.82(m,1H),1.84-1.96(m,1H),2.05(s,3H),2.09(dd,J=4,12Hz,1H),2.30-2 .49(m,3H),2.52-2.78(m,3H),2.81-2.91(m,1H),3.02(d,J=18Hz,1H),3.07(d,J=6Hz,1H),3.18-3.29(m,2H),3.3 9-3.48(m,1H),3.86(s,3H),4.36-4.52(m,2H),5.65(s,1H),6.60(d,J=8Hz,1H),6.71(d,J=8Hz,1H),7.29(s,2H).

[0231] (Example 20) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one

[0232] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-sp iro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-3-(4-methyl-1H-pyrazol-1-yl)propan-1-one

[0233] The title compound was obtained from the compound obtained in Example 19 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.18(m,2H),0.44-0.58(m,2H),0.78-0.89(m,1H),1.04-1.14(m,2H),1.27-1. 41(m,2H),1.50-1.68(m,2H),1.71-1.93(m,2H),2.04(s,3H),2.06-2.14(m,1H),2.30-2.48(m,3H),2.55(dd,J=6,1 8Hz,1H),2.65(dd,J=4,12Hz,1H),2.72-2.92(m,2H),3.00(d,J=18Hz,1H),3.07(d,J=6Hz,1H),3.17-3.28(m,2H),3 .35-3.44(m,1H),4.36-4.52(m,2H),5.65(s,1H),6.54(d,J=8Hz,1H),6.70(d,J=8Hz,1H),7.28(s,1H),7.30(s,1H).

[0234] (Example 21) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-3-yl)ethane-1-one

[0235] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5' H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(pyridin-3-yl)ethan-1-one

[0236] The title compound was obtained from the compound obtained in Example 1 and 2-(pyridine-3-yl) acetate hydrochloride according to the method described in Example 2. 1H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.13(m,2H),0.44-0.53(m,2H),0.75-0. 88(m,1H),1.03-1.28(m,3H),1.38-1.75(m,5H),1.81-2.10(m,2H),2.16-2.43 (m,3H),2.51-2.58(m,1H),2.68-3.09(m,3H),3.32(ddd,J=5,13,13Hz,0.8H) ,3.45-3.81(m,7.8H),4.05(d,J=15Hz,0.2H),4.26(d,J=15Hz,0.2H),4.58(br s,0.8H),4.73(br s,0.2H),6.68(dd,J=3,9Hz,0.8H),6.71(dd,J=3,9Hz,0.2H),6.84(d,J=3Hz,0.2H),6.86(d,J=3Hz,0.8H),6.98(d,J=9Hz,0.8H) ,7.01(d,J=9Hz,0.2H),7.24-7.30(m,1H),7.73-7.75(m,0.8H),7.94-7.96(m,0.2H),8.43-8.55(m,1.8H),8.72-8.73(m,0.2H).

[0237] (Example 22) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-3-yl)ethane-1-one

[0238] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7 'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(pyridin-3-yl)ethan-1-one

[0239] The title compound was obtained from the compound obtained in Example 21 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.15(m,2H),0.44-0.53(m,2H),0.76-0.88(m ,1H),1.00-1.32(m,3H),1.46-1.73(m,5H),1.82-1.98(m,2H),2.14-2.43(m,3H),2 .50-2.59(m,1H),2.67-2.84(m,1H),2.90-3.01(m,2H),3.25(ddd,J=5,13,13Hz,0 .7H),3.39-3.74(m,4.7H),4.08(d,J=15Hz,0.3H),4.23(d,J=15Hz,0.3H),4.56(br s,0.7H),4.73(br s,0.3H),5.37(br s,1H),6.61(dd,J=2,8Hz,0.7H),6.65(dd,J=2,8Hz,0.3H),6.79(d,J=2Hz,0.7H),6.82(d,J=2Hz,0.3H),6.92(d,J=8Hz,0.7H), 6.95(d,J=8Hz,0.3H),7.21-7.29(m,1H),7.74-7.77(m,0.7H),7.93-7.95(m,0.3H),8.45-8.50(m,1.7H),8.71-8.72(m,0.3H).

[0240] (Example 23) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-4-yl)ethane-1-one

[0241] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5' H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(pyridin-4-yl)ethan-1-one

[0242] The title compound was obtained from the compound obtained in Example 1 and 2-(pyridine-4-yl) acetate hydrochloride according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.15(m,2H),0.44-0.53(m,2H),0.77-0.88(m,1H),1.03-1.25(m,3H),1.37 -1.75(m,6H),1.82-2.09(m,2H),2.16-2.69(m,4H),2.76-3.09(m,3H),3.29-3.71(m,5H),3.77(s,3H),4.59(br s,0.8H),4.70(br s,0.2H),6.69(dd,J=2,8Hz,0.8H),6.72(dd,J=2,8Hz,0.2H),6.84(d,J=2Hz,0.2H),6.86(d,J=2Hz,0.8H), 6.98(d,J=8Hz,0.8H),7.01(d,J=8Hz,0.2H),7.25-7.26(m,1.6H),7.43-7.45(m,0.4H),8.53-8.59(m,2H).

[0243] (Example 24) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-4-yl)ethane-1-one

[0244] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7 'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(pyridin-4-yl)ethan-1-one

[0245] The title compound was obtained from the compound obtained in Example 23 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.45-0.52(m,2H),0.73-0.88(m,1H),1.00-1.30(m,3H),1.43-1 .77(m,6H),1.84-1.99(m,2H),2.11-2.66(m,4H),2.73-2.82(m,1H),2.89-3.00(m,2H),3.20-3.74(m,5H),4.61(br s,0.7H),4.71(br s,0.3H),6.63(dd,J=2,8Hz,0.7H),6.68(dd,J=2,8Hz,0.3H),6.82-6.85(m,1H),6.89(d,J=8H z,0.7H),6.93(d,J=8Hz,0.3H),7.25-7.27(m,1.4H),7.43-7.45(m,0.6H),8.49-8.52(m,2H).

[0246] (Reference example 10) Synthesis of (E)-3-(pyridine-2-yl)acrylic acid

[0247] [ka] (E)-3-(pyridin-2-yl)acrylic acid

[0248] Malonic acid (5.18 g, 49.8 mmol) was dissolved in pyridine (20 mL), and 2-pyridinecarboxaldehyde (1.80 mL, 18.8 mmol) and piperidine (500 μL, 5.06 mmol) were added. The mixture was stirred at 50°C for 1 hour, and then stirred again at 100°C for 17 hours. After the reaction mixture cooled to room temperature, it was concentrated under reduced pressure. The resulting concentrated residue was suspended in chloroform (12 mL) and stirred for 30 minutes. The insoluble material was then filtered off to obtain the title compound (742 mg, 26%) as a light brown solid. 1 H-NMR(400MHz,CD3OD)δ(ppm):6.84(d,J=16Hz,1H),7.37-7.42(m,1H),7.64-7.69(m,2H),7.67(d,J=16Hz,1H),7.83-7.90(m,1H).

[0249] (Example 25) Synthesis of (E)-1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one

[0250] [ka] (E)-1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1' H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one

[0251] The title compound was obtained from the compound obtained in Example 18 and the compound obtained in Reference Example 10, according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.08-0.17(m,2H),0.47-0.58(m,2H),0.80-0.92(m,1H),1.12-1. 47(m,4H),1.53-2.13(m,5H),2.31-2.72(m,5H),2.94-3.14(m,2H),3.32-3.43(m,1H),3.64-3.87 (m,2H),3.88(s,3H),5.83(s,1H),6.61(d,J=8Hz,1H),6.73(d,J=8Hz,1H),7.19-7.25(m,1H),7. 31-7.35(m,1H),7.37(d,J=15Hz,1H),7.65-7.72(m,1H),7.71(d,J=15Hz,1H),8.60-8.64(m,1H).

[0252] (Example 26) Synthesis of (E)-1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one

[0253] [ka] (E)-1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7 a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one

[0254] The title compound was obtained from the compound obtained in Example 25 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.08-0.16(m,2H),0.48-0.56(m,2H),0.80-0.91(m,1H),1.15-1.44 (m,5H),1.74-2.14(m,4H),2.32-2.71(m,5H),3.02(d,J=18Hz,1H),3.09(d,J=5Hz,1H),3.32-3.43( m,1H),3.65-3.85(m,2H),5.88(s,1H),6.56(d,J=8Hz,1H),6.70(d,J=8Hz,1H),7.21-7.25(m,1H), 7.31-7.36(m,1H),7.40(d,J=15Hz,1H),7.66-7.71(m,1H),7.73(d,J=15Hz,1H),8.60-8.65(m,1H).

[0255] (Example 27) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one

[0256] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H -spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

[0257] The title compound was obtained from the compound obtained in Example 18 and 2-(4-methyl-1H-pyrazole-1-yl)acetic acid according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.13(m,2H),0.44-0.55(m,2H),0.75-0.85(m,1H),1.09-1.21(m,2H),1.24-1.39(m,2H),1 .51-1.58(m,1H),1.69-1.83(m,2H),1.96-2.08(m,2H),2.09(s,3H),2.28-2.43(m,3H),2.56(d,J=6,18Hz,1H),2.63(dd,J=5,1 2Hz,1H),3.01(d,J=18Hz,1H),3.05(d,J=6Hz,1H),3.24(ddd,J=2,14,14Hz,1H),3.40-3.50(m,1H),3.56-3.64(m,1H),3.87(s, 3H),4.80(d,J=16Hz,1H),4.88(d,J=16Hz,1H),5.66(s,1H),6.60(d,J=8Hz,1H),6.72(d,J=8Hz,1H),7.31(s,1H),7.34(s,1H).

[0258] (Example 28) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one

[0259] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-sp iro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

[0260] The title compound was obtained from the compound obtained in Example 27 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.14(m,2H),0.46-0.55(m,2H),0.76-0.86(m,1H),1.10-1.21(m,2H),1 .26-1.37(m,2H),1.51-1.59(m,1H),1.69-1.82(m,2H),1.90-2.08(m,2H),2.09(s,3H),2.28-2.43(m,3H),2. 49-2.68(m,2H),2.99(d,J=18Hz,1H),3.02-3.08(m,1H),3.23(ddd,J=2,14,14Hz,1H),3.40-3.48(m,1H),3. 53-3.61(m,1H),4.87(s,2H),5.68(s,1H),6.55(d,J=8Hz,1H),6.70(d,J=8Hz,1H),7.33(s,1H),7.35(s,1H).

[0261] (Example 29) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyrrolidine-1-yl)propan-1-one

[0262] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H, 7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(pyrrolidin-1-yl)propan-1-one

[0263] The title compound was obtained from the compound obtained in Example 1 and 3-(pyrrolidine-1-yl)propanoic acid according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.02-0.16(m,2H),0.42-0.55(m,2H),0.76-0 .90(m,1H),1.00-1.17(m,1H),1.18-1.30(m,1H),1.40-2.12(m,10.2H),2.1 3-2.45(m,3H),2.46-2.89(m,11.4H),2.90-3.01(m,2H),3.31(ddd,J=5,13, 13Hz,0.8H),3.38-3.50(m,3.4H),3.75-3.79(m,0.2H),3.78(s,3H),4.54(br s,0.8H),4.60(br s,0.2H),6.65-6.71(m,0.2H),6.69(dd,J=3,9Hz,0.8H),6.77(d,J=3Hz,0 .2H),6.88(d,J=3Hz,0.8H),6.98(d,J=9Hz,0.8H),6.99(d,J=9Hz,0.2H).

[0264] (Example 30) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyrrolidine-1-yl)propan-1-one

[0265] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H -spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(pyrrolidin-1-yl)propan-1-one

[0266] The title compound was obtained from the compound obtained in Example 29 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.02-0.16(m,2H),0.42-0.54(m,2H),0.74-0.88(m,1H),1.00-1.08(m,0.8H),1.10-1.19(m,1H) ),1.23-1.34(m,1.2H),1.41-2.02(m,12H),2.12-2.33(m,1.8H),2.36(dd,J=6,13Hz,0.8H),2.37(dd,J=6,12Hz,0.2H),2.46- 2.66(m,6.6H),2.70-3.07(m,2.2H),2.77(dd,J=6,18Hz,0.8H),2.93(d,J=6Hz,0.8H),2.95(d,J=18Hz,0.8H),3.03(ddd,J=5, 12,12Hz,0.2H),3.13-3.24(m,1H),3.30-3.40(m,0.8H),3.42-3.48(m,0.8H),3.49-3.67(m,1H),3.69-3.78(m,0.2H),4.54(br s,0.8H),4.58(br s,0.2H),6.61(dd,J=2,8Hz,0.8H),6.67(dd,J=2,8Hz,0.2H),6.76-6.80(m ,0.8H),6.82(d,J=2Hz,0.2H),6.90(d,J=8Hz,0.8H),6.92(d,J=8Hz,0.2H).

[0267] (Example 31) Synthesis of ((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)(pyridine-2-yl)methanone

[0268] [ka] ((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro- 5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)(pyridin-2-yl)methane

[0269] The title compound was obtained from the compound obtained in Example 1 and picolinic acid according to the method described in Example 2. 1H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.16(m,2H),0.43-0.54(m,2H),0.77-0.88(m,1H),1.06-1.12(m,1H),1.23-1.38(m,2H),1.52-1.82(m ,5H),1.89(ddd,J=4,12,12Hz,1H),2.07-2.13(m,1H),2.19-2.33(m,1H),2.30(dd,J=7,13Hz,1H),2.40(dd,J=6,13Hz,1H),2.52-2.59(m,1 H),2.82(dd,J=5,18Hz,1H),2.97(d,J=18Hz,1H),2.99(dd,J=5Hz,1H),3.44-3.55(m,2H),3.59-3.70(m,2H),3.78(s,3H),6.70(dd,J=2,8H z,1H),6.93(d,J=2Hz,1H),6.99(d,J=8Hz,1H),7.29(ddd,J=1,4,7Hz,1H),7.70-7.74(m,1H),7.77(ddd,J=2,7,8Hz,1H),8.52-8.57(m,1H).

[0270] (Example 32) Synthesis of ((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)(pyridine-2-yl)methanone

[0271] [ka] ((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)(pyridin-2-yl)methanone

[0272] The title compound was obtained from the compound obtained in Example 31 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.41-0.53(m,2H),0.76-0.88(m,1H),1.05-1.13(m,1H),1 .23-1.32(m,1H),1.36(ddd,J=5,5,12Hz,1H),1.52-1.84(m,5H),1.89(ddd,J=4,12,12Hz,1H),2.08-2.15(m ,1H),2.23(ddd,J=5,13,13Hz,1H),2.28(dd,J=6,12Hz,1H),2.38(dd,J=6,12Hz,1H),2.50-2.58(m,1H),2.8 0(dd,J=6,18Hz,1H),2.94(d,J=18Hz,1H),2.97(d,J=6Hz,1H),3.36-3.48(m,2H),3.62-3.72(m,2H),4.61(br s,1H),6.63(dd,J=2,8Hz,1H),6.90-6.94(m,1H),6.92(d,J=8Hz,1H),7.31(ddd, J=1,5,8Hz,1H),7.68-7.73(m,1H),7.79(ddd,J=2,8,8Hz,1H),8.53-8.57(m,1H).

[0273] (Example 33) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinopropan-1-one synthesis

[0274] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro- 5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-morpholinopropane-1-one

[0275] The title compound was obtained from the compound obtained in Example 1 and 3-morpholinopropanoic acid according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.14(m,2H),0.44-0.53(m,2H),0.76-0.87(m,1H),1.02-1.43(m,3H),1.47-1.75(m,5H),1.82 -2.10(m,2H),2.16-2.68(m,10H),2.73-2.86(m,3H),2.91-3.00(m,2H),3.27-3.66(m,4H),3.71-3.76(m,4H),3.78(s,3H),4.56(br s,1H),6.69(dd,J=2,8Hz,0.8H),6.71(dd,J=2,8Hz,0.2H),6.86(d,J=2Hz, 0.2H),6.87(d,J=2Hz,0.8H),6.98(d,J=8Hz,0.8H),7.00(d,J=8Hz,0.2H).

[0276] (Example 34) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinopropan-1-one

[0277] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H ,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-morpholinopropane-1-one

[0278] The title compound was obtained from the compound obtained in Example 33 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.12(m,2H),0.45-0.51(m,2H),0.75-0.87(m,1H),1.03-1.33(m,3H),1.43-1.73 (m,5H),1.82-1.91(m,2H),2.16-2.60(m,10H),2.71-3.07(m,5.3H),3.16-3.23(m,0.7H),3.33-3.74(m,7H),4.54(br s,0.7H),4.56(br s,0.3H),5.60(br s,1H),6.61(dd,J=2,8Hz,0.7H),6.67(dd,J=2,8Hz,0.3H),6.77-6.82(m,1H),6.91(d,J=8Hz,0.7H),6.94(d,J=8Hz,0.3H).

[0279] (Example 35) Synthesis of (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one

[0280] [ka] (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5' H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one

[0281] The method described in Example 2 was used, the compound compound described in Example 1 was obtained, and the compound compound listed in Reference Example 10 was obtained and the compound of the title was obtained. 1 H-NMR (400MHz, CDCl3) δ (ppm): 0.05-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.78-0.90 (m,1H),1.05-1.34(m,3H),1.40-1.81(m,4.6H),1.83-2.13(m,2H),2.21-2.44(m ,3H),2.52-2.58(m,1H),2.71(d,J=14Hz,0.3H),2.79-2.87(m,1.4H),2.94-3.06 (m,2H),3.45(ddd,J=4,13,13Hz,0.7H),3.58-3.76(m,3H),3.79(s,3H),4.61(br s,0.7H),4.80(br s,0.3H),6.70(dd,J=3,9Hz,0.7H),6.72(dd,J=3,9Hz,0.3H),6.88(d,J=3Hz ,0.3H),6.91(d,J=3Hz,0.7H),6.99(d,J=8Hz,0.7H),7.02(d,J=8Hz,0.3H), 7.19-7.24(m,1H),7.33-7.34(m,0.7H),7.35(d,J=15Hz,0.7H),7.66-7.83( m,2.3H),8.00(d,J=15Hz,0.3H),8.61-8.62(m,0.7H),8.67-8.68(m,0.3H).

[0282] (Example 36) Synthesis of (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one

[0283] [ka] (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7 'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one

[0284] The title compound was obtained from the compound obtained in Example 35 according to the method described in Example 3. 1H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.15(m,2H),0.46-0.53(m,2H),0.77-0 .88(m,1H),1.04-1.12(m,1H),1.19-1.37(m,1H),1.44-1.78(m,6H),1.84-2. 02(m,2H),2.19-2.46(m,3.4H),2.51-2.55(m,0.6H),2.68-3.03(m,4H),3.3 5(ddd,J=5,13,13Hz,0.6H),3.61-3.76(m,2H),3.81-3.87(m,0.4H),4.57(br s,0.6H),4.73(br s,0.4H),5.41(br s,0.6H),6.63(dd,J=2,8Hz,0.6H),6.68(dd,J=2,8Hz,0.4H),6.78(br s,0.4H),6.82-6.83(m,1H),6.93(d,J=8Hz,0.6H),6.94(d,J=8Hz,0.4H),7.16-7.23(m,1H),7.32-7.34(m,0.4H) ,7.35(d,J=15Hz,0.6H),7.65-7.75(m,2.6H),8.03(d,J=15Hz,0.4H),8.60-8.61(m,0.6H),8.63-8.64(m,0.4H).

[0285] (Example 37) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-3-(pyridine-2-yl)propan-1-one

[0286] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7 a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-3-(pyridin-2-yl)propan-1-one

[0287] The compound obtained in Example 26 (5.0 mg, 9.7 μmol) was dissolved in methanol (1.5 mL), and 10% palladium-activated carbon (55% wet, 3.0 mg, 1.6 μmol) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (chloroform:10% aqueous ammonia-methanol solution = 10:1) to obtain the title compound (0.5 mg, 10%) as a colorless oil. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.07-0.15(m,2H),0.48-0.54(m,2H),0.79-0.89(m,1H),1.07-1.17(m,2H),1.24-1 .39(m,3H),1.63-1.79(m,2H),1.82-1.92(m,1H),2.07(ddd,J=4,12,12Hz,1H),2.29-2.59(m,3H),2.61-2.84(m,3H) ),3.00(d,J=18Hz,1H),3.06(d,J=5Hz,1H),3.10-3.31(m,3H),3.34-3.43(m,1H),3.47-3.56(m,2H),5.73(s,1H),6 .55(d,J=8Hz,1H),6.69(d,J=8Hz,1H),7.08-7.13(m,1H),7.23-7.27(m,1H),7.55-7.62(m,1H),8.50-8.54(m,1H).

[0288] (Example 38) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-2-(pyridine-2-yl)ethane-1-one

[0289] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1' H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-2-(pyridin-2-yl)ethan-1-one

[0290] The title compound was obtained from the compound obtained in Example 18 and 2-(pyridine-2-yl) acetate hydrochloride according to the method described in Example 2. 1H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.14(m,2H),0.45-0.55(m,2H),0.77- 0.87(m,1H),1.07-1.19(m,2H),1.29(ddd,J=3,3,14Hz,1H),1.33-1.40(m, 1H),1.54(ddd,J=3,3,13Hz,1H),1.60-1.72(m,1H),1.75-1.84(m,1H),1.8 9-1.99(m,1H),2.00-2.10(m,1H),2.28-2.46(m,3H),2.52-2.67(m,2H),3. 01(d,J=18Hz,1H),3.05(d,J=5Hz,1H),3.28(ddd,J=3,14,14Hz,1H),3.47- 3.56(m,1H),3.63-3.71(m,1H),3.84(d,J=15Hz,1H),3.86(s,3H),3.89(d, J=15Hz,1H),5.73(s,1H),6.60(d,J=8Hz,1H),6.71(d,J=8Hz,1H),7.13-7. 18(m,1H),7.41-7.46(m,1H),7.65(ddd,J=2,8,8Hz,1H),8.50-8.54(m,1H).

[0291] (Example 39) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-2-(pyridine-2-yl)ethane-1-one

[0292] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7 a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-2-(pyridin-2-yl)ethan-1-one

[0293] The title compound was obtained from the compound obtained in Example 38 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.13(m,2H),0.44-0.52(m,2H),0.74-0.85(m,1H),1.07-1.17(m,2H),1.23-1.35(m,2H),1.5 1(ddd,J=3,3,13Hz,1H),1.59-1.70(m,1H),1.73-1.93(m,2H),2.04(ddd,J=4,4,12Hz,1H),2.26-2.43(m,3H),2.48-2.63(m,2H), 2.97(d,J=18Hz,1H),3.03(d,J=5Hz,1H),3.23(ddd,J=2,13,13Hz,1H),3.44-3.52(m,1H),3.56-3.64(m,1H),3.87(s,2H),5.73(s ,1H),6.51(d,J=8Hz,1H),6.69(d,J=8Hz,1H),7.12-7.18(m,1H),7.39-7.45(m,1H),7.64(ddd,J=2,8,8Hz,1H),8.47-8.52(m,1H).

[0294] (Example 40) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-(pyridine-2-yl)propyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol

[0295] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-(pyridin-2-yl)propyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0296] The title compound was obtained from the compound obtained in Example 14 according to the method described in Example 8. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.13(m,2H),0.46-0.52(m,2H),0.76-0.86(m,1H),1.05-1.14(m,3H),1.46-1.57(m,6H),1.8 7-2.13(m,6H),2.27(dd,J=6,13Hz,1H),2.38(dd,J=6,13Hz,1H),2.42-2.55(m,3H),2.69-2.98(m,6H),3.04-3.11(m,1H),4.59(br s,1H),6.61(dd,J=2,8Hz,1H),6.88(d,J=8Hz,1H),6.95-6.96(m,1H),7.10(ddd,J=1, 5,8Hz,1H),7.21(d,J=8Hz,1H),7.59(ddd,J=2,8,8Hz,1H),8.54(ddd,J=1,2,5Hz,1H).

[0297] (Example 41) Synthesis of (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-9'-methoxy-1-(2-(pyridine-2-yl)ethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a'-ol

[0298] [ka] (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-9'-methoxy-1-(2-(pyridin-2-yl)ethyl)-1',2',3',4', 5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-4a'-ol

[0299] The title compound was obtained from the compound obtained in Example 38 according to the method described in Example 18. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.16(m,2H),0.46-0.55(m,2H),0.76-0.86(m,1H),0.97-1.07(m,1H), 1.09-1.16(m,1H),1.24-1.42(m,2H),1.47-1.57(m,2H),1.59-1.71(m,1H),1.78-1.90(m,1H),2.01-2.41( m,5H),2.52-2.64(m,2H),2.80-2.88(m,1H),2.91-3.11(m,7H),3.86(s,3H),4.64(s,1H),6.57(d,J=8Hz,1 H),6.70(d,J=8Hz,1H),7.08-7.14(m,1H),7.20-7.25(m,1H),7.60(ddd,J=2,8,8Hz,1H),8.52-8.57(m,1H).

[0300] (Example 42) Synthesis of (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1-(2-(pyridine-2-yl)ethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol

[0301] [ka] (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1-(2-(pyridin-2-yl)ethyl)-1',2',3',4',5',6'-he xahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinoline]-4a',9'-diol

[0302] The title compound was obtained from the compound obtained in Example 41 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.13(m,2H),0.45-0.54(m,2H),0.74-0.86(m,1H),0.96- 1.06(m,1H),1.14-1.41(m,3H),1.46-1.83(m,4H),2.01-2.14(m,2H),2.21-2.40(m,3H),2.49- 2.70(m,3H),2.79-2.89(m,1H),2.92-3.23(m,6H),4.66(s,1H),6.52(d,J=8Hz,1H),6.68(d,J =8Hz,1H),7.09-7.15(m,1H),7.20-7.25(m,1H),7.60(ddd,J=2,8,8Hz,1H),8.53-8.57(m,1H).

[0303] (Example 43) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(thiazole-4-yl)propan-1-one

[0304] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5' H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(thiazol-4-yl)propan-1-one

[0305] The title compound was obtained from the compound obtained in Example 1 and 3-(thiazole-4-yl)propanoic acid according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.42-0.54(m,2H),0.76-0.88(m,1H ),1.00-1.15(m,2H),1.18-1.37(m,1H),1.47-1.73(m,4H),1.80-1.97(m,2H),1.98-2. 11(m,1H),2.16-2.33(m,0.9H),2.28(dd,J=7,13Hz,0.9H),2.34-2.44(m,0.3H),2.38( dd,J=6,13Hz,0.9H),2.50-2.58(m,1H),2.59-2.65(m,0.2H),2.68(t,J=7Hz,1.8H),2. 80(dd,J=6,18Hz,1H),2.95(d,J=18Hz,1H),2.95(d,J=6Hz,1H),3.11-3.40(m,5H),3. 47(d,J=14Hz,1H),3.78(s,3H),6.66-6.72(m,0.1H),6.69(dd,J=3,8Hz,0.9H),6.81(d ,J=3Hz,0.1H),6.87(d,J=3Hz,0.9H),6.98(d,J=8Hz,0.9H),6.99(d,J=8Hz,0.1H),7.0 8(d,J=2Hz,0.9H),7.12(d,J=2Hz,0.1H),8.74(d,J=2Hz,0.9H),8.75(d,J=2Hz,0.1H).

[0306] (Example 44) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(thiazole-4-yl)propan-1-one

[0307] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7 'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(thiazol-4-yl)propan-1-one

[0308] The title compound was obtained from the compound obtained in Example 43 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.02-0.16(m,2H),0.40-0.53(m,2H),0.72-0.8 5(m,1H),0.99-1.14(m,1.6H),1.18-1.36(m,1.4H),1.37-1.74(m,5H),1.82-2 .02(m,2H),2.12-2.22(m,1H),2.23-2.40(m,2H),2.42-2.81(m,3.6H),2.86-2 .98(m,2H),3.07-3.39(m,5H),3.48-3.61(m,1H),3.62-3.77(m,0.4H),4.58(br s,0.2H),4.63(br s,0.8H),6.64(d,J=8Hz,0.8H),6.70(d,J=8Hz,0.2H),6.82(s,0.8H),6.85(s,0.2H),6.86-6.94( m,1H),7.07(d,J=2Hz,0.8H),7.09(d,J=2Hz,0.2H),8.72(d,J=2Hz,0.2H),8.73(d,J=2Hz,0.8H).

[0309] (Example 45) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(pyridine-4-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol

[0310] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(pyridin-4-yl)ethyl)-7',8',9' ,10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-8a'-ol

[0311] The title compound was obtained from the compound obtained in Example 23 according to the method described in Example 18. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.16(m,2H),0.42-0.54(m,2H),0.74-0.86(m,1H),1.00-1.1 6(m,3H),1.40-2.10(m,10H),2.27(dd,J=6,13Hz,1H),2.38(dd,J=6,13Hz,1H),2.48-2.54(m,1H) ,2.63-2.85(m,5H),2.90(d,J=6Hz,1H),2.94(d,J=19Hz,1H),2.95-3.07(m,2H),3.77(s,3H),6.6 8(dd,J=2,8Hz,1H),6.88(d,J=2Hz,1H),6.96(d,J=8Hz,1H),7.17-7.20(m,2H),8.48-8.52(m,2H).

[0312] (Example 46) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridine-4-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0313] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridin-4-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0314] The title compound was obtained from the compound obtained in Example 45 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.02-0.15(m,2H),0.41-0.53(m,2H),0.74-0.86(m,1H),1.00- 1.15(m,3H),1.38-1.61(m,4H),1.59(ddd,J=4,13,13Hz,1H),1.84-1.97(m,3H),2.03(d,J=14H) z,1H),2.04(ddd,J=5,12,12Hz,1H),2.27(dd,J=6,13Hz,1H),2.37(dd,J=6,13Hz,1H),2.49-2. 60(m,2H),2.64-2.72(m,1H),2.73-2.81(m,1H),2.84-2.96(m,4H),3.02-3.14(m,2H),4.59(br s,1H),6.63(dd,J=2,8Hz,1H),6.89(d,J=8Hz,1H),6.92-6.96(m,1H),7.20-7.24(m,2H),8.50-8.53(m,2H).

[0315] (Reference example 11) Synthesis of 2-(pyridine-3-yl)ethyl methanesulfonate

[0316] [ka] 2-(pyridin-3-yl)ethyl methanesulfonate

[0317] 2-(pyridine-3-yl)ethane-1-ol (51.2 mg, 416 μmol) was dissolved in chloroform (1.5 mL). Under ice cooling, triethylamine (0.30 mL, 2.2 mmol) and methanesulfonic anhydride (145 mg, 832 μmol) were added, and the mixture was stirred at 0°C for 25 minutes. Saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extract was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (106 mg) as an orange oil. The obtained compound was used in the next reaction without purification. 1 H-NMR(400MHz,CDCl3)δ(ppm):2.92(s,3H),3.08(t,J=7Hz,2H),4.44(t,J=7Hz,2H),7. 28(ddd,J=1,5,8Hz,1H),7.57-7.61(m,1H),8.51-8.53(m,1H),8.54(dd,J=2,5Hz,1H).

[0318] (Example 47) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(pyridine-3-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol

[0319] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(pyridin-3-yl)ethyl)-7',8',9' ,10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-8a'-ol

[0320] The compound obtained in Example 1 (7.00 mg, 18.3 μmol) and the compound obtained in Reference Example 11 (106 mg, 526 μmol) were dissolved in acetonitrile (1.0 mL), potassium carbonate (12.2 mg, 88.3 μmol) was added, and the mixture was stirred at 60°C for 16 hours. After cooling to room temperature, water was added to the reaction mixture under ice cooling, and the mixture was extracted three times with chloroform. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amino group-supported silica gel, 90-100% ethyl acetate / heptane → 0-50% methanol / ethyl acetate) and preparative thin-layer chromatography (chloroform:2M ammonia-methanol solution = 20:1) to obtain the title compound (1.6 mg, 18%) as a colorless amorphous material. 1H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.15(m,2H),0.42-0.53(m,2H),0.74-0.86(m,1H),1.01-1.15(m,3H),1.42-1.79(m,5H),1.78(d,J=14H) z,1H),1.89(ddd,J=3,12,12Hz,1H),1.96(ddd,J=4,13,13Hz,1H),2.02(d,J=14Hz,1H),2.04(ddd,J=5,12,12Hz,1H),2.27(dd,J=7,13Hz,1H) ,2.37(dd,J=6,13Hz,1H),2.47-2.54(m,1H),2.64-2.85(m,5H),2.87-3.00(m,3H),3.05(ddd,J=5,9,9Hz,1H),3.77(s,3H),6.68(dd,J=3,8Hz ,1H),6.88(d,J=3Hz,1H),6.96(d,J=8Hz,1H),7.21(dd,J=5,8Hz,1H),7.58(ddd,J=2,2,8Hz,1H),8.45(dd,J=2,5Hz,1H),8.51(d,J=2Hz,1H).

[0321] (Example 48) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridine-3-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0322] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridin-3-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0323] The title compound was obtained from the compound obtained in Example 47 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.16(m,2H),0.42-0.53(m,2H),0.74-0.85 (m,1H),1.03-1.12(m,3H),1.41-1.81(m,6H),1.83-2.07(m,4H),2.27(dd,J=7,1 2Hz,1H),2.37(dd,J=6,12Hz,1H),2.47-2.55(m,1H),2.57-2.71(m,2H),2.73-2 .86(m,3H),2.89(d,J=5Hz,1H),2.92(d,J=18Hz,1H),2.96-3.14(m,2H),4.56(br s,1H),6.60-6.65(m,1H),6.85-6.92(m,1H),6.90(d,J=8Hz,1H),7.24(dd,J =5,8Hz,1H),7.60(d,J=8Hz,1H),8.46(dd,J=1,5Hz,1H),8.53(d,J=1Hz,1H).

[0324] (Example 49) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(2-fluorophenyl)propan-1-one

[0325] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H ,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(2-fluorophenyl)propan-1-one

[0326] The title compound was obtained from the compound obtained in Example 1 and 3-(2-fluorophenyl)propanoic acid according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.43-0.54(m,2H),0.77- 0.87(m,1H),1.01-1.14(m,1.9H),1.18-1.29(m,1.1H),1.46-1.73(m,5H),1 .80-1.92(m,2H),1.99-2.10(m,1H),2.19-2.48(m,3.2H),2.49-2.66(m,2. 8H),2.80(dd,J=5,18Hz,1H),2.91-2.98(m,0.2H),2.95(d,J=18Hz,0.9H),2 .96(d,J=5Hz,0.9H),2.99-3.10(m,1.8H),3.29-3.39(m,2.3H),3.49(d,J= 14Hz,0.9H),3.77(s,3H),6.66-6.72(m,0.1H),6.67(dd,J=3,8Hz,0.9H),6. 81(d,J=2Hz,0.1H),6.87(d,J=3Hz,0.9H),6.95-7.09(m,3H),7.17(dddd,J= 2,5,8,8Hz,1H),7.28(ddd,J=2,8,8Hz,0.9H),7.36(ddd,J=2,8,8Hz,0.1H).

[0327] (Example 50) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(2-fluorophenyl)propan-1-one

[0328] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7' H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(2-fluorophenyl)propan-1-one

[0329] The title compound was obtained from the compound obtained in Example 49 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.16(m,2H),0.44-0.52(m,2H),0.74-0.86(m,1H),1.02-1.18(m,1.8H),1.22-1.38(m,1. 2H),1.42-1.70(m,5H),1.81-2.01(m,2H),2.17-2.61(m,6H),2.72-2.83(m,1H),2.89-3.12(m,4.6H),3.14-3.35(m,2.2H),3.5 5-3.78(m,1.2H),6.64(dd,J=2,8Hz,0.8H),6.70(dd,J=2,8Hz,0.2H),6.77(d,J=2Hz,0.8H),6.87(d,J=2Hz,0.2H),6.92(d,J= 8Hz,0.8H),6.93(d,J=8Hz,0.2H),6.96-7.07(m,2H),7.11-7.19(m,0.2H),7.17(dddd,J=2,5,8,8Hz,0.8H),7.25-7.31(m,1H).

[0330] (Reference example 12) Synthesis of 2-fluorophenethyl methanesulfonic acid

[0331] [ka] 2-fluorophenethyl methanesulfonate

[0332] The title compound was obtained from 2-(2-fluorophenyl)ethane-1-ol according to the method described in Reference Example 11. 1 H-NMR(400MHz,CDCl3)δ(ppm):2.89(s,3H),3.09-3.13(m,2H),4.44(t,J=7Hz,2H),7.02-7.13(m,2H),7.22-7.29(m,2H).

[0333] (Example 51) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol

[0334] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-8a'-ol

[0335] The compound obtained in Example 1 (8.0 mg, 21 μmol) and the compound obtained in Reference Example 12 (32 mg, 0.15 mmol) were dissolved in acetonitrile (1.0 mL), potassium carbonate (9.1 mg, 66 μmol) and sodium iodide (2.6 mg, 17 μmol) were added, and the mixture was stirred under reflux for 16 hours. After cooling to room temperature, aqueous sodium bicarbonate solution and water were added to the reaction mixture under ice cooling, and the mixture was extracted three times with ethyl acetate. The combined extract was washed with saturated brine, 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, 80-100% ethyl acetate / heptane → 0-5% methanol / ethyl acetate) and preparative thin-layer chromatography (chloroform:2M ammonia-methanol solution = 20:1) to obtain the title compound (5.1 mg, 48%) as a colorless amorphous material. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.42-0.53(m,2H),0.74-0 .85(m,1H),1.04-1.18(m,3H),1.42-1.79(m,4H),1.59(ddd,J=4,13,13Hz,1H ),1.84(d,J=15Hz,1H),1.89(ddd,J=3,12,12Hz,1H),1.99(ddd,J=4,13,13Hz ,1H),2.05-2.12(m,1H),2.06(ddd,J=5,13,13Hz,1H),2.27(dd,J=7,13Hz,1H ),2.37(dd,J=6,13Hz,1H),2.47-2.55(m,1H),2.63-3.00(m,6H),2.90(d,J=6 Hz,1H),2.93(d,J=18Hz,1H),3.06-3.15(m,1H),3.77(s,3H),6.68(dd,J=2,8 Hz,1H),6.90(d,J=2Hz,1H),6.96(d,J=8Hz,1H),7.02(ddd,J=1,8,10Hz,1H), 7.07(ddd,J=1,8,8Hz,1H),7.18(dddd,J=2,6,8,8Hz,1H),7.24-7.30(m,1H).

[0336] (Example 52) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0337] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0338] The title compound was obtained from the compound obtained in Example 51 according to the method described in Example 3. 1H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.41-0.54(m,2H),0.74-0.85(m,1H) ,1.02-1.13(m,2H),1.14-1.21(m,1H),1.32-1.65(m,5H),1.88(ddd,J=3,13,13Hz,1H) ,1.93(ddd,J=3,12,12Hz,1H),2.07(ddd,J=5,13,13Hz,1H),2.16(d,J=14Hz,1H),2.18 (d,J=14Hz,1H),2.27(dd,J=7,13Hz,1H),2.37(dd,J=6,13Hz,1H),2.49-2.66(m,3H),2. 77(dd,J=6,18Hz,1H),2.89(d,J=6Hz,1H),2.93(d,J=18Hz,1H),2.94-3.03(m,1H),3.0 5(ddd,J=5,12,12Hz,1H),3.14(ddd,J=6,12,12Hz,1H),3.29(ddd,J=4,10,10Hz,1H),6. 66(dd,J=2,8Hz,1H),6.88(d,J=8Hz,1H),7.03(ddd,J=2,8,10Hz,1H),7.05-7.08(m,1H) ),7.09(ddd,J=2,7,7Hz,1H),7.21(dddd,J=2,7,8,8Hz,1H),7.30(ddd,J=2,7,7Hz,1H).

[0339] (Example 53) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-(pyridine-3-yloxy)ethane-1-one

[0340] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H ,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(pyridin-3-yloxy)ethan-1-one

[0341] The title compound was obtained from the compound obtained in Example 1 and 2-(pyridine-3-yloxy) acetate hydrochloride according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.11(m,2H),0.44-0.52(m,2H),0.75 -0.85(m,1H),1.03-1.43(m,3H),1.49-1.98(m,7H),2.15-2.39(m,3H),2.5 1-2.55(m,1H),2.79(dd,J=6,18Hz,1H),2.92-2.99(m,2H),3.30(ddd,J=5 ,13,13Hz,1H),3.44-3.48(m,3H),3.78(s,3H),4.55-4.66(m,2.8H),5.04( d,J=12Hz,0.1H),5.17(d,J=12Hz,0.1H),6.69(dd,J=3,8Hz,0.9H),6.71( dd,J=3,8Hz,0.1H),6.85(d,J=3Hz,1H),6.99(d,J=8Hz,0.9H),7.01(d,J=8 Hz,0.1H),7.20-7.25(m,1H),7.32(ddd,J=1,4,8Hz,0.9H),7.39-7.41(m,0 .1H),8.23(dd,J=1,4Hz,1H),8.33(d,J=3Hz,0.9H),8.47(d,J=3Hz,0.1H).

[0342] (Example 54) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-3-yloxy)ethane-1-one

[0343] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7' H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(pyridin-3-yloxy)ethan-1-one

[0344] The title compound was obtained from the compound obtained in Example 53 according to the method described in Example 3. 1H-NMR (400MHz, CDCl3) δ (ppm): 0.04-0.11 (m, 2H), 0.44-0.51 (m, 2H), 0.75-0.85 (m, 1H), 1.00-1.32 (m, 3H), 1.49-1.92 (m, 7H), 2.13-2.20 (m,1H),2.24-2.38(m,2H),2.49-2.53(m,1H),2.77(dd,J=6,18Hz,1H),2.90-2.98(m,2H),3.25(ddd,J=5,13,13Hz,1H),3.46-3.75(m,3H ),4.57-5.25(m,3H),6.61(dd,J=2,8Hz,0.9H),6.66(dd,J=2,8Hz,0.1H),6.80(d,J=2Hz,0.9H),6.83(d,J=2Hz,0.1H),6.92(d,J=8Hz,0. 9H),6.95(d,J=8Hz,0.1H),7.22(dd,J=5,8Hz,1H),7.33-7.35(m,1H),8.24(dd,J=1,5Hz,1H),8.33(d,J=3Hz,0.9H),8.38-8.39(m,0.1H).

[0345] (See Example 13) (E)-2-(3-クロロプロプ-1-エン-1-イル)ピリジンの synthesis

[0346]

change

[0347] (E)-3-(pyridine-2-yl)prop-2-en-1-ol (synthesized by the method described in Organic Letters 2019, 21, 7965, 111 mg, 0.821 mmol) was dissolved in chloroform (5 mL) and stirred at 0°C. Thionyl chloride (600 μL, 8.22 mmol) was added and the mixture was stirred at 0°C for 3 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted three times with chloroform. The combined extract was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (40-60% ethyl acetate / heptane) to obtain the title compound (83.8 mg, 66%) as a pale yellow oil. 1 H-NMR(400MHz,CDCl3)δ(ppm):4.28(d,J=6Hz,2H),6.71-6.78(m,1H),6.79-6.89(m,1H ),7.14-7.19(m,1H),7.28-7.32(m,1H),7.65(ddd,J=2,8,8Hz,1H),8.55-8.60(m,1H).

[0348] (Example 55) Synthesis of ((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1-((E)-3-(pyridine-2-yl)aryl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol

[0349] [ka] ((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1-((E)-3-(pyridin-2-yl)allyl)-1',2',3',4',5',6'- hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinoline]-4a',9'-diol

[0350] To a solution of the compound obtained in Example 18 (5.2 mg, 13 μmol) in N,N-dimethylformamide (1.5 mL), N,N-diisopropylethylamine (9.0 μL, 52 μmol), sodium iodide (7.7 mg, 51 μmol), and the compound obtained in Reference Example 13 (7.8 mg, 51 μmol) were added, and the mixture was stirred at 80°C for 45 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and it was extracted three times with chloroform. The combined extract was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (chloroform:methanol = 10:1). The resulting pale yellow oily substance was dissolved in chloroform (1 mL), and 1 M boron tribromide-dichloromethane solution (0.50 mL, 0.50 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 28% aqueous ammonia (3 mL) and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and it was 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 preparative thin-layer chromatography (chloroform:10% aqueous ammonia-methanol solution = 10:1) to obtain the title compound (2.2 mg, 34%) as a colorless amorphous material. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.16(m,2H),0.48-0.55(m,2H),0.77-0.89(m,1H),0.99-1. 09(m,1H),1.22-1.45(m,3H),1.51-1.77(m,4H),2.05-2.17(m,2H),2.18-2.42(m,3H),2.46-2.66 (m,3H),2.94-3.12(m,3H),3.22-3.31(m,1H),3.63-3.72(m,1H),4.66(s,1H),6.53(d,J=8Hz,1H ),6.65-6.83(m,3H),7.04-7.10(m,1H),7.29-7.35(m,1H),7.55-7.62(m,1H),8.48-8.52(m,1H).

[0351] (Example 56) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(piperidine-1-yl)propan-1-one

[0352] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H ,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(piperidin-1-yl)propan-1-one

[0353] The title compound was obtained from the compound obtained in Example 1 and 3-(piperidine-1-yl)propanoic acid according to the method described in Example 2. 1H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.42-0.53(m,2H),0.75-0.86(m,1H),1.00-1.16 (m,2H),1.37-1.97(m,13H),2.04-2.33(m,0.8H),2.20(ddd,J=6,12,12Hz,0.8H),2.27(dd,J=7,13 Hz,0.8H),2.34-2.57(m,7H),2.37(dd,J=6,13Hz,0.8H),2.58-3.01(m,5.8H),3.30(ddd,J=4,13,1 3Hz,0.8H),3.37-3.43(m,1.6H),3.46(d,J=14Hz,0.8H),3.48-3.68(m,0.8H),3.78(s,3H),4.56(br s,1H),6.66-6.73(m,0.2H),6.68(dd,J=3,8Hz,0.8H),6.85-6.89(m,0.2H),6.87(d,J=3Hz,0.8H),6.96-7.02(m,0.2H),6.98(d,J=8Hz,0.8H).

[0354] (Example 57) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(piperidine-1-yl)propan-1-one

[0355] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7' H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(piperidin-1-yl)propan-1-one

[0356] The title compound was obtained from the compound obtained in Example 56 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.42-0.53(m,2H),0.75-0.87(m,1H),1.00- 1.08(m,0.8H),1.09-1.17(m,0.8H),1.22-1.34(m,1.4H),1.36-2.05(m,13.2H),2.14-2.66(m ,7.4H),2.19(ddd,J=5,12,12Hz,0.8H),2.27(dd,J=6,13Hz,0.8H),2.37(dd,J=6,13Hz,0.8H) ,2.68-3.09(m,5.2H),3.14-3.25(m,0.8H),3.31-3.40(m,0.8H),3.42-3.77(m,2.2H),4.53(br s,0.8H),4.59(br s,0.2H),6.61(dd,J=2,8Hz,0.8H),6.67(dd,J=2,8Hz,0.2H),6.78(d,J=2H z,0.8H),6.83(d,J=2Hz,0.2H),6.91(d,J=8Hz,0.8H),6.91-6.94(m,0.2H).

[0357] (Example 58) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-(pyridine-2-yl)butan-1-one

[0358] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5' H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-4-(pyridin-2-yl)butan-1-one

[0359] The title compound was obtained from the compound obtained in Example 1 and 4-(pyridine-2-yl)butanoate salt according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.02-0.16(m,2H),0.42-0.56(m,2H),0.75-0 .87(m,1H),1.00-1.14(m,1.8H),1.18-1.41(m,2H),1.44-1.97(m,5H),2.02 -2.45(m,7H),2.38(dd,J=6,12Hz,0.8H),2.49-2.73(m,1.2H),2.79(dd,J=6 ,18Hz,1H),2.80-3.09(m,4.6H),3.27-3.39(m,2.4H),3.48(d,J=14Hz,0.8H) ,3.51-3.68(m,0.4H),3.78(s,3H),6.68(dd,J=2,9Hz,0.8H),6.69-6.72(m, 0.2H),6.84(d,J=2Hz,0.2H),6.87(d,J=2Hz,0.8H),6.98(d,J=9Hz,0.8H),6. 99(d,J=8Hz,0.2H),7.07-7.14(m,1H),7.23(d,J=8Hz,0.8H),7.24-7.28(m, 0.2H),7.58-7.63(m,0.2H),7.60(ddd,J=2,8,8Hz,0.8H),8.49-8.55(m,1H).

[0360] (Example 59) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-(pyridine-2-yl)butan-1-one

[0361] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7 'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-4-(pyridin-2-yl)butan-1-one

[0362] The title compound was obtained from the compound obtained in Example 58 according to the method described in Example 3. 1H-NMR(400MHz,CDCl3)δ(ppm): 0.03-0.16(m,2H),0.43-0.54(m,2H),0.76-0.91(m,1H),1.00-1.16(m ,1.8H),1.22-1.35(m,1.2H),1.37-1.73(m,5H),1.79-1.97(m,2.6H), 2.02-2.44(m,7H),2.46-2.61(m,1.2H),2.72-3.00(m,5H),3.11-3.41 (m,2H),3.48-3.67(m,1H),3.68-3.76(m,0.2H),6.61-6.67(m,0.8H), 6.68(dd,J=2,8Hz,0.2H),6.81(d,J=2Hz,0.8H),6.83(d,J=2Hz,0.2H),6.91(d,J=8Hz,0.8H),6.92(d,J=8Hz,0.2H),7.04-7.09(m,0.2H),7. 10-7.15(m,0.2H),7.11(ddd,J=1,5,8Hz,0.8H),7.22(d,J=8Hz,0.8H),7.51-7.57(m,0.2H),7.61(ddd,J=2,8,8Hz,0.8H),8.46-8.52(m,1H).

[0363] (Example 60) Synthesis of 3-Cyclobutyl-1-((2R,4b'R,8a'S,9'R)-11'-(Cyclopropylmethyl)-8a'-Hydroxy-3'-Methoxy-8',8a',9',10'-Tetrahydro-5'H,7'H-Spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propan-1-one

[0364] [ka] 3-cyclobutyl-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10 '-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)propan-1-one

[0365] The title compound was obtained from the compound obtained in Example 1 and 3-cyclobutylpropanoic acid (synthesized by the method described in Organic Process Research & Development 2008, 12, 183) according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.12(m,2H),0.44-0.52(m,2H),0.76-0.86(m,1H),1.02-1.40(m,3H),1.47 -1.94(m,13H),2.00-2.41(m,8H),2.47-2.85(m,2H),2.92-3.01(m,2H),3.29-3.60(m,4H),3.78(s,3H),4.54(br s,1H),6.68(dd,J=2,8Hz,0.8H),6.71(dd,J=2,8Hz,0.2H),6.86(d,J=2Hz, 0.2H),6.88(d,J=2Hz,0.8H),6.98(d,J=8Hz,0.8H),7.00(d,J=8Hz,0.2H).

[0366] (Example 61) Synthesis of 3-Cyclobutyl-1-((2R,4b'R,8a'S,9'R)-11'-(Cyclopropylmethyl)-3',8a'-Dihydroxy-8',8a',9',10'-Tetrahydro-5'H,7'H-Spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propan-1-one

[0367] [ka] 3-cyclobutyl-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-t etrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)propan-1-one

[0368] The title compound was obtained from the compound obtained in Example 60 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.14(m,2H),0.45-0.52(m,2H),0.75-0.85(m,1H),1.04-1.32(m,3H),1.41-1.91(m,1 2H),1.95-2.41(m,8H),2.46-2.81(m,3.3H),2.90-2.97(m,2H),3.14(ddd,J=4,13,13Hz,0.7H),3.29-3.77(m,3H),4.53(br s,0.7H),4.56(br s,0.3H),6.62(dd,J=3,8Hz,0.7H),6.69(dd,J=3,8Hz,0.3H),6.73(d,J=3Hz ,0.7H),6.84(d,J=3Hz,0.3H),6.91(d,J=8Hz,0.7H),6.93(d,J=8Hz,0.3H).

[0369] (Example 62) Synthesis of 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2,2-dimethyl-5-oxopentannitrile

[0370] [ka] 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H, 7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2,2-dimethyl-5-oxopentanenitrile

[0371] The title compound was obtained from the compound obtained in Example 1 and 4-cyano-4-methylpentanoic acid (synthesized by the method described in WO2015180612) according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.12(m,2H),0.44-0.51(m,2H),0.76-0.86(m,1H),1.03-1.45(m,2H),1.36(s,3H),1.38 (s,3H),1.49-1.76(m,8H),1.82-1.99(m,3H),2.16-2.55(m,5H),2.77-3.00(m,4H),3.26-3.47(m,3H),3.78(s,3H),4.57(br s,1H),6.69(dd,J=2,8Hz,0.9H),6.71(dd,J=2,8Hz,0.1H),6.86(d,J=2Hz, 0.1H),6.88(d,J=2Hz,0.9H),6.99(d,J=8Hz,0.9H),7.01(d,J=8Hz,0.1H).

[0372] (Example 63) Synthesis of 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2,2-dimethyl-5-oxopentannitrile

[0373] [ka] 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H -spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2,2-dimethyl-5-oxopentanenitrile

[0374] The title compound was obtained from the compound obtained in Example 62 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.11(m,2H),0.47-0.51(m,2H),0.77-0.85(m,1H),1.02-1.42(m,2H),1.36(s,3H),1.37(s,3H), 1.48-1.76(m,11H),1.82-1.99(m,3H),2.16-2.46(m,4H),2.50-2.56(m,1H),3.24(ddd,J=4,13,13Hz,1H),3.39-3.68(m,3H),4.55(br s,1H),4.76(br s,1H),6.60(dd,J=3,8Hz,0.9H),6.64(dd,J=3,8Hz,0.1H),6.81(d,J=3Hz,1H),6.93(d,J=8Hz,0.9H),6.95(d,J=8Hz,0.1H).

[0375] (Example 64) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-3-morpholinopropan-1-one

[0376] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro- 1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-3-morpholinopropan-1-one

[0377] The title compound was obtained from the compound obtained in Example 18 and 3-morpholinopropanoic acid according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.07-0.15(m,2H),0.46-0.56(m,2H),0.78-0.89(m,1H),1. 07-1.18(m,2H),1.24-1.41(m,2H),1.50-1.58(m,1H),1.63-1.86(m,2H),1.90-2.11(m,2H ),2.30-2.68(m,11H),2.69-2.77(m,2H),3.02(d,J=18Hz,1H),3.07(d,J=5Hz,1H),3.21-3 .31(m,1H),3.35-3.43(m,1H),3.51-3.59(m,1H),3.65-3.74(m,4H),3.86(s,3H),5.14(br s,1H),5.68(s,1H),6.60(d,J=8Hz,1H),6.71(d,J=8Hz,1H).

[0378] (Example 65) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-3-morpholinopropan-1-one

[0379] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H ,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-3-morpholinopropan-1-one

[0380] The title compound was obtained from the compound obtained in Example 64 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.15(m,2H),0.45-0.55(m,2H),0.76-0.87(m,1H),1.09-1.19(m, 2H),1.24-1.36(m,2H),1.49-1.58(m,1H),1.65-1.77(m,1H),1.78-1.98(m,2H),2.03-2.12(m,1H),2.2 7-2.66(m,11H),2.70-2.78(m,2H),2.99(d,J=18Hz,1H),3.05(d,J=5Hz,1H),3.14-3.26(m,1H),3.34-3 .43(m,1H),3.46-3.55(m,1H),3.67-3.74(m,4H),5.65(s,1H),6.53(d,J=8Hz,1H),6.69(d,J=8Hz,1H).

[0381] (Reference example 14) Synthesis of (R)-3-(3-fluoropyrrolidine-1-yl)propanoate tert-butyl

[0382] [ka] tert-butyl (R)-3-(3-fluoropyrrolidin-1-yl)propanoate

[0383] The title compound was obtained from tert-butyl acrylate and (R)-3-fluoropyrrolidine hydrochloride according to the method described in Reference Example 6. 1 H-NMR(400MHz,CDCl3)δ(ppm):1.45(s,9H),1.94-2.22(m,2H),2.39-2.45(m,1H),2.44(t,J=8Hz,2H),2 .72(ddd,J=5,12,30Hz,1H),2.77(t,J=8Hz,2H),2.81-2.93(m,2H),5.15(ddddd,J=2,2,5,7,56Hz,1H).

[0384] (Reference example 15) Synthesis of (R)-3-(3-fluoropyrrolidine-1-yl)propanoate 2,2,2-trifluoroacetate

[0385] [ka] (R)-3-(3-fluoropyrrolidin-1-yl)propanoic acid

[0386] To a chloroform (2.0 mL) solution of the compound obtained in Reference Example 14 (0.15 g, 0.67 mmol), trifluoroacetic acid (2.0 mL) was added under ice cooling and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (10-50% methanol / chloroform) to obtain the title compound (35 mg, 19%) as a white solid. 1 H-NMR(400MHz,CD3OD)δ(ppm):2.30-2.54(m,2H),2.78-2.85(m,2H),3.44-3.72(m,5H),3.75-3.86(m,1H),5.35-5.53(m,1H).

[0387] (Example 66) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((R)-3-fluoropyrrolidine-1-yl)propan-1-one

[0388] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-sp iro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-((R)-3-fluoropyrrolidine-1-yl)propan-1-one

[0389] The title compound was obtained from the compound obtained in Example 1 and the compound obtained in Reference Example 15, according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.42-0.56(m,2H),0.75-0.91(m,1H),1.00-1.17(m,1.6H),1.19-1.29(m,1.4H),1.30 -1.92(m,6.4H),1.96-2.45(m,6.8H),2.46-2.58(m,2.8H),2.60-2.74(m,1H),2.75-3.09(m,7.6H),3.31(ddd,J=5,13,13Hz,0.8H),3.3 8-3.46(m,1.4H),3.46(d,J=14Hz,0.8H),3.50-3.68(m,0.4H),3.78(s,3H),5.15-5.34(m,0.2H),5.17(ddddd,J=1,1,5,6,56Hz,0.8H), 6.68-6.73(m,0.2H),6.69(dd,J=3,8Hz,0.8H),6.86(d,J=2Hz,0.2H),6.88(d,J=3Hz,0.8H),6.96-7.02(m,0.2H),6.98(d,J=8Hz,0.8H).

[0390] (Example 67) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((R)-3-fluoropyrrolidine-1-yl)propan-1-one

[0391] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro [pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-((R)-3-fluoropyrrolidine-1-yl)propan-1-one

[0392] The title compound was obtained from the compound obtained in Example 66 according to the method described in Example 3. 1H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.43-0.53(m,2H),0.74-0.86(m,1H),1 .01-1.07(m,0.7H),1.11-1.20(m,1H),1.24-1.36(m,1.3H),1.42-1.80(m,7H),1.82-2.7 2(m,10.3H),2.73-3.08(m,7H),3.15-3.23(m,0.3H),3.17(ddd,J=4,14,14Hz,0.7H),3.3 1-3.39(m,0.7H),3.44-3.60(m,1H),3.66(d,J=14Hz,0.7H),3.71-3.79(m,0.3H),4.56(br s,1H),5.04-5.26(m,1H),6.62(dd,J=2,8Hz,0.7H),6.68(dd,J=2,8Hz,0.3H),6.75 (d,J=2Hz,0.7H),6.83(d,J=2Hz,0.3H),6.91(d,J=8Hz,0.7H),6.91-6.95(m,0.3H).

[0393] (Example 68) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(pyridine-2-ylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol

[0394] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(pyridin-2-ylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-8a'-ol

[0395] The compound obtained in Example 1 (7.0 mg, 18 μmol) was dissolved in chloroform (1.0 mL), picoline aldehyde (2.7 μL, 28 μmol) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, sodium triacetoxyborohydride (7.0 mg, 33 μmol) was added, and the mixture was stirred at room temperature for 18 hours. Saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined extract was washed with saturated brine, 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, 80-100% ethyl acetate / heptane) to obtain the title compound (5.2 mg, 60%) as a colorless amorphous material. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.16(m,2H),0.43-0.55(m,2H),0.77-0.88(m,1H),1.10-1.30(m,3H),1.49-1.71(m,5H),1.92(ddd,J=3,12,1 2Hz,1H),1.99(d,J=14Hz,1H),2.06-2.17(m,2H),2.23(d,J=14Hz,1H),2. 29(dd,J=7,13Hz,1H),2.39(dd,J=6,13Hz,1H),2.50-2.56(m,1H),2.59(d dd,J=6,9,9Hz,1H),2.79-2.88(m,2H),2.95(d,J=6Hz,1H),2.96(d,J=18H z,1H),3.74(d,J=14Hz,1H),3.78(s,3H),4.12(d,J=14Hz,1H),6.69(dd,J =3,8Hz,1H),6.95(d,J=3Hz,1H),6.98(d,J=8Hz,1H),7.12(ddd,J=1,5,8Hz,1H),7.49(d,J=8Hz,1H),7.64(ddd,J=2,8,8Hz,1H),8.53-8.56(m,1H).

[0396] (Example 69) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(pyridine-2-ylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol

[0397] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(pyridin-2-ylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0398] The title compound was obtained from the compound obtained in Example 68 according to the method described in Example 3. 1H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.46-0.52(m,2H),0.76-0.8 7(m,1H),1.01-1.09(m,1H),1.16-1.35(m,3H),1.36-1.47(m,1H),1.51(ddd,J =3,3,13Hz,1H),1.56-1.68(m,2H),1.95(ddd,J=3,12,12Hz,1H),1.96-2.05(m ,1H),2.10(ddd,J=5,12,12Hz,1H),2.25(s,2H),2.28(dd,J=6,13Hz,1H),2.38( dd,J=6,13Hz,1H),2.45-2.57(m,2H),2.77(dd,J=6,18Hz,1H),2.84-2.92(m,1 H),2.91(d,J=18Hz,1H),2.93(d,J=6Hz,1H),3.63(d,J=14Hz,1H),4.28(d,J=14 Hz,1H),6.32(dd,J=2,8Hz,1H),6.80(d,J=8Hz,1H),7.05(d,J=2Hz,1H),7.16- 7.22(m,1H),7.51(d,J=8Hz,1H),7.69(ddd,J=2,8,8Hz,1H),8.59-8.62(m,1H).

[0399] (Example 70) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-(pyridine-2-yloxy)ethane-1-one

[0400] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H ,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(pyridin-2-yloxy)ethan-1-one

[0401] The title compound was obtained from the compound obtained in Example 1 and 2-(pyridine-2-yloxy) acetate hydrochloride (synthesized by the method described in WO2012046882) according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.10(m,2H),0.43-0.50(m,2H),0.75-0.84(m,1H ),1.01-1.28(m,3H),1.48-1.94(m,7H),2.18(ddd,J=5,13,13Hz,1H),2.26(dd,J=6,13 Hz,1H),2.36(dd,J=6,13Hz,1H),2.52(dd,J=5,12Hz,1H),2.79(dd,J=6,18Hz,1H),2. 91-2.96(m,2H),3.30(ddd,J=5,13,13Hz,1H),3.45-3.65(m,3H),3.79(s,3H),4.53(br s,1H),4.88(d,J=15Hz,0.9H),4.92(d,J=15Hz,0.9H),5.20(d,J=15Hz,0.1H),5.53(d,J=15Hz,0.1H),6.69( dd,J=2,8Hz,1H),6.85-6.92(m,3H),6.98(d,J=8Hz,1H),7.57(ddd,J=2,7,9Hz,1H),8.09(dd,J=2,5Hz,1H).

[0402] (Example 71) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-2-yloxy)ethane-1-one

[0403] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7' H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(pyridin-2-yloxy)ethan-1-one

[0404] The title compound was obtained from the compound obtained in Example 70 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.10(m,2H),0.44-0.49(m,2H),0.74-0.84(m,1H),1.02-1.31(m,4H),1.48-1.96(m ,6H),2.13-2.38(m,3H),2.51(dd,J=4,12Hz,1H),2.77(dd,J=6,18Hz,1H),2.90-2.98(m,2H),3.20-3.74(m,4H),4.50(br s,1H),4.86(d,J=15Hz,0.9H),4.92(d,J=15Hz,0.9H),5.25(d,J=15Hz,0.1H),5.55(d,J=15Hz,0.1H),6.61(dd,J=2,8Hz,0.9H),6.65 -6.68(m,0.1H),6.74-6.94(m,4H),7.49-7.53(m,0.1H),7.57(ddd,J=2,7,9Hz,0.9H),8.02-8.04(m,0.1H),8.08(dd,J=2,5Hz,0.9H).

[0405] (Example 72) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol

[0406] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-8a'-ol

[0407] The title compound was obtained from the compound obtained in Example 1 and 1-(2-bromoethyl)-3-fluorobenzene according to the method described in Example 51. 1H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.43-0.53(m,2H),0.75-0.86(m,1H),1.04-1.16(m,3H),1.41-1.78(m ,4H),1.59(ddd,J=4,13,13Hz,1H),1.82(d,J=14Hz,1H),1.90(ddd,J=3,12,12Hz,1H),1.99(ddd,J=4,14,14Hz,1H),2.01 -2.12(m,1H),2.07(d,J=14Hz,1H),2.27(dd,J=7,13Hz,1H),2.38(dd,J=6,13Hz,1H),2.51(ddd,J=1,4,11Hz,1H),2.64-2 .86(m,5H),2.90(d,J=6Hz,1H),2.92-3.00(m,1H),2.94(d,J=18Hz,1H),3.05(ddd,J=5,9,9Hz,1H),3.77(s,3H),4.56(br s,1H),6.68(dd,J=3,8Hz,1H),6.85-6.92(m,1H),6.89(d,J=3Hz,1H),6.94-6 .99(m,1H),6.96(d,J=8Hz,1H),7.00-7.04(m,1H),7.24(ddd,J=6,8,8Hz,1H).

[0408] (Example 73) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0409] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0410] The title compound was obtained from the compound obtained in Example 72 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.42-0.54(m,2H),0.74-0.86(m,1H),1.02-1.12(m,2H),1.13-1.19(m,1H),1.33-1.62(m, 4H),1.60(ddd,J=4,13,13Hz,1H),1.84-1.98(m,2H),2.07(ddd,J=5,12,12Hz,1H),2.12-2.18(m,2H),2.28(dd,J=6,13Hz,1H),2.37(dd,J=6, 13Hz,1H),2.49-2.66(m,3H),2.77(dd,J=6,18Hz,1H),2.90(d,J=6Hz,1H),2.91-2.99(m,3H),3.14(ddd,J=6,12,12Hz,1H),3.22(ddd,J=4,1 0,10Hz,1H),6.64(dd,J=2,8Hz,1H),6.88(d,J=8Hz,1H),6.89-6.94(m,1H),6.96-7.01(m,1H),7.02-7.07(m,2H),7.27(ddd,J=6,8,8Hz,1H).

[0411] (Example 74) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(4-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol

[0412] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(4-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-8a'-ol

[0413] The title compound was obtained from the compound obtained in Example 1 and 1-(2-chloroethyl)-4-fluorobenzene according to the method described in Example 51. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.16(m,2H),0.42-0.54(m,2H),0.74-0.86(m,1H),1.04-1.15(m,3H),1.42-1.78(m,4H),1.59(ddd,J= 4,13,13Hz,1H),1.82(d,J=14Hz,1H),1.90(ddd,J=3,12,12Hz,1H),1.99(ddd,J=4,13,13Hz,1H),2.01-2.11(m,1H),2.07(d,J=14Hz,1H),2. 27(dd,J=7,12Hz,1H),2.37(dd,J=7,12Hz,1H),2.51(ddd,J=2,5,12Hz,1H),2.61-2.84(m,5H),2.88-2.97(m,1H),2.90(d,J=6Hz,1H),2.94( d,J=18Hz,1H),3.05(ddd,J=5,10,10Hz,1H),3.77(s,3H),6.68(dd,J=3,8Hz,1H),6.89(d,J=3Hz,1H),6.93-7.01(m,3H),7.17-7.23(m,2H).

[0414] (Example 75) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(4-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0415] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(4-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0416] The title compound was obtained from the compound obtained in Example 74 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.45-0.51(m,2H),0.74-0.85(m,1H),1.03-1.12(m,2H),1.13-1.19(m,1H) ),1.35-1.65(m,5H),1.85-1.97(m,2H),2.07(ddd,J=4,13,13Hz,1H),2.11-2.16(m,2H),2.27(dd,J=7,13Hz,1H),2.37(dd,J =6,13Hz,1H),2.48-2.64(m,3H),2.77(dd,J=6,18Hz,1H),2.87-3.00(m,2H),2.89(d,J=6Hz,1H),2.93(d,J=18Hz,1H),3.11( ddd,J=6,10,10Hz,1H),3.18-3.26(m,1H),6.64(dd,J=2,8Hz,1H),6.88(d,J=8Hz,1H),6.96-7.05(m,3H),7.19-7.25(m,2H).

[0417] (Example 76) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)prop-2-en-1-one

[0418] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydr o-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)prop-2-en-1-one

[0419] To a solution of the compound obtained in Example 18 (43.8 mg, 0.110 mmol) in tetrahydrofuran (2.5 mL), N,N-diisopropylethylamine (48 μL, 0.28 mmol) and acrylate chloride (15 μL, 0.19 mmol) were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and chloroform (3.5 mL) and 1 M boron tribromide-dichloromethane solution (0.50 mL, 0.50 mmol) were added to the residue, and the mixture was stirred at 0°C for 1 hour. Saturated sodium bicarbonate aqueous solution (6 mL), chloroform (2 mL), and 2-propanol (1 mL) were added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted three times with chloroform, and the combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (20-46% methanol / ethyl acetate) to obtain the title compound (20.7 mg, 43%) as a white solid. 1H-NMR(400MHz,CD3OD)δ(ppm):0.12-0.22(m,2H),0.50-0.61(m,2H),0.82-0.94(m,1H),1.19-1.31(m,2H ),1.34-1.49(m,2H),1.51-1.59(m,1H),1.70-1.83(m,1H),1.86-2.11(m,2H),2.12-2.26(m,1H),2.35-2. 52(m,3H),2.57-2.74(m,2H),3.06(d,J=18Hz,1H),3.15(d,J=5Hz,1H),3.18-3.29(m,1H),3.52-3.73(m,2 H),5.62(s,1H),5.70(dd,J=2,11Hz,1H),6.28(dd,J=2,17Hz,1H),6.50-6.60(m,2H),6.67(d,J=8Hz,1H).

[0420] (Example 77) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-3-(piperidine-1-yl)propan-1-one

[0421] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a 'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-3-(piperidin-1-yl)propan-1-one

[0422] To a solution of the compound obtained in Example 76 (6.9 mg, 16 μmol) in N,N-dimethylformamide (2.5 mL), piperidine (20 μL, 0.20 mmol) was added and the mixture was stirred at 60°C for 17 hours. Then, piperidine (30 μL, 0.30 mmol) was added and the mixture was stirred at 90°C for 4 hours. After the reaction mixture was allowed to cool to room temperature, it was concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (chloroform:10% aqueous ammonia-methanol solution = 6:1) to obtain the title compound (7.4 mg, 90%) as a colorless amorphous material. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.15(m,2H),0.45-0.54(m,2H),0.76-0.87(m,1H),1.07-1.17 (m,2H),1.24-1.36(m,2H),1.38-1.47(m,2H),1.48-1.62(m,5H),1.63-1.74(m,1H),1.76-1.86(m,1 H),1.88-1.99(m,1H),2.07(ddd,J=4,12,12Hz,1H),2.27-2.67(m,11H),2.68-2.78(m,2H),2.99(d ,J=18Hz,1H),3.04(d,J=5Hz,1H),3.18-3.29(m,1H),3.34-3.43(m,1H),3.46-3.55(m,1H),5.12(br s,1H),5.67(d,J=4Hz,1H),6.53(d,J=8Hz,1H),6.69(d,J=8Hz,1H).

[0423] (Reference example 16) Synthesis of tert-butyl 3-(3-fluoropiperidine-1-yl)propanoate

[0424] [ka] tert-butyl 3-(3-fluoropiperidin-1-yl)propanoate

[0425] The title compound was obtained from tert-butyl acrylate and 3-fluoropiperidine hydrochloride according to the method described in Reference Example 6. 1 H-NMR(400MHz,CDCl3)δ(ppm):1.44(s,9H),1.47-1.66(m,2H),1.75-1.93(m,2H),2.29(ddd,J=3,9,1 1Hz,1H),2.39-2.51(m,4H),2.63-2.72(m,2H),2.73-2.82(m,1H),4.61(ddddd,J=4,4,7,7,48Hz,1H).

[0426] (Reference example 17) Synthesis of 3-(3-fluoropiperidine-1-yl)propanoate 2,2,2-trifluoroacetate

[0427] [ka] 3-(3-fluoropiperidin-1-yl)propanoic acid

[0428] The title compound was obtained from the compound obtained in Reference Example 16, following the method described in Reference Example 15. 1 H-NMR(400MHz,CD3OD)δ(ppm):1.70-1.93(m,2H),2.03-2.17(m,2H),2.77-2.91(m ,2H),3.03-3.15(m,1H),3.22-3.56(m,4H),3.66-3.79(m,1H),4.97-5.15(m,1H).

[0429] (Example 78) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(3-fluoropiperidine-1-yl)propan-1-one

[0430] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H -spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(3-fluoropiperidin-1-yl)propan-1-one

[0431] The title compound was obtained from the compound obtained in Example 1 and the compound obtained in Reference Example 17, according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.42-0.54(m,2H),0.75-0.89(m,1H),1.00-1.17(m,1.8H),1.19-1.43(m,1.2H),1. 45-1.97(m,11H),2.20(ddd,J=5,13,13Hz,1H),2.28(dd,J=7,13Hz,0.8H),2.29-2.59(m,7H),2.61-3.03(m,6.6H),3.31(ddd,J=5,13 ,13Hz,0.8H),3.37-3.43(m,1.6H),3.46(d,J=14Hz,0.8H),3.49-3.64(m,0.4H),3.78(s,3H),4.65(ddddd,J=3,3,6,6,48Hz,1H),6.6 9(dd,J=3,8Hz,0.8H),6.70-6.73(m,0.2H),6.86(d,J=3Hz,0.2H),6.88(d,J=3Hz,0.8H),6.98(d,J=8Hz,0.8H),6.99-7.02(m,0.2H).

[0432] (Example 79) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(3-fluoropiperidine-1-yl)propan-1-one

[0433] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-sp iro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(3-fluoropiperidin-1-yl)propan-1-one

[0434] The title compound was obtained from the compound obtained in Example 78 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.16(m,2H),0.42-0.53(m,2H),0.75-0 .88(m,1H),1.00-1.08(m,0.8H),1.09-1.20(m,1.2H),1.22-1.37(m,1H),1. 40-2.09(m,9.8H),2.14-2.65(m,9.4H),2.67-3.04(m,6.6H),3.15-3.28(m, 0.8H),3.31-3.40(m,0.8H),3.41-3.51(m,1H),3.53-3.78(m,1.6H),4.53(br s,1H),4.54-4.73(m,1H),6.58-6.63(m,0.8H),6.66(dd,J=2,8Hz,0.2H),6.77-6. 80(m,0.8H),6.83(dd,J=2,8Hz,0.2H),6.92(d,J=8Hz,0.8H),6.93-6.96(m,0.2H).

[0435] (Example 80) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol

[0436] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0437] The title compound was obtained from the compound obtained in Example 1 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.13(m,2H),0.45-0.53(m,2H),0.76-0.86(m,1H),1.09-1.15(m,2H),1.40-1.70(m,6H),1.81( ddd,J=3,12,12Hz,1H),1.92-2.08(m,2H),2.15-2.40(m,4H),2.49-2.54(m,1H),2.78(dd,J=6,18Hz,1H),2.90-3.00(m,4H),4.61(br s,1H),6.63(dd,J=2,8Hz,1H),6.91(d,J=8Hz,1H),6.97(d,J=2Hz,1H).

[0438] (Example 81) Synthesis of 1-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxopropyl)cyclopropane-1-carbonitrile

[0439] [ka] 1-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-s piro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-oxopropyl)cyclopropane-1-carbonitrile

[0440] To a solution of the compound obtained in Example 80 (19.7 mg, 0.0535 mmol) and 3-(1-cyanocyclopropyl)propanoic acid (synthesized by the method described in WO2015180612, 15.7 mg, 0.113 mmol) in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (45.5 μL, 0.268 mmol) and HATU (24.8 mg, 0.0652 mmol) were added, and the mixture was stirred at room temperature for 19 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and it was extracted three times with ethyl acetate. The combined extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (1 mL), potassium carbonate (38 mg, 0.27 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. Water was added to the reaction mixture, and it was extracted three times with ethyl acetate. The combined extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by preparative thin-layer chromatography (chloroform:2M ammonia-methanol solution = 95:5, 3 times) to obtain the title compound (10.4 mg, 40%) as white crystals. 1H-NMR (400MHz, CDCl3) δ (ppm): 0.04-0.11 (m, 2H), 0.45-0.51 (m, 2H), 0.77-0.94 (m, 3H), 1.03-1.33 (m, 5H), 1.42-1.76 (m, 5H), 1.80-1.93 (m, 4 H),2.14-2.40(m,3H),2.48-2.60(m,3H),2.78(dd,J=6,18Hz,1H),2.91-3.00(m,2H),3.22(ddd,J=5,13,13Hz,1H),3.42-3.75(m,3H),4.62(br s,1H),4.96(br s,1H),6.61(dd,J=3,8Hz,0.9H),6.64(dd,J=3,8Hz,0.1H),6.81(d,J=3Hz,1H),6.93(d,J=8Hz,0.9H),6.95(d,J=8Hz,0.1H).

[0441] (Refer to Example 18) 3-(2-(ベンジルオキシ)エチル)イソチアゾールの synthesis

[0442]

change

[0443] 5-(benzyloxy)pento-1-in-3-ol (synthesized by the method described in Tetrahedron Letters 2016, 57, 603, 1.39 g, 7.31 mmol) was dissolved in ethyl acetate (36 mL), to which 2-iodoxybenzoic acid (purity 39-50%, 6.82 g, 9.50 mmol) was added, and the mixture was heated under reflux for 17 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To a solution of the resulting brown oily substance (1.34 g) in water (15 mL), hydroxylamine-O-sulfonic acid (965 mg, 8.53 mmol) was added under ice cooling, and the mixture was stirred at 0°C for 30 minutes and at room temperature for 30 minutes. Sodium bicarbonate (718 mg, 8.55 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0°C, and a solution of sodium bisulfide n-hydrate (785 mg, 8.52 mmol) in water (6 mL) was added. The mixture was stirred at 0°C for 15 minutes and then at room temperature for 18 hours, followed by three extractions with ethyl acetate. The combined extracts were washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (13-34% ethyl acetate / heptane) to obtain the title compound (309 mg, 19%) as a pale yellow oil. 1 H-NMR(400MHz,CDCl3)δ(ppm):3.19(t,J=7Hz,2H),3.85(t,J=7Hz,2H),4.55(s,2H),7.15(d,J=5Hz,1H),7.28-7.36(m,5H),8.58(d,J=5Hz,1H).

[0444] (Reference example 19) Synthesis of 2-(isothiazole-3-yl)ethane-1-ol

[0445] [ka] 2-(isothiazol-3-yl)ethan-1-ol

[0446] To a chloroform (7 mL) solution of the compound obtained in Reference Example 18 (309 mg, 1.41 mmol), 1 M boron tribromide-dichloromethane solution (2.82 mL, 2.82 mmol) was added under ice cooling and stirred for 45 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted three times with ethyl acetate. The combined extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (64-85% ethyl acetate / heptane) to obtain the title compound (144 mg, 79%) as a pale yellow oily substance. 1 H-NMR(400MHz,CDCl3)δ(ppm):3.10(t,J=6Hz,2H),4.04(t,J=6Hz,2H),7.11(d,J=4Hz,1H),8.62(d,J=4Hz,1H).

[0447] (Reference example 20) Synthesis of 2-(isothiazole-3-yl)ethyl methanesulfonate

[0448] [ka] 2-(isothiazol-3-yl)ethyl methanesulfonate

[0449] To a solution of the compound obtained in Reference Example 19 (144 mg, 1.11 mmol) in tetrahydrofuran (5.5 mL), N,N-diisopropylethylamine (0.57 mL, 3.3 mmol) and methanesulfonic anhydride (291 mg, 1.67 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and it was extracted three times with ethyl acetate. The combined extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (50-71% ethyl acetate / heptane) to obtain the title compound (215 mg, 94%) as a pale yellow oil. 1H-NMR(400MHz,CDCl3)δ(ppm):2.96(s,3H),3.32(t,J=7Hz,2H),4.65(t,J=7Hz,2H),7.16(d,J=4Hz,1H),8.65(d,J=4Hz,1H).

[0450] (Example 82) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(isothiazol-3-yl)ethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol

[0451] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(isothiazol-3-yl)ethyl)-3'-methoxy-7',8', 9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-8a'-ol

[0452] The title compound was obtained from the compound obtained in Example 1 and the compound obtained in Reference Example 20, according to the method described in Example 51. 1H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.12(m,2H),0.46-0.52(m,2H),0.76-0.84(m,1H),1.08-1.28(m,3 H),1.44-1.77(m,8H),1.80-2.12(m,4H),2.25-2.41(m,2H),2.50-2.53(m,1H),2.64-3.18(m,7H),3.77( s,2.7H),3.78(s,0.3H),6.68(dd,J=2,8Hz,0.9H),6.72(dd,J=2,8Hz,0.1H),6.83(d,J=2Hz,0.1H),6.8 9(d,J=2Hz,0.9H),6.96(d,J=8Hz,0.9H),7.01(d,J=8Hz,0.1H),7.16(d,J=5Hz,1H),8.58(d,J=5Hz,1H).

[0453] (Example 83) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(isothiazol-3-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0454] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(isothiazol-3-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0455] The title compound was obtained from the compound obtained in Example 82 according to the method described in Example 3. 1H-NMR(400MHz,CDCl3)δ(ppm):0.05-0.12(m,2H),0.46-0.53(m,2H),0.76-0.86(m,1H),1.05-1.33(m,3H),1.46-1.71(m,7H),1.90-1 .99(m,2H),2.03-2.22(m,2H),2.25-2.41(m,2H),2.51-2.61(m,2H),2.75-2.84(m,2H),2.90-2.98(m,2H),3.08-3.28(m,3H),4.59(br s,1H),6.62(dd,J=2,8Hz,0.8H),6.64(dd,J=2,8Hz,0.2H),6.79(d,J=2Hz,0.2H),6.89-6.96(m,1.8H),7.18(d,J=4Hz,1H),8.59(d,J=4Hz,1H).

[0456] (Example 84) Synthesis of (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylisothiazol-3-yl)prop-2-en-1-one

[0457] [ka] (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H -spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(5-methylisothiazol-3-yl)prop-2-en-1-one

[0458] The title compound was obtained from the compound obtained in Example 1 and (E)-3-(5-methylisothiazol-3-yl)acrylic acid (synthesized by the method described in WO2021065898) according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.08-0.18(m,2H),0.48-0.55(m,2H),0.80-0.92(m,1H),1.05-1.34(m,3H),1.40-1.79(m,5H),1. 85-2.12(m,2H),2.21-2.46(m,3H),2.55-3.03(m,5H),2.58(s,1.5H),2.60(s,1.5H),3.37-3.75(m,3H),3.79(s,3H),6.70(dd,J =2,8Hz,0.5H),6.73(dd,J=2,8Hz,0.5H),6.87(d,J=2Hz,0.5H),6.89(d,J=2Hz,0.5H),7.00(d,J=8Hz,0.5H),7.01(d,J=16Hz,0. 5H),7.02(d,J=8Hz,0.5H),7.06(s,0.5H),7.52(s,0.5H),7.65(d,J=16Hz,0.5H),7.70(d,J=16Hz,0.5H),7.78(d,J=16Hz,0.5H).

[0459] (Example 85) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylisothiazol-3-yl)propan-1-one

[0460] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spi ro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(5-methylisothiazol-3-yl)propan-1-one

[0461] The title compound was obtained from the compound obtained in Example 84 according to the methods described in Example 37 and Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.11(m,2H),0.44-0.52(m,2H),0.76-0.85(m,1H),1.03-1.28(m,3H),1.48-1.76(m,5H) ),1.83-2.03(m,2H),2.16-2.39(m,3H),2.47-2.81(m,7H),2.90-2.97(m,2H),3.02-3.25(m,3H),3.34-3.69(m,3H),4.62(br s,1H),5.35(br s,1H),6.61(dd,J=2,8Hz,0.9H),6.67(dd,J=2,8Hz,0.1H),6.81-6.86(m,2H),6.92(d,J=8Hz,0.9H),6.93(d,J=8Hz,0.1H).

[0462] (Example 86) Synthesis of 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl) tert-butyl acetate

[0463] [ka] tert-butyl 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-h exahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)acetate

[0464] The title compound was obtained from the compound obtained in Example 18 and tert-butyl bromoacetate according to the method described in Example 47. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.07-0.16(m,2H),0.47-0.57(m,2H),0.78-0.88(m,1H),1.07-1.17(m, 1H),1.24-1.44(m,4H),1.48(s,9H),1.50-1.58(m,1H),1.62-1.73(m,1H),1.81-1.93(m,1H),2.03-2.1 4(m,2H),2.24(ddd,J=5,12,12Hz,1H),2.29-2.43(m,2H),2.53-2.66(m,2H),2.94-3.08(m,4H),3.32( d,J=16Hz,1H),3.42(d,J=16Hz,1H),3.86(s,3H),4.56(s,1H),6.57(d,J=8Hz,1H),6.71(d,J=8Hz,1H).

[0465] (Example 87) Synthesis of 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-1-morpholinoethane-1-one

[0466] [ka] 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro- 1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-1-morpholinoethan-1-one

[0467] To a chloroform (2 mL) solution of the compound obtained in Example 86 (4.9 mg, 9.6 μmol), trifluoroacetic acid (0.50 mL, 6.5 mmol) was added and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in N,N-dimethylformamide (1.5 mL). Morpholine (4.0 μL, 46 μmol), N,N-diisopropylethylamine (7.0 μL, 40 μmol), and HATU (9.0 mg, 24 μmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (amino group-supported silica gel, 50-80% ethyl acetate / heptane) to obtain the title compound (2.5 mg, 50%) as a colorless amorphous material. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.08-0.16(m,2H),0.48-0.57(m,2H),0.78-0 .88(m,1H),0.99-1.10(m,1H),1.16-1.45(m,5H),1.46-1.62(m,2H),1.98-2. 43(m,5H),2.53-2.67(m,2H),2.78-2.86(m,1H),2.91-3.08(m,3H),3.46-3.8 3(m,10H),3.87(s,3H),4.59(s,1H),6.59(d,J=8Hz,1H),6.71(d,J=8Hz,1H).

[0468] (Example 88) Synthesis of 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-1-morpholinoethane-1-one

[0469] [ka] 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H ,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-1-morpholinoethan-1-one

[0470] The title compound was obtained from the compound obtained in Example 87 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.08-0.16(m,2H),0.48-0.56(m,2H),0.78-0.88(m,1 H),0.99-1.09(m,1H),1.18-1.44(m,5H),1.49-1.69(m,2H),2.03-2.15(m,2H),2.18 -2.28(m,1H),2.29-2.43(m,2H),2.51-2.72(m,3H),2.95-3.09(m,3H),3.41-3.58(m ,2H),3.61-3.73(m,8H),4.57(d,J=3Hz,1H),6.54(d,J=8Hz,1H),6.71(d,J=8Hz,1H).

[0471] (Example 89) Synthesis of 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-(4-methylpiperazine-1-yl)propan-1-one

[0472] [ka] 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-s piro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one

[0473] The title compound was obtained from the compound obtained in Example 76 and N-methylpiperazine according to the method described in Example 77. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.15(m,2H),0.45-0.55(m,2H),0.76-0.88(m,1H),1.09-1.19(m, 2H),1.24-1.38(m,2H),1.49-1.57(m,1H),1.63-1.99(m,4H),2.07(ddd,J=4,12,12Hz,1H),2.29(s,3H) ),2.30-2.69(m,14H),2.75-2.85(m,2H),2.99(d,J=18Hz,1H),3.05(d,J=5Hz,1H),3.23(ddd,J=2,14, 14Hz,1H),3.36-3.44(m,1H),3.46-3.55(m,1H),5.68(s,1H),6.54(d,J=8Hz,1H),6.67(d,J=8Hz,1H).

[0474] (Example 90) Synthesis of 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl) tert-butyl propanoate

[0475] [ka] tert-butyl 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hex ahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)propanoate

[0476] To a solution of the compound obtained in Example 18 (5.4 mg, 14 μmol) in N,N-dimethylformamide (1.5 mL), tert-butyl acrylate (40 μL, 0.28 mmol), potassium carbonate (14.6 mg, 0.106 mmol), and DBU (21 μL, 0.14 mmol) were added and the mixture was stirred at 90°C for 3 hours. 100 μL, 0.686 mmol of tert-butyl acrylate was added and the mixture was stirred at 110°C for 19 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted three times with chloroform. The combined extract 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, 20-40% ethyl acetate / heptane) to obtain the title compound (5.3 mg, 74%) as a colorless amorphous material. 1H-NMR(400MHz,CDCl3)δ(ppm):0.08-0.16(m,2H),0.47-0.56(m,2H),0.78-0.89(m,1H),0.93-1.03(m,1 H),1.11-1.19(m,1H),1.26-1.44(m,2H),1.47(s,9H),1.48-1.56(m,2H),1.57-1.67(m,1H),1.74-1.85( m,1H),2.07(ddd,J=4,12,12Hz,1H),2.16(ddd,J=2,14,14Hz,1H),2.22-2.48(m,5H),2.51-2.75(m,3H), 2.76-2.86(m,1H),2.93-3.06(m,4H),3.86(s,3H),4.66(s,1H),6.56(d,J=8Hz,1H),6.70(d,J=8Hz,1H).

[0477] (Example 91) Synthesis of 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-1-morpholinopropan-1-one

[0478] [ka] 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro- 1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-1-morpholinopropane-1-one

[0479] The title compound was obtained from the compound obtained in Example 90 and morpholine according to the method described in Example 87. 1H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.14(m,2H),0.47-0.55(m,2H),0.76-0.88(m,1H), 0.94-1.05(m,1H),1.11-1.43(m,4H),1.45-1.88(m,4H),2.07(ddd,J=4,12,12Hz,1H),2. 12-2.42(m,3H),2.46-2.65(m,4H),2.67-2.77(m,1H),2.84-3.10(m,5H),3.46-3.53(m,2 H),3.59-3.74(m,6H),3.85(s,3H),4.64(s,1H),6.58(d,J=8Hz,1H),6.70(d,J=8Hz,1H).

[0480] (Example 92) Synthesis of 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-1-yl)-1-morpholinopropan-1-one

[0481] [ka] 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H ,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-1-morpholinopropan-1-one

[0482] The title compound was obtained from the compound obtained in Example 91 according to the method described in Example 3. 1H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.17(m,2H),0.48-0.56(m,2H),0.77-0.88(m,1H),0.95-1.0 5(m,1H),1.16-1.44(m,4H),1.49-1.75(m,3H),2.02-2.15(m,2H),2.21-2.41(m,3H),2.42-2.65(m ,5H),2.67-2.77(m,1H),2.98(d,J=18Hz,1H),3.03(d,J=5Hz,1H),3.04-3.12(m,1H),3.15-3.25( m,1H),3.46-3.53(m,2H),3.56-3.76(m,6H),4.67(s,1H),6.52(d,J=8Hz,1H),6.68(d,J=8Hz,1H).

[0483] (Example 93) Synthesis of 4-(3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-oxopropyl)piperazine-2-one

[0484] [ka] 4-(3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H ,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-3-oxopropyl)piperazin-2-one

[0485] To a solution of the compound obtained in Example 76 (4.7 mg, 11 μmol) in N,N-dimethylformamide (1.0 mL), 2-piperazinone (63 mg, 0.63 mmol) was added and the mixture was stirred at 100°C for 2 hours. 1,4-diazabicyclo[2.2.2]octane (1.2 mg, 11 μmol) was added and the mixture was stirred at 100°C for 3 hours. The reaction temperature was raised to 130°C and the mixture was stirred for 15 hours. After the reaction mixture cooled to room temperature, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted three times with ethyl acetate. The combined extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (chloroform:10% aqueous ammonia-methanol solution = 8:1) to obtain the title compound (1.4 mg, 24%) as a colorless amorphous material. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.07-0.15(m,2H),0.47-0.54(m,2H),0.77-0.89(m,1H), 1.09-1.21(m,2H),1.24-1.38(m,2H),1.50-1.81(m,5H),1.85-1.95(m,1H),2.02-2.12(m ,1H),2.26-2.68(m,7H),2.70-2.92(m,3H),3.00(d,J=18Hz,1H),3.06(d,J=5Hz,1H),3. 15-3.28(m,2H),3.34-3.60(m,4H),5.72(s,1H),6.55(d,J=8Hz,1H),6.69(d,J=8Hz,1H).

[0486] (Reference example 21) Synthesis of 2-(5-fluoropyridine-2-yl)acetic acid

[0487] [ka] 2-(5-fluoropyridin-2-yl)acetic acid

[0488] 2-(5-fluoropyridine-2-yl)acetonitrile (187 mg, 1.38 mmol) was dissolved in ethanol (1.5 mL), and 2 M potassium hydroxide aqueous solution (1.50 mL, 3.00 mmol) was added. The mixture was stirred at 100°C for 1 hour. After the reaction mixture cooled to room temperature, 2 M hydrochloric acid was added to adjust the pH to 3-4, and the mixture was extracted three times with tert-butyl methyl ether and three times with ethyl acetate. The organic layers were washed together with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting white solid was washed with a mixed solution of heptane:ethyl acetate = 10:1 (v / v) to obtain the title compound (101 mg, 47%) as a white powder. 1 H-NMR(400MHz,CDCl3)δ(ppm):3.91(s,2H),7.30(dd,J=4,8Hz,1H),7.54(ddd,J=3,8,8Hz,1H),8.42(d,J=3Hz,1H).

[0489] (Example 94) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-(5-fluoropyridine-2-yl)ethane-1-one

[0490] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7' H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-2-(5-fluoropyridin-2-yl)ethan-1-one

[0491] The method described in Example 2 was used, the compound compound described in Example 1 was obtained, and the compound compound listed in Reference Example 21 was obtained. 1 H-NMR (400MHz, CDCl3) δ (ppm): 0.02-0.14 (m, 2H), 0.41-0.54 (m, 2H), 0.74-0.85 (m, 1H), 0.99-1.06 (m, 0.8H), 1 .07-1.17(m,1H),1.19-1.37(m,1.2H),1.40-1.78(m,5H),1.85(ddd,J=4,12,12Hz,1H),1.89(d,J=14Hz,1H),1. 90-2.11(m,1H),2.12-2.23(m,0.2H),2.18(ddd,J=5,12,12Hz,0.8H),2.25-2.33(m,0.2H),2.27(dd,J=7,13Hz, 0.8H),2.35-2.41(m,0.2H),2.36(dd,J=6,13Hz,0.8H),2.48-2.65(m,1H),2.73-2.86(m,1.2H),2.92(d,J=6Hz, 0.8H),2.94(d,J=18Hz,0.8H),2.97-3.01(m,0.2H),3.30(ddd,J=5,13,13Hz,0.8H),3.45(d,J=14Hz,0.8H), 3.50-3.70(m,2H),3.75-3.83(m,1.4H),3.77(s,3H),6.64-6.71(m,0.2H),6.68(dd,J=3,8Hz,0.8H),6.86(d,J= 3Hz,0.8H),6.88(d,J=3Hz,0.2H),6.98(d,J=8Hz,0.8H),7.01(d,J=8Hz,0.2H),7.31-7.38(m,0.2H),7.36(ddd, J=3,9,9Hz,0.8H),7.43-7.46(m,0.2H),7.47(dd,J=4,9Hz,0.8H),8.36(d,J=3Hz,0.8H),8.41(d,J=3Hz,0.2H).

[0492] (Example 95) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(5-fluoropyridine-2-yl)ethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol

[0493] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(5-fluoropyridin-2-yl)ethyl)-3'-methoxy-7',8 ',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-8a'-ol

[0494] The title compound was obtained from the compound obtained in Example 94 according to the method described in Example 18. 1H-NMR(400MHz,CDCl3)δ(ppm):0.02-0.14(m,2H),0.41-0.51(m,2H),0.73-0.94(m,1H),1.01-1.13(m,3H),1.20-1.74(m,5H),1.78(d,J =14Hz,1H),1.88(ddd,J=4,12,12Hz,1H),1.98(ddd,J=4,14,14Hz,1H),2.05(ddd,J=5,12,12Hz,1H),2.08(d,J=14Hz,1H),2.26(dd,J=7 ,13Hz,1H),2.36(dd,J=6,12Hz,1H),2.46-2.53(m,1H),2.67(ddd,J=5,10,10Hz,1H),2.73-2.82(m,2H),2.86-3.13(m,6H),3.77(s,3H) ,6.67(dd,J=3,8Hz,1H),6.87(d,J=3Hz,1H),6.94(d,J=8Hz,1H),7.21(dd,J=5,8Hz,1H),7.31(ddd,J=3,8,8Hz,1H),8.38(d,J=3Hz,1H).

[0495] (Example 96) Synthesis of (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(5-fluoropyridine-2-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0496] [ka] (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(5-fluoropyridin-2-yl)ethyl)-7',8',9',10' -tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-3',8a'-diol

[0497] The title compound was obtained from the compound obtained in Example 95 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.02-0.15(m,2H),0.41-0.53(m,2H),0.74-0.85(m,1H),1.10-1.38(m,3H),1.44-1.52(m,1H),1.55-1.79 (m,4H),1.94(ddd,J=3,12,12Hz,1H),2.02(ddd,J=4,13,13Hz,1H),2.04-2.10(m,1H),2.12-2.32(m,2H),2.28(dd,J=7,13Hz,1H),2.38(d d,J=6,13Hz,1H),2.48-2.56(m,1H),2.60-2.69(m,1H),2.76(dd,J=6,18Hz,1H),2.88-2.96(m,2H),2.93(d,J=18Hz,1H),3.05-3.37(m,4 H),6.64(dd,J=3,8Hz,1H),6.89(d,J=8Hz,1H),6.94-7.01(m,1H),7.28(dd,J=5,9Hz,1H),7.35(ddd,J=3,8,8Hz,1H),8.40(d,J=3Hz,1H).

[0498] (Reference example 22) Synthesis of 4-cyanophenethyl methanesulfonic acid

[0499] [ka] 4-cyanophenethyl methanesulfonate

[0500] The title compound was obtained from 4-(2-hydroxyethyl)benzonitrile according to the method described in Reference Example 11. 1 H-NMR(400MHz,CDCl3)δ(ppm):2.93(s,3H),3.13(t,J=7Hz,2H),4.45(t,J=7Hz,2H),7.35-7.39(m,2H),7.62-7.66(m,2H).

[0501] (Example 97) Synthesis of 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)ethyl)benzonitrile

[0502] [ka] 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrah ydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)ethyl)benzonitrile

[0503] The title compound was obtained from the compound obtained in Example 1 and the compound obtained in Reference Example 22, according to the method described in Example 47. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.15(m,2H),0.43-0.53(m,2H),0.74-0.85(m,1H),1.01-1.15(m,3H),1. 41-1.80(m,6H),1.84-2.10(m,4H),2.27(dd,J=7,13Hz,1H),2.37(dd,J=6,13Hz,1H),2.47-2.53(m,1H),2.62 -2.87(m,5H),2.88-3.00(m,1H),2.90(d,J=6Hz,1H),2.94(d,J=18Hz,1H),3.01(ddd,J=5,10,10Hz,1H),3.77 (s,3H),6.68(dd,J=3,8Hz,1H),6.87(d,J=3Hz,1H),6.96(d,J=8Hz,1H),7.33-7.37(m,2H),7.56-7.60(m,2H).

[0504] (Example 98) Synthesis of 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzonitrile

[0505] [ka] 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydr o-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)ethyl)benzonitrile

[0506] The title compound was obtained from the compound obtained in Example 97 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.45-0.52(m,2H),0.74-0.85(m,1H),1.03-1.16(m,3H),1.46(ddd,J=3 ,3,13Hz,1H),1.50-1.69(m,4H),1.84-1.96(m,2H),1.97-2.10(m,3H),2.28(dd,J=6,13Hz,1H),2.37(dd,J=6,13Hz,1H), 2.49-2.61(m,2H),2.62-2.71(m,1H),2.77(dd,J=6,18Hz,1H),2.90(d,J=6Hz,1H),2.92-3.00(m,2H),2.93(d,J=18Hz,1H) ),3.04-3.20(m,2H),6.62(dd,J=3,8Hz,1H),6.89(d,J=8Hz,1H),6.93-6.96(m,1H),7.35-7.39(m,2H),7.57-7.62(m,2H).

[0507] (Example 99) Synthesis of 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzamide

[0508] [ka] 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetra hydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)ethyl)benzamide

[0509] The compound obtained in Example 97 (6.9 mg, 13 μmol), palladium(II) acetate (2.9 mg, 13 μmol), and triphenylphosphine (7.0 mg, 27 μmol) were suspended in toluene (1.0 mL), acetaldehyde oxime (8.2 μL, 0.13 mmol) was added, and the mixture was stirred at 80°C for 1 hour. After the reaction mixture cooled to room temperature, it was concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (chloroform:2 M ammonia-methanol solution = 10:1) to obtain the title compound (5.7 mg, 80%) as a colorless amorphous material. 1H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.15(m,2H),0.43-0.53(m,2H),0.74-0.86(m,1H),1.03-1 .15(m,3H),1.42-1.78(m,5H),1.82(d,J=14Hz,1H),1.89(ddd,J=3,12,12Hz,1H),1.99(ddd,J=4 ,13,13Hz,1H),2.00-2.10(m,1H),2.06(d,J=14Hz,1H),2.27(dd,J=6,13Hz,1H),2.37(dd,J=6,1 3Hz,1H),2.48-2.54(m,1H),2.64-3.02(m,8H),3.05(ddd,J=5,9,9Hz,1H),3.77(s,3H),5.59(br s,1H),6.04(br s,1H),6.68(dd,J=3,8Hz,1H),6.89(d,J=3Hz,1H),6.96(d,J=8Hz,1H),7.32-7.36(m,2H), 7.73-7.77(m,2H).

[0510] (Example 100) Synthesis of 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzamide

[0511] [ka] 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)ethyl)benzamide

[0512] The title compound was obtained from the compound obtained in Example 99 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.16(m,2H),0.43-0.51(m,2H),0.74-0.85(m,1H),1.07-1.1 6(m,3H),1.42-1.65(m,5H),1.87-1.97(m,2H),2.00-2.09(m,2H),2.11(d,J=14Hz,1H),2.27(dd, J=6,13Hz,1H),2.37(dd,J=6,13Hz,1H),2.48-2.62(m,2H),2.65-2.82(m,2H),2.86-3.06(m,2H), 2.90(d,J=6Hz,1H),2.93(d,J=18Hz,1H),3.15(ddd,J=6,11,11Hz,1H),3.18-3.26(m,1H),5.61(br s,1H),6.09(br s,1H),6.64(dd,J=2,8Hz,1H),6.89(d,J=8Hz,1H),6.97(d,J=2Hz,1H),7.33-7.38(m,2H),7.74-7.79(m,2H).

[0513] (Example 101) Synthesis of (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a',9'-diol

[0514] [ka] (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinoline]-4a',9'-diol

[0515] The title compound was obtained from the compound obtained in Example 18 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.17(m,2H),0.47-0.56(m,2H),0.78-0.89(m,1H),1.14-1.32(m,2H),1.37-1.54(m,2H),1.58-1.89(m,4H) ,1.90-2.00(m,1H),2.15-2.40(m,4H),2.55-2.66(m,2H),2.96-3.12(m ,4H),3.49(s,1H),4.44(s,1H),6.51(d,J=8Hz,1H),6.69(d,J=8Hz,1H).

[0516] (Example 102) Synthesis of 4-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-N,N-dimethyl-4-oxobutanamide

[0517] [ka] 4-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7 a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-N,N-dimethyl-4-oxobutanamide

[0518] To a solution of the compound obtained in Example 101 (5.6 mg, 15 μmol) in N,N-dimethylformamide (1.5 mL), succinic anhydride (6.0 mg, 60 μmol) was added and the mixture was stirred at 50°C for 15 hours. After the reaction mixture cooled to room temperature, dimethylamine (50% aqueous solution, 7.0 μL, 67 μmol), N,N-diisopropylethylamine (10 μL, 55 μmol), and HATU (14.1 mg, 37.1 μmol) were added and the mixture was stirred at room temperature for 1 hour. 2M aqueous sodium hydroxide solution (0.5 mL) was added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes. 2M hydrochloric acid (0.8 mL) and saturated aqueous sodium bicarbonate solution (4 mL) were added to the reaction mixture and extracted three times with chloroform. The combined extract was dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by preparative thin-layer chromatography (chloroform:10% aqueous ammonia-methanol solution = 10:1) to obtain the title compound (2.2 mg, 29%) as a white solid. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.15(m,2H),0.46-0.54(m,2H),0.77-0.87(m,1H),1.08-1.21(m, 2H),1.24-1.39(m,2H),1.49-1.56(m,1H),1.63-1.94(m,3H),2.08(ddd,J=4,12,12Hz,1H),2.29-2.45 (m,3H),2.50-2.79(m,6H),2.94(s,3H),2.99(d,J=18Hz,1H),3.02-3.05(m,1H),3.04(s,3H),3.15-3. 26(m,1H),3.41-3.50(m,1H),3.53-3.62(m,1H),5.68(s,1H),6.54(d,J=8Hz,1H),6.70(d,J=8Hz,1H).

[0519] (Example 103) Synthesis of 1-(3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-oxopropyl)cyclopropane-1-carbonitrile

[0520] [ka] 1-(3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H- spiro[pyrrolidine-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-1-yl)-3-oxopropyl)cyclopropane-1-carbonitrile

[0521] The title compound was obtained from the compound obtained in Example 101 and 3-(1-cyanocyclopropyl)propanoic acid (synthesized by the method described in WO2015180612) according to the method described in Example 2. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.06-0.15(m,2H),0.46-0.55(m,2H),0.77-0.96(m,3H),1.11-1.39(m ,6H),1.55(ddd,J=3,3,13Hz,1H),1.70-1.84(m,2H),1.85-2.01(m,3H),2.08(ddd,J=4,12,12Hz,1H) ,2.30-2.46(m,3H),2.51-2.67(m,4H),3.00(d,J=18Hz,1H),3.06(d,J=5Hz,1H),3.24(ddd,J=2,14,1 4Hz,1H),3.44-3.53(m,1H),3.55-3.64(m,1H),5.68(s,1H),6.56(d,J=8Hz,1H),6.70(d,J=8Hz,1H).

[0522] (Reference example 23) Synthesis of 3-cyanophenethyl methanesulfonic acid [ka] 3-cyanophenethyl methanesulfonate

[0523] The title compound was obtained from 3-(2-hydroxyethyl)benzonitrile according to the method described in Reference Example 11. 1 H-NMR(400MHz,CDCl3)δ(ppm):2.94(s,3H),3.11(t,J=7Hz,2H),4.33(t,J=7Hz,2H),7.46(dd,J=7,7Hz,1H),7.50(ddd,J=2,2,7Hz,1H),7.53-7.55 (m,1H),7.58(ddd,J=2,2,7Hz,1H).

[0524] (Example 104) Synthesis of 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)ethyl)benzonitrile

[0525] [ka] 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrah ydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)ethyl)benzonitrile

[0526] The title compound was obtained from the compound obtained in Example 1 and the compound obtained in Reference Example 23, according to the method described in Example 47. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.15(m,2H),0.43-0.53(m,2H),0.74-0. 86(m,1H),0.99-1.15(m,3H),1.41-1.53(m,2H),1.58(ddd,J=4,14,14Hz,1H), 1.59-1.77(m,2H),1.77(d,J=14Hz,1H),1.88-1.98(m,1H),1.90(ddd,J=3,12, 12Hz,1H),1.99-2.09(m,1H),2.00(d,J=14Hz,1H),2.27(dd,J=7,13Hz,1H),2. 30(dd,J=6,13Hz,1H),2.48-2.55(m,1H),2.64-2.74(m,2H),2.75-2.88(m,3H) ,2.89-3.00(m,1H),2.90(d,J=6Hz,1H),2.94(d,J=18Hz,1H),3.04(ddd,J=5,1 0,10Hz,1H),3.78(s,3H),6.68(dd,J=3,8Hz,1H),6.87(d,J=3Hz,1H),6.96(d, J=8Hz,1H),7.38(dd,J=8,8Hz,1H),7.46-7.52(m,2H),7.56(dd,J=1,1Hz,1H).

[0527] (Example 105) Synthesis of 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzonitrile

[0528] [ka] 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydr o-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)ethyl)benzonitrile

[0529] The title compound was obtained from the compound obtained in Example 104 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.03-0.15(m,2H),0.45-0.51(m,2H),0.74-0.85(m,1H),1.03-1.14(m,3H),1.46 (ddd,J=3,3,13Hz,1H),1.50-1.63(m,4H),1.83-1.98(m,3H),2.00-2.09(m,2H),2.27(dd,J=6,13Hz,1H),2.37(d d,J=6,13Hz,1H),2.48-2.69(m,3H),2.78(dd,J=6,18Hz,1H),2.87-2.96(m,4H),3.02-3.20(m,2H),6.62(dd,J=3 ,8Hz,1H),6.90(d,J=8Hz,1H),6.95(d,J=3Hz,1H),7.40(dd,J=7,7Hz,1H),7.48-7.53(m,2H),7.56-7.58(m,1H).

[0530] (Reference example 24) Synthesis of 3-(1-(trifluoromethyl)cyclopropyl)propyl ethyl

[0531] [ka] ethyl 3-(1-(trifluoromethyl)cyclopropyl)propanoate

[0532] Ethyl (E)-3-(1-(trifluoromethyl)cyclopropyl)acrylate (synthesized by the method described in WO2021 / 143803, 25.5 mg, 0.123 mmol) was dissolved in ethyl acetate (0.5 mL) and 10% palladium-activated carbon (13 mg, 0.012 mmol) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 23.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (15.9 mg, 62%) as a colorless oil. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.56-0.67(m,2H),0.92-1.02(m,2H),1.26(t,J=7Hz,3H),1.88-1.92(m,2H),2.47-2.51(m,2H),4.13(q,J=7Hz,2H).

[0533] (Reference example 25) Synthesis of 3-(1-(trifluoromethyl)cyclopropyl)propanoic acid

[0534] [ka] 3-(1-(trifluoromethyl)cyclopropyl)propanoic acid

[0535] To the compound obtained in Reference Example 24 (15.9 mg, 0.0756 mmol), ethanol (0.3 mL), water (0.3 mL), and sodium hydroxide (13.7 mg, 0.343 mmol) were added, and the mixture was stirred at room temperature for 4.5 hours. 1N hydrochloric acid was added to the reaction mixture, and it was extracted four times with chloroform. The combined extract was dried over sodium sulfate, concentrated under reduced pressure, and the title compound (14.4 mg, quantitative) was obtained as a colorless oil. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.57-0.68(m,2H),0.94-1.05(m,2H),1.88-1.92(m,2H),2.54-2.58(m,2H).

[0536] (Example 106) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-one

[0537] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spi ro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-one

[0538] The title compound was obtained from the compound obtained in Example 1 and the compound obtained in Reference Example 25, according to the method described in Example 2. 1H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.12(m,2H),0.44-0.52(m,2H),0.63-0.66(m,2H),0.74-0 .86(m,1H),0.93-0.95(m,2H),1.02-1.28(m,3H),1.47-1.75(m,5H),1.82-1.97(m,4H),2.20(dd d,J=5,13,13Hz,1H),2.27(dd,J=6,12Hz,1H),2.33-2.47(m,3H),2.51-2.55(m,1H),2.76-2.82( m,1H),2.92-3.01(m,2H),3.30(ddd,J=5,13,13Hz,1H),3.40-3.60(m,3H),3.78(s,3H),4.56(br s,1H),6.69(dd,J=2,8Hz,0.9H),6.71(dd,J=2,8Hz,0.1H),6.86(d,J=2Hz, 0.1H),6.87(d,J=2Hz,0.9H),6.98(d,J=8Hz,0.9H),7.00(d,J=8Hz,0.1H).

[0539] (Example 107) Synthesis of 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-one

[0540] [ka] 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[ pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthren]-1-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-one

[0541] The title compound was obtained from the compound obtained in Example 106 according to the method described in Example 3. 1 H-NMR(400MHz,CDCl3)δ(ppm):0.04-0.11(m,2H),0....

Claims

1. Compounds represented by the following general formula (I) or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, R １ C is a hydrogen atom. １－６ Alkyl alkyl group, C ３－６ Cycloalkyl groups, C ３－６ Cycloalkyl C １－６ Alkyl alkyl group, C ６－１０ Aryl group, heteroaryl group having 2 to 9 carbon atoms, aralkyl group having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, heteroarylalkyl group having 2 to 9 carbon atoms in the heteroaryl portion and 1 to 6 carbon atoms in the alkyl portion, C ２－６ Alkenyl group, C ２－６ Represents an alkynyl group, an acyl group, or a protected amino group. R ２ and R ３ are the same or different and are a hydrogen atom, C １－６ alkyl group, C １－６ alkoxy group, halogen atom, hydroxy group or R ２ and R ３ together represent a carbonyl group or a thiocarbonyl group or R ２ and R ３ are bonded to form a C ３－７ saturated hydrocarbon ring or a cyclic ketal of C １－６ and represent, R ４ and R ５ The hydrogen atoms are the same or different C １－６ Alkyl alkyl group, C １－６ Represents an alkoxy group, an amino group, a protected amino group, a halogen atom, or a hydroxyl group. R ６ C is a hydrogen atom. １－６ Represents an alkoxy group, amino group, amide group, protected amino group, halogen atom, hydroxyl group, cyano group, carboxyl group, carboxylic acid ester group, or carbamoyl group. R ７ and R ８ The hydrogen atoms are the same or different C １－６ Alkyl alkyl group, C １－６ Does it indicate an alkoxy group, a halogen atom, or a potentially protected hydroxyl group? or R ７ and R ８ The two atoms together represent one oxygen atom, and by forming an ether bond as shown in the general formula (II) below, they represent an epoxy ring. 【Chemistry 2】 R ９ and R １０ The hydrogen atoms are the same or different C １－６ Alkyl alkyl group, C １－６ Alkoxy group, halogen atom, hydroxyl group or R ９ and R １０ When combined, they form a carbonyl group or a thiocarbonyl group or R ９ and R １０ They combine to form C ３－７ Saturated hydrocarbon ring or C １－６ Represents a cyclic ketal, R １１ and R １２ The hydrogen atoms are the same or different C １－６ Alkyl alkyl group, C １－６ Alkoxy group, halogen atom, hydroxyl group or R １１ and R １２ When combined, they form a carbonyl group or a thiocarbonyl group or R １１ and R １２ They combine to form C ３－７ Saturated hydrocarbon ring or C １－６ Represents a cyclic ketal, R １３ C is a hydrogen atom. １－６ Alkyl alkyl group, C １－６ Alkoxy group, C １－６ Alkoxy C １－６ This represents an alkyl group, an aralkyloxy group with 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, an amino group, a protected amino group, a halogen atom, a hydroxyl group, or a cyano group. A may be a heterocycle or C that contains at least one heteroatom selected from N, O, and S as a ring constituent atom. ３－７ A saturated hydrocarbon ring is represented, and the ring contains 1 to 4 identical or different C １－６ Alkyl alkyl group; C １－６ Halogenated alkyl group; hydroxyalkyl group; C ２－８ dialkyl group; C ３－６ Cycloalkyl group; C １－６ Alkoxy group; C halogenated １－６ Alkoxy groups; halogen atoms; hydroxyl groups; nitro groups; cyano groups; optionally substituted amino groups; carbamoyl groups; amide groups; amino groups; oxo groups; protected amino groups; acyl groups; cyclic amino groups; may be substituted with substituents selected from lactams. A double line consisting of a solid and a dashed line represents a single bond or a double bond. W is C １－６ Represents an alkylene group, a carbonyl group, N, O, S, or a bond. X is C １－６ Alkylene group, C ２－６ Represents an alkenylene group, a carbonyl group, N, O, S, or a bond. Y is C １－６ Represents an alkylene group, a carbonyl group, N, O, S, or a bond. Z is a hydrogen atom, oxygen atom, hydroxyl group, C 1－6 Alkyl alkyl group, C 1－6 Alkoxy group, C 2－8 Alkenyl group, carbamoyl group, carboxyl group, amino group, C 1－6 Alkylamino group, C 2－8 Dialkylamino group, cyano group, C 6-10 Aryl group, heteroaryl group with 2 to 9 carbon atoms, C ３－７ Represents a saturated hydrocarbon ring, saturated heterocycle, lactam, or bond, However, R 1 ~R 5 , R 7 ~R 13 C of W, X, Y and Z １－６ The alkyl group consists of 1 to 4 identical or different halogen atoms; a hydroxyl group; and C １－６ They may be substituted with substituents selected from alkoxycarbonyl groups, cyano groups, amino groups, protected amino groups, acyl groups, cyclic amino groups, and lactams. R ６ and the amide group of Z and R ４ ~R ６ and R 13 The amino group of the C １－６ They may also be substituted with substituents selected from alkoxycarbonyl groups, acyl groups, cyclic amino groups, and lactams. R ２ ~R 13 and Z's C １－６ The alkoxy groups consist of 1 to 4 identical or different C １－６ They may also be substituted with substituents selected from alkoxy groups, phenoxy groups, and halogen atoms. R 1 、 X and the C of Z ２－６ alkenylene group, and R 1 of C ２－６ The alkynyl group may be the same or different and is 1 to 4, C １－６ alkoxycarbonyl group, an aralkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; C １－６ alkoxy group; an aralkyloxy group having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; C １－６ an amino group optionally substituted with a linear or branched alkyl group of C; a halogen atom; a carboxy group; and may be substituted with a substituent selected from a hydroxy group, The carboxyl group of Z and the amino group of Z are connected to at least one C 1－6 It may also be substituted with an alkyl group. R 1 of C ３－６ cycloalkyl group and C ３－６ cycloalkyl C １－６ alkyl group may be 1 to 4 identical or different C １－６ alkyl group; C １－６ alkyl halide; halogen atom; hydroxy group; amino group; protected amino group; acyl group; cyclic amino group; and may be substituted with a substituent selected from lactam R 1 and Z's C 6-10 Aryl group; a heteroaryl group having 2 to 9 carbon atoms; R １ The aryl portion of an aralkyl group has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; the heteroaryl portion of a heteroarylalkyl group has 2 to 9 carbon atoms in the heteroaryl portion and 1 to 6 carbon atoms in the alkyl portion; R 13 The aryl portion of an aralkyloxy group is one in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; R 9 ~R 12 and Z's C ３－７ A saturated hydrocarbon ring; a saturated heterocycle of Z; a lactam of Z, consisting of 1 to 4 identical or different C １－６ Alkyl alkyl group; C １－６ Halogenated alkyl group; hydroxyalkyl group; C ２－８ dialkyl group; C ３－６ Cycloalkyl group; C １－６ Alkoxy group; C halogenated １－６ Alkoxy groups; halogen atoms; hydroxyl groups; nitro groups; cyano groups; optionally substituted amino groups; carbamoyl groups; amino groups; oxo groups; protected amino groups; acyl groups; cyclic amino groups; may be substituted with substituents selected from lactams. R 1 , R ６ and R 13 The protecting groups for the protected amino group include carbamate protecting groups; sulfonamide protecting groups; imide protecting groups; and C ７―１９ It may also be substituted with at least one substituent selected from the aralkyl groups. R ７ and R ８ The protecting groups for the protected hydroxyl group are acetal protecting groups; silyl protecting groups; acyl protecting groups; and C ７－１９ It may also be substituted with at least one substituent selected from the aralkyl groups. R 2 , R 3 and R 9 ~R 12 C １－６ The cyclic ketal consists of 1 to 4 identical or different C １－６ It may also be substituted with an alkyl group. N, O, or S in W, X, and Y are at least one hydrogen atom, C １－６ Alkyl alkyl group, C ６－１０ It may also be substituted with an aryl group, a heteroaryl group having 2 to 9 carbon atoms, an aralkyl group having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, or a heteroarylalkyl group having 2 to 9 carbon atoms in the heteroaryl portion and 1 to 6 carbon atoms in the alkyl portion. (Except when the heterocycle of A is an imidazolidinone ring or an imidazolidinedione ring.)

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the heterocycle of A comprises a 3- to 7-membered saturated heterocycle or a 5- to 10-membered bicyclic saturated heterocycle, comprising 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring constituent atoms.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the heterocycle of A is a 3- to 7-membered saturated heterocycle containing 1 to 4 N atoms and at least 1 carbon atom as ring constituent atoms.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the heterocycle of A is a five-membered saturated heterocycle containing one or two N atoms and at least one carbon atom as ring constituent atoms.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the heterocycle of A is pyrrolidine.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the saturated hydrocarbon ring of A is a 3- to 7-membered saturated carbon ring.

7. The compound according to claim 1 or 6, or a pharmaceutically acceptable salt thereof, wherein the saturated hydrocarbon ring of A is a 4- to 6-membered saturated carbon ring.

8. The compound according to claim 1, 6, or 7, or a pharmaceutically acceptable salt thereof, wherein the saturated hydrocarbon ring of A is cyclobutane.

9. W is C １－６ Alkylene group, carbonyl group, or 1 to 4 identical or different hydrogen atoms or carbon atoms. １－６ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein N may be substituted with an alkyl group.

10. The compound according to any one of claims 1 to 9, wherein W is a carbonyl group, or a pharmaceutically acceptable salt thereof.

11. W is C １－６ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein N may be substituted with an alkyl group.

12. X is C １－６ Alkylene group, C ２－６ An alkenylene group, a carbonyl group, an amide group, N, O, or a bond, wherein the substituent or atom is one to four identical or different C atoms. １－６ A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which may be substituted with an alkyl group.

13. X consists of 1 to 4 identical or different C １－６ C may be substituted with an alkyl group. １－６ A compound according to any one of claims 1 to 12, which is an alkylene group, or a pharmaceutically acceptable salt thereof.

14. Y is C １－６ A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein the compound is an alkylene group, N, O, or a bond.

15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Y is a binding bond.

16. Z's C 6-10 The compound according to any one of claims 1 to 15, wherein the aryl is benzene, or a pharmaceutically acceptable salt thereof.

17. Z's C ３ - ７ A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the saturated hydrocarbon ring is cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

18. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl group of Z is isoxazole, oxazole, imidazole, pyrazole, isothiazole, thiazole, furan, thiophene, pyrrole, pyridine, pyrazine, pyrimidine, pyridazine, or 2-pyridone.

19. The saturated heterocycle of Z is found in azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperazine, piperidine, tetrahydropyran, morpholine, azepan, oxazepam, indole, benzofuran, benzothiophene, benzimidazole, indazole, benzoxazole, benzothiazole, quinoline, isoquinoline, 2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane, and 3-oxa-8-azabicyclo[3.2.1]octane. The compounds according to claims 1 to 15, or pharmaceutically acceptable salts thereof, are octane, 2-azabicyclo[2.2.2]octane, 8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-7-azabicyclo[3.3.1]nonane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, and hexahydro-1H-fl[3,4-c]pyrrole.

20. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the lactam of Z is a β-lactam, γ-lactam, or δ-lactam.

21. R １ C １－６ Alkyl alkyl group, C ３－６ Cycloalkyl C １－６ A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, which is an aralkyl group having 6 to 10 carbon atoms in the alkyl or aryl portion and 1 to 5 carbon atoms in the alkylene portion.

22. R １ C is substituted with a hydroxyl group ２－６ C substituted with alkyl groups and 1 to 6 halogen atoms １－６ Alkyl alkyl group or C １－６ C substituted with an alkoxy group ２－６ A compound according to any one of claims 1 to 21, which is an alkyl group, or a pharmaceutically acceptable salt thereof.

23. R １ C ３ - ６ Cycloalkyl C １ - ６ A compound according to any one of claims 1 to 22, which is an alkyl group, or a pharmaceutically acceptable salt thereof.

24. R １ The compound according to any one of claims 1 to 23, wherein is an amino protecting group, or a pharmaceutically acceptable salt thereof.

25. R ２ and R ３ They are the same or different hydrogen atoms, C １－６ Alkyl alkyl group, C １－６ A compound according to any one of claims 1 to 24, which is an alkoxy group, a halogen atom, or a hydroxyl group, or a pharmaceutically acceptable salt thereof.

26. R ２ and R ３ They are the same or different, hydrogen atoms or C １－６ A compound according to any one of claims 1 to 25, which is an alkyl group, or a pharmaceutically acceptable salt thereof.

27. R ２ and R ３ The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein the compound is a hydrogen atom.

28. R ４ and R ５ They are the same or different hydrogen atoms, C １－６ Alkyl alkyl group, C １－６ A compound according to any one of claims 1 to 27, which is an alkoxy group, an amino group, a halogen atom, or a hydroxyl group, or a pharmaceutically acceptable salt thereof.

29. R ４ and R ５ The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein is the same or different hydrogen atom or C1-6 alkyl group.

30. R ４ and R ５ The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein the compound is a hydrogen atom.

31. R ６ is C １－６ A compound according to any one of claims 1 to 30, which is an alkoxy group or a hydroxyl group, or a pharmaceutically acceptable salt thereof.

32. R ６ The compound according to any one of claims 1 to 31, wherein is a hydroxyl group, or a pharmaceutically acceptable salt thereof.

33. R ７ and R ８ The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein is the same or different and is a hydrogen atom, a halogen atom, a protected hydroxyl group, or an alkoxy group.

34. R ７ and R ８ The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein is the same or different, and is a hydrogen atom, a protected hydroxyl group, or an alkoxy group.

35. R ７ and R ８ The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein the compound is a hydrogen atom.

36. R ７ and R ８ The two atoms together represent one oxygen atom, and by forming an ether bond as shown in the general formula (II) below, an epoxy ring is formed: 【Transformation 3】 The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

37. R ９ and R １０ They are the same or different hydrogen atoms, C １－６ Alkyl alkyl group, C １－６ A compound according to any one of claims 1 to 36, which is an alkoxy group, a halogen atom, or a hydroxyl group, or a pharmaceutically acceptable salt thereof.

38. R ９ and R １０ They are the same or different hydrogen atoms, C １－６ Alkyl alkyl group or C １－６ A compound according to any one of claims 1 to 37, which is an alkoxy group, or a pharmaceutically acceptable salt thereof.

39. R ９ and R １０ They are the same or different, hydrogen atoms or C １－６ A compound according to any one of claims 1 to 38, which is an alkyl group, or a pharmaceutically acceptable salt thereof.

40. R ９ and R １０ The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein the compound is a hydrogen atom.

41. R １１ and R １２ They are the same or different, hydrogen atom, hydroxyl group, C １－６ Alkyl alkyl group, C １－６ A compound according to any one of claims 1 to 40, comprising an alkoxy group or a halogen atom, or a pharmaceutically acceptable salt thereof.

42. R １１ and R １２ They are the same or different hydrogen atoms, hydroxyl groups, or C １－６ A compound according to any one of claims 1 to 41, which is an alkyl group, or a pharmaceutically acceptable salt thereof.

43. R １１ and R １２ The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein is the same or different hydrogen atom or hydroxyl group.

44. R １３ is a hydrogen atom, a hydroxyl group, or C １－６ Alkoxy C １－６ A compound according to any one of claims 1 to 43, which is an alkyl group, or a pharmaceutically acceptable salt thereof.

45. R １３ The compound according to any one of claims 1 to 44, wherein the compound is a hydroxyl group, or a pharmaceutically acceptable salt thereof.

46. A compound or mixture of compounds selected from the group consisting of (1) to (224) below, or a pharmaceutically acceptable salt of the said compound or a mixture of pharmaceutically acceptable salts of the said compound: (1) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (2) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one; (3) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one; (4) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(4-methyl-1H-pyrazole-1-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol; (5) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(4-methyl-1H-pyrazole-1-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (6) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-2-yl)ethane-1-one; (7) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-2-yl)ethane-1-one; (8) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridine-2-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (9) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one; (10) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one; (11) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-(4-methyl-1H-pyrazole-1-yl)propyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (12) (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(furan-3-yl)prop-2-en-1-one; (13) (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(furan-3-yl)prop-2-en-1-one; (14) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)propan-1-one; (15) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)propan-1-one; (16) (1S,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-2-one; (17) (2S,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-5-one; (18) (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-9'-methoxy-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflo[3,2-e]isoquinoline]-4a'-ol; (19) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one; (20) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-(4-methyl-1H-pyrazole-1-yl)propan-1-one; (21) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-3-yl)ethane-1-one; (22) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-3-yl)ethane-1-one; (23) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-4-yl)ethane-1-one; (24) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-4-yl)ethane-1-one; (25) (E)-1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one; (26) (E)-1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one; (27) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one; (28) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-one; (29) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyrrolidine-1-yl)propan-1-one; (30) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyrrolidine-1-yl)propan-1-one; (31) ((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)(pyridine-2-yl)methanone; (32) ((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)(pyridine-2-yl)methanone; (33) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinopropan-1-one; (34) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinopropan-1-one; (35) (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one; (36) (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(pyridine-2-yl)prop-2-en-1-one; (37) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-1-yl)-3-(pyridine-2-yl)propan-1-one; (38) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-2-(pyridine-2-yl)ethane-1-one; (39) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-2-(pyridine-2-yl)ethane-1-one; (40) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-(pyridine-2-yl)propyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (41) (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-9'-methoxy-1-(2-(pyridine-2-yl)ethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a'-ol; (42) (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1-(2-(pyridine-2-yl)ethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-4a',9'-diol; (43) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(thiazole-4-yl)propan-1-one; (44) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(thiazole-4-yl)propan-1-one; (45) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(pyridine-4-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (46) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridine-4-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (47) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(2-(pyridine-3-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol; (48) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(pyridine-3-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (49) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(2-fluorophenyl)propan-1-one; (50) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(2-fluorophenyl)propan-1-one; (51) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (52) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (53) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-3-yloxy)ethane-1-one; (54) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-3-yloxy)ethane-1-one; (55) ((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1-((E)-3-(pyridine-2-yl)allyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (56) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(piperidine-1-yl)propan-1-one; (57) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(piperidine-1-yl)propan-1-one; (58) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-(pyridine-2-yl)butan-1-one; (59) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-(pyridine-2-yl)butan-1-one; (60) 3-Cyclobutyl-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)propan-1-one; (61) 3-Cyclobutyl-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propan-1-one; (62) 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2,2-dimethyl-5-oxopentannitrile; (63) 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2,2-dimethyl-5-oxopentannitrile; (64) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-1-yl)-3-morpholinopropan-1-one; (65) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-1-yl)-3-morpholinopropan-1-one; (66) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((R)-3-fluoropyrrolidine-1-yl)propan-1-one; (67) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((R)-3-fluoropyrrolidine-1-yl)propan-1-one; (68) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3'-methoxy-1-(pyridine-2-ylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (69) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(pyridine-2-ylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (70) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-2-yloxy)ethane-1-one; (71) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(pyridine-2-yloxy)ethane-1-one; (72) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (73) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (74) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(4-fluorophenethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-8a'-ol; (75) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(4-fluorophenethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (76) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)prop-2-en-1-one; (77) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-1-yl)-3-(piperidine-1-yl)propan-1-one; (78) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(3-fluoropiperidine-1-yl)propan-1-one; (79) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(3-fluoropiperidine-1-yl)propan-1-one; (80) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (81) 1-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxopropyl)cyclopropane-1-carbonitride; (82) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(isothiazol-3-yl)ethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol; (83) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(isothiazole-3-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (84) (E)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylisothiazol-3-yl)prop-2-en-1-one; (85) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylisothiazol-3-yl)propan-1-one; (86) 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl) tert-butyl acetate; (87) 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-1-morpholinoethane-1-one; (88) 2-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-1-morpholinoethane-1-one; (89) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-(4-methylpiperazine-1-yl)propan-1-one; (90) 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl) tert-butyl propanoate; (91) 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-1-yl)-1-morpholinopropan-1-one; (92) 3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-1-yl)-1-morpholinopropan-1-one; (93) 4-(3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-oxopropyl)piperazine-2-one; (94) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)-2-(5-fluoropyridine-2-yl)ethane-1-one; (95) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(5-fluoropyridine-2-yl)ethyl)-3'-methoxy-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-8a'-ol; (96) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(2-(5-fluoropyridine-2-yl)ethyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (97) 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzonitrile; (98) 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzonitrile; (99) 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzamide; (100) 4-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzamide; (101) (2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (102) 4-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-N,N-dimethyl-4-oxobutanamide; (103) 1-(3-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrrolidine-2,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-1-yl)-3-oxopropyl)cyclopropane-1-carbonitride; (104) 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)ethyl)benzonitrile; (105) 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzonitrile; (106) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-one; (107) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-one; (108) 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-5-oxopentannitrile; (109) 5-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-5-oxopentannitrile; (110) (S)-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinbutan-1-one and (R)-1 A diastereomer mixture of -((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinbutan-1-one; (111) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-morpholinbutan-1-one; (112) 1-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-2-oxoethyl)cyclopropane-1-carbonitride; (113) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propan-1-one; (114) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(isoxazole-3-yl)propan-1-one; (115) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(isoxazole-3-yl)propan-1-one; (116) 1-((2R,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[pyrroridine-2,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-1-yl)-3-(1,4-oxazepan-4-yl)propan-1-one; (117) 4-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-oxobutannitrile; (118) 4-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-oxobutanamide; (119) 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzamide; (120) 3-(2-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoethano)phenanthrene]-1-yl)ethyl)benzamide; (121) 4-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-4-oxobutannitrile; (122) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl) tert-butyl propanoate; (123) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propanoic acid; (124) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-1-(piperidine-1-yl)propan-1-one; (125) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-1-(piperidine-1-yl)propan-1-one; (126) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((S)-3-fluoropyrrolidine-1-yl)propan-1-one; (127) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((S)-3-fluoropyrrolidine-1-yl)propan-1-one; (128) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-8a'-hydroxy-3'-methoxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylisoxazole-3-yl)propan-1-one; (129) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylisoxazole-3-yl)propan-1-one; (130) 1-((E)-3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxoprop-1-en-1-yl)cyclopropane-1-carbonitrile; (131) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-methoxycyclopropyl)propan-1-one; (132) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-fluorocyclobutyl)propan-1-one; (133) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(1-(difluoromethyl)cyclopropyl)propan-1-one; (134) (R)-5-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxopropyl)pyrrolidine-2-one; (135) (S)-5-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxopropyl)pyrrolidine-2-one; (136) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrroridine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(dimethylamino)propan-1-one; (137) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((S)-3-methylpyrrolidine-1-yl)propan-1-one; (138) 3-Cyclohexyl-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propan-1-one; (139) 1-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxopropyl)cyclobutan-1-carbonitride; (140) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propanoic acid; (141) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-N,N-dimethylpropanamide; (142) 3-Cyclopropyl-1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)propan-1-one; (143) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-(5-methylfuran-2-yl)propan-1-one; (144) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-carboxylic acid (1-cyanocyclopropyl)methyl; (145) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-1-(3-cyclopropylpropyl)-7',8',9',10'-tetrahydro-5'H,8a'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-3',8a'-diol; (146) 1-(3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-oxopropyl)pyrrolidine-2-one; (147) (2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-cyclopropylmethyl carboxylate; (148) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)methyl propanoate; (149) 3-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-1-(pyrrolidine-1-yl)propan-1-one; (150) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-methoxypropan-1-one; (151) 1-((2R,4b'R,8a'S,9'R)-11'-(cyclopropylmethyl)-3',8a'-dihydroxy-8',8a',9',10'-tetrahydro-5'H,7'H-spiro[pyrrolidine-2,6'-[9,4b](epiminoetano)phenanthrene]-1-yl)-3-((S)-2-methylpyrrolidine-1-yl)propan-1-one; (152) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)methyl acetate; (153) (1S,4'R,4a'S,7a'S,12b'S,E)-3'-(cyclopropylmethyl)-9'-methoxy-2-(2-(pyrrolidine-1-yl)ethylidene)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a'-ol; (154) (1S,4'R,4a'S,7a'S,12b'S,E)-3'-(cyclopropylmethyl)-2-(2-(pyrrolidine-1-yl)ethylidene)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (155) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-2-ylidene)-1-(pyrrolidine-1-yl)ethane-1-one; (156) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(pyrrolidine-1-yl)ethane-1-one; (157) (E)-N-cyclopentyl-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)acetamide; (158) (E)-N-cyclopentyl-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)acetamide; (159) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)acetic acid; (160) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-morpholinoethane-1-one; (161) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-morpholinoethane-1-one; (162) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(piperidine-1-yl)ethane-1-one; (163) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(piperidine-1-yl)ethane-1-one; (164) (1S,4'R,4a'S,7a'S,12b'S,E)-3'-(cyclopropylmethyl)-2-(2-hydroxyethylidene)-9'-(methoxymethoxy)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a'-ol (compound 164A) and (E) A mixture of -2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-bis(methoxymethoxy)-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-ol (compound 164B); (165) (1S,4'R,4a'S,7a'S,12b'S,E)-3'-(cyclopropylmethyl)-2-(2-(pyridine-2-ylmethoxy)ethylidene)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (166) (1S,4'R,4a'S,7a'S,12b'S,E)-3'-(cyclopropylmethyl)-2-(2-(methyl(pyridine-2-ylmethyl)amino)ethylidene)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (167) (E)-1-(azetidine-1-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (168) (E)-1-(azetidine-1-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (169) (E)-1-(azepan-1-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (170) (E)-1-(azepan-1-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (171) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(2-azaspiro[3,3]heptan-2-yl)ethane-1-one; (172) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(2-azaspiro[3,3]heptan-2-yl)ethane-1-one; (173) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethyl acetate; (174) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(3-fluoropiperidine-1-yl)ethane-1-one; (175) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-2-ylidene)-1-(4-methylpiperazine-1-yl)ethane-1-one; (176) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(4-methylpiperazine-1-yl)ethane-1-one; (177) 2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-yl)-1-(piperidine-1-yl)ethane-1-one; (178) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)acetic acid; (179) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(1,4-oxazepan-4-yl)ethane-1-one; (180) (1S,4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-2-one; (181) (1S,4'R,4a'S,7a'S,12b'S,E)-1'H,7a'H-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-one O-pyridine-2-ylmethyloxime; (182) (E)-1-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (183) (E)-1-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (184) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-2-ylidene)-1-((2R,6S)-2,6-dimethylmorpholino)ethane-1-one; (185) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-2-ylidene)-1-((2R,6S)-2,6-dimethylmorpholino)ethane-1-one; (186) (E)-1-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (187) (E)-1-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)ethane-1-one; (188) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzoflou[3,2-e]isoquinoline]-2-ylidene)-1-(tetrahydro-1H-flou[3,4-c]pyrrole-5(3H)-yl)ethane-1-one; (189) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(4-methoxypiperidine-1-yl)ethane-1-one; (190) A diastereomer mixture (1:1) of (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(3-methoxypyrrolidine-1-yl)ethane-1-one; (191) (1S,4'R,4a'S,7a'S,12b'S,E)-1'H,7a'H-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-one O-cyclohexyloxime; (192) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-N-(2-methoxyethyl)-N-methylacetamide; (193) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((2-methoxyethyl)(methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (194) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide; (195) (1S,4'R,4a'S,7a'S,12b'S,E)-1'H,7a'H-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-one O-tetrahydro-2H-pyran-4-yloxime; (196) (1S,2S,4'R,4a'S,7a'S,12b'S)-2-(benzylamino)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (197) (1S,2S,4'R,4a'S,7a'S,12b'S)-2-(benzylamino)-3'-(cyclopropylmethyl)-9'-methoxy-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a'-ol; (198) (1S,2S,4'R,4a'S,7a'S,12b'S)-2-(benzyl(methyl)amino)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (199) (1S,2R,4'R,4a'S,7a'S,12b'S)-2-(benzyl(methyl)amino)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (200) N-((1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-yl)-N-methylbenzamide; (201) N-((1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-yl)-N-methylbenzamide; (202) N-((1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-yl)benzamide; (203) N-((1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-yl)benzamide; (204) N-((1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-9'-methoxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-yl)benzamide; (205) N-((1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-yl)benzamide; (206) (1S,2S,4'R,4a'S,7a'S,12b'S)-2-amino-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (207) (1S,2R,4'R,4a'S,7a'S,12b'S)-2-amino-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (208) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((pyridine-2-ylmethyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (209) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((pyridine-2-ylmethyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (210) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (211) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (212) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(3,3-difluoropiperidine-1-yl)ethane-1-one; (213) (E)-2-((1S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-4a',9'-dihydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-2-ylidene)-1-(4,4-difluoropiperidine-1-yl)ethane-1-one; (214) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((thiazole-2-ylmethyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-4a',9'-diol; (215) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((thiazole-2-ylmethyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-4a',9'-diol; (216) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((3-fluoropyridine-2-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (217) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((3-fluoropyridine-2-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (218) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((1-methyl-1H-imidazole-2-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (219) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-(((1-methyl-1H-imidazole-2-yl)methyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutan-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (220) (1S,2S,4'R,4a'S,7a'S,12b'S)-2-(((5-chloropyridine-2-yl)methyl)amino)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (221) (1S,2R,4'R,4a'S,7a'S,12b'S)-2-(((5-chloropyridine-2-yl)methyl)amino)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-4a',9'-diol; (222) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((2-fluorobenzyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofl[3,2-e]isoquinoline]-4a',9'-diol; (223) (1S,2R,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((2-fluorobenzyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-4a',9'-diol; and (224) (1S,2S,4'R,4a'S,7a'S,12b'S)-3'-(cyclopropylmethyl)-2-((1-(pyridine-2-yl)ethyl)amino)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[cyclobutane-1,7'-[4,12]methanobenzofloflo[3,2-e]isoquinoline]-4a',9'-diol.

47. A κ-opioid receptor agonist containing a compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof as an active ingredient.

48. An agent for the prevention or treatment of diseases or symptoms related to κ-opioid receptors, comprising a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof as an active ingredient.

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