Medicine containing a vitamin D derivative or a pharmaceutically acceptable salt or solvate thereof for use in combination with an immunomodulatory substance

Abstract

The purpose of the present invention is to provide a medicine for promoting differentiation induction from oligodendrocyte progenitor cells to oligodendrocytes, and a medicine for promoting remyelination. The present invention is a medicine containing a vitamin D derivative represented by formula (1) or a pharmaceutically acceptable salt or solvate thereof, used in combination with an immunomodulatory substance.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition for promoting the differentiation of oligodendrocyte precursor cells into oligodendrocytes and for promoting remyelination, which comprises a vitamin D derivative and is used in combination with an immunomodulatory substance. More specifically, the vitamin D derivative used in the present invention is a vitamin D derivative having a cyclic tertiary amine in the side chain, and includes pharmaceutically acceptable salts and solvates thereof. Pharmaceuticals that can be clinically applied as pharmaceuticals for promoting remyelination include pharmaceuticals for treating multiple sclerosis, neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-associated myelopathy, HIV-associated leukoencephalopathy, Krabbe disease, Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, depression due to drug addiction, autism, Alzheimer's disease, Down's syndrome, or ischemic stroke. [Background technology]

[0002] Oligodendrocytes form myelin sheaths around the axons of neurons, and their main role is to increase the conduction velocity by inducing saltatory conduction. They are also involved in the metabolism of neurons.

[0003] Demyelination and hypomyelination have been reported in several inflammatory demyelinating, neurodegenerative, and psychiatric disorders. Demyelination is the destruction and loss of myelin, which leads to various neurological symptoms. Multiple sclerosis is a well-known neuroimmune disease that causes demyelination. Other central nervous system inflammatory demyelinating diseases that cause demyelination include neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-associated myelopathy, HIV-associated leukoencephalopathy, and Krabbe disease. Peripheral nervous system demyelinating diseases include Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, and Charcot-Marie-Tooth disease. Furthermore, ischemic stroke often involves demyelination, which subsequently leads to functional decline. It has also been reported that in Alzheimer's disease, a neurodegenerative disease, demyelination inhibits plastic changes in the myelin sheath, leading to a decline in cognitive function.

[0004] Furthermore, hypomyelination has been confirmed in the brains of patients with various psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder (ASD), attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), and depression due to drug addiction, and a link between the disorders has been suggested.

[0005] Therefore, it is important to restore normal conditions of demyelination and hypomyelination in the central or peripheral nervous system.

[0006] Recently, it has been reported that 1α,25-dihydroxyvitamin D3 promotes the differentiation of oligodendrocyte precursor cells and neural stem cells into oligodendrocytes (Non-Patent Documents 1 and 2). Two pathways are known for the actions of 1α,25-dihydroxyvitamin D3 and its derivatives (Non-Patent Document 3). One pathway is genomic action, in which 1α,25-dihydroxyvitamin D3 binds to the vitamin D receptor (VDR), a nuclear receptor, to regulate gene expression. The other pathway is non-genomic action, in which 1α,25-dihydroxyvitamin D3 binds to protein disulfide isomerase A3 (PDIA3) to induce signal transduction. At present, it is not fully clear whether the oligodendrocyte differentiation-inducing effect of 1α,25-dihydroxyvitamin D3 reported in Non-Patent Documents 1 and 2 is due to a genomic or non-genomic pathway. Meanwhile, the primary action of 1α,25-dihydroxyvitamin D3 and its derivatives is calcium-phosphorus metabolism. In general, derivatives with strong genomic effects, as expressed by transcriptional activity, have strong calcium metabolism effects, which may increase blood calcium levels and cause hypercalcemia. For this reason, there is a limit to the dosage, and in some cases, the desired pharmacological effect may not be achieved.

[0007] Furthermore, it has been reported that the central transfer of 1α,25-dihydroxyvitamin D3 is extremely low (Non-Patent Documents 4 and 5). These documents indicate that extremely high doses of 1α,25-dihydroxyvitamin D3 are required to achieve sufficient concentrations in the brain. However, high-dose administration of 1α,25-dihydroxyvitamin D3 is difficult because it causes an increase in blood calcium levels.

[0008] Therefore, there is a strong demand for vitamin D derivatives with excellent central transport properties that can exert their effects in the brain, and even for vitamin D derivatives that uncouple their myelin regeneration promoting effect from their blood calcium increasing effect. However, no such derivatives have been reported to date.

[0009] Immunomodulatory agents such as fingolimod (FTY720), interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, natalizumab, siponimod, ozanimod, ponesimod, dimethyl fumarate, diroximel fumarate, cladribine, ocrelizumab, rituximab, ofatumumab, ublituximab, alemtuzumab, divozilimab, evobrutinib, orelabrutinib, trebrutinib, remibrutinib, and fenebrutinib are known as therapeutic agents for demyelinating diseases such as multiple sclerosis. While immunomodulators have been shown to prevent relapse and slow symptom progression, they do not directly promote axonal remyelination.

[0010] Furthermore, there is a report of a therapeutic agent for demyelinating diseases that uses a neurotransmitter receptor modulator selected from a muscarinic receptor antagonist, a dopamine receptor antagonist, a histamine receptor antagonist, a β-adrenergic receptor modulator, and an opioid receptor modulator in combination with an immunomodulatory substance (Patent Document 1). However, no pharmaceutical agent containing a vitamin D derivative for promoting remyelination that is used in combination with an immunomodulatory substance is known. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] Special Publication 2014-506583 [Non-patent literature]

[0012] [Non-Patent Document 1] AGde la Fuente et al.,Journal of Cell Biology,2015,211(5),975-985 [Non-patent document 2] HAShirazi et al., Experimental and Molecular Pathology,2015,98(2),240-245 [Non-patent document 3] MAZmijewski et al., Experimental Dermatology,2020,29,876-884 [Non-patent document 4] MRDurk et al.,The Journal of Neuroscience,2014,34(21),7091-7101 [Non-patent document 5] ECYChow et al.,The American Journal of Physiology:Endocrinology and Metabolism,2013,304(9),E977-989 Summary of the Invention [Problem to be solved by the invention]

[0013] An object of the present invention is to provide a vitamin D derivative or a pharmaceutically acceptable salt or solvate thereof having excellent central transport properties, which can be used in combination with an immunomodulatory substance as a pharmaceutical for promoting the induction of differentiation of oligodendrocyte precursor cells into oligodendrocytes and for promoting remyelination. [Means for solving the problem]

[0014] As a result of intensive research aimed at the above object, the present inventors have arrived at the following invention.

[0015] That is, the present invention provides a pharmaceutical for promoting the induction of differentiation from oligodendrocyte precursor cells to oligodendrocytes, and a pharmaceutical for promoting remyelination, which contains a vitamin D derivative represented by the following formula (1) or a pharmaceutically acceptable salt or solvate thereof, used in combination with an immunomodulatory substance.

[0016] [ka]

[0017] [In the formula, R represents any one of the structures Ra, Rb, Rc, Rd, and Re in the following formulas.]

[0018] [ka]

[0019] R 1 , R 3 , R 8 , and R 10 each independently represents a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms, a halogen atom, or a hydrogen atom. R 2 , R 4 , R 9 , and R 11 each independently represents a hydrogen atom, a hydroxy group, or a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms. (However, R 1 , R 3 , R 8 , and R 10 are each independently a C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms, or a halogen atom, then R 1 , R 3 , R 8 , and R 10 R substituted on the same carbon atom as 2 , R 4 , R 9 , and R 11 is not a hydroxy group.) R 6 , R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R18 , R 19 , R 20 , R 21 , R 22 , and R 23 each independently represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, or a C3-C6 cycloalkyl group. R 1 and R 2 , R 3 and R 4 , R 6 and R 7 , R 8 and R 9 , R 10 and R 11 , R 12 and R 13 , R 14 and R 15 , R 16 and R 17 , R 18 and R 19 , R 20 and R 21 , R 22 and R 23 can be bonded to each other to form a 3- to 5-membered ring structure. R 5 is a hydrogen atom, one -OR 501 a C1-C6 alkyl group optionally substituted with a group, or one -OR 501 represents a C3-C6 cycloalkyl group optionally substituted with a group, and R 501 represents a hydrogen atom or a C1 to C6 alkyl group. R 24 represents a hydrogen atom, a C1-C3 alkyl group, or a C1-C3 alkylsulfonyl group. The stereochemistry at the 2-position of the pyrrolidine ring (Rb) can be either the (R) or (S) configuration. X 1 , and X 2 each independently represents a hydrogen atom or a C1-C3 alkyl group, or X 1 and X 2 together form a methylidene group, or -(CH2) m - (where m is an integer of 2 to 5). X3 is a CH2 group or a C=CH2 group (where X 1 and X 2 When X 3 represents a C=CH2 group. n represents an integer of 1 to 3. The stereochemistry of the hydroxyl group at position 1 can be either the (R) or (S) configuration. The stereochemistry of the methyl group at position 20 can be either the (R) or (S) configuration. The present invention also provides a pharmaceutical for promoting the induction of differentiation of oligodendrocyte precursor cells into oligodendrocytes, and a pharmaceutical for promoting remyelination, which pharmaceutical comprises a vitamin D derivative represented by the above formula (1) or a pharmaceutically acceptable salt or solvate thereof, and an immunomodulatory substance. [Effects of the Invention]

[0020] According to the present invention, there is provided a clinically applicable pharmaceutical that promotes remyelination and is used to treat various central nervous system diseases, including multiple sclerosis, neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-associated myelopathy, HIV-associated leukoencephalopathy, Krabbe disease, Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, depression due to drug addiction, autism, Alzheimer's disease, and ischemic stroke. [Brief explanation of the drawings]

[0021]

Figure 1

Figure 2

[0022] Terms used alone or in combination in this specification are explained below. Unless otherwise specified, the explanation of each substituent is the same for each site. When any variable exists in any component, its definition is independent for each component. Furthermore, combinations of substituents and variables are permitted only if such combinations result in chemically stable compounds. When a substituent itself is substituted with two or more groups, these multiple groups may be present on the same carbon or different carbons as long as a stable structure is produced.

[0023] In the present invention, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0024] In the present invention, a "C1-C6 alkyl group" means a monovalent saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an isopropyl group, an isobutyl group, an s-butyl group, a t-butyl group, an isopentyl group, a 2-methylbutyl group, a neopentyl group, a 1-ethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a t-pentyl group, and an isohexyl group.

[0025] In the present invention, the term "methylidene group" refers to a =CH2 group.

[0026] In the present invention, the term "C3 to C6 cycloalkyl group" refers to a cycloalkyl group having 3 to 6 carbon atoms, including, but not limited to, cyclic alkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0027] In the present invention, the term "C1-C6 alkoxy group" refers to a group consisting of an alkyl group having 1 to 6 carbon atoms, selected from the above-mentioned "C1-C6 alkyl groups," and an oxy group. Examples include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butoxy group, an s-butoxy group, a 2-methylpropoxy group, an n-pentyloxy group, an isopentyloxy group, a 2-methylbutoxy group, a 1-ethylpropoxy group, a 2,2-dimethylpropoxy group, an n-hexyloxy group, a 4-methylpentoxy group, a 3-methylpentoxy group, a 2-methylpentoxy group, a 3,3-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 1,1-dimethylbutoxy group, and a t-butoxy group.

[0028] In the present invention, the term "C1-C6 alkylsulfonyl group" refers to a group consisting of the above-mentioned "C1-C6 alkyl group" and a sulfonyl group. Examples include a methylsulfonyl group, an ethylsulfonyl group, and an isopropylsulfonyl group.

[0029] In the above definitions, for example, "C" in "C1" represents a carbon atom, and the number following it represents the number of carbon atoms. For example, "C1-C6" represents a range of carbon atoms from 1 to 6. Of course, in the present invention, if the number of carbon atoms is different, it means the group having that number of carbon atoms. For example, "C1-C3 alkyl group" means an alkyl group defined as "C1-C6 alkyl group" having 1 to 3 carbon atoms. The carbon number in other groups is treated similarly.

[0030] In the present invention, "a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms" means a C1-C6 alkyl group optionally having 1 to 3 halogen atoms at substitutable positions. When a C1-C6 alkyl group is substituted with multiple halogen atoms, the C1-C6 alkyl groups may be substituted with the same halogen atoms or different halogen atoms. "A C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms" has the same meaning.

[0031] In the present invention, the term "vitamin D derivative" refers to a compound having a secosteroid structure (ie, 4-(2-cyclohexylideneethylidene)octahydro-1H-indene).

[0032] In the above formula (1), X 1 and X 2 each independently represents a hydrogen atom or a C1-C3 alkyl group, or X 1 and X 2 together form a methylidene group, or -(CH2) m - (where m is an integer of 2 to 5). 1 and X 2 each independently represents a hydrogen atom or a methyl group, or X 1 and X 2 and preferably together form a methylidene group.

[0033] In the above formula (1), X 3 is a CH2 or C=CH2 group (where X 1 and X 2 When X 3 represents a C=CH2 group.

[0034] X 1 , X 2 , and X 3 Preferred examples of the combination of (i) X 1 is a hydrogen atom or a methyl group, X 2 is a hydrogen atom, X 3represents a C=CH2 group, (ii) X 1 and X 2 is a hydrogen atom, X 3 represents a CH group, and (iii) X 1 and X 2 together form a methylidene group, X 3 represents a CH2 group.

[0035] In the above formula (1), n ​​represents an integer of 1 to 3.

[0036] The stereochemistry of the methyl group at the 20-position in the above formula (1) may be either the (R) configuration or the (S) configuration. The stereochemistry of the hydroxyl group at position 1 in the above formula (1) may be either the (R) configuration or the (S) configuration.

[0037] In the above formula (1), R represents the structures of Ra to Re described above, among which, a pyrrolidine ring (Rb) and a morpholine ring (Rd) are particularly preferred structures.

[0038] R 1 , R 3 , R 8 , and R 10 R each independently represents a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms, a halogen atom, or a hydrogen atom. 1 , R 3 , R 8 , and R 10 Preferred groups include a C1-C6 alkyl group optionally substituted with 1 to 3 fluorine atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted with 1 to 3 fluorine atoms, a fluorine atom, or a hydrogen atom, and more preferred groups include a methyl group, an ethyl group, a methoxy group, an ethoxy group, a difluoromethyl group, a 1,1-difluoroethyl group, a 2,2-difluoroethyl group, a difluoromethoxy group, a 2,2-difluoroethoxy group, a 3,3-difluoropropyl group, a 2,2-difluoropropyl group, and the like.

[0039] R 2 , R 4 , R 9 , and R 11 each independently represents a hydrogen atom, a hydroxy group, or a C1-C3 alkyl group which may be substituted with 1 to 3 halogen atoms. Among these, a hydrogen atom, a hydroxy group, or a C1-C3 alkyl group which may be substituted with 1 to 3 fluorine atoms is preferred, and a hydrogen atom or a hydroxy group is more preferred. 1 , R 3 , R 8 , and R 10 are each independently a C1-C3 alkoxy group optionally substituted with 1 to 3 halogen atoms, or a halogen atom, the R 1 , R 3 , R 8 , R 10 R substituted on the same carbon atom as 2 , R 4 , R 9 , R 11 is preferably not a hydroxy group but a hydrogen atom in this case.

[0040] R 6 , R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , and R 23 each independently represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, or a C3-C6 cycloalkyl group. Among these, a hydrogen atom, a C1-C6 alkyl group optionally substituted with 1 to 3 fluorine atoms, or a C3-C6 cycloalkyl group is preferred, and more preferred groups include a hydrogen atom, a methyl group, an ethyl group, and a difluoromethyl group.

[0041] Also, R 1and R 2 , R 3 and R 4 , R 6 and R 7 , R 8 and R 9 , R 10 and R 11 , R 12 and R 13 , R 14 and R 15 , R 16 and R 17 , R 18 and R 19 , R 20 and R 21 , R 22 and R 23 can be bonded to each other to form a 3- to 5-membered ring structure. Here, the 3- to 5-membered ring structure is a hydrocarbon ring, and R 1 and R 2 , R 3 and R 4 , R 6 and R 7 , R 8 and R 9 , R 10 and R 11 , R 12 and R 13 , R 14 and R 15 , R 16 and R 17 , R 18 and R 19 , R 20 and R 21 , R 22 and R 23 together with the carbon atom on which it is substituted, can form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring.

[0042] R 5 is a hydrogen atom, one -OR 501 a C1-C6 alkyl group optionally substituted with a group, or one -OR 501 represents a C3-C6 cycloalkyl group optionally substituted with a group, and R 501 represents a hydrogen atom or a C1-C6 alkyl group. 5 is a hydrogen atom or -C(CH3)2-OR 501 is preferred.

[0043] R 24 represents a hydrogen atom, a C1-C3 alkyl group, or a C1-C3 alkylsulfonyl group, with methylsulfonyl being particularly preferred.

[0044] Furthermore, among the vitamin D derivatives represented by formula (1) or pharmaceutically acceptable salts or solvates thereof, preferred specific examples of the present invention include vitamin D derivatives represented by formulas (1-1) and (1-2) or pharmaceutically acceptable salts or solvates thereof.

[0045] A vitamin D derivative represented by formula (1-1) or a pharmaceutically acceptable salt or solvate thereof

[0046] [ka]

[0047] [In the formula, the stereochemistry of the hydroxyl group at the 1-position is either the (R) configuration or the (S) configuration.] R 3 represents a C1-C6 alkyl group optionally substituted with 1 to 3 fluorine atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted with 1 to 3 fluorine atoms, a fluorine atom, or a hydrogen atom. R 4 represents a hydrogen atom, a hydroxy group, or a C1-C3 alkyl group optionally substituted with 1 to 3 fluorine atoms. (However, R 3 represents a C1-C3 alkoxy group optionally substituted with 1 to 3 fluorine atoms, or a fluorine atom, R 4 is not a hydroxy group.) R 3 and R 4 can be bonded to each other to form a 3- to 5-membered ring structure. R 5 is one -OR 501 represents a C1-C6 alkyl group optionally substituted with a group, and R 501represents a hydrogen atom or a C1 to C6 alkyl group. Also R 5 The stereochemistry of represents either the (R) or (S) configuration. X 1 , and X 2 each independently represents a hydrogen atom or a C1-C3 alkyl group, or X 1 and X 2 together form a methylidene group, or -(CH2) m - (where m is an integer of 2 to 5). X 3 is a CH2 group or a C=CH2 group (where X 1 and X 2 When X 3 represents a C=CH2 group. n represents an integer of 1 to 3. The stereochemistry at the 20-position in the above formula (1-1) may be either the (R) configuration or the (S) configuration.] A vitamin D derivative represented by formula (1-2) or a pharmaceutically acceptable salt or solvate thereof

[0048] [ka]

[0049] [In the formula, the stereochemistry of the hydroxyl group at the 1-position is either the (R) configuration or the (S) configuration.] R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 each independently represents a hydrogen atom, or a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, or a C3-C6 cycloalkyl group. R 12 and R 13 , R 14 and R 15 , R 16 and R17 , R 18 and R 19 can be bonded to each other to form a 3- to 5-membered ring structure. X 1 , and X 2 each independently represents a hydrogen atom or a methyl group, or X 1 and X 2 together form a methylidene group. X 3 is a CH2 group or a C=CH2 group (where X 1 and X 2 When X 3 represents a C=CH2 group. n represents an integer of 1 to 3. The stereochemistry at the 20-position in the above formula (1-2) may be either the (R) configuration or the (S) configuration.] In addition, R of the vitamin D derivatives represented by formulas (1-1) and (1-2) or pharmaceutically acceptable salts or solvates 3 , R 4 , R 5 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , n, X 1 , X 2 , and X 3 The elements described for the vitamin D derivative represented by formula (1) or a pharmaceutically acceptable salt or solvate thereof can be applied as they are. That is, preferred groups in the vitamin D derivative represented by formula (1) are also preferred groups in the vitamin D derivatives represented by formulae (1-1) and (1-2), and combinations of the preferred components described for the vitamin D derivative represented by formula (1) are also preferred for the vitamin D derivatives represented by formulae (1-1) and (1-2).

[0050] Furthermore, among the vitamin D derivatives represented by formulas (1-1) and (1-2) or pharmaceutically acceptable salts or solvates thereof, preferred specific examples include vitamin D derivatives represented by formula (1A) below or pharmaceutically acceptable salts or solvates thereof.

[0051] A vitamin D derivative represented by formula (1A) or a pharmaceutically acceptable salt or solvate thereof:

[0052] [ka]

[0053] [In the formula, R represents either the structure of Rb or Rd in the following formula:

[0054] [ka]

[0055] R 3 is substituted with two fluorine atoms tei It represents a C1 to C6 alkyl group. R 3 The stereochemistry of represents either the (R) or (S) configuration. R 14 , and R 15 R each independently represents a hydrogen atom or a C1 to C6 alkyl group. 14 , and R 15 The stereochemistry of each independently represents either the (R) configuration or the (S) configuration. n represents an integer of 1 or 2. Preferred specific examples of the vitamin D derivatives of the present invention represented by formula (1) include the compounds shown in the following table.

[0056] [Table 1-1]

[0057] Table 1-2

[0058] Table 1-3

[0059] Table 1-4

[0060] Table 1-5

[0061] Table 1-6

[0062] Table 1-7

[0063] Table 1-8

[0064] Table 1-9

[0065] Table 1-10

[0066] Table 1-11

[0067] Table 1-12

[0068] Table 1-13

[0069] Table 1-14

[0070] Table 1-15

[0071] Table 1-16

[0072] Table 1-17

[0073] Table 1-18

[0074] Table 1-19

[0075] Table 1-20

[0076] Table 1-21

[0077] Table 1-22

[0078] Table 1-23

[0079] Table 1-24

[0080] Table 1-25

[0081] Table 1-26

[0082] Table 1-27

[0083] Table 1-28

[0084] Table 1-29

[0085] Table 1-30

[0086] Table 1-31

[0087] Table 1-32

[0088] [Table 1-33]

[0089] Among these, more preferred compounds are: (1) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B022) (2) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B026) (3) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B034) (4) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B043) (5) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D023) (6) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound G006) Examples include:

[0090] The vitamin D derivatives of the present invention can be converted into their pharmaceutically acceptable salts as needed. Examples of such salts include hydrochloride, hydrobromide, methanesulfonate, paratoluenesulfonate, acetate, trifluoroacetate, fumarate, maleate, malate, succinate, oxalate, citrate, and benzoate. Particularly preferred are hydrochloride, acetate, fumarate, maleate, malate, and succinate.

[0091] Furthermore, the vitamin D derivatives of the present invention can be converted into their pharmaceutically acceptable solvates as needed. Examples of such solvents include water, methanol, ethanol, 1-propanol, 2-propanol, butanol, acetonitrile, acetone, methyl ethyl ketone, methyl acetate, and ethyl acetate. Particularly preferred are water, methanol, ethanol, and acetonitrile. <General synthesis example> The vitamin D derivative represented by the above formula (1) may be synthesized by any method. For example, when n=1 in the above formula (1), it can be synthesized as shown in Scheme 1. That is, compound (2) and cyclic amine compound (3) are coupled in the presence of a base, and then the protecting group of the hydroxy group is deprotected and the resulting product is purified to obtain the target compound (1). [Scheme 1]

[0092] [ka]

[0093] (Here, R in compound (2) in Scheme 1 above) 30 represents a leaving group. Examples of the leaving group include a chlorine atom (Cl), a bromine atom (Br), an iodine atom (I), a methanesulfonyl group (OMs), and a paratoluenesulfonyl group (OTs). In particular, an iodine atom and a paratoluenesulfonyl group are preferred leaving groups.

[0094] Also, R in compound (2) 31 represents a protecting group for a hydroxy group. Examples of the protecting group include a trimethylsilyl group (TMS), a triethylsilyl group (TES), a t-butyldimethylsilyl group (TBS), and a t-butyldiphenylsilyl group (TBDPS). Of these, a t-butyldimethylsilyl group (TBS) is preferred. The cyclic amine compound (3) used in the coupling reaction (Step 1) with compound (2) may be in the free form or a salt. The amount of amine compound (3) used in this reaction is 1 to 5 equivalents, preferably 3 to 5 equivalents. The base used in this step is not particularly limited, but preferred bases include potassium carbonate, potassium bicarbonate, and cesium carbonate. The base is added in 1 to 5 equivalents, preferably 3 to 5 equivalents. To accelerate this reaction, potassium iodide or sodium iodide may be added to the reaction mixture. The amount of potassium iodide or sodium iodide added is preferably 1 to 2 equivalents. The solvent is also not particularly limited, but preferred solvents include N,N-dimethylformamide and N-methyl-2-pyrrolidone. The reaction temperature for this coupling reaction is preferably 40°C to 70°C, and the reaction time is preferably 6 to 48 hours.

[0095] In step 1, the product may be purified in this step before proceeding to the deprotection reaction (step 2), or the crude product from step 1 may be used in the deprotection reaction (step 2).

[0096] The conditions for the deprotection reaction (Step 2) in Scheme 1 above are not particularly limited as long as they are conditions for deprotecting silyl protecting groups, but examples include deprotection with tetrabutylammonium fluoride (TBAF) and deprotection with hydrochloric acid. Preferred conditions include adding 1 to 3 equivalents of tetrabutylammonium fluoride (TBAF) per hydroxy group in tetrahydrofuran (THF) and stirring at room temperature to reflux temperature. Another preferred condition is adding 1 to 3 equivalents of hydrochloric acid per hydroxy group in a solvent such as acetone or 2-butanone and stirring at room temperature. The concentration of hydrochloric acid is preferably 1 M to 6 M. After the post-treatment of this reaction, the vitamin D derivative (1) of the present invention can be obtained by purification using a commonly used purification method such as silica gel column chromatography or HPLC.

[0097] The compound of the above formula (2) can be synthesized, for example, as shown in Scheme 2 below. [Scheme 2]

[0098] [ka]

[0099] (wherein X in Scheme 2 above 1 , X 2 , and X 3 is the same as defined in the above formula (1). 30 , R 31 is the same as defined in Scheme 1.) That is, compound (2) can be obtained by coupling reaction of phosphine oxide derivative (4) with ketone (5) under basic conditions. Preferred bases for this coupling reaction include sodium hydride, n-butyllithium, lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LHMDS), potassium bis(trimethylsilyl)amide (KHMDS), and sodium bis(trimethylsilyl)amide (NaHMDS). The amount of base used is preferably 1.1 to 2 equivalents of compound 4. This reaction is preferably carried out at −78 to −0°C for 1 to 3 hours.

[0100] In the above formula (2), R 30 is a paratoluenesulfonyl group (OTs), and R 31 When is a t-butyldimethylsilyl group (TBS), each compound in the combination shown in the table below is known.

[0101] [Table 2]

[0102] Furthermore, when the compound represented by the above formula (2) is not a known compound, it can be synthesized as follows.

[0103] For example, X 1 is a methyl group, X 2 is a hydrogen atom, X 3 When C=CH2, compound (2g) can be synthesized as shown in Scheme 3 below. That is, compound (2g) can be synthesized by coupling known compound (6c) (CAS Registry No. 173388-39-1) with known compound (7b) (CAS Registry No. 203126-90-3) in the presence of a Pd catalyst. Compound (2g) can be coupled with cyclic amine compound (3) and deprotected in the same manner as in Scheme 1 to obtain the desired vitamin D derivative (1). [Scheme 3]

[0104] [ka]

[0105] As another method for synthesizing the vitamin D derivative represented by the above formula (1), known compound (6c) is coupled with cyclic amine compound (3) in the presence of a base to synthesize compound (8), which is then coupled with compound (9) in the presence of a Pd catalyst, followed by a deprotection reaction, to obtain the vitamin D derivative represented by the above formula (1). [Scheme 4]

[0106] [ka]

[0107] [where R and X in the above scheme 1 , and X 2 is the same as defined in the above formula (1). The stereochemistry at the 1-position of compound (1) and compound (9) is either the (R) configuration or the (S) configuration. Furthermore, when n=2 in the above formula (1), it can be synthesized, for example, as shown in Scheme 5 below. That is, the primary hydroxy group of known compound (10) (CAS Registry No. 300344-39-2) is tosylated, followed by desilylation and oxidation to obtain compound (11). Compound (11) is coupled with compound (4) described in Scheme 2 to obtain compound (12). Using compound (12), a coupling reaction and deprotection reaction of cyclic amine compound (3) are carried out in the same manner as in Scheme 1, whereby the vitamin D derivative (1) of the present invention can be obtained. [Scheme 5]

[0108] [ka]

[0109] [where R and X in the above scheme 1 , X 2 , and X 3 is the same as defined in the above formula (1), and R 30 and R 31 is the same as defined in Scheme 1. In the vitamin D derivative (1) in this scheme, n=2.] In addition, compound (2) (n = 1) in Scheme 1 can be used to synthesize vitamin D derivative (1) (n = 2) as shown in Scheme 6 below. Specifically, compound (2) is nitrilated to obtain compound (13), which is then treated with diisobutylaluminum hydride (DIBAL-H) ​​to obtain aldehyde (14), which is then reduced to obtain alcohol (15). Compound (15) is tosylated to obtain OTs (16), which is then coupled with cyclic amine compound (3) as in Scheme 1 and deprotected to obtain the desired vitamin D derivative represented by formula (1). The cyanation, DIBAL reduction, and aldehyde reduction reactions in Scheme 6 proceed under commonly used conditions. For example, cyanation proceeds by reacting 1 to 3 equivalents of KCN with 0.1 to 0.3 equivalents of 18-crown-6 in N,N-dimethylformamide. The reaction temperature is preferably 80 to 100°C. DIBAL reduction proceeds in approximately 0.5 to 2 hours by adding 1 to 2 equivalents of diisobutylaluminum hydride (DIBAL-H) ​​in toluene at -78 to 0°C. The reduction of aldehydes can be carried out with 1 to 3 equivalents of sodium tetrahydroborate at 0 to room temperature for approximately 1 to 3 hours to obtain compound (16). [Scheme 6]

[0110] [ka]

[0111] [where R and X in the above scheme 1 , X 2 , and X 3 is the same as defined in the above formula (1), and R30 and R 31 is defined as in Scheme 1.] In addition to the above scheme, the vitamin D derivative represented by the above formula (1) can also be synthesized by reductive amination of the aldehyde (14) with the cyclic amine compound (3), followed by deprotection, as shown in Scheme 7 below. [Scheme 7]

[0112] [ka]

[0113] [where R and X in the above scheme 1 , X 2 , and X 3 is the same as defined in the above formula (1), and R 31 is defined as in Scheme 1.] Preferred reductive amination reagents include sodium triacetoxyborohydride and sodium cyanoborohydride. The solvent is not particularly limited, but a preferred example is THF. Alternatively, the reaction may be carried out using cyclic amine compound (3) as the solvent. The reductive amination reaction proceeds, for example, in tetrahydrofuran (THF), by reacting 1 to 5 equivalents of amine compound (3) with a reducing agent (1 to 3 equivalents) relative to compound (14), followed by deprotection to obtain compound (1).

[0114] Furthermore, when R=Rc and Re, n=2, the compound can be synthesized, for example, as shown in the following scheme 8. That is, compound (2) (R 30The tosyl group of (R = OTs) is replaced with a cyano group to obtain compound (13b), which is then reduced with DIBAL to obtain compound (14b). Compound (14b) is subjected to reductive amination with amine (3) to obtain compound (15), which is then deprotected to obtain vitamin D derivative (1) (R = Rc, Re) of the present invention. The cyanation, DIBAL reduction, and reductive amination reactions in Scheme 8 proceed under the same conditions as those described in Scheme 6 and Scheme 7. The reductive amination reaction proceeds under the same conditions as those described in Scheme 7. [Scheme 8]

[0115] [ka]

[0116] [where R and X in the above scheme 1 , X 2 , and X 3 is the same as defined in the above formula (1), and R 31 is defined as in Scheme 1.] The vitamin D derivative represented by formula (1), or a pharmaceutically acceptable salt or solvate thereof, has excellent central delivery and also has an excellent effect of promoting the differentiation of oligodendrocyte precursor cells or neural stem cells into oligodendrocytes. Due to its excellent effect of promoting the induction of oligodendrocyte differentiation, the vitamin D derivative represented by formula (1), or a pharmaceutically acceptable salt or solvate thereof, is useful as a remyelination promoter.

[0117] The vitamin D derivative represented by formula (1), or a pharmaceutically acceptable salt or solvate thereof, can be clinically applied as a remyelination promoter and can be used as a therapeutic agent for diseases associated with demyelination or dysmyelination, such as multiple sclerosis, neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-associated myelopathy, HIV-associated leukoencephalopathy, Krabbe disease, Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, depression due to drug addiction, autism, Alzheimer's disease, and ischemic stroke.

[0118] The present invention relates to a pharmaceutical for promoting the differentiation of oligodendrocyte precursor cells into oligodendrocytes, and a pharmaceutical for promoting remyelination, which contains a vitamin D derivative represented by formula (1) used in combination with an immunomodulatory substance. While immunomodulatory substances can reduce the frequency and severity of attacks or the accumulation of lesions, they are not known to promote the remyelination of damaged axons. The combined use of the vitamin D derivative represented by formula (1) and the immunomodulatory substance is expected to enhance the therapeutic effect of the immunomodulatory substance and further promote the differentiation of oligodendrocyte precursor cells into oligodendrocytes.

[0119] Immunomodulatory substances that can be used in combination with the vitamin D derivative represented by formula (1) include fingolimod (FTY720), interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, natalizumab, siponimod, ozanimod, ponesimod, dimethyl fumarate, diroximel fumarate, cladribine, ocrelizumab, rituximab, ofatumumab, ublituximab, alemtuzumab, divozilimab, evobrutinib, orelabrutinib, trebrutinib, remibrutinib, and fenebrutinib, with fingolimod (FTY720) being particularly preferred.

[0120] Pharmaceutical compositions containing a vitamin D derivative represented by formula (1) or a pharmaceutically acceptable salt or solvate thereof for promoting differentiation of oligodendrocyte precursor cells into oligodendrocytes and for promoting remyelination are prepared using carriers, bases, excipients, and other additives commonly used in pharmaceutical formulations. The carriers, bases, and excipients used in pharmaceutical compositions may be solid or liquid, and examples include lactose, magnesium stearate starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and medium-chain triglycerides, as well as other commonly used carriers. Administration may be oral, such as in the form of tablets, pills, capsules, soft capsules, granules, powders, or liquids, or parenterally, such as by injection (intravenous or intramuscular), suppository, transdermal, or nasal route.

[0121] The present invention relates to a pharmaceutical for promoting the induction of differentiation of oligodendrocyte precursor cells into oligodendrocytes and a pharmaceutical for promoting remyelination, which contain a vitamin D derivative represented by formula (1) and an immunomodulatory substance. As described above, the pharmaceutical containing the vitamin D derivative represented by formula (1) and the immunomodulatory substance can be prepared into a pharmaceutical composition using carriers, bases, excipients, and other additives typically used in formulations, and administered in the same manner.

[0122] In some embodiments, the invention involves the use of a therapeutically effective or optimal dose of one or both of a vitamin D derivative of Formula (1) and an immunomodulatory agent. In some embodiments, the invention involves the use of a subtherapeutic dose of one or both of a vitamin D derivative of Formula (1) and an immunomodulatory agent. In some embodiments, the invention involves the use of a therapeutically effective or optimal dose of a vitamin D derivative of Formula (1) and a subtherapeutic dose of an immunomodulatory agent. In some embodiments, the invention involves the use of a therapeutically effective or optimal dose of an immunomodulatory agent and a subtherapeutic dose of a vitamin D derivative of Formula (1).

[0123] In some embodiments, one or both of the vitamin D derivative of Formula (1) and the immunomodulatory substance are formulated as a therapeutically effective dose or an optimal dose. In some embodiments, one or both of the vitamin D derivative of Formula (1) and the immunomodulatory substance are formulated as a subtherapeutic dose. In some embodiments, the vitamin D derivative of Formula (1) is formulated as a therapeutically effective dose or an optimal dose, and the immunomodulatory substance is formulated as a subtherapeutic dose. In some embodiments, the immunomodulatory substance is formulated as a therapeutically effective dose or an optimal dose, and the vitamin D derivative of Formula (1) is formulated as a subtherapeutic dose.

[0124] As used herein, the term "therapeutically effective dose or optimal dose" refers to the dose that produces the therapeutic effect for which it is administered when administered alone.The exact dose will vary depending on the purpose of treatment and can be ascertained by those skilled in the art using known methods (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0125] As used herein, the term "subtherapeutic dose" refers to a dose of a pharmacologically active agent, either as an administered dose of a pharmacologically active agent, or as an actual level of a pharmacologically active agent in a subject, that is functionally insufficient to induce an intended pharmacological effect by itself when administered alone, or that is quantitatively less than the established therapeutic dose of that particular pharmacological agent (e.g., as listed in references consulted by those skilled in the art, such as the doses for pharmacological agents listed in Physicians' Desk Reference, 66th Ed., 2012, PDR Network, LLC; or Brunton, et al., Goodman & Gilman's *The Pharmacological Basis of Therapeutics*, 12th edition, 2011, McGraw-Hill Professional). A "subtherapeutic dose" can be defined in relative terms (i.e., as a percentage (less than 100%) of the amount of a pharmacologically active agent that is conventionally administered). For example, a subtherapeutic dose amount can be about 1% to about 75% of the amount of the pharmacologically active agent that is conventionally administered, hi some embodiments, a subtherapeutic dose amount can be about 75%, 50%, 30%, 25%, 20%, 10% or less of the amount of the pharmacologically active agent that is conventionally administered. The therapeutically effective dose of the active ingredient in the pharmaceutical composition of the present invention containing the vitamin D derivative of formula (1) varies depending on the route of administration, the patient's age, sex, and severity of the disease, but is typically about 0.1 to 10,000 μg / day. The frequency of administration is typically 1 to 3 times / day or 1 to 3 times / week. It is preferable to prepare the formulation to satisfy these conditions. However, since the dosage varies depending on various conditions, a lower dose than the above-mentioned dose may be sufficient, or a dose exceeding the above-mentioned range may be required. When used in combination with an immunomodulatory substance, the active ingredient may be used at a subtherapeutic dose, for example, less than about 75%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the aforementioned dose.

[0126] Immunomodulatory substances used in combination with the pharmaceutical compositions of the present invention containing a vitamin D derivative represented by Formula (1) are used at therapeutically effective doses or subtherapeutic doses. For example, the therapeutically effective dose of benztropine is from about 1 mg per day to about 10 mg per day, the therapeutically effective dose of fingolimod is from about 0.1 mg per day to about 1.5 mg per day, the therapeutically effective dose of interferon beta-1a is about 30 μg per week, and the therapeutically effective dose of interferon beta-1b is from about 250 μg every other day to about 500 μg every other day. The immunomodulatory substance may be used at a subtherapeutic dose, for example, at a dose that is less than about 75%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the dose conventionally administered for the immunomodulatory substance. For example, fingolimod may be used at subtherapeutic doses of from about 0.005 mg per day to about 0.375 mg per day; interferon beta-1a may be used at subtherapeutic doses of from about 0.3 μg per week to about 23 μg per week, and interferon beta-1b may be used at subtherapeutic doses of from about 2 μg every other day to about 190 μg every other day.

[0127] Fingolimod (FTY720) is conventionally administered at a therapeutically effective dose of from about 0.5 mg per day to about 1.5 mg per day (e.g., about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5 mg per day). See, e.g., Kappos et al., N Engl J Med 362:387-401 (2010). Thus, in some embodiments, the subtherapeutic dose of fingolimod is from about 0.005 mg per day to about 0.375 mg per day (e.g., about 0.005, about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35 or about 0.375 mg per day). The present invention provides a method for the combined use of a pharmaceutical containing a vitamin D derivative represented by formula (1) and an immunomodulatory substance to promote the induction of differentiation of oligodendrocyte precursor cells into oligodendrocytes or to promote remyelination.

[0128] The medicament containing the vitamin D derivative of formula (1) and the immunomodulatory substance may be administered together or separately, and may be administered at the same time or at different times. When administered, the medicament containing the vitamin D derivative of formula (1) and the immunomodulatory substance can be independently administered once, twice, three times, four times, or more or less frequently daily as needed. In some embodiments, these active substances are administered once daily. In some embodiments, these active substances are administered at the same time or multiple times, for example, as a mixture. One or more of the active substances can be administered as a sustained-release formulation.

[0129] In some embodiments, co-administration of a medicament containing a vitamin D derivative of Formula (1) and an immunomodulatory agent in combination includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering the two active agents at the same time, at approximately the same time (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both active agents (i.e., administered as a medicament containing a vitamin D derivative of Formula (1) and an immunomodulatory agent). In another embodiment, the active agents and / or auxiliary agents can be linked or conjugated to each other.

[0130] In some embodiments, one or both of the medicament containing the vitamin D derivative of formula (1) and the immunomodulatory agent can be administered prophylactically to prevent the undesired recurrence of symptoms of a demyelinating disease such as multiple sclerosis (e.g., to prevent or delay the recurrence of clinical attacks in multiple sclerosis), or therapeutically to achieve a desired alleviation of symptoms of a demyelinating disease and maintain such alleviation of symptoms of a demyelinating disease over a sustained period of time.

[0131] In another aspect, the present invention provides kits for use in treating multiple sclerosis, neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-associated myelopathy, HIV-associated leukoencephalopathy, Krabbe disease, Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, depression due to drug addiction, autism, Alzheimer's disease, and ischemic stroke. In some embodiments, the kit comprises a medicament containing a vitamin D derivative represented by Formula (1) and an immunomodulatory substance. [Example]

[0132] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. The abbreviations used in the present invention are as follows. Boc = t-butoxycarbonyl DAST = diethylaminosulfur trifluorolide DIBAL-H = diisobutylaluminum hydride DMF = N,N-dimethylformamide LHMDS = lithium hexamethylenedisilazane MBP = Myelin Basic Protein MS4A = Molecular Sieve 4A NMO = N-methylmorpholine N-oxide NMP = N-methyl-2-pyrrolidone PTLC = thin layer chromatography TBAF = tetrabutylammonium fluoride TBS = t-butyldimethylsilyl group TES = triethylsilyl group TESCl = chlorotriethylsilane THF = tetrahydrofuran TPAP = Tetrapropylammonium perruthenate Ts = p-toluenesulfonyl TsCl = p-toluenesulfonyl chloride In the following examples, when the compound of the present invention is obtained by preparative HPLC, the preparative conditions are as follows. Column: YMC-Pack ODS AM, inner diameter 3cm-30cm, manufactured by YMC Co., Ltd. Mobile phase A: 5% acetonitrile water (0.1% acetic acid added) Mobile phase B: 95% acetonitrile water (0.1% acetic acid added) Amount added: Dissolve the crude material in 1.3 mL of methanol and inject Fluid flow rate: 12 mL / min UV: 265 nm Fluid delivery program: 0~5 minutes: 5% B solution / 95% A solution 5-45 min: Gradient to 100% solution B in 40 min 45 minutes to 50 minutes: 100% B solution 50-55 min: Gradient to 5% solution B / 95% solution A in 5 min In the examples below, when analysis is performed by HPLC / MS, the analysis conditions are as follows. Column: Phenomenex Gemini C18 3 μm, inner diameter 4.6 mm-30 mm Mobile phase A: 5% acetonitrile in water (with 0.1% trifluoroacetic acid added) Mobile phase B: 95% acetonitrile water (with 0.1% trifluoroacetic acid added) Fluid flow rate: 1.2 mL / min UV: 254 nm Fluid delivery program: 0~0.01 min: 2% B liquid / 98% A liquid 0.01-0.3 min: Gradient to 40% solution B / 60% solution A 0.3 to 2.3 min: Gradient to 100% solution B 2.3 minutes to 4.2 minutes: 100% B solution 4.2-4.3 min: Gradient to 2% solution B / 98% solution A 4.3 minutes to 5.2 minutes: 2% B solution / 98% A solution 5.2 minutes: Analysis complete [Reference example 1] Synthesis of (2S)-2-((1R,3aS,7aR,E)-4-((Z)-2((3S,5R)-3,5-bis((t-butyldimethylsilyl)oxy)-2-methylenecyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (compound (2a))

[0133] [ka]

[0134] Under an argon atmosphere, a 50 mL THF solution of ((Z)-2-((3S,5R)-3,5-bis((t-butyldimethylsilyl)oxy)-2-methylenecyclooxylidene)ethyl)diphenylphosphine oxide (Compound 4a, CAS Registry No. 81522-68-1) [7.42 g, 12.7 mmol] was added to 10 mL of 1 M LHMDS in toluene and stirred at −78°C for 1 hour. A 20 mL THF solution of (2S)-2-((1R,3aR,7aR)-7a-methyl-4-oxooctadehydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (Compound 5a, CAS Registry No. 342645-83-4) [3.6 g, 9.9 mmol] was added, and the mixture was stirred at the same temperature for an additional 1 hour. The reaction mixture was warmed to room temperature and stirred for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with a mixed solvent of heptane and ethyl acetate (1 / 1). The organic phase was washed with water, followed by 50% aqueous methanol, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound (2a) [4.79 g, 6.57 mmol] (yield: 67%). 1H-NMR (CDCl3) δ: 7.79 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 6.22 (1H, d, J = 11.0 Hz), 5.99 (1H, d, J = 11.0 Hz), 5.17 (1H, d, J = 2.0 Hz), 4.84 (1H, d, J = 2.0 Hz), 4.38-4.16 (2H, m), 3.98 (1H, dd, J = 9.1, 3.2 Hz), 3.80 (1H, dd, J = 9.1, 6.4 Hz), 2.83 (1H, d, J = 12.3 Hz), 2.45 (3H, s), 2.42 (1H, d, J = 4.1 Hz), 2.22 (1H, dd, J = 13.0, 7.5 Hz), 1.97-1.57 (8H, m), 1.53-1.15 (9H, m), 0.99 (3H, d, J = 6.4 Hz), 0.87 (9H, s), 0.86 (9H, s), 0.49 (3H, s), 0.06 (9H, s), 0.04 (3H, s). [Reference example 2] Synthesis of (2S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (Compound 2b)

[0135] [ka]

[0136] Under an argon atmosphere, a 1M toluene solution of LHMDS (20 mL) was added to a THF solution (85 mL) of (2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethyl)diphenylphosphine oxide (Compound 4b, CAS Registry No. 139356-39-1) [8.55 g, 15.0 mmol] and (2S)-2-((1R,3aR,7aR)-7a-methyl-4-oxooctadehydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (Compound 5a, CAS Registry No. 342645-83-4) [5.06 g, 13.9 mmol] at -78°C. The mixture was stirred at -78°C for 2 hours. The reaction mixture was then warmed to 0°C and stirred for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture at room temperature, and the mixture was extracted with a mixed solvent of heptane and ethyl acetate (1 / 1). The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Methanol was added to the residue to form a precipitate. The suspension was stirred for 2 hours. The precipitate was collected and dried to obtain compound (2b) [6.40 g, 8.92 mmol] (yield = 64%). 1H-NMR (CDCl3) δ: 7.79 (2H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 6.15 (1H, d, J = 11.0 Hz), 5.79 (1H, d, J = 11.4 Hz), 4.12-4.02 (2H, m), 3.98 (1H, dd, J = 9.1, 2.7 Hz), 3.81 (1H, dd, J = 9.1, 6.4 Hz), 2.80 (1H, dd, J = 12.1, 3.9 Hz), 2.46 (3H, s), 2.36 (2H, dd, J = 13.0, 4.8 Hz), 2.25 (1H, dd, J = 14.2, 2.7 Hz), 2.10 (1H, dd, J = 12.8, 8.2 Hz), 2.00-1.90 (2H, m), 1.80-1.60 (6H, m), 1.55-1.16 (6H, m), 0.99 (3H, d, J = 6.4 Hz), 0.87 (9H, s), 0.85 (9H, s), 0.50 (3H, s), 0.05 (3H, s), 0.05 (3H, s), 0.04 (6H, s). [Reference example 3] Synthesis of (S)-2-((1R,3aS,7aR,E)-4-(2-((3S,5R)-3,5-bis((t-butyldimethylsilyl)oxy)-4-methylenecyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (Compound 2c)

[0137] [ka]

[0138] To a 40 mL THF solution of (2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)-4-methylcyclohexylidene)ethyl)diphenylphosphine oxide (compound (4c), CAS Registry No. 213250-64-7, 2.50 g, 4.29 mmol) and (2S)-2-((1R,3aR,7aR)-7a-methyl-4-oxooctadehydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (compound (5a), CAS Reg No. 342645-83-4, 2.35 g, 6.45 mmol), LHMDS (1M THF solution, 8.5 mL) was added under an argon atmosphere at −78°C, and the mixture was stirred at −78°C for 2 hours. The reaction mixture was warmed to room temperature and quenched by the addition of saturated aqueous ammonium chloride. The reaction mixture was extracted with ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound (2c) (1.70 g, 2.30 mmol) (yield: 54%). 1H-NMR (CDCl3) δ: 7.79 (2H, d, J = 8.8 Hz), 7.35 (2H, d, J = 7.8 Hz), 6.20 (1H, d, J = 11.2 Hz), 5.82 (1H, d, J = 11.2 Hz), 4.97 (1H, s), 4.92 (1H, s), 4.45-4.40 (2H, m), 3.99 (1H, dd, J = 9.3, 2.9 Hz), 3.81 (1H, dd, J = 9.0, 6.6 Hz), 2.81 (1H, dd, J = 12.2, 3.4 Hz), 2.54-2.42 (2H, m), 2.45 (3H, s), 2.32 (1H, dd, J = 13.2, 3.4 Hz), 2.17 (1H, dd, J = 12.7, 8.3 Hz), 2.02-1.90 (2H, m), 1.78-1.63 (4H, m), 1.55-1.15 (9H, m), 1.00 (3H, d, J = 6.3 Hz), 0.89 (9H, s), 0.85 (9H, s), 0.51 (3H, s), 0.07 (3H, s), 0.05 (3H, s), 0.04 (3H, s), 0.02 (3H, s). [Reference example 4] Synthesis of (S)-2-((1R,3aS,7aR,E)-4-((Z)-2-((3S,4s,5R)-3,5-bis((t-butyldimethylsilyl)oxy)-4-methyl-2-methylenecyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl-4-methylbenzenesulfonate (Compound 2g)

[0139] [ka]

[0140] Process 1 Pivaloyl chloride (0.22 mL, 1.78 mmol) was added to a pyridine solution (7 mL) of (2S)-2-((1R,3aS,7aR,E)-4-(bromomethylene)-7a-methyloctahydro-1H-inden-1-yl)propan-1-ol (compound (6a), CAS Registry No. 218437-70-8) (345 mg, 1.20 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate, transferred to saturated brine, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 6b (415 mg, 1.12 mmol). (Yield: 93%) 1 H-NMR (CDCl3) δ: 5.67 (1H, d, J = 1.5 Hz), 4.07 (1H, dd, J = 10.7, 3.0 Hz), 3.79 (1H, dd, J = 10.7, 7.3 Hz), 2.95-2.85 (1H, m), 2.02-1.59 (9H, m), 1.55-1.25 (7H, m), 1.21 (9H, s), 1.03 (3H, d, J = 6.8 Hz), 0.59 (3H, s). Process 2 Compound 6b (415 mg, 1.12 mmol) obtained in Step 1, (5R,6S,7R)-2,2,3,3,6,9,9,10,10-nonamethyl-5-(prop-2-yn-1-yl)-7-vinyl-4,8-dioxa-3,9-disilaundecane (compound (7b), CAS Registry No. 203126-90-3) [513 mg, 1.34 mmol], and tetrakis(triphenylphosphine)palladium(0) [134.4 mg, 0.116 mmol] were added to a mixture of toluene [4 mL] and triethylamine [4 mL] and heated and stirred at 100°C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, saturated brine was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.82 g of a crude product containing the coupling product. Process 3 Lithium aluminum hydride [LAH, 115 mg, 3.03 mmol] was added to a THF solution [20 mL] of the crude product [0.82 g] obtained in Step 2 at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with methanol at 0°C, and 5M aqueous sodium hydroxide solution [6 mL] was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed successively with saturated brine and saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.47 g of the deprotected product. Process 4 To a solution of the deprotected product obtained in Step 3 (0.47 g, 0.8 mmol), trimethylamine hydrochloride (160 mg, 1.67 mmol), and triethylamine (0.3 mL, 2 mmol) in acetonitrile (10 mL), p-toluenesulfonyl chloride (0.25 g, 1.3 mmol) was added at room temperature and stirred for 2 hours. The reaction mixture was quenched with methanol and saturated brine was added. The reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 2g (0.43 g, 0.58 mmol). 1H-NMR (CDCl3) δ: 7.79 (2H, d, J = 7.8 Hz), 7.34 (2H, d, J = 8.3 Hz), 6.22 (1H, d, J = 11.2 Hz), 6.01 (1H, d, J = 11.2 Hz), 5.12 (1H, d, J = 2.4 Hz), 4.86 (1H, d, J = 2.4 Hz), 4.20 (1H, d, J = 2.4 Hz), 3.98 (1H, dd, J = 9.0, 2.7 Hz), 3.83-3.78 (2H, m), 2.82 (1H, d, J = 12.2 Hz), 2.51-2.45 (5H, m), 2.16 (1H, dd, J = 13.2, 8.3 Hz), 1.97-1.63 (11H, m), 1.53-1.04 (10H, m), 0.99 (3H, d, J = 6.3 Hz), 0.95 (3H, d, J = 6.8 Hz), 0.88 (9H, s), 0.85 (9H, s), 0.49 (3H, s), 0.07 (3H, s), 0.05 (3H, s), 0.05 (3H, s), 0.02 (3H, s). [Example 1] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((R)-1-(3-fluoroazetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound A001)

[0141] [ka]

[0142] Process 1 A DMF solution (1 mL) of compound (2a) (90 mg, 0.123 mmol) described in Reference Example 1, 3-fluoroazetidine hydrochloride compound (3a1) (50 mg, 0.448 mmol), and K2CO3 (90 mg, 0.651 mmol) was heated and stirred at 60 °C overnight. After cooling to room temperature, saturated brine was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crudely purified by PTLC to obtain the coupling product (21.0 mg, 0.0332 mmol). Process 2 To a THF solution [1 mL] of the coupling product obtained in Step 1 [21.0 mg, 0.0332 mmol], TBAF [1 M THF solution, 0.3 mL, 0.3 mmol] was added and the mixture was heated and stirred at 50 °C overnight. After cooling to room temperature, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound A001 [5.8 mg, 0.014 mmol]. 1 H-NMR (CD3OD) δ: 6.31 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.2, 1.2 Hz), 5.26-5.03 (1H, m), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.09 (1H, m), 3.90-3.80 (2H, m), 3.54-3.40 (2H, m), 2.86 (1H, dd, J = 12.2, 3.9 Hz), 2.71 (1H, dd, J = 12.2, 2.9 Hz), 2.53-2.46 (2H, m), 2.25 (1H, dd, J = 13.4, 6.6 Hz), 2.05-1.97 (3H, m), 1.92-1.28 (14H, m), 1.00 (3H, d, J = 6.8 Hz), 0.59 (3H, s). LC-MS: Exact Mass = 403.29(C 25 H 38FNO2)Obs. mass = 404.45 (M+H), In the following examples, each compound was synthesized in the same manner as in Example 1 for the synthesis of compound A001. In each example, only the raw materials and the amine compounds used are described. As in Example 1, potassium carbonate was used as the base, and the equivalent amount was appropriately changed according to the raw materials used under the conditions of Example 1.

[0143] [Example 2] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-fluoroazetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A002) Compound (2c) [50 mg, 0.069 mmol] and 3-fluoroazetidine hydrochloride [30 mg, 0.269 mmol] were reacted in the same manner as in Example 1 to obtain compound A002 [9.0 mg, 0.022 mmol]. 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.30-5.08 (1H, m), 5.05 (2H, d, J = 6.8 Hz), 4.42-4.36 (2H, m), 3.96-3.87 (2H, m), 3.61-3.48 (2H, m), 2.87-2.46 (5H, m), 2.31-2.25 (2H, m), 2.10-2.00 (2H, m), 1.70-1.28 (9H, m), 1.01 (3H, d, J = 6.3 Hz), 0.60 (3H, s). LC-MS: Exact Mass = 403.29(C 25 H 38 FNO2)Obs. mass = 404.45 (M+H), [Example 3] Synthesis of (1R,3R,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-(difluoromethyl)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound A003) Compound (2a) [90 mg, 0.123 mmol] and 3-(difluoromethyl)azetidine hydrochloride [50 mg, 0.448 mmol] were reacted in the same manner as in Example 1 to obtain compound A003 [8.7 mg, 0.022 mmol]. 1 H-NMR (CD3OD) δ: 6.31 (1H, d, J = 10.7 Hz), 6.22-5.93 (2H, m), 5.28 (1H, dd, J = 2.2, 1.2 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.09 (1H, m), 3.85-3.60 (4H, m), 3.20-3.08 (1H, m), 2.86 (2H, dt, J = 12.2, 3.0 Hz), 2.60-2.48 (2H, m), 2.25 (1H, dd, J = 13.4, 6.6 Hz), 2.05-2.00 (3H, m), 1.93-1.27 (13H, m), 1.01 (3H, d, J = 6.8 Hz), 0.60 (3H, s). LC-MS:Exact Mass = 435.29(C26H39F2NO2)Obs. mass = 436.45 (M+H), [Example 4] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-1-(3-(difluoromethyl)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A004) Compound (2c) [50 mg, 0.069 mmol] and 3-(difluoromethyl)azetidine hydrochloride [30 mg, 0.269 mmol] were reacted in the same manner as in Example 1 to obtain compound A004 [7.8 mg, 0.018 mmol]. 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7 Hz), 6.08 (1H, td, J = 56.5, 4.6 Hz), 5.91 (1H, d, J = 11.7 Hz), 5.05 (2H, d, J = 7.5 Hz), 4.42-4.36 (2H, m), 3.80 (2H, q, J = 8.0 Hz), 3.66-3.61 (2H, m), 3.16-3.05 (1H, m), 2.86 (2H, dd, J = 12.2, 2.4 Hz), 2.66 (1H, dd, J = 13.2, 4.4 Hz), 2.57 (1H, dd, J = 12.2, 10.2 Hz), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.31-2.25 (2H, m), 2.10-2.00 (3H, m), 1.70-1.31 (10H, m), 1.01 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 435.29(C26H39F2NO2)Obs. mass = 436.45 (M+H), [Example 5] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-(difluoromethyl)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound A005) Compound (2g) [50 mg, 0.067 mmol] and 3-(difluoromethyl)azetidine hydrochloride [30 mg, 0.269 mmol] were reacted in the same manner as in Example 1 to obtain compound A005 [4.5 mg, 0.010 mmol]. 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 10.7 Hz), 6.23-5.90 (2H, m), 5.22 (1H, d, J = 2.0 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.78-3.68 (3H, m), 3.57 (2H, dd, J = 15.6, 6.8 Hz), 3.13-3.02 (1H, m), 2.88-2.78 (2H, m), 2.62-2.48 (2H, m), 2.17 (1H, dd, J = 13.2, 8.3 Hz), 2.02 (2H, dd, J = 12.4, 4.6 Hz), 1.91-1.26 (12H, m), 1.03 (3H, d, J = 6.8 Hz), 1.00 (3H, d, J = 6.3 Hz), 0.58 (3H, s). Exact Mass = 435.29(C27H41F2NO2)Obs. mass = 436.45 (M+H) [Example 6] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-(1,1-difluoroethyl)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound A006) Compound (2a) [90 mg, 0.123 mmol] and 3-(1,1-difluoroethyl)azetidine hydrochloride [60 mg, 0.381 mmol] were reacted in the same manner as in Example 1 to obtain compound A006 [6.8 mg, 0.015 mmol]. 1H-NMR (CD3OD) δ: 6.31 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.2, 1.2 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.08 (1H, m), 3.95-3.85 (2H, m), 3.68 (2H, q, J = 8.5 Hz), 3.29-3.10 (2H, m), 2.88 (2H, td, J = 12.0, 3.3 Hz), 2.61 (1H, dd, J = 12.2, 10.2 Hz), 2.51 (1H, dd, J = 13.7, 3.4 Hz), 2.25 (1H, dd, J = 13.4, 6.6 Hz), 2.08-1.95 (4H, m), 1.93-1.26 (18H, m), 1.01 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 449.31(C27H41F2NO2)Obs. mass = 450.50 (M+H) [Example 7] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-(1,1-difluoroethyl)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A007) Compound (2c) [50 mg, 0.069 mmol] and 3-(1,1-difluoroethyl)azetidine hydrochloride [30 mg, 0.19 mmol] were reacted in the same manner as in Example 1 to obtain compound A007 [7.6 mg, 0.017 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.05 (2H, dd, J = 7.0, 2.0 Hz), 4.43-4.34 (2H, m), 3.97-3.88 (2H, m), 3.75-3.65 (2H, m), 3.26-3.15 (1H, m), 2.93 (1H, dd, J = 12.4, 2.7 Hz), 2.85 (1H, dd, J = 12.0, 3.7 Hz), 2.69-2.60 (2H, m), 2.48 (1H, dd, J = 13.4, 4.1 Hz), 2.32-2.25 (2H, m), 2.11-2.00 (3H, m), 1.68-1.52 (9H, m), 1.42-1.30 (3H, m), 1.02 (3H, d, J = 6.8 Hz), 0.61 (3H, s). Exact Mass = 449.31(C27H41F2NO2)Obs. mass = 450.45 (M+H) [Example 8] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-(1,1-difluoroethyl)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound A008) Compound (2g) [50 mg, 0.067 mmol] and 3-(1,1-difluoroethyl)azetidine hydrochloride [60 mg, 0.38 mmol] were reacted in the same manner as in Example 1 to obtain compound A008 [4.7 mg, 0.010 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 10.7 Hz), 5.22 (1H, d, J = 2.0 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.92-3.83 (2H, m), 3.75-3.61 (3H, m), 3.27-3.12 (1H, m), 2.87 (2H, dd, J = 11.0, 3.7 Hz), 2.63-2.55 (2H, m), 2.20-2.00 (3H, m), 1.92-1.27 (15H, m), 1.03 (3H, d, J = 6.8 Hz), 1.01 (3H, d, J = 6.8 Hz), 0.59 (3H, s). Exact Mass = 463.32(C28H43F2NO2)Obs. mass = 464.50 (M+H) [Example 9] (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound A009) Compound (2a) [90 mg, 0.123 mmol] and 3-(trifluoromethyl)-3-azetidinol hydrochloride [44 mg, 0.247 mmol] were reacted in the same manner as in Example 1 to obtain compound A009 [7.5 mg, 0.016 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.29 (1H, dd, J = 2.4, 1.5 Hz), 4.35 (1H, t, J = 5.9 Hz), 4.16-4.10 (1H, m), 3.62 (2H, dd, J = 9.3, 2.9 Hz), 3.25 (2H, t, J = 8.8 Hz), 2.87 (1H, dd, J = 11.5, 4.1 Hz), 2.58 (1H, dd, J = 12.0, 3.2 Hz), 2.52 (1H, dd, J = 13.2, 3.4 Hz), 2.34-2.24 (2H, m), 2.06-2.04 (1H, m), 2.03-2.00 (3H, m), 1.93-1.20 (14H, m), 0.99 (3H, d, J = 6.8 Hz), 0.59 (3H, s). Exact Mass = 469.28(C26H38F3NO3)Obs. mass = 470.60 (M+H) [Example 10] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A010) Compound (2b) [50 mg, 0.070 mmol] and 3-(trifluoromethyl)-3-azetidinol hydrochloride [37 mg, 0.208 mmol] were reacted in the same manner as in Example 1 to obtain compound A010 [8.4 mg, 0.018 mmol]. 1H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2 Hz), 5.89 (1H, d, J = 11.2 Hz), 4.07-3.95 (2H, m), 3.62 (2H, dd, J = 9.3, 2.9 Hz), 3.25 (2H, t, J = 9.0 Hz), 2.84 (1H, dd, J = 12.7, 3.9 Hz), 2.62-2.57 (2H, m), 2.41 (1H, dd, J = 13.2, 3.4 Hz), 2.32 (1H, dd, J = 11.7, 9.8 Hz), 2.25-2.11 (2H, m), 2.05-2.00 (2H, m), 1.95-1.26 (13H, m), 1.00 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 457.28(C25H38F3NO3)Obs. mass = 458.65 (M+H) [Example 11] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A011) Compound (2c) [50 mg, 0.069 mmol] and 3-(trifluoromethyl)-3-azetidinol hydrochloride [40.2 mg, 0.226 mmol] were reacted in the same manner as in Example 1 to obtain compound A011 [11.0 mg, 0.023 mmol]. Exact Mass = 469.28(C26H38F3NO3)Obs. mass = 470.35 (M+H) [Example 12] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-methoxy-3-trifluoromethylazetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A012) Compound (2b) [50 mg, 0.070 mmol] and 3-methoxy-3-(trifluoromethyl)-azetidine hydrochloride [30 mg, 0.157 mmol] were reacted in the same manner as in Example 1 to obtain compound A012 [3.0 mg, 0.006 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.89 (1H, d, J = 11.4 Hz), 4.05-3.96 (2H, m), 3.45 (3H, s), 3.45 (3H, dd, J = 8.0, 3.0 Hz), 3.35 (4H, t, J = 12.1 Hz), 2.83 (1H, dd, J = 11.7, 3.9 Hz), 2.59 (1H, dd, J = 13.3, 3.7 Hz), 2.52 (1H, dd, J = 11.9, 3.2 Hz), 2.40 (1H, dd, J = 13.5, 3.4 Hz), 2.30-2.13 (3H, m), 2.04-1.28 (17H, m), 0.99 (3H, d, J = 6.4 Hz), 0.58 (3H, s). Exact Mass = 471.30(C26H40F3NO3)Obs. mass = 472.35 (M+H) [Example 13] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-(3-trifluoromethoxy)azetidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A013) Compound (2b) [50 mg, 0.070 mmol] and 3-(trifluoromethoxy)-azetidine hydrochloride [50 mg, 0.169 mmol] were reacted in the same manner as in Example 1 to obtain compound A013 [1.5 mg, 0.003 mmol]. Exact Mass = 457.28(C25H38F3NO3)Obs. mass = 458.25 (M+H) [Example 14] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A014) Compound (2b) [50 mg, 0.070 mmol] and 3-(2,2,2-trifluoroethoxy)-azetidine hydrochloride [30 mg, 0.193 mmol] were reacted in the same manner as in Example 1 to obtain compound A014 [7.4 mg, 0.016 mmol]. 1H-NMR (CD3OD) δ: 6.19 (1H, d, J = 11.0 Hz), 5.87 (1H, d, J = 11.0 Hz), 4.26-4.20 (1H, m), 4.05-3.93 (2H, m), 3.88 (2H, q, J = 9.0 Hz), 3.61 (2H, q, J = 7.6 Hz), 2.99 (1H, t, J = 6.9 Hz), 2.93 (1H, t, J = 6.9 Hz), 2.81 (1H, dd, J = 11.9, 4.1 Hz), 2.57 (1H, dd, J = 13.3, 3.7 Hz), 2.47 (1H, dd, J = 11.7, 3.0 Hz), 2.39 (1H, dd, J = 13.3, 3.2 Hz), 2.27 (1H, dd, J = 11.9, 9.6 Hz), 2.21-2.11 (2H, m), 2.02-1.25 (15H, m), 0.97 (3H, d, J = 6.4 Hz), 0.56 (3H, s). Exact Mass = 471.30(C26H40F3NO3)Obs. mass = 472.25 (M+H) [Example 15] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-(2,2-difluoroethoxy)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A015) Compound (2b) [50 mg, 0.070 mmol] and 3-(2,2-difluoroethoxy)-azetidine hydrochloride [35 mg, 0.202 mmol] were reacted in the same manner as in Example 1 to obtain compound A015 [12.8 mg, 0.028 mmol]. 1H-NMR (CD3OD) δ: 6.16 (1H, d, J = 10.7 Hz), 5.85 (1H, tt, J = 3.5, 55.0 Hz), 5.84 (1H, d, J = 10.7 Hz), 4.17-4.11 (1H, m), 4.02-3.90 (2H, m), 3.63-3.52 (4H, m), 2.92 (2H, dt, J = 22.9, 6.8 Hz), 2.78 (1H, dd, J = 12.0, 3.7 Hz), 2.54 (1H, dd, J = 13.2, 3.4 Hz), 2.44 (1H, dd, J = 12.2, 2.9 Hz), 2.36 (1H, dd, J = 13.2, 3.4 Hz), 2.26-2.09 (3H, m), 1.99-1.24 (15H, m), 0.94 (3H, d, J = 6.3 Hz), 0.53 (3H, s). Exact Mass = 453.31(C26H41F2NO3)Obs. mass = 454.25 (M+H) [Example 16] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-(2,2-difluoroethoxy)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A016) Compound (2c) [100 mg, 0.137 mmol] and 3-(2,2-difluoroethoxy)-azetidine hydrochloride [70 mg, 0.403 mmol] were reacted in the same manner as in Example 1 to obtain compound A016 [20.6 mg, 0.044 mmol]. 1H-NMR (CD3OD) δ: 6.24 (1H, d, J = 11.0 Hz), 6.03-5.74 (2H, m), 5.03 (2H, d, J = 6.9 Hz), 4.43-4.30 (2H, m), 4.20-4.14 (1H, m), 3.68-3.55 (4H, m), 2.97 (1H, t, J = 6.9 Hz), 2.92 (1H, t, J = 6.9 Hz), 2.83 (1H, dd, J = 11.9, 3.7 Hz), 2.65 (1H, dd, J = 13.3, 4.6 Hz), 2.49-2.42 (2H, m), 2.30-2.20 (3H, m), 2.03-1.87 (3H, m), 1.68-1.44 (6H, m), 1.40-1.25 (3H, m), 0.97 (3H, d, J = 6.4 Hz), 0.57 (3H, s). Exact Mass = 453.31(C27H41F2NO3)Obs. mass = 454.25 (M+H) [Example 17] Synthesis of (1R,3R,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-(2,2-difluoroethoxy)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound A017) Compound (2a) [100 mg, 0.137 mmol] and 3-(2,2-difluoroethoxy)-azetidine hydrochloride [70 mg, 0.403 mmol] were reacted in the same manner as in Example 1 to obtain compound A017 [24.6 mg, 0.053 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7 Hz), 6.04 (1H, d, J = 11.2 Hz), 5.85 (1H, tt, J = 55.4, 3.8 Hz), 5.24 (1H, d, J = 1.0 Hz), 4.85 (1H, s), 4.30 (1H, t, J = 5.9 Hz), 4.18-4.03 (2H, m), 3.63-3.50 (4H, m), 2.97-2.80 (3H, m), 2.49-2.41 (2H, m), 2.25-2.18 (2H, m), 1.96-1.20 (17H, m), 0.94 (3H, d, J = 6.3 Hz), 0.53 (3H, s). Exact Mass = 465.31(C27H41F2NO3)Obs. mass = 466.30 (M+H) [Example 18] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-difluoromethoxy)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A018) Compound (2c) [50 mg, 0.069 mmol] and 3-(difluoromethoxy)-azetidine hydrochloride [33 mg, 0.207 mmol] were reacted in the same manner as in Example 1 to obtain compound A018 [15 mg, 0.033 mmol]. 1H-NMR (CD3OD) δ: 6.43 (1H, t, J = 75.0 Hz), 6.27 (1H, d, J = 11.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.06 (2H, d, J = 6.8 Hz), 4.89-4.82 (1H, m), 4.40 (2H, ddd, J = 13.7, 7.1, 4.6 Hz), 3.98 (2H, q, J = 7.5 Hz), 3.50 (2H, ddd, J = 18.8, 9.5, 6.1 Hz), 2.88-2.84 (1H, m), 2.80 (1H, dd, J = 12.2, 2.9 Hz), 2.68 (1H, dd, J = 13.4, 4.1 Hz), 2.57 (1H, dd, J = 12.0, 10.0 Hz), 2.49 (1H, dd, J = 13.4, 3.7 Hz), 2.32-2.26 (2H, m), 2.09-2.00 (2H, m), 1.95-1.90 (1H, m), 1.71-1.49 (6H, m), 1.42-1.30 (3H, m), 1.02 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 451.30(C26H39F2NO3)Obs. mass = 452.40 (M+H) [Example 19] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-(2,2-difluoroethyl)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A019) Compound (2c) [50 mg, 0.069 mmol] and 3-(2,2-difluoroethyl)-azetidine hydrochloride [35 mg, 0.222 mmol] were reacted in the same manner as in Example 1 to obtain compound A019 [10.1 mg, 0.0225 mmol]. Exact Mass = 449.31(C27H41F2NO2)Obs. mass = 450.25 (M+H) [Example 20] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-difluoromethoxy)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A020) Compound (2b) [50 mg, 0.070 mmol] and 3-(difluoromethoxy)-azetidine hydrochloride [30 mg, 0.244 mmol] were reacted in the same manner as in Example 1 to obtain compound A020 ​​[10.0 mg, 0.023 mmol]. 1 H-NMR (CD3OD) δ: 6.36 (1H, t, J = 75.0 Hz), 6.21 (1H, d, J = 11.2 Hz), 5.89 (1H, d, J = 11.2 Hz), 4.74-4.68 (1H, m), 4.08-3.95 (2H, m), 3.65 (2H, q, J = 6.8 Hz), 3.09 (1H, t, J = 6.8 Hz), 3.03 (1H, t, J = 6.8 Hz), 2.83 (1H, dd, J = 12.4, 3.7 Hz), 2.59 (1H, dd, J = 13.7, 3.9 Hz), 2.49 (1H, dd, J = 11.7, 2.9 Hz), 2.41 (1H, t, J = 6.6 Hz), 2.29 (1H, dd, J = 11.7, 9.3 Hz), 2.23-1.27 (18H, m), 0.99 (3H, d, J = 6.3 Hz), 0.58 (3H, s). Exact Mass = 439.29(C25H39F2NO3)Obs. mass = 440.20 (M+H) [Example 21] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3-(2,2-difluoroethyl)azetidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A021) Compound (2b) [50 mg, 0.070 mmol] and 3-(2,2-difluoroethyl)-azetidine hydrochloride [35 mg, 0.222 mmol] were reacted in the same manner as in Example 1 to obtain compound A021 [12.2 mg, 0.028 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4 Hz), 6.00-5.69 (2H, m), 4.06-3.95 (2H, m), 3.52 (2H, dd, J = 17.2, 7.5 Hz), 2.93-2.78 (3H, m), 2.73-2.65 (1H, m), 2.59 (1H, dd, J = 13.3, 3.7 Hz), 2.48 (1H, dd, J = 11.9, 2.7 Hz), 2.40 (1H, dd, J = 13.5, 3.4 Hz), 2.25-1.97 (7H, m), 1.95-1.72 (3H, m), 1.68-1.44 (6H, m), 1.38-1.23 (3H, m), 0.98 (3H, d, J = 6.4 Hz), 0.58 (3H, s). Exact Mass = 437.31(C26H41F2NO2)Obs. mass = 438.35 (M+H) [Example 22] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((S)-3-methylpyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B001) Compound (2a) [90 mg, 0.123 mmol] and 3-(S)-methylpyrrolidine hydrochloride [40 mg, 0.331 mmol] were reacted in the same manner as in Example 1 to obtain compound B001 [17.5 mg, 0.042 mmol]. 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.89 (1H, dd, J = 2.4, 1.5 Hz), 4.34 (1H, dd, J = 6.3, 5.4 Hz), 4.15-4.10 (1H, m), 3.55 (1H, dd, J = 11.0, 7.6 Hz), 3.42-3.35 (2H, m), 3.09 (1H, dd, J = 12.7, 2.9 Hz), 2.99 (1H, t, J = 12.0 Hz), 2.87 (1H, dd, J = 12.0, 3.7 Hz), 2.78 (1H, t, J = 10.0 Hz), 2.53-2.44 (2H, m), 2.30-2.16 (2H, m), 2.07-1.96 (4H, m), 1.90-1.30 (15H, m), 1.14 (3H, d, J = 6.6 Hz), 1.13 (3H, d, J = 6.3 Hz), 0.63 (3H, s). Exact Mass = 413.31(C27H43NO2)Obs. mass = 414.45 (M+H) [Example 23] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((S)-3-methylpyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B002) Compound (2c) [50 mg, 0.069 mmol] and 3-(S)-methylpyrrolidine hydrochloride [20 mg, 0.235 mmol] were reacted in the same manner as in Example 1 to obtain compound B002 [13.7 mg, 0.033 mmol]. 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 5.9 Hz), 4.44-4.35 (2H, m), 3.55 (1H, dd, J = 10.7, 7.8 Hz), 3.43-3.35 (2H, m), 3.10 (1H, dd, J = 12.7, 2.9 Hz), 2.99 (1H, t, J = 12.0 Hz), 2.89-2.75 (2H, m), 2.66 (1H, dd, J = 13.2, 4.4 Hz), 2.52-2.41 (2H, m), 2.32-2.17 (3H, m), 2.10-1.95 (3H, m), 1.89-1.34 (11H, m), 1.14 (3H, d, J = 6.6 Hz), 1.13 (3H, d, J = 6.3 Hz), 0.64 (3H, s). Exact Mass = 413.33(C27H43NO2)Obs. mass = 414.45 (M+H) [Example 24] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((R)-3-methylpyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B003) Compound (2c) [50 mg, 0.069 mmol] and 3-(R)-methylpyrrolidine hydrochloride [30 mg, 0.247 mmol] were reacted in the same manner as in Example 1 to obtain compound B003 [5.7 mg, 0.014 mmol]. Exact Mass = 413.33(C27H43NO2)Obs. mass = 414.25 (M+H) [Example 25] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((R)-3-methylpyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B004) Compound (2b) [55.3 mg, 0.077 mmol] and 3-(R)-methylpyrrolidine hydrochloride [28.3 mg, 0.233 mmol] were reacted in the same manner as in Example 1 to obtain compound B004 [15.3 mg, 0.038 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7 Hz), 5.89 (1H, d, J = 10.7 Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.0, 3.7 Hz), 2.74-2.50 (5H, m), 2.46-2.12 (7H, m), 2.07-1.47 (17H, m), 1.35 (2H, ddd, J = 23.4, 10.7, 2.9 Hz), 1.26 (1H, dd, J = 18.5, 9.3 Hz), 1.05 (3H, d, J = 6.8 Hz), 0.60 (3H, s). Exact Mass = 401.33(C26H43NO2)Obs. mass = 402.25 (M+H) [Example 26] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-ethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B005) Compound (2c) [50 mg, 0.069 mmol] and 3-(S)-ethylpyrrolidine hydrochloride [30 mg, 0.221 mmol] were reacted in the same manner as in Example 1 to obtain compound B005 [7.0 mg, 0.016 mmol]. Exact Mass = 427.35(C28H45NO2)Obs. mass = 428.25 (M+H) [Example 27] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-ethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B006) Compound (2c) [50 mg, 0.069 mmol] and 3-(R)-ethylpyrrolidine hydrochloride [30 mg, 0.221 mmol] were reacted in the same manner as in Example 1 to obtain compound B006 [5.0 mg, 0.011 mmol]. 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.4 Hz), 5.91 (1H, d, J = 11.4 Hz), 5.05 (2H, d, J = 6.9 Hz), 4.41 (1H, dd, J = 6.4, 4.6 Hz), 4.37 (1H, dd, J = 7.8, 4.6 Hz), 2.85 (1H, dd, J = 11.9, 4.1 Hz), 2.74 (2H, q, J = 7.6 Hz), 2.67 (1H, dd, J = 13.7, 4.6 Hz), 2.48 (1H, dd, J = 13.5, 3.9 Hz), 2.38-2.22 (5H, m), 2.12-1.92 (6H, m), 1.70-1.22 (12H, m), 1.05 (3H, d, J = 6.9 Hz), 0.90 (3H, t, J = 7.5 Hz), 0.60 (3H, s). Exact Mass = 427.35(C28H45NO2)Obs. mass = 428.25 (M+H) [Example 28] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-ethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B007) Compound (2b) [50 mg, 0.070 mmol] and 3-(S)-ethylpyrrolidine hydrochloride [37 mg, 0.273 mmol] were reacted in the same manner as in Example 1 to obtain compound B007 [9.4 mg, 0.023 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.89 (1H, d, J = 11.0 Hz), 4.08-3.95 (2H, m), 2.85-2.71 (3H, m), 2.59 (1H, d, J = 11.0 Hz), 2.42-2.28 (4H, m), 2.23-1.51 (16H, m), 1.45-1.23 (6H, m), 1.05 (3H, d, J = 5.9 Hz), 0.90 (3H, t, J = 7.5 Hz), 0.60 (3H, s). [Example 29] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-ethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B008) Compound (2b) [50 mg, 0.070 mmol] and 3-(R)-ethylpyrrolidine hydrochloride [39 mg, 0.288 mmol] were reacted in the same manner as in Example 1 to obtain compound B008 [8.6 mg, 0.021 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4 Hz), 5.89 (1H, d, J = 11.4 Hz), 4.07-3.95 (2H, m), 2.93 (1H, t, J = 8.0 Hz), 2.83 (1H, dd, J = 11.9, 3.7 Hz), 2.68 (1H, t, J = 7.5 Hz), 2.59 (1H, dd, J = 13.5, 3.7 Hz), 2.48-2.13 (6H, m), 2.10-1.20 (20H, m), 1.05 (3H, d, J = 6.9 Hz), 0.90 (3H, t, J = 7.3 Hz), 0.60 (3H, s). [Example 30] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-fluoropyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B012) Compound (2b) [50 mg, 0.070 mmol] and 3-(S)-fluoropyrrolidine hydrochloride [30 mg, 0.239 mmol] were reacted in the same manner as in Example 1 to obtain compound B012 [8.9 mg, 0.022 mmol]. 1 H-NMR (CD3OD) δ: 6.20 (1H, d, J = 11.0 Hz), 5.87 (1H, d, J = 11.4 Hz), 5.19-5.02 (1H, m), 4.05-3.93 (2H, m), 2.84-2.65 (4H, m), 2.59-2.54 (1H, m), 2.39 (1H, dd, J = 13.3, 3.2 Hz), 1.04 (3H, d, J = 6.4 Hz), 0.93 (1H, t, J = 7.3 Hz), 0.58 (3H, s). Exact Mass = 405.30(C25H40FNO2)Obs. mass = 406.30 (M+H) [Example 31] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-fluoropyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B013) Compound (2b) [50 mg, 0.070 mmol] and 3-(R)-fluoropyrrolidine hydrochloride [30 mg, 0.239 mmol] were reacted in the same manner as in Example 1 to obtain compound B013 [8.4 mg, 0.021 mmol]. 1 H-NMR (CD3OD) δ: 6.20 (1H, d, J = 11.0 Hz), 5.87 (1H, d, J = 11.0 Hz), 5.20-5.03 (1H, m), 4.04-3.93 (2H, m), 2.92-1.47 (25H, m), 1.38-1.23 (4H, m), 1.04 (3H, d, J = 6.9 Hz), 0.58 (3H, s). Exact Mass = 405.30(C25H40FNO2)Obs. mass = 406.30 (M+H) [Example 32] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B020) Compound (2a) [90 mg, 0.123 mmol] and 3-(S)-(difluoromethyl)pyrrolidine hydrochloride [60 mg, 0.381 mmol] were reacted in the same manner as in Example 1 to obtain compound B020 [22.8 mg, 0.051 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.89 (1H, td, J = 56.7, 4.7 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.09 (1H, m), 3.21 (1H, dd, J = 10.5, 8.5 Hz), 3.00-2.00 (14H, m), 1.90-1.27 (13H, m), 1.09 (3H, d, J = 6.3 Hz), 0.62 (3H, s). Exact Mass = 449.31(C27H41F2NO2)Obs. mass = 450.30 (M+H) [Example 33] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound B021) Compound (2g) [50 mg, 0.067 mmol] and 3-(S)-(difluoromethyl)pyrrolidine hydrochloride [35 mg, 0.222 mmol] were reacted in the same manner as in Example 1 to obtain compound B021 [3.8 mg, 0.008 mmol]. 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.81 (1H, td, J = 57.0, 5.7 Hz), 5.22 (1H, d, J = 2.0 Hz), 4.88 (1H, d, J = 2.0 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.2, 4.2 Hz), 2.98-2.83 (2H, m), 2.76-2.52 (5H, m), 2.44 (2H, d, J = 7.3 Hz), 2.17 (1H, dd, J = 13.2, 8.3 Hz), 2.07-1.93 (3H, m), 1.84-1.24 (11H, m), 1.06 (3H, d, J = 6.3 Hz), 1.03 (3H, d, J = 6.8 Hz), 0.59 (3H, s). Exact Mass = 463.32(C28H43F2NO2)Obs. mass = 464.35 (M+H) [Example 34] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B022) Compound (2b) [55 mg, 0.077 mmol] and 3-(S)-(difluoromethyl)pyrrolidine hydrochloride [25 mg, 0.208 mmol] were reacted in the same manner as in Example 1 to obtain compound B022 [10.5 mg, 0.024 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7 Hz), 5.89 (1H, d, J = 10.7 Hz), 5.78 (1H, td, J = 57.0, 6.0 Hz), 4.06-3.95 (2H, m), 2.82 (2H, dd, J = 18.8, 10.0 Hz), 2.66-2.50 (4H, m), 2.44-1.92 (11H, m), 1.86-1.23 (13H, m), 1.05 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 437.31(C26H41F2NO2)Obs. mass = 438.35 (M+H) [Example 35] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2 methylenecyclohexane-1,3-diol (Compound B023) Compound (2c) [50 mg, 0.069 mmol] and 3-(S)-(difluoromethyl)pyrrolidine hydrochloride [33 mg, 0.209 mmol] were reacted in the same manner as in Example 1 to obtain compound B023 [9.0 mg, 0.020 mmol]. 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7 Hz), 6.05-5.76 (2H, m), 5.05 (2H, d, J = 6.3 Hz), 4.42-4.36 (2H, m), 3.25 (1H, t, J = 9.5 Hz), 3.03 (2H, t, J = 7.1 Hz), 2.91-2.72 (5H, m), 2.66 (1H, dd, J = 13.7, 4.4 Hz), 2.48 (1H, dd, J = 13.4, 4.1 Hz), 2.32-1.96 (7H, m), 1.93-1.29 (10H, m), 1.10 (3H, d, J = 6.3 Hz), 0.63 (3H, s). Exact Mass = 449.31(C27H41F2NO2)Obs. mass = 450.30 (M+H) [Example 36] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B024) Compound (2a) [90 mg, 0.123 mmol] and 3-(R)-(difluoromethyl)pyrrolidine hydrochloride [45 mg, 0.372 mmol] were reacted in the same manner as in Example 1 to obtain compound B024 [7.2 mg, 0.016 mmol]. 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.75 (1H, td, J = 57.0, 5.0 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.89 (1H, dd, J = 2.4, 1.0 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.09 (1H, m), 2.86 (1H, dd, J = 12.2, 3.4 Hz), 2.61-1.19 (27H, m), 1.04 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 449.31(C27H41F2NO2)Obs. mass = 450.45 (M+H) [Example 37] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound B0025) Compound (2g) [50 mg, 0.067 mmol] and 3-(R)-(difluoromethyl)pyrrolidine hydrochloride [25 mg, 0.206 mmol] were reacted in the same manner as in Example 1 to obtain compound B025 [7.0 mg, 0.015 mmol]. 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 10.7 Hz), 5.75 (1H, td, J = 57.3, 5.2 Hz), 5.22 (1H, d, J = 1.5 Hz), 4.89 (1H, s), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.1, 4.4 Hz), 2.86 (1H, dd, J = 11.0, 4.0 Hz), 2.63-1.24 (29H, m), 1.04 (3H, d, J = 7.3 Hz), 1.04 (3H, d, J = 6.8 Hz), 0.58 (3H, s). Exact Mass = 463.32(C28H43F2NO2)Obs. mass = 464.35 (M+H) [Example 38] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B026) Compound (2b) [55 mg, 0.077 mmol] and 3-(R)-(difluoromethyl)pyrrolidine hydrochloride [27 mg, 0.226 mmol] were reacted in the same manner as in Example 1 to obtain compound B026 [7.2 mg, 0.016 mmol]. 1 H-NMR (CD3OD) δ: 6.22 (1H, d, J = 10.7 Hz), 5.89 (1H, d, J = 10.7 Hz), 5.76 (1H, td, J = 57.0, 5.0 Hz), 4.06-3.96 (2H, m), 2.84 (1H, dd, J = 12.0, 3.8 Hz), 2.65-2.52 (5H, m), 2.47-1.49 (21H, m), 1.40-1.22 (4H, m), 1.05 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 437.31(C26H41F2NO2)Obs. mass = 438.3 (M+H) [Example 39] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2 methylenecyclohexane-1,3-diol (Compound B027) Compound (2c) [50 mg, 0.069 mmol] and 3-(R)-(difluoromethyl)pyrrolidine hydrochloride [25 mg, 0.206 mmol] were reacted in the same manner as in Example 1 to obtain compound B027 [11.0 mg, 0.025 mmol]. 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.77 (1H, td, J = 57.0, 5.0 Hz), 5.05 (2H, d, J = 6.3 Hz), 4.43-4.34 (2H, m), 2.85 (1H, dd, J = 12.2, 3.9 Hz), 2.71-2.25 (11H, m), 2.07-1.92 (4H, m), 1.83-1.24 (10H, m), 1.05 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 449.31(C27H41F2NO2)Obs. mass = 450.45 (M+H) [Reference example 5] Synthesis of 3-(S)-(1,1-difluoroethyl)pyrrolidine hydrochloride (compound 3b6)

[0144] [ka]

[0145] Process 1 A solution of dimethyl sulfoxide (4.1 mL, 58 mmol) in dichloromethane (10 mL) was added to a solution of oxalyl chloride (2.45 mL, 28.6 mmol) in dichloromethane (25 mL) while cooling to -78 °C, and the mixture was stirred at the same temperature for 10 minutes. To this mixture was added a solution of tert-butyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (3.84 g, 19.1 mmol) in dichloromethane (15 mL). The mixture was stirred at -78 °C for 45 minutes. Triethylamine (15 mL, 92 mmol) was added and the mixture was stirred at the same temperature for an additional 30 minutes. The reaction mixture was warmed to 0 °C and stirred at the same temperature for 30 minutes. The reaction mixture was quenched with water and extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl (S)-3-formylpyrrolidine-1-carboxylate (compound 3b2) [3.78 g, 19.0 mmol] (yield=99%). 1 H-NMR(CDCl3) δ:9.69 (1H, J = 1.5 Hz), 3.72-3.65 (1H, m), 3.53-3.35 (3H, m), 3.03 (1H, s), 2.25-2.05 (2H, m), 1.46 (9H, s). Process 2 Methylmagnesium bromide [1M in THF, 15.1 mL, 15.1 mmol] was added to a THF solution [40 mL] of t-butyl (S)-3-formylpyrrolidine-1-carboxylate (compound 3b2) [2.00 g, 10 mmol] at -78°C under a nitrogen atmosphere, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was warmed to 0°C and stirred for an additional hour. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl (S)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (compound 3b3) [1.60 g, 7.41 mmol] (yield=74%). 1 H-NMR(CDCl3) δ: 3.70-2.90 (5H, m), 2.15-2.03 (1H, m), 1.46 (9H, s), 1.30-1.21 (4H, m). Process 3 A solution of dimethyl sulfoxide (1.6 mL, 23 mmol) in dichloromethane (10 mL) was added to a solution of oxalyl chloride (1 mL, 11.7 mmol) in dichloromethane (10 mL) while cooling to -78 °C, and the mixture was stirred at the same temperature for 10 minutes. To this mixture was added a solution of t-butyl (S)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (Compound 3b3) (1.60 g, 7.41 mmol) in dichloromethane (10 mL). The mixture was stirred at -78 °C for 45 minutes. Triethylamine (4.2 mL, 30 mmol) was added and the mixture was stirred at the same temperature for an additional 30 minutes. The reaction mixture was warmed to 0 °C and stirred at the same temperature for 30 minutes. The reaction mixture was quenched with water and extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl (S)-3-acetylpyrrolidine-1-carboxylate (compound 3b4) [1.45 g, 6.80 mmol] (yield=91%). 1 H-NMR(CDCl3) δ: 3.65-3.10 (5H, m), 3.14 (1H, s), 2.08 (3H, s), 2.05-1.95 (2H, m), 1.46 (9H, s). Process 4 A solution of t-butyl (S)-3-acetylpyrrolidine-1-carboxylate (compound 3b4) [1.10 g, 5.16 mmol] in dichloromethane was cooled to 0 °C. DAST [0.93 mL, 2.5 mmol] was added to the solution. The reaction mixture was stirred overnight and allowed to warm to room temperature. The reaction mixture was cooled on ice and carefully quenched with water. The mixture was extracted with dichloromethane at room temperature, and the organic phase was washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl (S)-3-(1,1-difluoroethyl)pyrrolidine-1-carboxylate (compound 3b5) [0.58 g, 2.5 mmol]. (Yield=48%) Process 5 Subsequently, the above t-butyl (S)-3-(1,1-difluoroethyl)pyrrolidine-1-carboxylate (Compound 3b5) [0.58 g, 2.5 mmol] was added to 4 M hydrogen chloride-dioxane solution [10 mL] and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give 3-(S)-(1,1-difluoroethyl)pyrrolidine hydrochloride (Compound 3b6) [354 mg, 2.06 mmol]. 1 H-NMR(DMSO-d6) δ: 9.40 (2H, s), 3.40-3.0 (4H, m), 2.92-2.38 (1H, m), 2.05-2.00 (1H, m), 1.90-1.80 (1H, m), 1.65 (3H, t, J = 20Hz). [Reference example 6] Synthesis of 3-(R)-(1,1-difluoroethyl)pyrrolidine hydrochloride (3b12)

[0146] [ka]

[0147] Process 1 t-Butyl (R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (3b7) [3.16 g, 15.7 mmol] was used as a starting material and reacted in the same manner as in Step 1 of Reference Example 5 to obtain t-butyl (R)-3-formylpyrrolidine-1-carboxylate (compound 3b8) ​​[2.42 g, 12.1 mmol]. Process 2 t-Butyl (R)-3-formylpyrrolidine-1-carboxylate (compound 3b8) ​​[2.42 g, 12.1 mmol] was used as the starting material and reacted in the same manner as in Step 2 of Reference Example 5 to obtain t-butyl (R)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (compound 3b9) [1.64 g, 7.62 mmol]. Process 3 t-Butyl (R)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (Compound 3b9) [1.64 g, 7.62 mmol] was used as the starting material and reacted in the same manner as in Step 3 of Reference Example 5 to give t-butyl (R)-3-acetylpyrrolidine-1-carboxylate (Compound 3b10) [1.50 g, 7.03 mmol] (yield=92%). Process 4 To a 30 mL solution of t-butyl (R)-3-acetylpyrrolidine-1-carboxylate (Compound 3b10) [1.50 g, 7.03 mmol] in dichloromethane, DAST [1.8 mL, 13.6 mmol] was added at 0 °C and stirred overnight at room temperature. The next morning, an additional 1.8 mL, 13.6 mmol] of DAST was added, and the mixture was stirred at room temperature for another day. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous sodium carbonate, and extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl (R)-3-(1,1-difluoroethyl)pyrrolidine-1-carboxylate (Compound 3b11) [0.87 g, 3.7 mmol] (yield = 53%). Process t-Butyl (R)-3-(1,1-difluoroethyl)pyrrolidine-1-carboxylate (compound 3b11) [0.87 g, 3.7 mmol] was used as a starting material and reacted in the same manner as in Step 5 of Reference Example 5 to obtain 3-(R)-(1,1-difluoroethyl)pyrrolidine hydrochloride (3b12) [0.63 g, 3.7 mmol] (yield=100%). 1 H-NMR (DMSO-D6) δ: 9.60 (1H, br s), 9.40 (1H, br s), 3.37-3.30 (1H, br m), 3.25-3.00 (3H, br m), 2.96-2.81 (1H, m), 2.12-2.03 (1H, m), 1.91-1.77 (1H, m), 1.66 (3H, t, J = 19.3 Hz). [Example 40] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B028) Compound (2a) [90 mg, 0.123 mmol] and 3-(S)-(1,1-difluoroethyl)pyrrolidine hydrochloride (3b6) [45 mg, 0.262 mmol] were reacted in the same manner as in Example 1 to obtain compound B028 [12.7 mg, 0.027 mmol]. 1H-NMR (CD3OD) δ: 6.31 (1H, d, J = 10.7 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.4, 1.0 Hz), 4.33 (1H, d, J = 5.4 Hz), 4.14-4.09 (1H, m), 3.43 (1H, dd, J = 10.7, 8.3 Hz), 3.25-2.78 (8H, m), 2.51 (1H, dd, J = 13.7, 3.4 Hz), 2.28-1.97 (7H, m), 1.92-1.28 (17H, m), 1.11 (3H, d, J = 6.3 Hz), 0.63 (3H, d, J = 7.3 Hz). [Example 41] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound B029) Compound (2g) [50 mg, 0.067 mmol] and 3-(S)-(1,1-difluoroethyl)pyrrolidine hydrochloride (3b6) [35 mg, 0.204 mmol] were reacted in the same manner as in Example 1 to obtain compound B029 [5.8 mg, 0.012 mmol]. 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.22 (1H, d, J = 1.5 Hz), 4.89 (1H, d, J = 1.5 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.2, 4.2 Hz), 3.01 (1H, t, J = 9.0 Hz), 2.87 (1H, dd, J = 12.0, 3.7 Hz), 2.82-2.38 (8H, m), 2.17 (1H, dd, J = 13.2, 8.3 Hz), 2.06-1.94 (4H, m), 1.88-1.43 (13H, m), 1.39-1.24 (3H, m), 1.06 (3H, d, J = 6.8 Hz), 1.04 (3H, d, J = 7.3 Hz), 0.59 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.45 (M+H) [Example 42] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B030) Compound (2b) [55 mg, 0.077 mmol] and 3-(S)-(1,1-difluoroethyl)pyrrolidine hydrochloride (3b6) [29.2 mg, 0.216 mmol] were reacted in the same manner as in Example 1 to obtain compound B030 [13.5 mg, 0.030 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.89 (1H, d, J = 11.2 Hz), 4.06-3.95 (2H, m), 2.93 (1H, t, J = 9.0 Hz), 2.83 (1H, dd, J = 12.0, 3.2 Hz), 2.73-2.50 (4H, m), 2.42-2.31 (4H, m), 2.23-1.47 (20H, m), 1.41-1.22 (3H, m), 1.06 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 451.33(C27H43F2NO2)Obs. mass = 452.45 (M+H) [Example 43] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2 methylenecyclohexane-1,3-diol (Compound B031) Compound (2c) [50 mg, 0.069 mmol] and 3-(S)-(1,1-difluoroethyl)pyrrolidine hydrochloride (3b6) [35 mg, 0.204 mmol] were reacted in the same manner as in Example 1 to obtain compound B031 [12.9 mg, 0.028 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.3 Hz), 4.43-4.34 (2H, m), 3.42 (1H, dd, J = 10.7, 8.3 Hz), 3.24-2.78 (7H, m), 2.66 (1H, dd, J = 13.2, 4.4 Hz), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.32-1.97 (7H, m), 1.83-1.30 (13H, m), 1.12 (3H, d, J = 6.8 Hz), 0.64 (3H, s). Exact Mass = 463.33(C28H43F2NO2)Obs. mass = 464.3 (M+H) [Example 44] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B032) Compound (2a) [90 mg, 0.123 mmol] and 3-(R)-(1,1-difluoroethyl)pyrrolidine hydrochloride (3b12) [50 mg, 0.291 mmol] were reacted in the same manner as in Example 1 to obtain compound B032 [12.7 mg, 0.027 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.2, 1.2 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.10 (1H, m), 3.12-3.00 (2H, m), 2.94-2.75 (5H, m), 2.66 (2H, d, J = 7.3 Hz), 2.51 (1H, dd, J = 13.4, 3.2 Hz), 2.26 (1H, dd, J = 13.7, 6.8 Hz), 2.13-1.94 (5H, m), 1.90-1.23 (16H, m), 1.09 (3H, d, J = 6.3 Hz), 0.62 (3H, s). Exact Mass = 463.33(C28H43F2NO2)Obs. mass = 464.45 (M+H) [Example 45] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound B033) Compound (2g) [50 mg, 0.067 mmol] and 3-(R)-(1,1-difluoroethyl)pyrrolidine hydrochloride (3b12) [25 mg, 0.146 mmol] were reacted in the same manner as in Example 1 to obtain compound B033 [6.8 mg, 0.014 mmol]. 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.22 (1H, d, J = 2.0 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.2, 4.2 Hz), 2.89-1.94 (16H, m), 1.88-1.22 (16H, m), 1.05 (6H, d, J = 6.8 Hz), 1.03 (6H, d, J = 6.8 Hz), 0.59 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.5 (M+H) [Example 46] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B034) Compound (2b) [55 mg, 0.077 mmol] and 3-(R)-(1,1-difluoroethyl)pyrrolidine hydrochloride (3b12) [28.2 mg, 0.164 mmol] were reacted in the same manner as in Example 1 to obtain compound B034 [11.8 mg, 0.026 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7 Hz), 5.89 (1H, d, J = 10.7 Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.0, 3.7 Hz), 2.74-2.50 (5H, m), 2.46-2.12 (7H, m), 2.07-1.47 (17H, m), 1.35 (2H, ddd, J = 23.4, 10.7, 2.9 Hz), 1.26 (1H, dd, J = 18.5, 9.3 Hz), 1.05 (3H, d, J = 6.8 Hz), 0.60 (3H, s). Exact Mass = 451.33(C27H43F2NO2)Obs. mass = 452.3 (M+H) [Example 47] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2 methylenecyclohexane-1,3-diol (Compound B035) Compound (2c) [50 mg, 0.069 mmol] and 3-(R)-(1,1-difluoroethyl)pyrrolidine hydrochloride (3b12) [26 mg, 0.152 mmol] were reacted in the same manner as in Example 1 to obtain compound B035 [12.9 mg, 0.028 mmol]. 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.3 Hz), 4.43-4.34 (2H, m), 3.17-3.05 (2H, m), 2.99-2.64 (8H, m), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.31-2.25 (2H, m), 2.16-1.96 (5H, m), 1.78-1.28 (13H, m), 1.10 (3H, d, J = 6.3 Hz), 0.63 (3H, s). Exact Mass = 463.33(C28H43F2NO2)Obs. mass = 464.5 (M+H) [Reference example 7] Synthesis of 3-(R)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b16)

[0148] [ka]

[0149] ​ A solution of dimethyl sulfoxide (1.0 mL, 14 mmol) in dichloromethane (10 mL) was added to a solution of oxalyl chloride (0.66 mL, 7.7 mmol) in dichloromethane (10 mL) while cooling to -78 °C, and the mixture was stirred at the same temperature for 10 minutes. To this mixture was added a solution of t-butyl-3-(R)-(2-hydroxyethyl)pyrrolidine-1-carboxylate (Compound 3b13) (1.0 g, 4.64 mmol) in dichloromethane (10 mL). The mixture was stirred at -78 °C for 1 hour. Triethylamine (3.3 mL, 23 mmol) was added and the mixture was stirred at the same temperature for an additional 40 minutes. The reaction mixture was warmed to 0 °C and stirred at the same temperature for 30 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain t-butyl-3-(R)-(2-oxoethyl)pyrrolidine-1-carboxylate (compound 3b14) [0.85 g, 4.0 mmol] (yield=86%). ​ To a solution of t-butyl-3-(R)-(2-oxoethyl)pyrrolidine-1-carboxylate (compound 3b14) [0.85 g, 4.0 mmol] in dichloromethane [20 mL] was added DAST [0.7 mL, 5 mmol] at 0 °C and stirred at room temperature overnight. The reaction mixture was cooled to 0 °C, quenched with water, and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl-3-(R)-(2,2-difluoroethyl)pyrrolidine-1-carboxylate (compound 3b15) [799 mg, 3.4 mmol]. (Yield = 85%) ​ t-Butyl-3-(R)-(2,2-difluoroethyl)pyrrolidine-1-carboxylate (compound 3b15) [799 mg, 3.4 mmol] was added to a 4 M solution of hydrogen chloride in dioxane [6 mL] and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and dried to give 3-(R)-(2,2-difluoroethyl)pyrrolidine hydrochloride (compound 3b16) [562.7 mmol]. (Yield=96%) 1 H-NMR (DMSO-d6) δ: 9.88 (2H, br s), 5.90 (1H, tt, J = 55.9, 3.8 Hz), 3.53 (2H, d, J = 40.5 Hz), 3.29 (1H, br s), 2.95 (1H, br s), 2.62-2.54 (1H, m), 2.33-2.20 (1H, m), 2.11-1.99 (2H, m), 1.80-1.65 (1H, m). [Reference example 8] Synthesis of 3-(S)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b20)

[0150] [ka]

[0151] ​ t-Butyl-3-(S)-(2-hydroxyethyl)pyrrolidine-1-carboxylate (compound 3b17) [1.0 g, 4.64 mmol] was used as a starting material and reacted in a manner similar to Step 1 of Reference Example 7 to obtain t-butyl-3-(S)-(2-oxoethyl)pyrrolidine-1-carboxylate (compound 3b18) [0.72 g, 3.4 mmol] (yield=73%). ​ t-Butyl-3-(S)-(2-oxoethyl)pyrrolidine-1-carboxylate (Compound 3b18) [0.72 g, 3.4 mmol] was used as a starting material and reacted in a manner similar to Step 2 of Reference Example 7 to obtain t-butyl-3-(S)-(2,2-difluoroethyl)pyrrolidine-1-carboxylate (Compound 3b19) [679 mg, 2.89 mmol] (yield=62%). ​ t-Butyl-3-(S)-(2,2-difluoroethyl)pyrrolidine-1-carboxylate (Compound 3b19) [679 mg, 2.89 mmol] was used as a starting material and reacted in a manner similar to Step 3 of Reference Example 7 to obtain 3-(S)-(2,2-difluoroethyl)pyrrolidine hydrochloride (Compound 3b20) [524.9 mg, 3.06 mmol] (yield=quant). 1 H-NMR (DMSO-d6) δ: 9.86 (2H, br s), 5.91 (1H, tt, J = 55.9, 3.7 Hz), 3.53 (2H, d, J = 38.5 Hz), 3.29 (1H, br s), 2.95 (1H, br s), 2.65-2.50 (1H, m), 2.35-2.20 (1H, m), 2.15-2.00 (2H, m), 1.80-1.65 (1H, m). [Example 48] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylcyclohexane-1,3-diol (Compound B036) Compound (2a) [90 mg, 0.123 mmol] and 3-(R)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b16) [50 mg, 0.292 mmol] were reacted in the same manner as in Example 1 to obtain compound B036 [17.2 mg, 0.037 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 10.7 Hz), 6.12-5.81 (2H, m), 5.28 (1H, d, J = 1.0 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.10 (1H, m), 3.45 (1H, dd, J = 10.2, 7.8 Hz), 3.23-3.18 (2H, m), 2.95-2.80 (3H, m), 2.74 (1H, t, J = 10.2 Hz), 2.59-2.45 (2H, m), 2.30-1.90 (8H, m), 1.89-1.31 (14H, m), 1.11 (3H, d, J = 6.3 Hz), 0.63 (3H, s). Exact Mass = 463.33(C28H43F2NO2)Obs. mass = 464.5 (M+H) [Example 49] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B037) Compound (2a) [90 mg, 0.123 mmol] and 3-(S)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b20) [50 mg, 0.292 mmol] were reacted in the same manner as in Example 1 to obtain compound B037 [24.1 mg, 0.052 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 10.7 Hz), 6.09 (1H, d, J = 10.7 Hz), 5.98 (1H, tt, J = 3.0, 56.0 Hz), 5.29 (1H, t, J = 1.2 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.12 (1H, td, J = 6.5, 3.3 Hz), 3.55 (1H, dd, J = 11.0, 8.1 Hz), 3.41-3.34 (2H, m), 3.08-2.93 (4H, m), 2.88 (1H, dd, J = 12.0, 3.7 Hz), 2.69-2.55 (1H, m), 2.51 (1H, dd, J = 13.7, 3.4 Hz), 2.35-2.04 (8H, m), 2.01-1.96 (3H, m), 1.90-1.33 (16H, m), 1.13 (3H, d, J = 6.8 Hz), 0.63 (3H, s). Exact Mass = 463.33(C28H43F2NO2)Obs. mass = 464.5 (M+H) [Example 50] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound B038) Compound (2g) [55 mg, 0.074 mmol] and 3-(R)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b16) [40 mg, 0.184 mmol] were reacted in the same manner as in Example 1 to obtain compound B038 [10.2 mg, 0.021 mmol]. 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.88 (1H, tt, J = 56.6, 4.6 Hz), 5.22 (1H, d, J = 1.5 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.1, 4.2 Hz), 2.94 (1H, t, J = 8.3 Hz), 2.86 (1H, dd, J = 12.4, 4.1 Hz), 2.68-2.52 (3H, m), 2.33-2.03 (9H, m), 1.98-1.24 (20H, m), 1.05 (3H, d, J = 7.0 Hz), 1.03 (3H, d, J = 6.3 Hz), 0.96-0.87 (1H, m), 0.58 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.3 (M+H) [Example 51] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound B039) Compound (2g) [55 mg, 0.074 mmol] and 3-(S)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b20) [40 mg, 0.184 mmol] were reacted in the same manner as in Example 1 to obtain compound B039 [9.2 mg, 0.019 mmol]. 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 10.7 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.87 (1H, tt, J = 56.6, 4.6 Hz), 5.22 (1H, d, J = 1.5 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.1, 4.4 Hz), 2.86 (1H, dd, J = 12.4, 4.1 Hz), 2.79-2.68 (2H, m), 2.59 (1H, dd, J = 13.4, 4.1 Hz), 2.39-1.21 (23H, m), 1.04 (3H, d, J = 6.3 Hz), 1.03 (3H, d, J = 7.0 Hz), 0.58 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.35 (M+H) [Example 52] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2 methylenecyclohexane-1,3-diol (Compound B040) Compound (2c) [50 mg, 0.069 mmol] and 3-(R)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b16) [30 mg, 0.175 mmol] were reacted in the same manner as in Example 1 to obtain compound B040 [11.4 mg, 0.025 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.96 (1H, tt, J = 56.5, 4.0 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 5.9 Hz), 4.39 (2H, ddd, J = 14.3, 7.2, 4.5 Hz), 3.44 (1H, dd, J = 10.7, 7.8 Hz), 3.24-3.12 (2H, m), 2.94-2.82 (3H, m), 2.74 (1H, t, J = 10.2 Hz), 2.66 (1H, dd, J = 13.2, 4.4 Hz), 2.56 (1H, q, J = 8.1 Hz), 2.48 (1H, dd, J = 13.7, 3.9 Hz), 2.34-2.17 (3H, m), 2.08-1.93 (5H, m), 1.83-1.28 (10H, m), 1.12 (3H, d, J = 6.3 Hz), 0.63 (3H, s). Exact Mass = 463.32(C28H43F2NO2)Obs. mass = 464.35 (M+H) [Example 53] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2 methylenecyclohexane-1,3-diol (Compound B041) Compound (2c) [50 mg, 0.069 mmol] and 3-(S)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b20) [30 mg, 0.175 mmol] were reacted in the same manner as in Example 1 to obtain compound B041 [11.8 mg, 0.026 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.96 (2H, tt, J = 56.5, 4.0 Hz), 5.92 (2H, d, J = 11.2 Hz), 5.05 (2H, d, J = 5.9 Hz), 4.39 (2H, ddd, J = 14.4, 7.1, 4.4 Hz), 3.37 (1H, dd, J = 10.2, 8.3 Hz), 3.26-3.20 (1H, m), 3.15-3.05 (1H, m), 2.92-2.74 (4H, m), 2.66 (1H, dd, J = 13.4, 4.1 Hz), 2.62-2.53 (1H, m), 2.48 (1H, dd, J = 13.4, 4.1 Hz), 2.32-2.19 (3H, m), 2.08-1.92 (5H, m), 1.83-1.30 (10H, m), 1.11 (3H, d, J = 6.3 Hz), 0.63 (3H, s). Exact Mass = 463.32(C28H43F2NO2)Obs. mass = 464.40 (M+H) [Example 54] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B042) Compound (2b) [50 mg, 0.070 mmol] and 3-(R)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b16) [30 mg, 0.175 mmol] were reacted in the same manner as in Example 1 to obtain compound B042 [14.2 mg, 0.031 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.92 (1H, tt, J = 56.5, 4.2 Hz), 5.89 (1H, d, J = 10.0 Hz), 4.06-3.95 (2H, m), 3.17 (1H, t, J = 8.3 Hz), 2.97-2.80 (3H, m), 2.61-1.91 (15H, m), 1.86-1.26 (13H, m), 1.08 (3H, d, J = 6.8 Hz), 0.61 (3H, s). Exact Mass = 451.33(C27H43F2NO2)Obs. mass = 452.30 (M+H) [Example 55] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B043) Compound (2b) [50 mg, 0.070 mmol] and 3-(S)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b20) [30 mg, 0.175 mmol] were reacted in the same manner as in Example 1 to obtain compound B043 [8.3 mg, 0.018 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7 Hz), 5.91 (1H, tt, J = 56.6, 4.0 Hz), 5.89 (1H, d, J = 10.7 Hz), 4.05-3.96 (2H, m), 3.05-2.80 (3H, m), 2.65-2.39 (8H, m), 2.23-1.90 (10H, m), 1.87-1.25 (14H, m), 1.07 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 451.33(C27H43F2NO2)Obs. mass = 452.25 (M+H) [Example 56] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B044a, Compound B044b)

[0152] [ka]

[0153] ​ A DMF solution (1 mL) of compound (2a) (100 mg, 0.137 mmol), triethyl[3-(trifluoromethyl)pyrrolidin-3-yl]oxysilane (compound 3b21) (80 mg, 0.297 mmol), and potassium carbonate (60 mg, 0.434 mmol) was stirred at 60 °C overnight. The reaction mixture was quenched with saturated brine and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and TLC yielded the less polar product (compound B044-TBSLP) (32.2 mg, 0.039 mmol) and the more polar product (compound B044-TBSMP) (35.5 mg, 0.043 mmol). ​ To a THF solution [1 mL] of compound B044-TBSLP [32.2 mg, 0.039 mmol], TBAF [1 M in THF, 0.5 mL, 0.5 mmol] was added and stirred at 50 °C overnight. The reaction mixture was quenched with saturated magnesium bicarbonate, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to give compound B044a [7.7 mg, 0.016 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2 Hz), 6.04 (1H, d, J = 11.2 Hz), 5.24 (1H, dd, J = 2.4, 1.5 Hz), 4.30 (1H, t, J = 6.0 Hz), 4.12-4.00 (1H, m), 2.92 (1H, d, J = 10.7 Hz), 2.84-2.73 (2H, m), 2.52-2.41 (3H, m), 2.28-2.08 (5H, m), 2.02-1.22 (18H, m), 1.00 (3H, d, J = 6.3 Hz), 0.55 (3H, s). Exact Mass = 483.3(C27H40F3NO3)Obs. mass = 484.3 (M+H) ​ Compound B044-TBSMP [35.5 mg, 0.043 mmol] was treated in the same manner as in Step 2a above to give compound B044b [10.0 mg, 0.021 mmol]. 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2 Hz), 6.04 (1H, d, J = 10.7 Hz), 5.24 (1H, dd, J = 2.4, 1.0 Hz), 4.30 (1H, t, J = 5.9 Hz), 4.08 (1H, dt, J = 10.9, 3.8 Hz), 2.84-2.41 (7H, m), 2.26-1.20 (24H, m), 1.00 (3H, d, J = 6.3 Hz), 0.55 (3H, s). Exact Mass = 483.3(C27H40F3NO3)Obs. mass = 484.3 (M+H) [Example 57] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B045a, Compound B045b) Compound 2b [100 mg, 0.139 mmol] and triethyl[3-(trifluoromethyl)pyrrolidin-3-yl]oxysilane (compound 3b21) [100.4 mg, 0.373 mmol] were used as starting materials and reacted in the same manner as in Example 56 to obtain compound B045a [9.3 mg, 0.020 mmol] and compound B045b [7.9 mg, 0.017 mmol]. ​ 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7 Hz), 5.88 (1H, d, J = 11.2 Hz), 4.06-3.94 (2H, m), 3.08 (1H, d, J = 11.2 Hz), 2.94 (1H, q, J = 8.0 Hz), 2.83 (1H, dd, J = 11.2, 4.4 Hz), 2.74-2.55 (3H, m), 2.48-2.37 (3H, m), 2.26-2.03 (6H, m), 2.02-1.95 (2H, m), 1.94-1.24 (15H, m), 1.05 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 471.30(C26H40F3NO3)Obs. mass = 472.25(M+H) ​ 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7 Hz), 5.89 (1H, d, J = 11.2 Hz), 4.06-3.94 (2H, m), 2.85-2.75 (4H, m), 2.66 (1H, dd, J = 15.6, 7.3 Hz), 2.61-2.13 (8H, m), 2.10-1.98 (2H, m), 1.93-1.24 (13H, m), 1.06 (3H, d, J = 6.8 Hz), 0.60 (3H, s). Exact Mass = 471.30(C26H40F3NO3)Obs. mass = 472.25 (M+H) [Example 58] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B046a, Compound B046b) Compound 2c [100 mg, 0.137 mmol] and triethyl[3-(trifluoromethyl)pyrrolidin-3-yl]oxysilane (compound 3b21) [144.3 mg, 0.536 mmol] were used as starting materials and reacted in the same manner as in Example 56 to obtain compound B046a [8.1 mg, 0.017 mmol] and compound B046b [5.6 mg, 0.012 mmol]. ​ 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.43-4.35 (2H, m), 3.03 (1H, d, J = 11.2 Hz), 2.91-2.83 (2H, m), 2.69-2.17 (10H, m), 2.08-2.00 (2H, m), 1.95-1.85 (2H, m), 1.70-1.49 (6H, m), 1.40-1.25 (3H, m), 1.05 (3H, d, J = 6.3 Hz), 0.61 (3H, s).Exact Mass = 483.3(C27H40F3NO3)Obs. mass = 484.25 (M+H) ​ 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 10.7 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.39 (2H, ddd, J = 13.9, 7.1, 4.6 Hz), 2.87-2.77 (4H, m), 2.71-2.65 (2H, m), 2.50-2.18 (6H, m), 2.09-2.00 (2H, m), 1.98-1.90 (2H, m), 1.71-1.52 (6H, m), 1.39-1.25 (3H, m), 1.06 (3H, d, J = 6.3 Hz), 0.61 (3H, s).Exact Mass = 483.3(C27H40F3NO3)Obs. mass = 484.30 (M+H) [Example 59] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B047) Compound (2a) [50 mg, 0.069 mmol] and 3-(S)-(difluoromethoxy)pyrrolidine hydrochloride [30 mg, 0.173 mmol] were reacted in the same manner as in Example 1 to obtain compound B047 [14.5 mg, 0.031 mmol]. 1 H-NMR (CD3OD) δ: 6.40 (1H, t, J = 75.0 Hz), 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.29 (1H, dd, J = 2.2, 1.2 Hz), 4.80-4.75 (1H, m), 4.35 (1H, t, J = 5.9 Hz), 4.17-4.10 (1H, m), 3.03 (1H, dd, J = 11.2, 5.9 Hz), 2.95-2.85 (2H, m), 2.74 (1H, dd, J = 11.0, 3.2 Hz), 2.67-2.60 (1H, m), 2.55-2.42 (3H, m), 2.30-2.20 (2H, m), 2.08-1.95 (4H, m), 1.93-1.83 (3H, m), 1.77-1.22 (10H, m), 1.08 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 465.31(C27H41F2NO3)Obs. mass = 466.30 (M+H) [Example 60] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B048) Compound (2a) [50 mg, 0.069 mmol] and 3-(R)-(difluoromethoxy)pyrrolidine hydrochloride [30 mg, 0.173 mmol] were reacted in the same manner as in Example 1 to obtain compound B048 [9.2 mg, 0.020 mmol]. 1 H-NMR (CD3OD) δ: 6.39 (1H, t, J = 75.0 Hz), 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.29 (1H, dd, J = 2.4, 1.5 Hz), 4.80-4.73 (1H, m), 4.35 (1H, t, J = 6.1 Hz), 4.17-4.10 (1H, m), 2.90-1.94 (14H, m), 1.89 (3H, t, J = 5.4 Hz), 1.74-1.24 (10H, m), 1.07 (3H, d, J = 6.8 Hz), 0.61 (3H, s). Exact Mass = 465.31(C27H41F2NO3)Obs. mass = 466.40 (M+H) [Example 61] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B049) Compound (2c) [50 mg, 0.069 mmol] and 3-(S)-(difluoromethoxy)pyrrolidine hydrochloride [30 mg, 0.173 mmol] were reacted in the same manner as in Example 1 to obtain compound B049 [13.4 mg, 0.029 mmol]. 1H-NMR (CD3OD) δ: 6.39 (1H, t, J = 75.0 Hz), 6.27 (1H, d, J = 11.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.06 (2H, dd, J = 7.0, 2.0 Hz), 4.77-4.72 (1H, m), 4.40 (2H, ddd, J = 14.0, 7.0, 4.5 Hz), 2.96 (1H, dd, J = 11.0, 6.1 Hz), 2.90-2.76 (2H, m), 2.70-2.60 (2H, m), 2.54-2.18 (8H, m), 2.09-1.85 (4H, m), 1.71-1.50 (6H, m), 1.42-1.25 (3H, m), 1.07 (3H, d, J = 6.3 Hz), 0.62 (3H, s). Exact Mass = 465.31(C27H41F2NO3)Obs. mass = 466.40 (M+H) [Example 62] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B050) Compound (2c) [50 mg, 0.069 mmol] and 3-(R)-(difluoromethoxy)pyrrolidine hydrochloride [30 mg, 0.173 mmol] were reacted in the same manner as in Example 1 to obtain compound B050 [13.0 mg, 0.028 mmol]. 1H-NMR (CD3OD) δ: 6.44 (1H, t, J = 75.0 Hz), 6.27 (1H, d, J = 11.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.06 (2H, d, J = 5.9 Hz), 4.88-4.84 (1H, m), 4.40 (2H, ddd, J = 14.3, 7.2, 4.5 Hz), 3.08 (2H, d, J = 4.4 Hz), 3.06-2.85 (3H, m), 2.71-2.63 (3H, m), 2.49 (1H, dd, J = 13.4, 3.7 Hz), 2.35-1.98 (7H, m), 1.78-1.50 (6H, m), 1.41-1.28 (3H, m), 1.10 (3H, d, J = 6.3 Hz), 0.63 (3H, s). Exact Mass = 465.31(C27H41F2NO3)Obs. mass = 466.40 (M+H) [Example 63] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B051) Compound (2b) [50 mg, 0.070 mmol] and 3-(S)-(difluoromethoxy)pyrrolidine hydrochloride [30 mg, 0.173 mmol] were reacted in the same manner as in Example 1 to obtain compound B051 [7.6 mg, 0.017 mmol]. 1H-NMR (CD3OD) δ: 6.42 (1H, t, J = 75.0 Hz), 6.22 (1H, d, J = 11.2 Hz), 5.90 (1H, d, J = 11.2 Hz), 4.84-4.79 (1H, m), 4.07-3.96 (2H, m), 3.12 (1H, dd, J = 11.7, 6.3 Hz), 3.03-2.96 (1H, m), 2.85 (2H, dd, J = 11.5, 3.2 Hz), 2.77-2.50 (4H, m), 2.41 (1H, dd, J = 13.7, 3.4 Hz), 2.33-1.96 (7H, m), 1.91-1.27 (12H, m), 1.09 (3H, d, J = 6.8 Hz), 0.62 (3H, s). Exact Mass = 453.31(C26H41F2NO3)Obs. mass = 454.35 (M+H) [Example 64] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B052) Compound (2b) [50 mg, 0.070 mmol] and 3-(R)-(difluoromethoxy)pyrrolidine hydrochloride [30 mg, 0.173 mmol] were reacted in the same manner as in Example 1 to obtain compound B052 [6.6 mg, 0.015 mmol]. 1H-NMR (CD3OD) δ: 6.43 (1H, t, J = 75.0 Hz), 6.22 (1H, d, J = 11.2 Hz), 5.90 (1H, d, J = 11.2 Hz), 4.88-4.81 (1H, m), 4.07-3.95 (2H, m), 3.04-2.81 (5H, m), 2.65-2.55 (3H, m), 2.42 (1H, dd, J = 13.4, 3.2 Hz), 2.33-1.97 (7H, m), 1.91-1.27 (12H, m), 1.09 (3H, d, J = 6.8 Hz), 0.62 (3H, s). Exact Mass = 453.31(C26H41F2NO3)Obs. mass = 454.35 (M+H) [Reference example 9] Synthesis of 3-(S)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (compound 3b24)

[0154] [ka]

[0155] ​ To a THF solution (17 mL) of t-butyl-3-(S)-hydroxypyrrolidine-1-carboxylate (compound 3b22) (1.20 g, 6.41 mmol), sodium hydride (60% in oil, 0.32 g, 8 mmol) was added at 0 °C and stirred for 20 minutes. 2,2-Difluoroethyl trifluoromethanesulfonate (1.65 g, 7.71 mmol) was added, and the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride, and saturated brine was added. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl-3-(S)-(2,2-difluoroethoxy)pyrrolidine-1-carboxylate (compound 3b23) (1.51 g, 6.01 mmol). (Yield: 94%) ​ t-Butyl-3-(S)-(2,2-difluoroethoxy)pyrrolidine-1-carboxylate (compound 3b23) [1.51 g, 6.01 mmol] was added to a 4 M solution of hydrogen chloride in dioxane [15 mL] and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and dried to give 3-(S)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (compound 3b24) [1.12 g, 5.97 mmol]. (Yield=99%) 1 H-NMR (DMSO-D6) δ: 9.41 (2H, s), 6.14 (1H, tt, J = 54.9, 3.7 Hz), 4.34-4.27 (1H, m), 3.72 (2H, td, J = 15.1, 3.9 Hz), 3.25-3.06 (4H, m), 2.08-2.02 (1H, m), 1.97-1.87 (1H, m). [Reference example 10] Synthesis of 3-(R)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (compound 3b27)

[0156] [ka]

[0157] ​ t-Butyl-3-(R)-hydroxypyrrolidine-1-carboxylate (compound 3b25) [1.13 g, 6.04 mmol] was used as the starting material and reacted in a manner similar to Step 1 of Reference Example 9 to give t-butyl-3-(R)-(2,2-difluoroethoxy)pyrrolidine-1-carboxylate (compound 3b26) [1.37 g, 5.45 mmol] (yield=90%). ​ t-Butyl-3-(R)-(2,2-difluoroethoxy)pyrrolidine-1-carboxylate (Compound 3b26) [1.37 g, 5.45 mmol] was used as the starting material and reacted in a manner similar to Step 2 of Reference Example 9 to give 3-(R)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (Compound 3b27) [1.04 g, 5.54 mmol] (yield=92%). 1 H-NMR (DMSO-D6) δ: 9.54 (2H, s), 6.14 (1H, tt, J = 54.9, 3.7 Hz), 4.31 (1H, dd, J = 5.1, 3.2 Hz), 3.72 (2H, td, J = 15.1, 3.9 Hz), 3.24-3.06 (4H, m), 2.07-2.02 (1H, m), 1.98-1.86 (1H, m). [Example 65] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B053) Compound 2a [50 mg, 0.069 mmol] and 3-(S)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (compound 3b24) [40 mg, 213 mmol] were reacted in the same manner as in Example 1 to obtain compound B053 [13.8 mg, 0.029 mmol]. 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.10 (1H, d, J = 11.2 Hz), 5.94 (1H, tt, J = 55.0, 4.0 Hz), 5.29 (1H, dd, J = 2.4, 1.0 Hz), 4.37-4.30 (2H, m), 4.17-4.10 (1H, m), 3.71 (2H, tdd, J = 14.5, 3.7, 2.8 Hz), 3.28-3.08 (4H, m), 2.92-2.83 (2H, m), 2.76 (1H, t, J = 11.5 Hz), 2.52 (1H, dd, J = 13.2, 3.4 Hz), 2.30-2.17 (2H, m), 2.12-2.00 (4H, m), 1.91-1.29 (13H, m), 1.11 (3H, d, J = 6.3 Hz), 0.63 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.4 (M+H) [Example 66] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B054) Compound 2a [50 mg, 0.069 mmol] and 3-(R)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (compound 3b27) [35 mg, 187 mmol] were reacted in the same manner as in Example 1 to obtain compound B054 [13.7 mg, 0.029 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.89 (1H, tt, J = 55.4, 4.0 Hz), 5.28 (1H, dd, J = 1.2, 2.0 Hz), 4.89 (1H, d, J = 2.0 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.16-4.10 (2H, m), 3.69-3.54 (2H, m), 2.86 (1H, dd, J = 12.2, 3.4 Hz), 2.68-2.23 (8H, m), 2.13-1.21 (17H, m), 1.04 (3H, d, J = 6.3 Hz), 0.59 (3H, s). [Example 67] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B055) Compound 2c [50 mg, 0.069 mmol] and 3-(S)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (compound 3b24) [40 mg, 213 mmol] were reacted in the same manner as in Example 1 to obtain compound B055 [15.0 mg, 0.031 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2 Hz), 5.94 (1H, tt, J = 4.0, 55.0 Hz), 5.93 (1H, d, J = 11.2 Hz), 5.06 (2H, d, J = 5.9 Hz), 4.43-4.29 (3H, m), 3.78-3.64 (2H, m), 3.28-3.07 (4H, m), 2.87 (2H, dd, J = 12.4, 2.7 Hz), 2.76 (1H, t, J = 11.5 Hz), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.49 (1H, dd, J = 13.2, 3.9 Hz), 2.33-2.04 (6H, m), 1.81-1.26 (9H, m), 1.12 (3H, d, J = 6.3 Hz), 0.64 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.35 (M+H) [Example 68] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B056) Compound 2c [50 mg, 0.069 mmol] and 3-(R)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (compound 3b27) [35 mg, 187 mmol] were reacted in the same manner as in Example 1 to obtain compound B056 [13.2 mg, 0.028 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.89 (1H, tt, J = 56.0, 4.0 Hz), 5.05 (2H, d, J = 8.0 Hz), 4.42-4.36 (2H, m), 4.17-4.10 (1H, m), 3.70-3.55 (2H, m), 2.85 (1H, dd, J = 12.0, 3.7 Hz), 2.69-2.24 (10H, m), 2.13-1.23 (15H, m), 1.05 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.35 (M+H) [Example 69] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B057) Compound 2b [50 mg, 0.070 mmol] and 3-(S)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (compound 3b24) [40 mg, 214 mmol] were reacted in the same manner as in Example 1 to obtain compound B057 [15.1 mg, 0.032 mmol]. 1H-NMR (CD3OD) δ: 6.22 (1H, d, J = 10.7 Hz), 5.94 (1H, tt, J = 55.0, 4.0 Hz), 5.91 (1H, d, J = 10.7 Hz), 4.33-4.29 (1H, m), 4.07-3.96 (2H, m), 3.71 (2H, dtd, J = 3.0, 14.0, 4.0 Hz), 3.29-3.05 (4H, m), 2.86 (2H, d, J = 12.2 Hz), 2.75 (1H, t, J = 11.5 Hz), 2.60 (1H, dd, J = 13.4, 3.7 Hz), 2.42 (1H, dd, J = 13.4, 3.2 Hz), 2.26-1.95 (7H, m), 1.88-1.30 (11H, m), 1.11 (3H, d, J = 6.3 Hz), 0.64 (3H, s). [Example 70] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B058) Compound 2b [50 mg, 0.070 mmol] and 3-(R)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (compound 3b27) [35 mg, 187 mmol] were reacted in the same manner as in Example 1 to obtain compound B058 [10.3 mg, 0.022 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.89 (1H, tt, J = 55.0, 4.0 Hz), 5.88 (1H, d, J = 11.2 Hz), 4.16-4.10 (1H, m), 4.06-3.95 (2H, m), 3.62 (2H, tt, J = 14.4, 4.0 Hz), 2.83 (1H, dd, J = 11.7, 3.9 Hz), 2.68-2.56 (4H, m), 2.49 (1H, q, J = 7.8 Hz), 2.40 (1H, dd, J = 13.2, 3.4 Hz), 2.35-1.21 (21H, m), 1.04 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 467.32(C27H43F2NO3)Obs. mass = 468.25 (M+H) [Reference example 11] Synthesis of 3-(S)-(3,3-difluoropropyl)pyrrolidine hydrochloride (compound 3b32)

[0158] [ka]

[0159] ​ A solution of t-butyl-3-(R)-(2-hydroxyethyl)pyrrolidine-1-carboxylate (compound 3b13) [1.05 g, 4.88 mmol] and p-toluenesulfonyl chloride [1.08 g, 5.66 mmol] in pyridine [10 mL] was stirred at room temperature overnight. The reaction mixture was transferred to brine and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl-3-(R)-(2-(tosyloxy)ethyl)pyrrolidine-1-carboxylate (compound 3b28) [1.46 g, 3.95 mmol]. (Yield=81%) ​ To a DMF solution [20 mL] of t-butyl-3-(R)-(2-(tosyloxy)ethyl)pyrrolidine-1-carboxylate (compound 3b28) [1.46 g, 3.95 mmol], potassium cyanide [1.009 g, 15.50 mmol] and 18-crown-6 [114 mg, 0.431 mmol] were added, and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was transferred to saturated brine at room temperature and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl-3-(S)-(2-cyanoethyl)pyrrolidine-1-carboxylate (compound 3b29) [0.74 g, 3.3 mmol]. (Yield = 68%) ​ A toluene solution (30 mL) of t-butyl-3-(S)-(2-cyanoethyl)pyrrolidine-1-carboxylate (Compound 3b29) (0.74 g, 3.3 mmol) was cooled to −78°C under a nitrogen atmosphere. A toluene solution (1.5 M, 4 mL, 6 mmol) of diisobutylaluminum hydride (DIBAL-H) ​​was added to this solution and stirred at the same temperature for 1.5 hours. The reaction mixture was warmed to room temperature and quenched with saturated ammonium chloride. 2 M aqueous sodium hydroxide solution (10 mL) was added to this mixture and stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl-3-(S)-(2-oxopropyl)pyrrolidine-1-carboxylate (Compound 3b30) (280 mg, 1.23 mmol). (Yield: 37%) ​ A solution of t-butyl-3-(R)-(2-oxopropyl)pyrrolidine-1-carboxylate (Compound 3b30) [280 mg, 1.23 mmol] in dichloromethane [10 mL] was cooled to 0 °C, and DAST [0.60 mL, 4.55 mmol] was added and stirred overnight. The next morning, additional DAST [0.60 mL, 4.55 mmol] was added at 0 °C and stirred for another day. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl-3-(S)-(3,3-difluoropropyl)pyrrolidine-1-carboxylate (Compound 3b31) [230.1 mg, 0.923 mmol] (yield = 75%). ​ t-Butyl-3-(S)-(3,3-difluoropropyl)pyrrolidine-1-carboxylate (Compound 3b31) [230.1 mg, 0.923 mmol] was added to 4 M hydrogen chloride in dioxane [5 mL, 20 mmol] at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and dried to give 3-(S)-(3,3-difluoropropyl)pyrrolidine hydrochloride (Compound 3b32) [173.7 mg, 0.923 mmol]. (Yield = 100%) 1 H-NMR (DMSO-D6) δ: 9.22 (2H, s), 6.07 (1H, tt, J = 56.7, 4.3 Hz), 3.35-3.15 (2H, m), 3.09-3.00 (1H, m), 2.68 (1H, dd, J = 11.4, 8.7 Hz), 2.23-2.11 (1H, m), 2.08-1.98 (1H, m), 1.91-1.76 (2H, m), 1.56-1.39 (3H, m). [Reference example 12] Synthesis of 3-(R)-(3,3-difluoropropyl)pyrrolidine hydrochloride (compound 3b37)

[0160] [ka]

[0161] ​ A solution of t-butyl-3-(S)-(2-hydroxyethyl)pyrrolidine-1-carboxylate (Compound 3b17) [1.06 g, 4.92 mmol], p-toluenesulfonyl chloride [1.08 g, 5.66 mmol], and 4-dimethylaminopyridine [20 mg, 0.163 mmol] in 10 mL of pyridine was stirred at room temperature for 1.5 hours. The reaction mixture was transferred to brine and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl-3-(S)-(2-(tosyloxy)ethyl)pyrrolidine-1-carboxylate (Compound 3b33) [1.28 g, 3.46 mmol]. (Yield=70%) ​ To a DMF solution [20 mL] of t-butyl-3-(S)-(2-(tosyloxy)ethyl)pyrrolidine-1-carboxylate (Compound 3b33) [1.28 g, 3.46 mmol], potassium cyanide [618 mg, 9.49 mmol] and 18-crown-6 ether [97.2 mg, 0.368 mmol] were added, and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was transferred to saturated brine and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl-3-(R)-(2-cyanoethyl)pyrrolidine-1-carboxylate (Compound 3b34) [0.81 g, 3.46 mmol]. (Yield = 100%) ​ A toluene solution (30 mL) of t-butyl-3-(R)-(2-cyanoethyl)pyrrolidine-1-carboxylate (Compound 3b34) (0.81 g, 3.46 mmol) was cooled to −78 °C under a nitrogen atmosphere. A toluene solution (1.5 M, 5.4 mL, 8.1 mmol) of diisobutylaluminum hydride (DIBAL-H) ​​was added to this solution and stirred at the same temperature for 1.5 hours. The reaction mixture was warmed to room temperature and quenched with saturated ammonium chloride. 2 M aqueous sodium hydroxide solution (10 mL) was added to this mixture and stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl-3-(R)-(2-oxopropyl)pyrrolidine-1-carboxylate (Compound 3b35) (447.3 mg, 1.97 mmol). (Yield = 54%) ​ A solution of t-butyl-3-(R)-(2-oxopropyl)pyrrolidine-1-carboxylate (compound 3b35) [447.3 mg, 1.97 mmol] in dichloromethane [30 mL] was cooled to 0 °C, and DAST [0.63 mL, 4.77 mmol] was added and stirred overnight. The next morning, additional DAST [0.63 mL, 4.77 mmol] was added at 0 °C, and the mixture was stirred for another day. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl-3-(R)-(3,3-difluoropropyl)pyrrolidine-1-carboxylate (compound 3b36) [269.7 mg, 1.08 mmol]. ​ t-Butyl-3-(R)-(3,3-difluoropropyl)pyrrolidine-1-carboxylate (Compound 3b36) [269.7 mg, 1.08 mmol] was added to 4 M hydrogen chloride in dioxane [5 mL, 20 mmol] at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and dried to give 3-(R)-(3,3-difluoropropyl)pyrrolidine hydrochloride (Compound 3b37) [203.2 mg, 1.08 mmol]. (Yield = 100%) 1 H-NMR (DMSO-D6) δ: 9.03 (2H, s), 6.03 (1H, tt, J = 56.8, 4.3 Hz), 3.24 (1H, dd, J = 11.2, 7.8 Hz), 3.19-3.13 (1H, m), 3.06-2.98 (1H, m), 2.65 (1H, dd, J = 11.2, 8.8 Hz), 2.18-2.10 (1H, m), 2.08-1.97 (1H, m), 1.87-1.73 (2H, m), 1.53-1.36 (3H, m). [Example 71] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B059) Compound (2a) [50.0 mg, 0.069 mmol] and 3-(S)-(3,3-difluoropropyl)pyrrolidine hydrochloride (compound 3b32) [30 mg, 0.162 mmol] were reacted in the same manner as in Example 1 to obtain compound B059 [12.3 mg, 0.257 mmol]. 1H-NMR (CD3OD) δ: 6.30 (1H, d, J = 11.4 Hz), 6.07 (1H, d, J = 11.4 Hz), 5.83 (1H, tt, J = 56.9, 4.4 Hz), 5.27 (1H, dd, J = 2.3, 1.4 Hz), 4.33 (1H, t, J = 5.9 Hz), 4.13-4.07 (1H, m), 2.91-2.83 (2H, m), 2.65-2.58 (1H, m), 2.54-2.43 (2H, m), 2.28-1.20 (32H, m), 1.03 (3H, d, J = 6.4 Hz), 0.58 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.25 (M+H) [Example 72] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B060) Compound (2a) [50.0 mg, 0.069 mmol] and 3-(R)-(3,3-difluoropropyl)pyrrolidine hydrochloride (compound 3b37) [35 mg, 0.189 mmol] were reacted in the same manner as in Example 1 to obtain compound B060 [13.4 mg, 0.28 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.85 (1H, tt, J = 56.0, 4.0 Hz), 5.28 (1H, dd, J = 2.0, 1.2 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.10 (1H, m), 2.86 (1H, dd, J = 12.0, 4.6 Hz), 2.79-2.70 (2H, m), 2.51 (1H, dd, J = 13.4, 3.2 Hz), 2.40-1.24 (28H, m), 1.05 (3H, d, J = 6.8 Hz), 0.59 (3H, s). [Example 73] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B061) Compound (2c) [50.0 mg, 0.069 mmol] and 3-(S)-(3,3-difluoropropyl)pyrrolidine hydrochloride (compound 3b32) [30 mg, 0.162 mmol] were reacted in the same manner as in Example 1 to obtain compound B061 [14.7 mg, 0.31 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.0 Hz), 5.91 (1H, d, J = 11.0 Hz), 5.85 (1H, tt, J = 57.5, 4.0 Hz), 5.05 (2H, d, J = 6.4 Hz), 4.42-4.35 (2H, m), 2.92 (1H, t, J = 8.5 Hz), 2.85 (1H, dd, J = 12.1, 3.4 Hz), 2.70-2.60 (2H, m), 2.51-2.46 (2H, m), 2.31-2.25 (4H, m), 2.21-1.22 (22H, m), 1.05 (3H, d, J = 6.4 Hz), 0.61 (3H, s). [Example 74] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B062) Compound (2c) [50.0 mg, 0.069 mmol] and 3-(R)-(3,3-difluoropropyl)pyrrolidine hydrochloride (compound 3b37) [30 mg, 0.205 mmol] were reacted in the same manner as in Example 1 to obtain compound B062 [17.7 mg, 0.037 mmol]. 1H-NMR (CD3OD) δ: 6.28 (1H, d, J = 11.2 Hz), 5.93 (1H, d, J = 11.2 Hz), 5.91 (2H, tt, J = 57.0, 4.0 Hz), 5.06 (2H, d, J = 5.9 Hz), 4.40 (2H, ddd, J = 14.4, 7.1, 4.4 Hz), 3.51 (1H, dd, J = 11.0, 8.1 Hz), 3.42-3.26 (3H, m), 3.07-2.85 (4H, m), 2.67 (1H, dd, J = 13.4, 4.1 Hz), 2.49 (1H, dd, J = 13.7, 3.9 Hz), 2.45-2.20 (4H, m), 2.12-1.95 (3H, m), 1.90-1.33 (15H, m), 1.14 (3H, d, J = 6.8 Hz), 0.65 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.40 (M+H) [Example 75] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B063) Compound (2b) [50.0 mg, 0.070 mmol] and 3-(S)-(3,3-difluoropropyl)pyrrolidine hydrochloride (compound 3b32) [30 mg, 0.162 mmol] were reacted in the same manner as in Example 1 to obtain compound B063 [9.8 mg, 0.021 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.89 (2H, d, J = 11.0 Hz), 5.85 (1H, tt, J = 4.5, 57.0 Hz), 4.06-3.95 (2H, m), 2.92 (1H, t, J = 8.5 Hz), 2.83 (1H, dd, J = 11.7, 3.9 Hz), 2.68-2.55 (2H, m), 2.52-2.45 (1H, m), 2.41 (1H, dd, J = 13.3, 3.2 Hz), 2.32-1.22 (31H, m), 1.05 (3H, d, J = 6.4 Hz), 0.60 (3H, s). Exact Mass = 465.34(C28H45F2NO2)Obs. mass = 466.30 (M+H) [Example 76] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B064) Compound (2b) [50.0 mg, 0.070 mmol] and 3-(R)-(3,3-difluoropropyl)pyrrolidine hydrochloride (compound 3b37) [40 mg, 0.215 mmol] were reacted in the same manner as in Example 1 to obtain compound B064 [10.3 mg, 0.022 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.88 (1H, d, J = 11.2 Hz), 5.85 (1H, tt, J = 57.0, 4.0 Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.0, 3.7 Hz), 2.77-2.70 (2H, m), 2.59 (1H, dd, J = 13.4, 3.7 Hz), 2.42-1.21 (31H, m), 1.05 (3H, d, J = 6.8 Hz), 0.60 (3H, s). Exact Mass = 465.34(C28H45F2NO2)Obs. mass = 466.35 (M+H) [Example 77] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((S)-3-(trifluoromethoxy)pyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B065) Compound (2a) [50.0 mg, 0.069 mmol] and 3-(S)-(trifluoromethoxy)pyrrolidine hydrochloride [35 mg, 0.183 mmol] were reacted in the same manner as in Example 1 to obtain compound B065 [5.7 mg, 0.012 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 1.8, 1.0 Hz), 4.89 (1H, dd, J = 1.8, 1.0 Hz), 4.86-4.80 (2H, m), 4.34 (1H, t, J = 5.9 Hz), 4.14-4.05 (1H, m), 2.86 (2H, dd, J = 10.7, 5.9 Hz), 2.81-2.75 (1H, m), 2.62 (1H, dd, J = 10.7, 2.4 Hz), 2.51 (1H, dd, J = 13.2, 3.4 Hz), 2.38-2.16 (6H, m), 2.07-1.87 (7H, m), 1.73-1.21 (11H, m), 1.06 (3H, t, J = 8.1 Hz), 0.59 (3H, s). Exact Mass = 483.30(C27H40F3NO3)Obs. mass = 484.35 (M+H) [Example 78] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((R)-3-(trifluoromethoxy)pyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B066) Compound (2a) [50.0 mg, 0.069 mmol] and 3-(R)-(trifluoromethoxy)pyrrolidine hydrochloride [35 mg, 0.183 mmol] were reacted in the same manner as in Example 1 to obtain compound B066 [6.1 mg, 0.013 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.89 (1H, dd, J = 2.2, 1.5 Hz), 4.86-4.82 (1H, m), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.09 (1H, m), 2.86 (1H, dd, J = 12.2, 3.4 Hz), 2.78 (1H, dd, J = 11.2, 2.4 Hz), 2.67-2.62 (2H, m), 2.55-2.43 (2H, m), 2.35-2.20 (4H, m), 2.07-1.91 (4H, m), 1.88 (2H, t, J = 5.9 Hz), 1.75-1.63 (2H, m), 1.60-1.21 (8H, m), 1.04 (3H, d, J = 6.8 Hz), 0.59 (3H, s). Exact Mass = 483.30(C27H40F3NO3)Obs. mass = 484.20 (M+H) [Example 79] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((S)-3-(trifluoromethoxy)pyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B067) Compound (2c) [50.0 mg, 0.069 mmol] and 3-(S)-(trifluoromethoxy)pyrrolidine hydrochloride [35 mg, 0.183 mmol] were reacted in the same manner as in Example 1 to obtain compound B067 [5.7 mg, 0.012 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 7.3 Hz), 4.88-4.80 (2H, m), 4.42-4.36 (2H, m), 2.89-2.77 (3H, m), 2.65 (2H, td, J = 13.0, 4.0 Hz), 2.48 (1H, dd, J = 13.4, 4.1 Hz), 2.40-2.22 (7H, m), 2.07-1.90 (5H, m), 1.60 (7H, tt, J = 24.6, 8.1 Hz), 1.38-1.21 (4H, m), 1.05 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 483.30(C27H40F3NO3)Obs. mass = 484.40 (M+H) [Example 80] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((R)-3-(trifluoromethoxy)pyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B068) Compound (2c) [50.0 mg, 0.069 mmol] and 3-(R)-(trifluoromethoxy)pyrrolidine hydrochloride [35 mg, 0.183 mmol] were reacted in the same manner as in Example 1 to obtain compound B068 [6.7 mg, 0.014 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.86-4.83 (1H, m), 4.43-4.35 (2H, m), 2.87-2.79 (2H, m), 2.68-2.63 (3H, m), 2.49 (2H, dd, J = 15.9, 6.6 Hz), 2.37-2.20 (5H, m), 2.07-1.90 (4H, m), 1.70-1.21 (10H, m), 1.05 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 483.30(C27H40F3NO3)Obs. mass = 484.30 (M+H) [Example 81] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((S)-3-(trifluoromethoxy)pyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B069) Compound (2b) [50.0 mg, 0.070 mmol] and 3-(S)-(trifluoromethoxy)pyrrolidine hydrochloride [35 mg, 0.183 mmol] were reacted in the same manner as in Example 1 to obtain compound B069 [6.8 mg, 0.014 mmol]. 1 H-NMR (CD3OD) δ: 6.20 (1H, d, J = 11.0 Hz), 5.87 (1H, d, J = 11.0 Hz), 4.85-4.80 (1H, m), 4.04-3.93 (2H, m), 2.87-2.73 (3H, m), 2.66-2.53 (2H, m), 2.41-2.11 (7H, m), 2.05-1.47 (12H, m), 1.37-1.23 (3H, m), 1.03 (3H, d, J = 6.4 Hz), 0.58 (3H, s). Exact Mass = 471.30(C26H40F3NO3)Obs. mass = 472.25 (M+H) [Example 82] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((R)-3-(trifluoromethoxy)pyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B070) Compound (2b) [50.0 mg, 0.070 mmol] and 3-(R)-(trifluoromethoxy)pyrrolidine hydrochloride [35 mg, 0.183 mmol] were reacted in the same manner as in Example 1 to obtain compound B070 [6.2 mg, 0.013 mmol]. 1 H-NMR (CD3OD) δ: 6.20 (1H, d, J = 11.4 Hz), 5.87 (1H, d, J = 11.0 Hz), 4.85-4.81 (1H, m), 4.04-3.93 (2H, m), 2.82 (1H, dd, J = 11.7, 3.9 Hz), 2.78 (1H, dd, J = 3.0, 12.0 Hz), 2.66-2.61 (2H, m), 2.57 (1H, dd, J = 13.3, 3.7 Hz), 2.46 (1H, q, J = 7.9 Hz), 2.39 (1H, dd, J = 13.3, 3.2 Hz), 2.34-2.11 (5H, m), 2.05-1.71 (6H, m), 1.65-1.47 (6H, m), 1.38-1.21 (3H, m), 1.03 (3H, d, J = 6.4 Hz), 0.58 (3H, s). Exact Mass = 471.30(C26H40F3NO3)Obs. mass = 472.25 (M+H) [Example 83] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B071) Compound (2a) [50.0 mg, 0.069 mmol] and (S)-3-methylpyrrolidin-3-ol hydrochloride [30 mg, 0.218 mmol] were reacted in the same manner as in Example 1 to obtain compound B071 [10.7 mg, 0.025 mmol]. 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 10.7 Hz), 5.28 (1H, s), 4.34 (1H, t, J = 5.9 Hz), 4.18-4.08 (2H, m), 2.86 (1H, dd, J = 12.2, 3.4 Hz), 2.76 (1H, q, J = 8.0 Hz), 2.63-2.40 (4H, m), 2.35-2.20 (4H, m), 2.07-1.25 (21H, m), 1.05 (3H, d, J = 6.8 Hz), 0.59 (3H, s). Exact Mass = 429.32(C27H43NO3)Obs. mass = 430.30(M+H) [Example 84] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B072) Compound (2b) [50.0 mg, 0.070 mmol] and (S)-3-methylpyrrolidin-3-ol hydrochloride [30 mg, 0.218 mmol] were reacted in the same manner as in Example 1 to obtain compound B072 [9.7 mg, 0.023 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.88 (1H, d, J = 11.2 Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 11.7, 3.9 Hz), 2.77 (1H, dd, J = 16.6, 7.3 Hz), 2.61-2.13 (9H, m), 2.06-1.72 (7H, m), 1.69-1.48 (6H, m), 1.40-1.33 (2H, m), 1.33 (3H, s), 1.29-1.21 (1H, m), 1.05 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 417.32(C26H43NO3)Obs. mass = 418.30(M+H) [Example 85] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B073) Compound (2c) [50.0 mg, 0.069 mmol] and (S)-3-methylpyrrolidin-3-ol hydrochloride [30 mg, 0.218 mmol] were reacted in the same manner as in Example 1 to obtain compound B073 [9.6 mg, 0.022 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.42-4.36 (2H, m), 2.85 (1H, dd, J = 12.0, 3.7 Hz), 2.77 (1H, dd, J = 16.6, 7.3 Hz), 2.67 (1H, dd, J = 13.4, 4.1 Hz), 2.63-2.40 (4H, m), 2.36-2.25 (4H, m), 2.10-1.90 (3H, m), 1.86-1.75 (2H, m), 1.72-1.50 (6H, m), 1.37 (2H, td, J = 11.8, 3.1 Hz), 1.33 (3H, s), 1.30-1.21 (2H, m), 1.05 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 429.32(C27H43NO3)Obs. mass = 430.30(M+H) [Example 86] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound B074) Compound (2a) [50.0 mg, 0.069 mmol] and (R)-3-methylpyrrolidin-3-ol hydrochloride [30 mg, 0.218 mmol] were reacted in the same manner as in Example 1 to obtain compound B074 [10.3 mg, 0.024 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.34 (1H, t, J = 6.1 Hz), 4.16-4.05 (1H, m), 2.86 (1H, dd, J = 12.0, 3.7 Hz), 2.75-2.53 (3H, m), 2.51 (1H, dd, J = 13.4, 3.7 Hz), 2.38 (1H, d, J = 9.8 Hz), 2.34-2.22 (3H, m), 2.07-1.77 (9H, m), 1.73-1.36 (9H, m), 1.33 (3H, s), 1.31-1.23 (3H, m), 1.05 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 429.32(C27H43NO3)Obs. mass =430.30 (M+H) [Example 87] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B075) Compound (2b) [50.0 mg, 0.070 mmol] and (R)-3-methylpyrrolidin-3-ol hydrochloride [30 mg, 0.218 mmol] were reacted in the same manner as in Example 1 to obtain compound B075 [9.5 mg, 0.023 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.88 (1H, d, J = 10.7 Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.2, 3.4 Hz), 2.73-2.52 (4H, m), 2.42-2.13 (6H, m), 2.07-1.48 (14H, m), 1.42-1.35 (2H, m), 1.33 (3H, s), 1.31-1.22 (2H, m), 1.05 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 417.32(C26H43NO3)Obs. mass = 418.30(M+H) [Example 88] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B076) Compound (2c) [50.0 mg, 0.069 mmol] and (R)-3-methylpyrrolidin-3-ol hydrochloride [30 mg, 0.218 mmol] were reacted in the same manner as in Example 1 to obtain compound B076 [13.3 mg, 0.031 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.42-4.36 (2H, m), 2.85 (1H, dd, J = 12.2, 3.9 Hz), 2.73-2.62 (3H, m), 2.58 (1H, dd, J = 14.6, 8.3 Hz), 2.48 (1H, dd, J = 13.4, 3.7 Hz), 2.40-2.16 (5H, m), 2.07-1.77 (5H, m), 1.70-1.49 (6H, m), 1.43-1.23 (6H, m), 1.06 (3H, d, J = 6.8 Hz), 0.60 (3H, s). Exact Mass = 429.32(C27H43NO3)Obs. mass = 430.25(M+H) [Example 89] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-cyclopropyl-3-hydroxypyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (B077) Compound (2c) [50.0 mg, 0.069 mmol] and 3-cyclopropylpyrrolidin-3-ol hydrochloride [30 mg, 0.183 mmol] were reacted in the same manner as in Example 1 to obtain compound B077 [9.6 mg, 0.021 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.42-4.36 (2H, m), 2.99-2.24 (12H, m), 2.07-1.28 (16H, m), 1.08-1.00 (1H, m), 1.05 (3H, d, J = 6.3 Hz), 0.60 (3H, s), 0.45-0.30 (4H, m). Exact Mass = 455.34(C29H45NO3)Obs. mass = 456.35(M+H) [Example 90] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((2S)-1-(3-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B078) Compound (2b) [50.0 mg, 0.070 mmol] and 3-trifluoromethylpyrrolidine hydrochloride [48.3 mg, 0.275 mmol] were reacted in the same manner as in Example 1 to obtain compound B078 [7.2 mg, 0.016 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7 Hz), 5.89 (1H, d, J = 11.2 Hz), 4.06-3.95 (2H, m), 2.99-2.81 (3H, m), 2.69-2.49 (4H, m), 2.45-2.10 (6H, m), 2.07-1.48 (14H, m), 1.39-1.20 (4H, m), 1.04 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 455.30(C26H40F3NO2)Obs. mass = 456.30(M+H) [Example 91] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((2S)-1-(3-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B079) Compound (2c) [100.0 mg, 0.137 mmol] and 3-trifluoromethylpyrrolidine hydrochloride [48.3 mg, 0.275 mmol] were reacted in the same manner as in Example 1 to obtain compound B079 [11.4 mg, 0.024 mmol]. Exact Mass = 467.30(C27H40F3NO2)Obs. mass = 468.35(M+H) [Example 92] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C001)

[0162] [ka]

[0163] ​ A DMF solution (2.5 mL) of (2S)-2-((1R,3aS,7aR,E)-4-(bromomethylene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (Compound 6c, CAS Registry No. 173388-39-1) [388 mg, 0.879 mmol], triethyl-[[4-(trifluoromethyl)-4-piperidyl]oxy]silane (Compound 3c01) [653 mg, 2.30 mmol], and potassium carbonate [551 mg, 3.99 mmol] was heated and stirred at 100°C for 4 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1-((2S)-2-((1R,3aS,7aR,E)-4-(bromomethylene)-7a-methyloctahydro-1H-inden-1-yl)propyl)-4-(trifluoromethyl)piperidin-4-ol (compound 3c02) [266.4 mg, 0.608 mmol]. 1 H-NMR (CDCl3) δ: 5.65 (1H, s), 2.91-2.85 (1H, m), 2.80 (1H, d, J = 11.2 Hz), 2.63 (1H, dd, J = 5.9 Hz), 4.15-4.06 (1H, m), 2.89-2.81 (2H, m), 2.63 (1H, d, J = 11.2 Hz), 2.51 (1H, dd, J = 11.2, 4.0 Hz), 2.37 (1H, td, J = 12.0, 2.3 Hz), 2.28 (1H, dd, J = 12.2, 3.4 Hz), 2.09-1.84 (8H, m), 1.68-1.23 (16H, m), 1.00 (3H, d, J = 6.9 Hz), 0.59 (3H, s). ​ Compound 3c02 (47.1 mg, 0.107 mmol) synthesized in step 1, (5R,7S)-2,2,3,3,9,9,10,10-octamethyl-5-(prop-2-yn-1-yl)-7-vinyl-4,8-dioxa-3,9-disilaundecane (Compound 7a, CAS Registry No. 161055-41-0) (49.4 mg, 0.134 mmol), and tetrakis(triphenylphosphine)palladium(0) (12.4 mg, 0.011 mmol) were dissolved in a mixture of toluene (0.5 mL) and triethylamine (0.5 mL) and heated and stirred at 100 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure and partially purified by thin-layer chromatography to yield a crude product containing compound 3c03 (73.9 mg). ​ The crude product (73.9 mg) containing compound 3c03 obtained in step 2 was dissolved in acetone (1 mL), and 6N hydrochloric acid (0.2 mL) was added. The mixture was stirred at room temperature for 8 hours. The reaction mixture was quenched, diluted with saturated brine, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography to give compound C001 (6.3 mg, 0.013 mmol). 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, t, J = 1.2 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.06 (1H, m), 2.89-2.81 (2H, m), 2.63 (1H, d, J = 11.2 Hz), 2.51 (1H, dd, J = 13.2, 3.4 Hz), 2.41-2.23 (3H, m), 2.11-2.02 (3H, m), 1.98-1.21 (19H, m), 1.03 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 497.31(C28H42F3NO3)Obs. mass = 498.4(M+H) [Example 93] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound C002) Compound (2b) [100 mg, 0.139 mmol] and triethyl-[[4-(trifluoromethyl)-4-piperidyl]oxy]silane [86.4 mg, 0.305 mmol] were reacted in the same manner as in Example 1 to obtain compound C002 [7.2 mg, 0.015 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.89 (1H, d, J = 11.4 Hz), 4.06-3.95 (2H, m), 2.87-2.80 (2H, m), 2.65-2.57 (2H, m), 2.44-2.28 (3H, m), 2.23-1.48 (20H, m), 1.38-1.24 (4H, m), 1.03 (3H, d, J = 6.4 Hz), 0.60 (3H, s). Exact Mass = 485.31(C27H42F3NO3)Obs.mass = 486.25(M+H) [Example 94] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound C003) Compound 3c02 [46.8 mg, 0.107 mmol] obtained in Step 1 of Example 92, (5R,6S,7R)-2,2,3,3,6,9,9,10,10-nonamethyl-5-(prop-2-yn-1-yl)-7-vinyl-4,8-dioxa-3,9-disilaundecane (Compound 7b) [50 mg, 0.131 mmol], and tetrakis(triphenylphosphine)palladium(0) [12.4 mg, 0.011 mmol] were treated in the same manner as in Steps 2 and 3 of Example 92 to obtain Compound C003 [10.0 mg, 0.019 mmol]. 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.10 (1H, d, J = 11.2 Hz), 5.22 (1H, d, J = 2.0 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.1, 4.1 Hz), 3.17 (1H, d, J = 10.2 Hz), 3.00 (1H, d, J = 11.2 Hz), 2.89-2.75 (2H, m), 2.67 (1H, d, J = 12.7 Hz), 2.62-2.52 (2H, m), 2.42 (1H, t, J = 11.7 Hz), 2.19-1.97 (5H, m), 1.93-1.20 (13H, m), 1.08 (3H, d, J = 6.8 Hz), 1.03 (3H, d, J = 6.8 Hz), 0.61 (3H, s). Exact Mass = 511.33(C29H44F3NO3)Obs. mass = 512.4 (M+H) [Example 95] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C004) Compound (2c) [60.0 mg, 0.082 mmol] and triethyl-[[4-(trifluoromethyl)-4-piperidyl]oxy]silane [70 mg, 0.247 mmol] were reacted in the same manner as in Example 1 to obtain compound C004 [18.7 mg, 0.038 mmol]. 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.3 Hz), 4.43-4.34 (2H, m), 3.28-3.24 (1H, m), 3.10 (1H, d, J = 11.7 Hz), 2.95-2.64 (5H, m), 2.56-2.46 (2H, m), 2.32-2.25 (2H, m), 2.12-1.96 (6H, m), 1.87-1.29 (12H, m), 1.10 (3H, d, J = 6.3 Hz), 0.63 (3H, s). Exact Mass = 497.31(C28H42F3NO3)Obs. mass = 498.4(M+H) [Example 96] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-(4-(trifluoromethyl)piperidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C007)

[0164] [ka]

[0165] ​ Compound 6c [62.1 mg, 0.141 mmol] and 4-trifluoromethylpiperidine hydrochloride (compound 3c04) [57.0 mg, 0.201 mmol] were used as starting materials and treated in the same manner as in Step 1 of Example 92 to obtain 1-((2S)-2-((1R,3aS,7aR,E)-4-(bromomethylene)-7a-methyloctahydro-1H-inden-1-yl)propyl)-4-(trifluoromethyl)piperidine (compound 3c05) [36.0 mg, 0.085 mmol]. ​ Compound C007 [5.5 mg, 0.011 mmol] was obtained by treating 3c05 [36.0 mg, 0.085 mmol], compound 7a [41.0 mg, 0.111 mmol], and tetrakis(triphenylphosphine)palladium(0) [12.4 mg, 0.011 mmol] as raw materials in the same manner as in steps 2 and 3 of Example 92. 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.7 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.12 (1H, br s), 3.04 (1H, d, J = 11.2 Hz), 2.90-2.82 (2H, m), 2.53-2.49 (1H, m), 2.30-2.22 (3H, m), 2.09-1.22 (30H, m), 1.02 (3H, d, J = 6.8 Hz), 0.59 (3H, s). Exact Mass = 481.32(C28H42F3NO2)Obs. mass = 482.4(M+H) [Example 97] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-(4-(trifluoromethyl)piperidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound C008) Compound (2b) [50.0 mg, 0.070 mmol] and 4-trifluoromethylpiperidine hydrochloride [30 mg, 0.196 mmol] were reacted in the same manner as in Example 1 to obtain compound C008 [9.8 mg, 0.021 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.88 (1H, d, J = 11.4 Hz), 4.06-3.95 (2H, m), 3.04 (1H, d, J = 11.4 Hz), 2.88-2.80 (2H, m), 2.59 (1H, dd, J = 13.3, 3.7 Hz), 2.40 (1H, dd, J = 13.3, 3.7 Hz), 2.26 (1H, dd, J = 12.1, 3.0 Hz), 2.23-1.73 (13H, m), 1.67-1.48 (8H, m), 1.38-1.22 (4H, m), 1.02 (3H, d, J = 6.4 Hz), 0.60 (3H, s). Exact Mass = 469.32(C27H42F3NO2)Obs. mass = 470.30(M+H) [Example 98] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-(4-(trifluoromethyl)piperidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C009) Compound (2c) [60.0 mg, 0.082 mmol] and 4-trifluoromethylpiperidine hydrochloride [50 mg, 0.326 mmol] were reacted in the same manner as in Example 1 to obtain compound C009 [7.6 mg, 0.016 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 5.9 Hz), 4.43-4.35 (2H, m), 3.35-3.31 (1H, m), 3.14 (1H, d, J = 11.7 Hz), 2.86 (1H, dd, J = 12.4, 3.7 Hz), 2.69-2.04 (12H, m), 1.92-1.27 (13H, m), 1.07 (3H, d, J = 6.3 Hz), 0.62 (3H, s). Exact Mass = 481.32(C28H42F3NO2)Obs. mass = 482.4(M+H) [Example 99] Synthesis of (1R,2S,3S,Z)-2-methyl-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-(4-(trifluoromethyl)piperidin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C010) Compound 3c05 [42.0 mg, 0.099 mmol] obtained in Step 1 of Example 96, compound 7b [50 mg, 0.131 mmol], and tetrakis(triphenylphosphine)palladium(0) [20.0 mg, 0.017 mmol] were used as starting materials and treated in the same manner as in Steps 2 and 3 of Example 92 to obtain compound C010 [12.0 mg, 0.024 mmol]. 1H-NMR (DMSO-D6) δ: 6.19 (1H, d, J = 11.2 Hz), 5.99 (1H, d, J = 11.2 Hz), 5.17 (1H, d, J = 2.4 Hz), 4.75 (2H, dd, J = 11.7, 3.4 Hz), 4.57 (1H, d, J = 4.4 Hz), 4.15 (1H, t, J = 3.4 Hz), 3.63-3.59 (1H, m), 2.93 (1H, d, J = 11.2 Hz), 2.77 (2H, t, J = 12.7 Hz), 2.46 (1H, dd, J = 14.1, 3.4 Hz), 2.22-1.14 (27H, m), 0.95 (3H, d, J = 5.9 Hz), 0.85 (3H, d, J = 6.8 Hz), 0.52 (3H, s). Exact Mass = 495.33(C29H44F3NO2)Obs. mass = 496.4 (M+H) [Example 100] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-(difluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methylcyclohexane-4H-indene-4-indene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C013)

[0166] [ka]

[0167] ​ Compound 6c [59.7 mg, 0.135 mmol] and 4-difluoromethylpiperidine hydrochloride (compound 3c07) [79.4 mg, 0.294 mmol] were used as starting materials and treated in the same manner as in Step 1 of Example 92 to obtain 1-((2S)-2-((1R,3aS,7aR,E)-4-(bromomethylene)-7a-methyloctahydro-1H-inden-1-yl)propyl)-4-(difluoromethyl)piperidine (compound 3c08) [16.0 mg, 0.0394 mmol]. ​ Compound C013 [2.5 mg, 0.0054 mmol] was obtained by treating 3c08 [16.0 mg, 0.0394 mmol], compound 7a [20.0 mg, 0.0542 mmol], and tetrakis(triphenylphosphine)palladium(0) [10.0 mg, 0.0086 mmol] as raw materials in the same manner as in steps 2 and 3 of Example 92. 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.68 (1H, td, J = 57.0, 5.0 Hz), 5.28 (1H, d, J = 1.5 Hz), 4.34 (1H, d, J = 5.9 Hz), 4.12 (1H, brs), 3.05-2.82 (3H, m), 2.51 (1H, dd, J = 10.2, 5.1 Hz), 2.28-2.22 (2H, m), 2.06-1.22 (22H, m), 1.02 (3H, d, J = 6.8 Hz), 0.59 (3H, s). Exact Mass = 463.33(C28H43F2NO2)Obs. mass = 464.4 (M+H) [Example 101] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-(difluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound C014) Compound (2b) [50.0 mg, 0.070 mmol] and 4-difluoromethylpiperidine hydrochloride [30 mg, 0.222 mmol] were reacted in the same manner as in Example 1 to obtain compound C014 [8.3 mg, 0.018 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.88 (1H, d, J = 11.0 Hz), 5.65 (1H, td, J = 56.8, 4.3 Hz), 4.05-3.95 (2H, m), 3.02 (1H, d, J = 11.0 Hz), 2.83 (2H, dd, J = 12.3, 3.0 Hz), 2.59 (1H, dd, J = 13.3, 3.7 Hz), 2.40 (1H, dd, J = 13.3, 3.2 Hz), 2.27-2.13 (3H, m), 2.05-1.21 (22H, m), 1.02 (3H, d, J = 6.4 Hz), 0.60 (3H, s). Exact Mass = 451.33(C27H43F2NO2)Obs. mass = 452.25(M+H) [Example 102] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-(difluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C015) Compound (2c) [50.0 mg, 0.069 mmol] and 4-difluoromethylpiperidine hydrochloride [35 mg, 0.204 mmol] were reacted in the same manner as in Example 1 to obtain compound C015 [14.2 mg, 0.031 mmol]. 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7 Hz), 5.91 (2H, d, J = 10.7 Hz), 5.76 (2H, td, J = 56.0, 5.0 Hz), 5.05 (2H, d, J = 5.9 Hz), 4.42-4.36 (2H, m), 3.48 (2H, t, J = 11.5 Hz), 2.88-2.00 (15H, m), 1.91-1.32 (13H, m), 1.10 (3H, d, J = 6.3 Hz), 0.64 (3H, s). Exact Mass = 463.33(C28H43F2NO2)Obs. mass = 464.40(M+H) [Example 103] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-(difluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound C016) Compound 3c08 [35.7 mg, 0.093 mmol] obtained in Step 1 of Example 100, compound 7b [50 mg, 0.131 mmol], and tetrakis(triphenylphosphine)palladium(0) [20.0 mg, 0.017 mmol] were used as starting materials and treated in the same manner as in Steps 2 and 3 of Example 100 to obtain compound C016 [8.0 mg, 0.017 mmol]. 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.67 (1H, td, J = 56.8, 4.2 Hz), 5.22 (1H, d, J = 1.5 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.2, 4.2 Hz), 3.10 (1H, d, J = 11.2 Hz), 2.89 (2H, dd, J = 16.6, 11.7 Hz), 2.59 (1H, dd, J = 13.4, 4.1 Hz), 2.35 (1H, t, J = 6.1 Hz), 2.21-1.90 (7H, m), 1.86-1.26 (19H, m), 1.03 (6H, d, J = 6.8 Hz), 0.59 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.4(M+H) [Example 104] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-(difluoromethyl)-4-hydroxypiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C021) Compound (2a) [90.0 mg, 0.123 mmol] and 4-(difluoromethyl)-4-((trimethylsilyl)oxy)piperidine [83.2 mg, 0.373 mmol] were reacted in the same manner as in Example 1 to obtain compound C021 [18.3 mg, 0.038 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.51 (1H, t, J = 56.4 Hz), 5.28 (1H, t, J = 1.2 Hz), 4.89 (1H, d, J = 2.4 Hz), 4.34 (1H, t, J = 6.0 Hz), 4.16-4.09 (1H, m), 2.86 (1H, dd, J = 12.2, 3.4 Hz), 2.79 (1H, d, J = 10.7 Hz), 2.60 (1H, d, J = 11.2 Hz), 2.51 (1H, dd, J = 13.2, 3.4 Hz), 2.45-2.36 (1H, m), 2.34-2.03 (7H, m), 1.98-1.27 (21H, m), 1.03 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.4(M+H) [Example 105] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-(difluoromethyl)-4-hydroxypiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C022) Compound (2c) [50.0 mg, 0.069 mmol] and 4-(difluoromethyl)-4-((trimethylsilyl)oxy)piperidine [38.5 mg, 0.172 mmol] were reacted in the same manner as in Example 1 to obtain compound C022 [13.4 mg, 0.028 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.63 (1H, t, J = 56.1 Hz), 5.05 (2H, d, J = 6.3 Hz), 4.42-4.35 (2H, m), 3.19-2.25 (11H, m), 2.09-1.96 (5H, m), 1.90-1.28 (13H, m), 1.11 (3H, d, J = 6.3 Hz), 0.64 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.30(M+H) [Example 106] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-(difluoromethyl)-4-hydroxypiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound C023)

[0168] [ka]

[0169] ​ Compound 6c [89.2 mg, 0.202 mmol] and 4-(difluoromethyl)-4-((trimethylsilyl)oxy)piperidine [94.3 mg, 0.422 mmol] were used as starting materials and treated in the same manner as in Step 1 of Example 92 to obtain 1-((2S)-2-((1R,3aS,7aR,E)-4-(bromomethylene)-7a-methyloctahydro-1H-inden-1-yl)propyl)-4-(difluoromethyl)-4-((trimethylsilyl)oxy)piperidine (Compound 3c11) [54.2 mg, 0.110 mmol]. ​ Compound C023 [16.4 mg, 0.033 mmol] was obtained by treating 3c11 [50.7 mg, 0.103 mmol], compound 7b [49.5 mg, 0.129 mmol], and tetrakis(triphenylphosphine)palladium(0) [23.0 mg, 0.020 mmol] as raw materials in the same manner as in steps 2 and 3 of Example 92. 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.51 (1H, t, J = 56.4 Hz), 5.22 (1H, d, J = 2.0 Hz), 4.89 (1H, d, J = 2.4 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.2, 4.2 Hz), 2.86 (1H, dd, J = 12.0, 3.7 Hz), 2.78 (1H, d, J = 11.2 Hz), 2.59 (2H, dd, J = 13.2, 3.9 Hz), 2.40 (1H, td, J = 11.6, 2.1 Hz), 2.30 (1H, dd, J = 12.2, 2.4 Hz), 2.19-1.20 (23H, m), 1.04 (6H, d, J = 8.0 Hz), 1.03 (6H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 493.34(C29H45F2NO3)Obs. mass = 494.40(M+H) [Example 107] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-hydroxy-4-methylpiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C028) Compound (2a) [90.0 mg, 0.069 mmol] and 4-methylpiperidin-4-ol [42 mg, 0.365 mmol] were reacted in the same manner as in Example 1 to obtain compound C028 [10.0 mg, 0.0225 mmol]. 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.35 (1H, t, J = 6.1 Hz), 4.15-4.10 (1H, m), 3.50-3.18 (4H, m), 3.10-2.92 (2H, m), 2.89-2.86 (1H, m), 2.77 (1H, t, J = 12.0 Hz), 2.51 (1H, dd, J = 13.2, 3.4 Hz), 2.26 (1H, dd, J = 13.2, 6.8 Hz), 2.08-2.01 (3H, m), 1.95-1.30 (17H, m), 1.28 (3H, s), 1.12 (3H, d, J = 6.3 Hz), 0.64 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.40(M+H) [Example 108] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C030a, Compound C030b)

[0170] [ka]

[0171] ​ A DMF solution (1 mL) of compound (2a) (100 mg, 0.137 mmol), 3-(trifluoromethyl)piperidin-3-ol hydrochloride (compound 3c13) (60 mg, 0.292 mmol), and potassium carbonate (60 mg, 0.434 mmol) was stirred at 60 °C overnight. The reaction mixture was quenched with saturated brine and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and TLC yielded the less polar product (compound C030-TBSLP) (21.2 mg, 0.0292 mmol) and the more polar product (compound C030-TBSMP) (22.3 mg, 0.0307 mmol). ​ To a THF solution (1 mL) of compound C030-TBSLP (21.2 mg, 0.0292 mmol), TBAF (1 M in THF, 0.5 mL, 0.5 mmol) was added and the mixture was stirred at 50 °C overnight. The reaction mixture was quenched with saturated magnesium bicarbonate, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to give compound C030a (10.3 mg, 0.0207 mmol). 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, t, J = 1.2 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.09 (1H, m), 3.05-2.93 (1H, m), 2.87 (1H, dd, J = 12.2, 3.4 Hz), 2.80 (1H, d, J = 11.7 Hz), 2.53-2.44 (4H, m), 2.25 (1H, dd, J = 13.2, 6.8 Hz), 2.13 (2H, t, J = 11.5 Hz), 2.07-2.00 (4H, m), 1.94-1.24 (20H, m), 1.06 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 497.31(C28H42F3NO3)Obs. mass = 498.40(M+H) ​ Compound C030-TBSMP [22.3 mg, 0.0307 mmol] was reacted in the same manner as in Step 2a above to obtain compound C030b [9.7 mg, 0.019 mmol]. 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.09 (1H, m), 2.98 (1H, d, J = 11.2 Hz), 2.87 (2H, d, J = 11.2 Hz), 2.53 (2H, td, J = 12.3, 3.1 Hz), 2.45-1.98 (9H, m), 1.92-1.23 (18H, m), 1.05 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 497.31(C28H42F3NO3)Obs. mass = 498.40(M+H) [Example 109] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound C031a, Compound C031b)

[0172] [ka]

[0173] ​ To a DMF solution [4 mL] of compound 6c [220.6 mg, 0.500 mmol] and 3-(trifluoromethyl)piperidin-3-ol hydrochloride (compound 3c13) [315 mg, 1.53 mmol], potassium carbonate [390 mg, 2.82 mmol] was added at room temperature, and the reaction mixture was heated and stirred at 60 °C for 20 hours. After cooling to room temperature, the reaction mixture was poured into saturated brine and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3c14-LP [65.6 mg, 0.150 mmol], which was less polar by TLC, and compound 3c14-MP [57.2 mg, 0.130 mmol], which was more polar by TLC.

[0174] ​ C ​ ​ To a solution of compound 3c14-LP (29.9 mg, 0.0682 mmol) obtained in step 1 and compound 7b (38.7 mg, 0.101 mmol) in toluene (1 mL) / triethylamine (1 mL), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) was added and the mixture was heated and stirred at 100°C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography to give compound 3c15-LP (38.5 mg). ​ To a THF solution (1 mL) of compound 3c15-LP (38.5 mg, 0.052 mmol), TBAF (1 M in THF, 0.6 mL, 0.6 mmol) was added and the mixture was heated and stirred at 60 °C overnight. After cooling to room temperature, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified to give compound C031a (10.5 mg, 0.0205 mmol). 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 10.7 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.22 (1H, d, J = 2.0 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.1, 4.2 Hz), 2.97 (1H, d, J = 11.2 Hz), 2.86 (1H, dd, J = 11.7, 3.4 Hz), 2.77 (1H, d, J = 11.7 Hz), 2.59 (1H, dd, J = 13.4, 4.1 Hz), 2.47-2.41 (2H, m), 2.19-2.00 (5H, m), 1.94-1.23 (17H, m), 1.06 (3H, d, J = 6.3 Hz), 1.03 (3H, d, J = 6.8 Hz), 0.59 (3H, s). Exact Mass = 511.33(C29H44F3NO3)Obs. mass = 512.4(M+H) ​ C ​ Compound 3c14-MP [26.6 mg, 0.0595 mmol] obtained in step 1 and compound 7b [33.2 mg, 0.0868 mmol] were used as starting materials and treated in the same manner as in steps 2a and 3a to obtain compound C031b [11.5 mg, 0.0225 mmol]. 1H-NMR (DMSO-D6) δ: 6.19 (1H, d, J = 11.2 Hz), 5.99 (1H, d, J = 11.2 Hz), 5.58 (1H, s), 5.17 (1H, d, J = 2.4 Hz), 4.77 (1H, d, J = 2.9 Hz), 4.75 (1H, d, J = 4.4 Hz), 4.57 (1H, d, J = 3.4 Hz), 4.15 (1H, t, J = 2.4 Hz), 3.61 (1H, br s), 2.79 (1H, dd, J = 12.7, 3.9 Hz), 2.66 (1H, d, J = 10.7 Hz), 2.46 (2H, dd, J = 14.9, 3.7 Hz), 2.18 (1H, dd, J = 12.2, 2.9 Hz), 2.11-1.13 (23H, m), 0.96 (3H, d, J = 6.3 Hz), 0.85 (3H, d, J = 6.8 Hz), 0.52 (3H, s). Exact Mass = 511.33(C29H44F3NO3)Obs. mass = 512.4(M+H) [Example 110] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C032a, Compound C032b) Compound (2c) [110 mg, 151 mmol] and 3-(trifluoromethyl)piperidin-3-ol hydrochloride (compound 3c13) [125 mg, 0.608 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound C032a [11.0 mg, 0.0221 mmol] and compound C032b [14.4 mg, 0.0289 mmol]. ​ 11H-NMR (in CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.3 Hz), 4.39 (2H, ddd, J = 13.9, 7.1, 4.4 Hz), 3.00 (1H, d, J = 10.7 Hz), 2.88 - 2.77 (2H, m), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.50 - 2.46 (3H, m), 2.31 - 2.25 (2H, m), 2.16 - 2.00 (5H, m), 1.98 - 1.48 (12H, m), 1.39 - 1.21 (3H, m), 1.07 (3H, d, J = 6.3 Hz), 0.62 (3H, s). Exact Mass = 497.31 (for C28H42F3NO3), Obs. mass = 498.40 (M+H) ​ 1 1H-NMR (in CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 7.0 Hz), 4.42 - 4.33 (2H, m), 3.03 (1H, d, J = 11.7 Hz), 2.93 (1H, d, J = 11.7 Hz), 2.86 (1H, dd, J = 12.2, 3.4 Hz), 2.69 - 2.60 (2H, m), 2.50 - 2.25 (6H, m), 2.09 - 2.00 (4H, m), 1.93 - 1.25 (14H, m), 1.06 (3H, d, J = 6.3 Hz), 0.63 (3H, s). Exact Mass = 497.31 (for C28H42F3NO3), Obs. mass = 498.40 (M+H) [Example 111] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-(difluoromethyl)-3-hydroxypiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C034a, Compound C034b) Compound (2a) [100 mg, 0.137 mmol] and 3-(difluoromethyl)piperidin-3-ol hydrochloride [50 mg, 0.267 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound C034a [8.2 mg, 0.017 mmol] and compound C034b [3.7 mg, 0.0077 mmol]. ​ 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.85 (1H, t, J = 55.9 Hz), 5.29 (1H, dd, J = 2.4, 1.0 Hz), 4.35 (1H, t, J = 5.9 Hz), 4.16-4.10 (1H, m), 2.90-2.75 (3H, m), 2.54-2.42 (4H, m), 2.32-2.18 (2H, m), 2.07-1.99 (3H, m), 1.94-1.24 (18H, m), 1.06 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.45 (M+H) ​ 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 10.7 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.84 (1H, t, J = 55.9 Hz), 5.29 (1H, t, J = 1.2 Hz), 4.35 (1H, t, J = 5.9 Hz), 4.16-4.10 (1H, m), 2.88 (1H, dd, J = 12.4, 3.2 Hz), 2.67-2.40 (6H, m), 2.26 (1H, dd, J = 13.4, 7.1 Hz), 2.15 (1H, t, J = 11.2 Hz), 2.09-1.98 (2H, m), 1.91-1.22 (17H, m), 1.04 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.35 (M+H) [Example 112] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-(difluoromethyl)-3-hydroxypiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound C035a, Compound C035b) Compound (2b) [116.1 mg, 0.162 mmol] and 3-(difluoromethyl)piperidin-3-ol hydrochloride [70.0 mg, 0.373 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound C035a [15.5 mg, 0.033 mmol] and compound C035b [15.0 mg, 0.032 mmol]. ​ 1H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2 Hz), 5.89 (1H, d, J = 11.2 Hz), 5.89 (1H, t, J = 56.0 Hz), 4.07-3.96 (2H, m), 2.84 (1H, dd, J = 11.5, 4.1 Hz), 2.67-2.55 (2H, m), 2.49-2.35 (2H, m), 2.29-2.04 (7H, m), 2.01-1.21 (19H, m), 1.02 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 467.32(C27H43F2NO3)Obs. mass = 468.35 (M+H) ​ 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.88 (1H, d, J = 11.2 Hz), 5.85 (1H, t, J = 56.0 Hz), 4.06-3.94 (2H, m), 2.83 (1H, dd, J = 11.5, 3.7 Hz), 2.59 (1H, dd, J = 13.2, 3.4 Hz), 2.46-1.50 (28H, m), 1.37-1.25 (3H, m), 1.02 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 467.32(C27H43F2NO3)Obs. mass = 468.35 (M+H) [Example 113] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-(difluoromethyl)-3-hydroxypiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C036a, Compound C036b) Compound (2c) [100 mg 0.137 mmol] and 3-(difluoromethyl)piperidin-3-ol hydrochloride [49.8 mg 329 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound C036a [17.0 mg, 0.0354 mmol] and compound C036b [14.5 mg, 0.030 mmol]. ​ 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.84 (1H, t, J = 57.0 Hz), 5.06 (2H, d, J = 6.3 Hz), 4.40 (2H, ddd, J = 14.1, 7.1, 4.4 Hz), 2.86 (1H, dd, J = 12.2, 3.4 Hz), 2.80 (2H, d, J = 11.7 Hz), 2.68 (1H, dd, J = 13.4, 4.1 Hz), 2.56 (1H, dd, J = 11.7, 3.2 Hz), 2.51-2.45 (3H, m), 2.33-2.20 (3H, m), 2.10-2.00 (2H, m), 1.94-1.26 (14H, m), 1.07 (3H, d, J = 6.3 Hz), 0.63 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.40 (M+H) ​ 1 H-NMR (CD3OD) δ: 6.28 (1H, d, J = 10.7 Hz), 5.93 (1H, d, J = 10.0 Hz), 5.81 (1H, t, J = 55.0 Hz), 5.06 (2H, d, J = 7.0 Hz), 4.45-4.36 (2H, m), 3.01-1.99 (16H, m), 1.94-1.29 (14H, m), 1.07 (3H, d, J = 6.3 Hz), 0.65 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.40 (M+H) [Example 114] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-hydroxy-3-methylpiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C037a, Compound C037b) Compound (2a) [90 mg, 0.123 mmol] and 3-methylpiperidin-3-ol [42 mg, 0.365 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound C037a [8.1 mg, 0.018 mmol] and compound C037b [10.2 mg, 0.023 mmol]. ​ 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.0 Hz), 6.08 (1H, d, J = 11.0 Hz), 5.28 (1H, s), 4.34 (1H, t, J = 5.9 Hz), 4.12-4.06 (1H, m), 2.87 (1H, dd, J = 12.3, 3.0 Hz), 2.51 (1H, dd, J = 13.3, 3.2 Hz), 2.28-1.21 (24H, m), 1.18 (3H, s), 1.03 (3H, d, J = 6.4 Hz), 0.59 (3H, s). ​ 1H-NMR (DMSO-D6) δ: 6.19 (1H, d, J = 11.4 Hz), 5.98 (1H, d, J = 11.4 Hz), 5.22 (1H, d, J = 1.4 Hz), 4.88 (1H, d, J = 5.0 Hz), 4.75 (1H, d, J = 1.8 Hz), 4.56 (1H, d, J = 3.7 Hz), 4.25-3.95 (3H, m), 2.79 (1H, dd, J = 11.0, 4.0 Hz), 2.36 (1H, d, J = 13.7 Hz), 2.18-1.15 (23H, m), 1.11 (3H, s), 0.96 (3H, d, J = 6.4 Hz), 0.52 (3H, s). [Example 115] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-hydroxy-3-methylpiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound C038) Compound (2b) [50 mg, 0.070 mmol] and (R)-3-methylpiperidin-3-ol hydrochloride [30 mg, 0.198 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C038 [13.9 mg, 0.032 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.88 (1H, d, J = 11.2 Hz), 4.05-3.94 (2H, m), 2.83 (1H, dd, J = 12.2, 3.9 Hz), 2.59 (1H, dd, J = 13.2, 3.4 Hz), 2.42-2.13 (7H, m), 2.07-1.21 (21H, m), 1.18 (3H, s), 1.03 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 431.34(C27H45NO3)Obs. mass = 432.30 (M+H) [Example 116] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-hydroxy-3-methylpiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound C039) Compound (2b) [50 mg, 0.070 mmol] and (S)-3-methylpiperidin-3-ol [30 mg, 0.198 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C039 [10.9 mg, 0.025 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.88 (1H, d, J = 11.2 Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.2, 3.4 Hz), 2.59 (1H, dd, J = 13.2, 3.4 Hz), 2.40 (1H, dd, J = 13.2, 3.4 Hz), 2.31-1.20 (26H, m), 1.18 (3H, s), 1.03 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 431.34(C27H45NO3)Obs. mass = 432.30(M+H) [Example 117] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-hydroxy-3-methylpiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C040) Compound (2c) [50 mg, 0.069 mmol] and (R)-3-methylpiperidin-3-ol [30 mg, 0.198 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C040 [7.3 mg, 0.016 mmol]. 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.90 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.43-4.35 (2H, m), 2.85 (1H, dd, J = 11.7, 3.4 Hz), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.43-2.25 (6H, m), 2.10-1.90 (5H, m), 1.76-1.21 (15H, m), 1.18 (3H, s), 1.03 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.35 (M+H) [Example 118] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-hydroxy-3-methylpiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C041) Compound (2c) [50 mg, 0.069 mmol] and (S)-3-methylpiperidin-3-ol [30 mg, 0.198 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C041 [8.2 mg, 0.018 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.42-4.36 (2H, m), 2.85 (1H, dd, J = 12.2, 3.4 Hz), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.48 (2H, dd, J = 13.4, 3.7 Hz), 2.31-2.25 (4H, m), 2.15-1.88 (6H, m), 1.68-1.21 (14H, m), 1.18 (3H, s), 1.03 (3H, d, J = 6.3 Hz), 0.62 (3H, d, J = 14.6 Hz). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.35 (M+H) [Example 119] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-ethyl-3-hydroxypiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C042a, Compound C042b) Compound (2a) [100 mg, 0.137 mmol] and 3-ethylpiperidin-3-ol [40 mg, 0.310 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound C042a [18.0 mg, 0.041 mmol] and compound C042b [5.7 mg, 0.012 mmol]. ​ 11H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.0 Hz), 6.08 (1H, d, J = 11.0 Hz), 5.28 (1H, s), 4.34 (1H, t, J = 5.9 Hz), 4.14 - 4.10 (1H, m), 2.86 (1H, dd, J = 12.6, 3.0 Hz), 2.51 (2H, dd, J = 13.0, 3.0 Hz), 2.25 (3H, dd, J = 13.3, 6.4 Hz), 2.10 - 1.85 (8H, m), 1.73 - 1.25 (15H, m), 1.03 (3H, d, J = 6.4 Hz), 0.89 (3H, t, J = 7.5 Hz), 0.59 (3H, s). Exact Mass = 457.36(C29H47NO3)Obs. mass = 458.25 (M+H) ​ 1 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.0 Hz), 6.08 (1H, d, J = 11.4 Hz), 5.28 (1H, s), 4.34 (1H, t, J = 5.9 Hz), 4.15 - 4.07 (1H, m), 2.8 (1H, dd, J = 12.3, 4.6 Hz), 2., 2.51 (1H, dd, J = 13.3, 3.2 Hz), 2.42 - 2.20 (5H, m), 2.07 - 1.20 (22H, m), 1.03 (3H, d, J = 6.4 Hz), 0.90 (3H, t, J = 7.5 Hz), 0.59 (3H, s). Exact Mass = 457.36(C29H47NO3)Obs. mass = 458.25 (M+H) [Example 120] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-methoxy-3-methylpiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C043a, Compound C043b) Compound (2a) [100 mg, 0.310 mmol] and 3-methoxy-3-methylpiperidine [40 mg, 0.310 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound C043a [5.2 mg, 0.011 mmol] and compound C043b [18.5 mg, 0.040 mmol]. ​ 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.4 Hz), 6.08 (1H, d, J = 11.0 Hz), 5.28 (1H, s), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.10 (1H, m), 3.22 (3H, s), 2.86 (1H, dd, J = 11.9, 3.7 Hz), 2.51 (1H, dd, J = 13.5, 3.4 Hz), 2.42 (1H, br s), 2.28-2.20 (5H, m), 2.07-1.87 (6H, m), 1.68-1.21 (13H, m), 1.17 (3H, s), 1.02 (3H, d, J = 6.4 Hz), 0.59 (3H, s). Exact Mass = 457.36(C29H47NO3)Obs. mass = 458.25 (M+H) ​ 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.0 Hz), 6.08 (1H, d, J = 11.4 Hz), 5.28 (1H, d, J = 0.9 Hz), 4.34 (1H, t, J = 5.7 Hz), 4.13-4.08 (1H, m), 3.20 (3H, s), 2.86 (1H, dd, J = 12.1, 4.3 Hz), 2.58-2.48 (2H, m), 2.35-2.20 (4H, m), 2.07-1.21 (20H, m), 1.17 (3H, s), 1.03 (3H, d, J = 6.4 Hz), 0.59 (3H, s). Exact Mass = 457.36(C29H47NO3)Obs. mass = 458.25 (M+H) [Example 121] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-ethyl-3-hydroxypiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol compound (C044a, compound C044b) Compound (2b) [100 mg, 0.139 mmol] and 3-ethylpiperidin-3-ol [40 mg, 0.310 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound C044a [15.8 mg, 0.035 mmol] and compound C044b [7.5 mg, 0.017 mmol]. ​ 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.88 (1H, d, J = 11.0 Hz), 4.06-3.95 (2H, m), 2.84 (1H, dd, J = 12.3, 3.2 Hz), 2.59 (1H, dd, J = 13.3, 3.7 Hz), 2.40 (1H, dd, J = 13.5, 3.4 Hz), 2.29-1.20 (27H, m), 1.03 (3H, d, J = 6.4 Hz), 0.89 (3H, t, J = 7.3 Hz), 0.60 (3H, s). Exact Mass = 445.36(C28H47NO3)Obs. mass = 446.30(M+H) ​ 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4 Hz), 5.88 (1H, d, J = 11.0 Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.0, 4.0 Hz), 2.59 (1H, dd, J = 14.0, 4.0 Hz), 2.42-1.21 (33H, m), 1.03 (3H, d, J = 6.4 Hz), 0.90 (3H, t, J = 7.3 Hz), 0.60 (3H, s). Exact Mass = 445.36(C28H47NO3)Obs. mass = 446.30 (M+H) [Example 122] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-methoxy-3-methylpiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound C045a, Compound C045b) Compound (2b) [100 mg, 0.139 mmol] and 3-methoxy-3-methylpiperidine [40 mg, 0.310 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound C045a [6.5 mg, 0.015 mmol] and compound C045b [18.4 mg, 0.041 mmol]. ​ 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4 Hz), 5.88 (1H, d, J = 11.0 Hz), 4.06-3.95 (2H, m), 3.22 (3H, s), 2.83 (1H, dd, J = 12.1, 3.9 Hz), 2.59 (1H, dd, J = 13.3, 3.7 Hz), 2.40 (2H, dd, J = 13.3, 3.7 Hz), 2.26-2.11 (6H, m), 2.07-1.51 (17H, m), 1.37-1.19 (4H, m), 1.17 (3H, s), 1.02 (3H, d, J = 6.4 Hz), 0.59 (3H, s). Exact Mass = 445.36(C28H47NO3)Obs. mass = 446.30 (M+H) ​ 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.88 (1H, d, J = 11.0 Hz), 4.06-3.95 (2H, m), 3.21 (3H, s), 2.83 (1H, dd, J = 11.0, 4.6 Hz), 2.59 (2H, dd, J = 13.7, 3.7 Hz), 2.57-2.52 (2H, br m), 2.40 (1H, dd, J = 13.5, 3.4 Hz), 2.30-1.21 (26H, m), 1.17 (3H, s), 1.04 (3H, d, J = 6.4 Hz), 0.60 (3H, s). Exact Mass = 445.36(C28H47NO3)Obs. mass = 446.30 (M+H) [Example 123] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-ethyl-3-hydroxypiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (C046a, compound C046b) Compound (2c) [100 mg, 0.137 mmol] and 3-ethylpiperidin-3-ol [60 mg, 0.464 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound C046a [16.8 mg, 0.037 mmol] and compound C046b [15.3 mg, 0.033 mmol]. ​ 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.43-4.33 (2H, m), 2.85 (1H, dd, J = 12.2, 3.4 Hz), 2.67 (1H, dd, J = 13.4, 4.1 Hz), 2.57-2.49 (1H, br m), 2.48 (1H, dd, J = 10.0, 5.0 Hz), 2.31-1.88 (11H, m), 1.68-1.25 (16H, m), 1.03 (3H, d, J = 6.3 Hz), 0.89 (3H, t, J = 7.6 Hz), 0.60 (3H, s). Exact Mass = 457.36(C29H47NO3)Obs. mass = 458.35 (M+H) ​ 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.45-4.35 (2H, m), 2.85 (1H, dd, J = 11.0, 3.8 Hz), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.42-2.25 (6H, m), 2.07-1.88 (6H, m), 1.76-1.21 (17H, m), 1.03 (3H, d, J = 6.3 Hz), 0.90 (3H, t, J = 7.6 Hz), 0.60 (3H, s). Exact Mass = 457.36(C29H47NO3)Obs. mass = 458.35 (M+H) [Example 124] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((2S)-1-(3-methoxy-3-methylpiperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C047a, Compound C047b) Compound (2c) [100 mg, 0.137 mmol] and 3-methoxy-3-methylpiperidine [60 mg, 0.464 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound C047a [18.1 mg, 0.040 mmol] and compound C047b [14.9 mg, 0.033 mmol]. ​ 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.90 (1H, d, J = 11.2 Hz), 5.05 (2H, t, J = 3.9 Hz), 4.42-4.36 (2H, m), 3.22 (3H, s), 2.85 (1H, dd, J = 12.0, 3.7 Hz), 2.67 (1H, dd, J = 13.4, 4.1 Hz), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.40-1.85 (12H, m), 1.70-1.20 (15H, m), 1.17 (3H, s), 1.03 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 457.36(C29H47NO3)Obs. mass = 458.35 (M+H) ​ 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.42-4.36 (2H, m), 3.20 (3H, s), 2.85 (1H, dd, J = 12.2, 3.9 Hz), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.56 (1H, s), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.31-1.20 (28H, m), 1.17 (3H, s), 1.04 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 457.36(C29H47NO3)Obs. mass = 458.35 (M+H) [Example 125] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C048) Compound (2a) [90 mg, 0.123 mmol] and (S)-3(difluoromethyl)piperidine hydrochloride (CAS Registry No. 2227197-58-0) [90 mg, 0.524 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C048 [6.0 mg, 0.013 mmol]. 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.77 (1H, td, J = 56.7, 4.7 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.09 (1H, m), 3.05-2.70 (3H, m), 2.51 (1H, dd, J = 13.7, 3.4 Hz), 2.42 (1H, d, J = 9.8 Hz), 2.30-2.15 (3H, m), 2.10-1.96 (4H, m), 1.91-1.21 (18H, m), 1.04 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 463.33(C28H43F2NO2)Obs. mass = 464.50 (M+H) [Example 126] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C049) Compound (2c) [50 mg, 0.069 mmol] and (S)-3(difluoromethyl)piperidine hydrochloride [50 mg, 0.291 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C049 [5.3 mg, 0.011 mmol]. 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (2H, d, J = 11.2 Hz), 5.74 (2H, td, J = 56.5, 5.0 Hz), 5.05 (2H, d, J = 7.3 Hz), 4.45-4.35 (2H, m), 2.92-2.82 (2H, m), 2.69-2.61 (2H, m), 2.48 (1H, dd, J = 12.9, 4.1 Hz), 2.31-1.21 (28H, m), 1.02 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 463.33(C28H43F2NO2)Obs. mass = 464.50 (M+H) [Example 127] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound C050) Compound (2g) [50 mg, 0.067 mmol] and (S)-3(difluoromethyl)piperidine hydrochloride [50 mg, 0.291 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C050 [6.0 mg, 0.013 mmol]. 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.74 (1H, td, J = 56.8, 4.9 Hz), 5.22 (1H, d, J = 2.0 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.2, 4.2 Hz), 2.92-2.80 (2H, m), 2.64-2.57 (2H, m), 2.27 (1H, dd, J = 12.2, 2.9 Hz), 2.21-1.93 (7H, m), 1.81-1.20 (17H, m), 1.03 (3H, d, J = 7.1 Hz), 1.02 (3H, d, J = 6.5 Hz), 0.59 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.50 (M+H) [Example 128] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound C051) Compound (2b) [50 mg, 0.070 mmol] and (R)-3-(2,2-difluoroethyl)piperidine hydrochloride [35 mg, 0.189 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C051 [12.2 mg, 0.026 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 6.10-5.79 (2H, m), 4.06-3.95 (2H, m), 2.90-2.81 (2H, m), 2.70-2.60 (1H,m), 2.59 (1H, dd, J = 13.7, 3.7 Hz), 2.41 (1H, dd, 13.3, 3.2 Hz), 2.27-2.13 (3H, m), 2.07-1.47 (20H, m), 1.37-1.20 (3H, m), 1.02 (3H, d, J = 6.4 Hz), 0.60 (3H, s). Exact Mass = 465.34(C28H45F2NO2)Obs. mass = 466.25(M+H) [Example 129] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C052) Compound (2a) [90 mg, 0.123 mmol] and (S)-3-(1,1-difluoroethyl)piperidine hydrochloride [100 mg, 0.539 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C052 [13.9 mg, 0.029 mmol]. 1H-NMR (CD3OD) δ: 5.85 (1H, d, J = 10.7 Hz), 5.63 (1H, d, J = 11.2 Hz), 4.82 (1H, dd, J = 2.4, 1.5 Hz), 3.88 (1H, t, J = 6.1 Hz), 3.70-3.60 (1H, m), 2.78 (1H, d, J = 8.3 Hz), 2.57 (1H, d, J = 11.7 Hz), 2.41 (1H, dd, J = 12.0, 3.7 Hz), 2.15 (1H, dd, J = 12.7, 2.9 Hz), 2.05 (1H, dd, J = 13.2, 3.4 Hz), 1.94-1.53 ​​(9H, m), 1.46-0.80 (22H, m), 0.60 (3H, d, J = 6.8 Hz), 0.16 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.50(M+H) [Example 130] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C053) Compound (2c) [50 mg, 0.069 mmol] and (S)-3-(1,1-difluoroethyl)piperidine hydrochloride [50 mg, 0.269 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C053 [7.8 mg, 0.016 mmol].

[0175] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.5 Hz), 4.43-4.35 (2H, m), 3.20 (1H, d, J = 10.7 Hz), 2.99-2.93 (1H, m), 2.90-2.81 (1H, m), 2.69-1.94 (12H, m), 1.88-1.49 (13H, m), 1.40-1.20 (4H, m), 1.06 (3H, d, J = 6.8 Hz), 0.63 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.50 (M+H) [Example 131] Synthesis of (1R,2S,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methyl-4-methylenecyclohexane-1,3-diol (Compound C054) Compound (2g) [50 mg, 0.067 mmol] and (S)-3-(1,1-difluoroethyl)piperidine hydrochloride [50 mg, 0.269 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C054 [8.0 mg, 0.016 mmol]. 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.22 (1H, d, J = 2.0 Hz), 4.22 (1H, d, J = 3.4 Hz), 3.72 (1H, td, J = 8.1, 4.2 Hz), 3.13 (1H, d, J = 9.3 Hz), 2.87 (2H, d, J = 12.2 Hz), 2.59 (1H, dd, J = 13.7, 3.9 Hz), 2.43 (1H, d, J = 12.2 Hz), 2.31-1.98 (9H, m), 1.89-1.17 (27H, m), 1.04 (3H, d, J = 6.3 Hz), 1.04 (3H, d, J = 6.8 Hz), 0.60 (3H, s). Exact Mass = 491.36(C30H47F2NO2)Obs. mass = 492.55 (M+H) [Example 132] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-(1,1-difluoroethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C055) Compound (2c) [95.0 mg, 0.130 mmol] and 4-(1,1-difluoroethyl)piperidine hydrochloride [75.0 mg, 0.404 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C055 [25.0 mg, 0.0523 mmol].

[0176] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.43-4.35 (2H, m), 3.15 (1H, d, J = 11.7 Hz), 2.98-2.83 (2H, m), 2.67 (1H, dd, J = 13.4, 4.1 Hz), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.39-1.92 (9H, m), 1.86-1.23 (19H, m), 1.04 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass =478.45 (M+H) [Example 133] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-(2,2-difluoroethyl)piperidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound C059) Compound (2c) [95.0 mg, 0.130 mmol] and 4-(2,2-difluoroethyl)piperidine hydrochloride [75.0 mg, 0.404 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound C059 [32.1 mg, 0.0672 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.99 (2H, tt, J = 57.0, 5.0 Hz), 5.92 (2H, d, J = 11.0 Hz), 5.05 (2H, d, J = 8.0 Hz), 4.43-4.35 (2H, m), 3.43 (1H, d, J = 12.7 Hz), 2.87-2.57 (6H, m), 2.48 (1H, dd, J = 13.4, 4.1 Hz), 2.32-2.25 (2H, m), 2.09-1.96 (5H, m), 1.90-1.28 (16H, m), 1.10 (3H, d, J = 6.3 Hz), 0.64 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass =478.45 (M+H) [Example 134] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-morpholinopropan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D001)

[0177] [ka]

[0178] ​ Compound 6c [437.6 mg, 0.991 mmol] and morpholine [0.26 mL, 3.0 mmol] were used as starting materials and reacted in the same manner as in Step 1 of Example 92 to obtain 4-((2S)-2-((1R,3aS,7aR,E)-4-(bromomethylene)-7a-methyloctahydro-1H-inden-1-yl)propyl)morpholine (Compound 3d01) [317.6 mg, 0.891 mmol]. ​ Compound 3d01 [38 mg, 0.107 mmol] obtained in step 1, compound 7a [53.2 mg, 0.144 mmol], and tetrakis(triphenylphosphine)palladium(0) [15.0 mg, 0.013 mmol] were treated in the same manner as in steps 2 and 3 of Example 92 to obtain compound D001 [7.7 mg, 0.019 mmol]. 1 H-NMR (CD3OD) δ: 6.31 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.89 (1H, s), 4.34 (1H, t, J = 5.9 Hz), 4.14-4.08 (1H, m), 3.76-3.66 (5H, m), 2.86 (1H, dd, J = 12.0, 3.7 Hz), 2.72-2.64 (3H, m), 2.53-2.40 (5H, m), 2.27-2.16 (3H, m), 2.11-1.98 (3H, m), 1.93-1.84 (4H, m), 1.79-1.25 (12H, m), 1.08-1.06 (1H, m), 1.05 (3H, d, J = 6.0 Hz), 0.60 (3H, s). Exact Mass = 415.31(C26H41NO3)Obs. mass = 416.40(M+H) [Example 135] Synthesis of (1R,2S,3S,Z)-2-methyl-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-morpholinopropan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D002) Compound 3d01 [38 mg, 0.107 mmol] obtained in Step 1 of Example 134, compound 7b [55.7 mg, 0.146 mmol], and tetrakis(triphenylphosphine)palladium(0) [15.0 mg, 0.013 mmol] were treated in the same manner as in Steps 2 and 3 of Example 92 to obtain compound D002 [2.6 mg, 0.006 mmol]. 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.22 (1H, d, J = 2.4 Hz), 4.89 (1H, s), 4.22 (1H, d, J = 3.4 Hz), 3.75-3.61 (6H, m), 2.87 (1H, d, J = 12.7 Hz), 2.59 (1H, dd, J = 13.7, 4.4 Hz), 2.54-2.46 (2H, m), 2.25 (3H, dd, J = 12.2, 2.9 Hz), 2.17 (1H, dd, J = 13.4, 8.1 Hz), 2.06-1.21 (14H, m), 1.03 (3H, d, J = 6.6 Hz), 1.03 (3H, d, J = 7.0 Hz), 0.59 (3H, d, J = 7.3 Hz). Exact Mass = 429.32(C27H43NO3)Obs. mass = 430.40(M+H) [Example 136] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-morpholinopropan-2-yl)-octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D004) Compound (2b) [50 mg, 0.07 mmol] and morpholine [0.05 mL] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound D004 [9.2 mg, 0.023 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.88 (1H, d, J = 11.2 Hz), 4.12-3.95 (2H, m), 3.72-3.61 (4H, m), 2.83 (1H, dd, J = 13.4, 3.7 Hz), 2.59 (1H, dd, J = 13.4, 3.7 Hz), 2.53-2.49 (2H, m), 2.40 (1H, dd, J = 13.7, 3.4 Hz), 2.28-2.13 (5H, m), 2.06-1.21 (17H, m), 1.03 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 403.31(C25H41NO3)Obs. mass = 404.30 (M+H) [Example 137] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-2-(difluoromethyl)morpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D005)

[0179] [ka]

[0180] ​ A solution of dimethyl sulfoxide (1 mL, 14 mmol) in dichloromethane (4 mL) was added to a solution of oxalyl chloride (0.6 mL, 7 mmol) in dichloromethane (9 mL) while cooling to -78 °C, and the mixture was stirred at the same temperature for 10 minutes. To this mixture was added a solution of t-butyl-(S)-2-(hydroxymethyl)morpholine-4-carboxylate (Compound 3d03) (1.0 g, 4.6 mmol) in dichloromethane (10 mL). The mixture was stirred at -78 °C for 45 minutes. Triethylamine (3.3 mL, 23 mmol) was added and the mixture was stirred at the same temperature for an additional 30 minutes. The reaction mixture was warmed to 0 °C and stirred at the same temperature for 30 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain t-butyl-(S)-2-formylmorpholine-4-carboxylate (compound 3d04) [0.72 g, 3.3 mmol] (yield = 73%). ​ A dichloromethane solution (20 mL) of t-butyl-(S)-2-formylmorpholine-4-carboxylate (compound 3d04) (0.72 g, 3.3 mmol) was cooled to 0 °C, and diethylaminosulfur trifluoromethane (DAST) (1 mL, 7.57 mmol) was added and stirred overnight. The reaction mixture was cooled to 0 °C, quenched with water, and extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give t-butyl-(S)-2-(difluoromethyl)morpholine-4-carboxylate (compound 3d05) (0.58 g, 2.4 mmol). (Yield = 53%) ​ t-Butyl-(S)-2-(difluoromethyl)morpholine-4-carboxylate (compound 3d05) [0.58 g, 2.4 mmol] was added to a 4 M solution of hydrogen chloride in dioxane [10 mL, 40 mmol] and stirred overnight. The reaction mixture was concentrated under reduced pressure and dried to give (S)-2-(difluoromethyl)morpholine hydrochloride (compound 3d06) [382.5 mg, 2.20 mmol] (yield=90%). 1 H-NMR (DMSO-D6) δ: 9.79 (2H, s), 6.13 (1H, td, J = 54.0, 3.3 Hz), 4.18-4.09 (1H, m), 4.03 (1H, dd, J = 12.7, 3.9 Hz), 3.85 (1H, td, J = 12.4, 2.4 Hz), 3.27 (1H, d, J = 12.2 Hz), 3.20 (1H, d, J = 13.2 Hz), 2.99 (1H, td, J = 12.4, 4.0 Hz), 2.92 (1H, t, J = 12.0 Hz). ​ Compound (2a) [90 mg, 0.123 mmol] and compound (3d06) [65 mg, 0.374 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound D005 [6.0 mg, 0.013 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.77 (1H, td, J = 55.4, 4.2 Hz), 5.28 (1H, dd, J = 2.2, 1.2 Hz), 4.89 (1H, d, J = 1.5 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.14-4.09 (1H, m), 3.86 (1H, d, J = 10.7 Hz), 3.70-3.61 (2H, m), 2.89-2.80 (2H, m), 2.57-2.49 (2H, m), 2.31-2.23 (3H, m), 2.07-1.21 (18H, m), 1.04 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 465.31(C27H41F2NO3)Obs. mass = 466.40 (M+H) [Example 138] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-2-(difluoromethyl)morpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D006)

[0181] [ka]

[0182] ​ t-Butyl-(R)-2-(hydroxymethyl)morpholine-4-carboxylate (Compound 3d07) [1.00 g, 3.3 mmol] was used as the starting material and treated in a manner similar to Step 1 of Example 137 to afford t-butyl-(R)-2-formylmorpholine-4-carboxylate (Compound 3d08) [0.70 g, 3.3 mmol] (yield = 71%). ​ t-Butyl-(R)-2-formylmorpholine-4-carboxylate (Compound 3d08) [0.70 g, 3.3 mmol] was used as the starting material and treated in a manner similar to Step 2 of Example 137 to afford t-butyl-(R)-2-(difluoromethyl)morpholine-4-carboxylate (Compound 3d09) [0.55 g, 2.3 mmol] (yield = 50%). ​ t-Butyl-(R)-2-(difluoromethyl)morpholine-4-carboxylate (compound 3d09) [0.55 g, 2.3 mmol] was used as the starting material and treated in the same manner as in Step 3 of Example 137 to obtain (R)-2-(difluoromethyl)morpholine hydrochloride (compound 3d10) [384.8 mg, 2.22 mmol]. (Yield=96%) 1 H-NMR (DMSO-D6) δ: 9.62 (2H, s), 6.13 (1H, td, J = 54.0, 3.3 Hz), 4.11 (1H, tdd, J = 14.8, 7.6, 3.8 Hz), 4.03 (1H, dd, J = 12.7, 3.9 Hz), 3.83 (1H, td, J = 12.4, 2.4 Hz), 3.28 (1H, d, J = 12.2 Hz), 3.20 (1H, dd, J = 12.0, 2.4 Hz), 3.00 (1H, td, J = 12.0, 3.9 Hz), 2.93 (1H, t, J = 12.0 Hz). ​ Compound (2a) [90 mg, 0.123 mmol] and compound (3d10) [65 mg, 0.374 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound D006 [7.6 mg, 0.016 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 10.7 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.76 (1H, td, J = 55.4, 4.2 Hz), 5.28 (1H, t, J = 1.2 Hz), 4.34 (1H, t, J = 6.1 Hz), 4.15-4.09 (1H, m), 3.88 (1H, dt, J = 11.4, 2.6 Hz), 3.78-3.69 (1H, m), 3.61 (1H, td, J = 11.2, 2.4 Hz), 2.87 (1H, dd, J = 12.2, 3.4 Hz), 2.71 (2H, dd, J = 28.8, 11.2 Hz), 2.51 (1H, dd, J = 13.7, 3.4 Hz), 2.31 (1H, dd, J = 12.2, 2.9 Hz), 2.25 (1H, dd, J = 13.7, 6.8 Hz), 2.16 (1H, t, J = 10.7 Hz), 2.07-1.99 (4H, m), 1.96-1.26 (14H, m), 1.04 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 465.31(C27H41F2NO3)Obs. mass = 466.40 (M+H) [Example 139] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-2-(difluoromethyl)morpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D007) Compound (2c) [90 mg, 0.123 mmol] and compound (3d06) [65 mg, 0.374 mmol] described in Example 137 were used as starting materials, and the reaction was carried out in the same manner as in Example 1 to obtain compound D007 [17.0 mg, 0.037 mmol]. 1H-NMR (DMSO-D6) δ: 6.14 (2H, d, J = 11.2 Hz), 6.02 (2H, td, J = 55.0, 4.0 Hz), 5.82 (1H, d, J = 11.2 Hz), 4.93-4.75 (2H, m), 4.91 (2H, d, J = 6.0 Hz), 4.24 (2H, td, J = 4.0, 16.0 Hz), 3.83 (1H, d, J = 10.7 Hz), 3.67-3.47 (2H, m), 2.78 (2H, d, J = 10.7 Hz), 2.55-2.50 (2H, m), 2.34 (1H, dd, J = 12.9, 3.7 Hz), 2.22-1.18 (21H, m), 0.98 (3H, d, J = 6.3 Hz), 0.54 (3H, s). Exact Mass = 465.31(C27H41F2NO3)Obs. mass = 466.35 (M+H) [Example 140] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-2-(difluoromethyl)morpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D008) Compound (2c) [90 mg, 0.123 mmol] and compound (3d10) [65 mg, 0.374 mmol] described in Example 138 were used as starting materials, and the reaction was carried out in the same manner as in Example 1 to obtain compound D008 [17.3 mg, 0.037 mmol]. 1H-NMR (DMSO-D6) δ: 6.14 (2H, d, J = 11.2 Hz), 6.01 (2H, td, J = 55.0, 4.0 Hz), 5.82 (1H, d, J = 11.2 Hz), 4.91 (2H, d, J = 10.0 Hz), 4.89-4.80 (1H, m), 4.28-4.21 (2H, m), 3.84 (1H, d, J = 11.2 Hz), 3.74-3.65 (1H, m), 3.58-3.45 (2H, m), 2.79-2.74 (1H, m), 2.69 (1H, d, J = 11.7 Hz), 2.62 (1H, d, J = 11.2 Hz), 2.53 (1H, d, J = 6.0 Hz), 2.34 (1H, dd, J = 13.2, 3.4 Hz), 2.23-1.77 (9H, m), 1.65-1.18 (10H, m), 0.98 (3H, d, J = 6.3 Hz), 0.53 (3H, s). Exact Mass = 465.31(C27H41F2NO3)Obs. mass = 466.40(M+H) [Example 141] Synthesis of (1R,2S,3S,Z)-2-methyl-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((2S)-1-(2-(trifluoromethyl)morpholino)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D009a, Compound D009b)

[0183] [ka]

[0184] ​ A DMF suspension of compound 6c [203 mg, 0.46 mmol], 2-(trifluoromethyl)morpholine (compound 3d11) [153 mg, 0.986 mmol], and potassium carbonate [227 mg, 1.64 mmol] was stirred at 60 °C overnight. The reaction mixture was quenched with saturated brine and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was partially purified by silica gel column chromatography to give compound 3d12 [92.3 mg, 0.218 mmol] as a diastereomeric mixture. ​ To a solution of compound 3d12 (92.3 mg, 0.218 mmol) obtained in step 1 and compound 7b (90 mg, 0.235 mmol) in toluene (1 mL) / triethylamine (1 mL), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.021 mmol) was added and the mixture was heated and stirred at 100 °C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partially purified by preparative thin-layer chromatography to give compound D009-LP (56.3 mg), which exhibited low polarity on TLC, and compound D009-MP (42.0 mg), which exhibited high polarity on TLC. D009-LP:Exact Mass = 725.48(C40H70F3NO3Si2)Obs. mass = 726.60 (M+H) D009-MP:Exact Mass = 725.48(C40H70F3NO3Si2)Obs. mass = 726.60 (M+H) ​ To a THF solution (1 mL) of compound D009-LP (56.3 mg) obtained in Step 2, TBAF (1 M in THF, 1 mL) was added and stirred at 50°C overnight. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to give compound D009a (16.7 mg, 0.0336 mmol). 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2 Hz), 6.09 (1H, d, J = 11.2 Hz), 5.22 (1H, d, J = 2.0 Hz), 4.89 (1H, d, J = 2.0 Hz), 4.22 (1H, d, J = 3.4 Hz), 4.05-3.96 (1H, m), 3.92 (1H, dd, J = 11.0, 3.0 Hz), 3.72 (1H, td, J = 8.1, 4.4 Hz), 3.63 (1H, td, J = 11.3, 2.3 Hz), 2.87 (1H, dd, J = 11.0, 4.4 Hz), 2.77 (2H, d, J = 11.7 Hz), 2.59 (1H, dd, J = 13.4, 4.1 Hz), 2.32 (1H, dd, J = 12.2, 2.9 Hz), 2.23-2.14 (2H, m), 2.06-1.18 (18H, m), 1.03 (6H, d, J = 7.3 Hz), 0.58 (3H, s). Exact Mass = 497.31(C28H42F3NO3)Obs. mass = 498.40 (M+H) ​ D009-MP [42.0 mg] obtained in Step 2 was used as a starting material and treated in the same manner as in Step 3a to give compound D009b [9.1 mg, 0.018 mmol]. 1H-NMR (DMSO-D6) δ: 6.19 (1H, d, J = 10.7 Hz), 5.99 (1H, d, J = 11.2 Hz), 5.17 (1H, d, J = 2.4 Hz), 4.77 (1H, d, J = 2.4 Hz), 4.75 (1H, d, J = 4.4 Hz), 4.57 (1H, d, J = 4.4 Hz), 4.15 (1H, t, J = 3.7 Hz), 4.10-4.00 (1H, m), 3.89 (1H, d, J = 10.2 Hz), 3.66-3.55 (2H, m), 2.88 (1H, d, J = 10.2 Hz), 2.79 (1H, d, J = 9.3 Hz), 2.56 (2H, d, J = 11.7 Hz), 2.25-1.16 (22H, m), 0.97 (3H, d, J = 5.9 Hz), 0.85 (3H, d, J = 6.8 Hz), 0.53 (3H, s). Exact Mass = 497.31(C28H42F3NO3)Obs. mass = 498.40 (M+H) [Example 142] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((S)-2-methylmorpholino)propan-2-yl)-octahydro-4H-inden-4-ylidene)ethylidene)-2-methylene-cyclohexane-1,3-diol (Compound D010) Compound (2c) [50 mg, 0.069 mmol] and (S)-2-methylmorpholine hydrochloride [30 mg, 0.297 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D010) [11.6 mg, 0.027 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.43-4.35 (2H, m), 3.79 (1H, dd, J = 11.5, 1.7 Hz), 3.68-3.57 (2H, m), 2.85 (1H, dd, J = 12.0, 3.7 Hz), 2.75 (1H, d, J = 11.7 Hz), 2.69-2.61 (2H, m), 2.48 (1H, dd, J = 13.4, 4.1 Hz), 2.31-2.22 (3H, m), 2.07-1.82 (6H, m), 1.70-1.49 (6H, m), 1.38-1.25 (3H, m), 1.10 (3H, d, J = 6.3 Hz), 1.03 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 429.32(C27H43NO3)Obs. mass = 430.35 (M+H) [Example 143] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D011) Compound (2c) [50 mg, 0.069 mmol] and 4-oxa-7-azaspiro[2,5]octane hydrochloride [35 mg, 0.234 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D011) [11.3 mg, 0.0256 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7 Hz), 5.92 (1H, d, J = 10.7 Hz), 5.06 (2H, d, J = 7.3 Hz), 4.43-4.37 (2H, m), 3.80-3.68 (2H, m), 2.86 (1H, dd, J = 12.2, 3.9 Hz), 2.68 (1H, dd, J = 13.7, 4.4 Hz), 2.57-2.25 (8H, m), 2.08-1.90 (4H, m), 1.71-1.50 (6H, m), 1.40-1.26 (3H, m), 1.04 (3H, d, J = 6.3 Hz), 0.71 (2H, s), 0.61 (3H, s), 0.59-0.48 (2H, m). Exact Mass = 441.32(C28H43NO3)Obs. mass = 442.35 (M+H) [Example 144] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(6-oxa-9-azaspiro[4.5]decan-9-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D012) Compound (2c) [50 mg, 0.069 mmol] and 6-oxa-9-azaspiro[4,5]decane hydrochloride [35 mg, 0.248 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D012) [9.9 mg, 21 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 7.3 Hz), 4.45-4.33 (2H, m), 3.72-3.60 (2H, m), 2.85 (1H, dd, J = 12.7, 3.4 Hz), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.39-2.19 (6H, m), 2.16-1.88 (5H, m), 1.84-1.25 (18H, m), 1.04 (3H, d, J = 6.8 Hz), 0.60 (3H, s). Exact Mass = 469.36(C30H47NO3)Obs. mass = 470.35 (M+H) [Example 145] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((2S,6R)-2,6-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D013) Compound (2c) [50 mg, 0.069 mmol] and (2S,6R)-2,6-dimethylmorpholine [35 mg, 0.304 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D013) [17.6 mg, 0.040 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, t, J = 3.9 Hz), 4.42-4.36 (2H, m), 3.73-3.59 (2H, m), 2.85 (1H, dd, J = 12.0, 3.7 Hz), 2.79 (1H, d, J = 11.2 Hz), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.62 (1H, d, J = 11.2 Hz), 2.48 (1H, dd, J = 13.7, 3.9 Hz), 2.27 (2H, td, J = 12.7, 6.0 Hz), 2.22 (1H, dd, J = 12.0, 3.2 Hz), 2.16-1.89 (4H, m), 1.79 (1H, dd, J = 25.9, 15.6 Hz), 1.70-1.21 (12H, m), 1.12 (3H, d, J = 5.0 Hz), 1.10 (3H, d, J = 5.0 Hz), 1.03 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.30 (M+H) [Example 146] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(2,2-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D014) Compound (2c) [50 mg, 0.069 mmol] and 2,2-dimethylmorpholine [35 mg, 0.304 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D014) [10.8 mg, 0.024 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 7.3 Hz), 4.43-4.35 (2H, m), 3.75-3.64 (2H, m), 2.85 (1H, dd, J = 11.0, 3.9 Hz), 2.67 (1H, dd, J = 13.4, 4.1 Hz), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.40-1.88 (13H, m), 1.68-1.21 (18H, m), 1.04 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.30 (M+H) [Example 147] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((S)-3-methylmorpholino)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D015) Compound (2c) [50 mg, 0.069 mmol] and (S)-3-methylmorpholine hydrochloride [30 mg, 0.218 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D015) [2.0 mg, 0.0047 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 10.7 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.45-4.35 (2H, m), 3.75 (1H, dt, J = 11.4, 3.3 Hz), 3.60 (2H, ddd, J = 24.4, 11.2, 2.4 Hz), 3.21 (1H, dd, J = 11.0, 9.5 Hz), 2.84 (2H, td, J = 11.3, 3.3 Hz), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.37 (1H, t, J = 11.5 Hz), 2.31-2.25 (3H, m), 2.08-2.02 (5H, m), 1.96 (1H, dd, J = 11.5, 8.1 Hz), 1.68-1.52 (6H, m), 1.32 (4H, dt, J = 32.9, 10.5 Hz), 1.02 (3H, d, J = 6.3 Hz), 0.93 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 429.32(C27H43NO3)Obs. mass = 430.25 (M+H) [Example 148] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((2R,5S)-2,5-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D016) Compound (2c) [50 mg, 0.069 mmol] and (2R,5S)-2,5-dimethylmorpholine [30 mg, 0.260 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D016) [5.0 mg, 0.011 mmol]. Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.30 (M+H) [Example 149] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((2R,5R)-2,5-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D017) Compound (2c) [50 mg, 0.069 mmol] and (2R,5R)-2,5-dimethylmorpholine [30 mg, 0.260 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D017) [8.2 mg, 0.018 mmol]. Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.30 (M+H) [Example 150] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-((R)-2-methylmorpholino)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D018) Compound (2c) [50 mg, 0.069 mmol] and (R)-2-methylmorpholine hydrochloride [40 mg, 0.291 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D018) [5.3 mg, 0.012 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.4 Hz), 5.91 (1H, d, J = 11.0 Hz), 5.05 (2H, d, J = 7.3 Hz), 4.42-4.36 (2H, m), 3.80-3.73 (1H, m), 3.67 (1H, td, J = 11.3, 2.4 Hz), 3.62-3.53 (1H, m), 2.85 (1H, dd, J = 12.1, 3.9 Hz), 2.80 (1H, d, J = 11.0 Hz), 2.67 (1H, dd, J = 13.3, 4.1 Hz), 2.56 (1H, dd, J = 11.9, 1.8 Hz), 2.48 (1H, dd, J = 13.3, 4.1 Hz), 2.31-2.22 (3H, m), 2.17 (1H, td, J = 11.5, 3.5 Hz), 2.07-1.89 (4H, m), 1.70-1.50 (7H, m), 1.38-1.21 (3H, m), 1.11 (3H, d, J = 5.9 Hz), 1.03 (3H, d, J = 6.4 Hz), 0.61 (3H, s). Exact Mass = 429.32(C27H43NO3)Obs. mass = 430.40 (M+H) [Example 151] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D019) Compound (2b) [50 mg, 0.070 mmol] and 4-oxa-7azaspiro-[2,5]octane hydrochloride [35 mg, 0.234 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D019) [11.2 mg, 0.0261 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.88 (1H, d, J = 11.2 Hz), 4.06-3.95 (2H, m), 3.79-3.67 (2H, m), 2.83 (1H, dd, J = 11.0, 3.9 Hz), 2.62-2.50 (2H, m), 2.44-2.13 (8H, m), 2.07-1.48 (14H, m), 1.38-1.20 (4H, m), 1.03 (3H, d, J = 6.3 Hz), 0.70 (2H, s), 0.59 (3H, s), 0.57-0.49 (2H, m). Exact Mass = 429.32(C27H43NO3)Obs. mass = 430.30 (M+H) [Example 152] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((2R,5S)-2,5-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D020) Compound (2b) [50 mg, 0.070 mmol] and (2R,5S)-2,5-dimethylmorpholine [30 mg, 0.260 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D020) [4.3 mg, 0.010 mmol]. Exact Mass = 431.34(C27H45NO3)Obs. mass = 432.25 (M+H) [Example 153] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((2R,5R)-2,5-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D021) Compound (2b) [50 mg, 0.070 mmol] and (2R,5R)-2,5-dimethylmorpholine [30 mg, 0.260 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (D021) [5.4 mg, 0.013 mmol]. Exact Mass = 431.34(C27H45NO3)Obs. mass = 432.30 (M+H) [Example 154] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-(4-(methylsulfonyl)piperazin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound E001) In Step 1 of Example 92, 1-methylsulfonylpiperazine was used instead of the starting material triethyl-[[4-(trifluoromethyl)-4-piperidyl]oxy]silane, and the reaction was carried out in the same manner as in Example 92 to obtain compound (E001) [14.3 mg, 0.029 mmol]. 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 10.7 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, t, J = 1.2 Hz), 4.34 (1H, t, J = 6.1 Hz), 4.15-4.05 (1H, m), 3.25-3.15 (5H, m), 2.89-2.80 (4H, m), 2.66-2.03 (11H, m), 1.94-1.22 (13H, m), 1.04 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 492.30(C27H44N2O4S)Obs. mass = 493.40 (M+H) [Example 155] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((S)-1-(4-(methylsulfonyl)piperazin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound E003) Compound (2c) [50 mg, 0.069 mmol] and 1-(methylsulfonyl)piperazine [40 mg, 0.254 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (E003) [9.4 mg, 0.019 mmol]. 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.0 Hz), 5.91 (1H, d, J = 11.0 Hz), 5.05 (2H, d, J = 7.3 Hz), 4.42-4.35 (2H, m), 3.26-3.13 (4H, m), 2.88-2.80 (1H, m), 2.82 (3H, s), 2.70-2.58 (3H, m), 2.48 (1H, dd, J = 13.3, 4.1 Hz), 2.40-2.25 (5H, m), 2.09-2.00 (3H, m), 1.98-1.90 (1H, m), 1.75-1.52 (6H, m), 1.39-1.28 (3H, m), 1.04 (3H, d, J = 6.4 Hz), 0.61 (3H, s). Exact Mass = 492.30(C27H44N2O4S)Obs. mass = 493.25 (M+H) [Example 156] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((2S)-1-(3-(trifluoromethyl)piperazin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compounds E005a and E005b) Compound (2a) [100 mg, 0.137 mmol] and 2-(trifluoromethyl)piperazine [50 mg, 0.324 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound (E005a) [11.3 mg, 0.0234 mmol] and compound (E005b) [9.7 mg, 0.020 mmol]. ​ 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.09 (1H, m), 3.43-3.37 (1H, m), 3.00-2.95 (1H, m), 2.90-2.76 (4H, m), 2.51 (1H, dd, J = 13.4, 3.2 Hz), 2.34-1.99 (7H, m), 1.94-1.21 (15H, m), 1.02 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 482.31(C27H41F3N2O2)Obs. mass = 483.4 (M+H) ​ 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.09 (1H, m), 3.35-3.30 (1H, m), 2.95 (2H, d, J = 11.2 Hz), 2.85 (2H, td, J = 11.7, 2.9 Hz), 2.63 (1H, d, J = 11.7 Hz), 2.51 (1H, dd, J = 13.7, 3.4 Hz), 2.33-1.97 (7H, m), 1.94-1.21 (15H, m), 1.02 (3H, d, J = 6.8 Hz), 0.60 (3H, s). Exact Mass = 482.31(C27H41F3N2O2)Obs. mass = 483.3 (M+H) [Example 157] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((2S)-1-(3-(trifluoromethyl)piperazin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compounds E006a and E006b) Compound (2b) [100 mg, 0.139 mmol] and 2-(trifluoromethyl)piperazine [70 mg, 0.454 mmol] were used as starting materials and reacted in the same manner as in Example 108 to obtain compound (E006a) [7.0 mg, 0.015 mmol] and compound (E006b) [7.0 mg, 0.015 mmol]. ​ 11H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4 Hz), 5.89 (1H, d, J = 11.0 Hz), 4.06 - 3.93 (2H, m), 3.41 - 3.37 (1H, m), 2.97 (1H, d, J = 12.3 Hz), 2.86 - 2.74 (4H, m), 2.59 (1H, dd, J = 13.5, 3.4 Hz), 2.40 (1H, dd, J = 13.3, 3.7 Hz), 2.31 (1H, dd, J = 11.9, 3.2 Hz), 2.23 - 1.48 (17H, m), 1.38 - 1.21 (4H, m), 1.02 (3H, d, J = 6.4 Hz), 0.60 (3H, s). Exact Mass = 470.31(C26H41F3N2O2)Obs. mass = 471.25 (M+H) ​ 1 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4 Hz), 5.89 (1H, d, J = 11.0 Hz), 4.06 - 3.93 (2H, m), 3.36 - 3.30 (1H, m), 2.95 (2H, d, J = 11.9 Hz), 2.85 (2H, td, J = 11.5, 2.9 Hz), 2.65 - 2.54 (2H, m), 2.40 (1H, dd, J = 13.3, 3.7 Hz), 2.31 (1H, dd, J = 12.1, 3.0 Hz), 2.23 - 1.49 (16H, m), 1.38 - 1.21 (4H, m), 1.03 (3H, d, J = 6.4 Hz), 0.60 (3H, s). Exact Mass = 470.31(C26H41F3N2O2)Obs. mass = 471.25 (M+H) [Example 158] Synthesis of (1R,2S,3S,Z)-2-methyl-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((2S)-1-(3-(trifluoromethyl)piperazin-1-yl)propan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (compounds E007a and E007b) Compound (6c) [264.5 mg, 0.599 mmol] and 2-(trifluoromethyl)piperazine [220.7 mg, 1.43 mmol] were used as starting materials and reacted in the same manner as in Example 109 to obtain compound (E007a) [20.9 mg, 0.042 mmol] and compound (E007b) [27.4 mg, 0.055 mmol]. ​ 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.0 Hz), 6.09 (1H, d, J = 11.0 Hz), 5.22 (1H, d, J = 2.0 Hz), 4.88 (1H, brs), 4.22 (1H, d, J = 3.4 Hz), 3.75-3.68 (1H, m), 3.47-3.30 (2H, m), 2.99-2.75 (6H, m), 2.59 (1H, dd, J = 13.7, 3.9 Hz), 2.33 (1H, dd, J = 12.0, 3.2 Hz), 2.19-2.01 (6H, m), 1.93-1.42 (12H, m), 1.38-1.21 (4H, m), 1.04 (3H, d, J = 6.3 Hz), 1.02 (3H, d, J = 6.4 Hz), 0.58 (3H, s). ​ 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.0 Hz), 6.09 (1H, d, J = 11.0 Hz), 5.22 (1H, d, J = 2.0 Hz), 4.89 (1H, brs), 4.22 (1H, d, J = 3.4 Hz), 3.75-3.69 (1H, m), 3.38-3.30 (1H, m), 2.98-2.80 (4H, m), 2.63-2.57 (2H, m), 2.30 (1H, dd, J = 12.2, 3.4 Hz), 2.17 (2H, dd, J = 11.2, 2.9 Hz), 2.06-1.97 (4H, m), 1.91-1.20 (13H, m), 1.04 (3H, d, J = 6.3 Hz), 1.02 (3H, d, J = 6.3 Hz), 0.59 (3H, s). [Example 159] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-(ethylsulfonyl)piperazin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound E009) Compound (2a) [100 mg, 0.137 mmol] and 4-(ethylsulfonyl)piperazine [55 mg, 0.309 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (E009) [20.6 mg, 0.041 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, dd, J = 2.4, 1.0 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.09 (1H, m), 3.28-3.23 (3H, m), 3.02 (2H, q, J = 7.3 Hz), 2.87 (1H, dd, J = 12.0, 3.7 Hz), 2.65-2.55 (2H, m), 2.51 (1H, dd, J = 13.4, 3.2 Hz), 2.39-2.30 (3H, m), 2.25 (1H, dd, J = 13.4, 6.6 Hz), 2.10-1.99 (3H, m), 1.94-1.21 (17H, m), 1.03 (3H, d, J = 6.3 Hz), 0.59 (3H, s). [Reference example 13] Synthesis of (3R)-3-((1R,3aS,7aR,E)-4-((Z)-2-((3S,5R)-3,5-bis((t-butyldimethylsilyl)oxy)-2-methylenecyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)butyl 4-methylbenzenesulfonate (Compound 16a)

[0185] [ka]

[0186] ​ To a pyridine solution (12 mL) of (3R)-3-((1R,4S,7aR)-7a-methyl-4-((triethylsilyl)oxy)octahydro-1H-inden-1-yl)butan-1-ol (Compound 10, CAS Registry No. 300344-39-2) (2.37 g, 6.68 mmol), p-toluenesulfonyl chloride (1.6 g, 8.4 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was transferred to saturated brine and extracted with ethyl acetate. The organic phase was washed with 1 M hydrochloric acid, saturated sodium bicarbonate, and saturated brine, successively. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude Compound 17. ​ The crude compound 17 was dissolved in acetone [30 mL], and 2M hydrochloric acid [10 mL, 20 mmol] was added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (3R)-3-((1R,4S,7aR)-4-hydroxy-7a-methyloctahydro-1H-inden-1-yl)butyl 4-methylbenzenesulfonate (compound 18) [1.37 g, 3.47 mmol]. (Yield for two steps = 52%) ​ A dichloromethane solution (30 mL) of compound 18 (1.37 g, 3.47 mmol) obtained in Step 2, 4-methylmorpholine N-oxide (NMO) (0.67 g, 5.0 mmol), and molecular sieves 4A (MS4A) (1.5 g) was stirred at 0 °C for 1 h. Tetrabutylammonium perruthenate (TPAP) (120 mg, 0.342 mmol) was added to the reaction mixture, and the mixture was stirred at 0 °C for 1 h. Heptane (30 mL) was added to the reaction mixture at room temperature, and the mixture was filtered through Celite. The filtrate was washed with saturated aqueous ammonium chloride and saturated brine, successively. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (3R)-3-((1R,3aR,7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl)butyl 4-methylbenzenesulfonate (compound 11) [1.15 g, 2.93 mmol] (yield=84%). 1 H-NMR(CDCl3) δ:7.79 (2H, d, J = 7.8 Hz), 7.35 (2H, d, J = 7.8 Hz), 4.06-3.94 (2H, m), 2.45 (3H, s), 2.43 (1H, dd, J = 12.2 7.8 Hz), 2.33-2.17 (2H, m), 2.11-1.65 (6H, m), 1.60-0.99 (9H, m), 0.91 (3H, d, J = 6.3 Hz), 0.60 (3H, s). ​ Under a nitrogen atmosphere, LHMDS (1 M in THF, 5 mL, 5 mmol) was added to a THF solution (21 mL) of compound 4a (2.1 g, 3.6 mmol) at -78 °C, and the reaction mixture was stirred at the same temperature for 30 min. To this mixture, a THF solution (10 mL) of compound 11 (0.85 g, 2.2 mmol) obtained in step 3 was added, and the reaction mixture was stirred at the same temperature for an additional 1.5 h. The reaction mixture was warmed to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 16a (1.21 g, 1.63 mmol). (Yield: 72%) 1 H-NMR (CDCl3) δ: 7.80 (2H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 6.23 (1H, d, J = 11.0 Hz), 6.00 (1H, d, J = 11.4 Hz), 5.18 (1H, s), 4.86 (1H, d, J = 2.3 Hz), 4.37 (1H, dd, J = 7.0, 4.0 Hz), 4.23-4.16 (1H, m), 4.15-4.03 (2H, m), 2.82 (1H, d, J = 11.9 Hz), 2.48-2.41 (1H, m), 2.45 (3H, s), 2.21 (1H, dd, J = 13.0, 7.5 Hz), 1.96-1.58 (8H, m), 1.53-1.18 (10H, m), 0.88 (9H, s), 0.88 (9H, s), 0.84 (3H, d, J = 6.9 Hz), 0.49 (3H, s), 0.07 (3H, s), 0.06 (9H, s). [Reference example 14] Synthesis of (3R)-3-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)butyl 4-methylbenzenesulfonate (Compound 16b)

[0187] [ka]

[0188] ​ To a 100 mL DMF solution of compound 2b (11.94 g, 16.65 mmol) and 18-crown-6 (0.45 g, 1.7 mmol), potassium cyanide (2.16 g, 33.2 mmol) was added and the mixture was heated and stirred at 60°C for 4 hours. After cooling to room temperature, the reaction mixture was transferred to saturated brine and extracted with ethyl acetate. The organic phase was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 13b (8.02 g, 14.0 mmol). (Yield: 84.2%) 1 H-NMR (CDCl3) δ: 6.16 (1H, d, J = 11.4 Hz), 5.82 (1H, d, J = 11.0 Hz), 4.11-4.02 (2H, m), 2.82 (1H, dd, J = 12.3, 2.7 Hz), 2.40-2.35 (3H, m), 2.30-2.22 (2H, m), 2.08 (2H, dt, J = 23.0, 7.9 Hz), 1.98-1.88 (2H, m), 1.82-1.59 (6H, m), 1.55-1.26 (8H, m), 1.18 (3H, d, J = 6.4 Hz), 0.87 (9H, s), 0.86 (9H, s), 0.56 (3H, s), 0.06 (3H, s), 0.05 (9H, s). ​ Under a nitrogen atmosphere, a THF solution (120 mL) of compound 13b (8.02 g, 14.0 mmol) was added to a hexane solution (1 M, 42 mL, 42 mmol) of diisobutylaluminum hydride (DIBAL-H) ​​at -10°C under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride. A saturated aqueous solution of sodium potassium tartrate (Rochelle's salt) was added to the mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 14b (4.93 g, 8.57 mmol). (Yield: 61%) 1 H-NMR (CDCl3) δ: 9.76 (1H, dd, J = 3.2, 1.4 Hz), 6.16 (1H, d, J = 11.4 Hz), 5.82 (1H, d, J = 11.4 Hz), 4.10-4.04 (2H, m), 2.82 (1H, dd, J = 11.7, 3.9 Hz), 2.48 (1H, dd, J = 15.3, 3.0 Hz), 2.42-2.35 (2H, m), 2.27-1.77 (9H, m), 1.70-1.60 (4H, m), 1.58-1.50 (3H, m), 1.40-1.25 (5H, m), 1.03 (3H, d, J = 6.9 Hz), 0.87 (9H, s), 0.86 (9H, s), 0.59 (3H, s), 0.06 (3H, s), 0.05 (6H, s). ​ Compound 14b (4.92 g, 8.56 mmol) was dissolved in a mixture of THF (50 mL) and methanol (50 mL). Sodium borohydride (0.65 g, 17.0 mmol) was added to this solution at 0°C and stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride at 0°C, poured into saturated brine, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 15b (4.32 g, 7.49 mmol). (Yield: 87%) 1 H-NMR (CDCl3) δ: 6.17 (1H, d, J = 10.5 Hz), 5.82 (1H, d, J = 11.0 Hz), 4.12-4.03 (2H, m), 3.78-3.60 (2H, m), 2.81 (1H, d, J = 11.9 Hz), 2.42-2.35 (2H, m), 2.26 (1H, d, J = 13.3 Hz), 2.11 (1H, t, J = 10.1 Hz), 2.04-1.90 (3H, m), 1.82-1.60 (6H, m), 1.59-1.48 (4H, m), 1.35-1.22 (5H, m), 1.16 (1H, s), 0.99-0.92 (3H, m), 0.87 (9H, s), 0.86 (9H, s), 0.55 (3H, s), 0.08-0.03 (12H, m) ​ To a pyridine solution [40 mL] of compound 15b [4.17 g, 7.23 mmol], TsCl [3.45 g, 18.1 mmol] and 4-dimethylaminopyridine [94 mg, 0.77 mmol] were added and stirred at room temperature for 2 hours. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 16b [4.60 g, 6.29 mmol]. (Yield = 87%) 1 H-NMR (CDCl3) δ: 7.80 (2H, d, J = 8.3 Hz), 7.35 (2H, d, J = 8.3 Hz), 6.16 (1H, d, J = 11.2 Hz), 5.80 (1H, d, J = 11.2 Hz), 4.17-4.01 (4H, m), 2.85-2.70 (1H, m), 2.45 (3H, s), 2.41-2.23 (2H, m), 1.98-1.60 (8H, m), 1.51-1.18 (10H, m), 0.87-0.85 (27H, m), 0.50 (3H, s), 0.05 (6H, s), 0.05 (6H, s). [Reference example 15] Synthesis of (3R)-3-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)-4-methylenecyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)butyl 4-methylbenzenesulfonate (Compound 16c)

[0189] [ka]

[0190] A THF solution (15 mL) of (3R)-3-((1R,3aR,7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl)butyl 4-methylbenzenesulfonate (Compound 11) (1.24 g, 3.28 mmol) and Compound 4c (1.3 g, 2.2 mmol) as described in Reference Example 13, Step 3, was cooled to -78°C under a nitrogen atmosphere. LHMDS (1 M THF solution, 4.5 mL, 4.5 mmol) was added dropwise to this solution, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was warmed to room temperature and quenched with saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Compound 16c (0.83 g, 1.1 mmol). (Yield: 50%) 1H-NMR (CDCl3) δ: 7.80 (2H, d, J = 8.3 Hz), 7.35 (2H, d, J = 8.8 Hz), 6.21 (1H, d, J = 11.2 Hz), 5.83 (1H, d, J = 11.2 Hz), 4.97 (1H, s), 4.92 (1H, s), 4.43 (2H, dd, J = 7.6, 4.1 Hz), 4.11-4.02 (2H, m), 2.81 (1H, dd, J = 10.0, 3.8 Hz), 2.55-2.45 (2H, m), 2.45 (3H, s), 2.31 (1H, dd, J = 13.4, 3.2 Hz), 2.17 (1H, dd, J = 12.4, 8.5 Hz), 1.99-1.60 (6H, m), 1.52-1.18 (8H, m), 0.90 (9H, s), 0.87 (9H, s), 0.50 (3H, s), 0.07 (3H, s), 0.05 (3H, s), 0.03 (3H, s). [Example 160] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-(difluoromethyl)azetidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A022) Compound (16b) [100 mg, 0.137 mmol] and 3-difluoromethylazetidine hydrochloride [60 mg, 0.418 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound (A022) [14.7 mg, 0.0336 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 6.00 (1H, td, J = 57.0, 5.0 Hz), 5.88 (1H, d, J = 11.2 Hz), 4.05 (2H, s), 4.05-3.94 (2H, m), 3.38 (2H, t, J = 8.3 Hz), 3.17 (2H, t, J = 7.3 Hz), 2.91 (1H, td, J = 13.5, 7.3 Hz), 2.82 (1H, dd, J = 12.2, 3.9 Hz), 2.58 (1H, dd, J = 13.7, 3.4 Hz), 2.52 (1H, dd. J = 6.3 Hz), 0.57 (3H, s). Exact Mass = 437.31(C26H41F2NO2)Obs. mass = 438.25 (M+H) [Example 161] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A023) Compound (16c) [50 mg, 0.067 mmol] and 3-hydroxy-3-(trifluoromethyl)azetidine [30 mg, 0.213 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound A023 [9.8 mg, 0.020 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.06 (2H, d, J = 6.8 Hz), 4.43-4.37 (2H, m), 3.70 (2H, d, J = 10.7 Hz), 2.86 (1H, dd, J = 12.0, 3.7 Hz), 2.75-2.53 (3H, m), 2.49 (1H, dd, J = 13.2, 3.9 Hz), 2.32-2.25 (2H, m), 2.08-1.98 (2H, m), 1.95-1.13 (12H, m), 0.98 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 483.30(C27H40F3NO3)Obs. mass = 484.25 (M+H) [Example 162] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-(2,2-difluoroethyl)azetidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A024) Compound (16b) [100 mg, 0.137 mmol] and 3-(2,2-difluoroethyl)azetidine hydrochloride [70 mg, 0.444 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound A024 [17.0 mg, 0.376 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.88 (1H, d, J = 11.2 Hz), 5.86 (1H, tt, J = 56.0, 4.5 Hz), 4.06-3.95 (2H, m), 3.49 (2H, t, J = 7.6 Hz), 2.87 (2H, dt, J = 3.0, 8.0 Hz), 2.83 (1H, dd, J = 13.0, 4.0 Hz), 2.75-2.63 (1H, m), 2.58 (1H, dd, J = 13.2, 3.9 Hz), 2.54-2.49 (1H, m), 2.44-2.36 (2H, m), 2.23-1.91 (7H, m), 1.87-1.44 (9H, m), 1.33 (3H, td, J = 9.6, 6.0 Hz), 1.15-1.05 (1H, m), 0.96 (3H, d, J = 6.8 Hz), 0.57 (3H, s). Exact Mass = 451.33(C27H43F2NO2)Obs. mass = 452.25 (M+H) [Example 163] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-(difluoromethoxy)azetidin-1yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A025) Compound (16b) [100 mg, 0.137 mmol] and 3-(difluoromethoxy)azetidine [70 mg, 0.444 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound A025 [21.6 mg, 0.476 mmol]. 1H-NMR (CD3OD) δ: 6.38 (1H, t, J = 75.0 Hz), 6.21 (1H, d, J = 10.7 Hz), 5.88 (1H, d, J = 10.7 Hz), 4.76-4.70 (1H, m), 4.06-3.95 (2H, m), 3.64 (2H, td, J = 6.1, 2.4 Hz), 3.12-3.07 (2H, m), 2.83 (1H, dd, J = 11.5, 4.1 Hz), 2.61-2.44 (3H, m), 2.40 (1H, dd, J = 13.7, 3.4 Hz), 2.23-2.13 (2H, m), 2.05-1.92 (3H, m), 1.87-1.73 (2H, m), 1.68-1.45 (7H, m), 1.38-1.28 (3H, m), 1.17-1.06 (1H, m), 0.96 (3H, d, J = 6.3 Hz), 0.57 (3H, s). Exact Mass = 453.31(C26H41F2NO3)Obs. mass = 454.25 (M+H) [Example 164] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-(2,2-difluoroethoxy)azetidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A026) Compound (16b) [50 mg, 0.068 mmol] and 3-(2,2-difluoroethoxy)azetidine hydrochloride [35 mg, 0.202 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound A026 [12.8 mg, 0.0282 mmol]. 1H-NMR (CD3OD) δ: 6.16 (1H, d, J = 10.7 Hz), 5.85 (1H, tt, J = 3.5, 55.0 Hz), 5.84 (1H, d, J = 10.7 Hz), 4.17-4.11 (1H, m), 4.02-3.90 (2H, m), 3.63-3.52 (4H, m), 2.92 (2H, dt, J = 22.9, 6.8 Hz), 2.78 (1H, dd, J = 12.0, 3.7 Hz), 2.54 (1H, dd, J = 13.2, 3.4 Hz), 2.44 (1H, dd, J = 12.2, 2.9 Hz), 2.36 (1H, dd, J = 13.2, 3.4 Hz), 2.26-2.09 (3H, m), 1.99-1.24 (15H, m), 0.94 (3H, d, J = 6.3 Hz), 0.53 (3H, s). [Example 165] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-methoxy-3-(trifluoromethyl)azetidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A027) Compound (16b) [50 mg, 0.068 mmol] and 3-methoxy-3-(trifluoromethyl)azetidine hydrochloride [30 mg, 0.157 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound A027 [1.6 mg, 0.0033 mmol]. Exact Mass = 485.31(C27H42F3NO3)Obs.mass = 486.25(M+H) [Example 166] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-(3-(trifluoromethoxy)azetidin-1-yl)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A028) Compound (16b) [50 mg, 0.068 mmol] and 3-(trifluoromethoxy)azetidine hydrochloride [30 mg, 0.169 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound A028 [1.1 mg, 0.0023 mmol]. Exact Mass = 471.30(C26H40F3NO3)Obs. mass = 472.25 (M+H) [Example 167] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-(2,2-difluoroethoxy)azetidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A029) Compound (16c) [50 mg, 0.067 mmol] and 3-(2,2-difluoroethoxy)azetidine hydrochloride [35 mg, 0.202 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound A029 [15.9 mg, 0.0332 mmol]. 1 H-NMR (CD3OD) δ: 6.24 (1H, d, J = 11.4 Hz), 6.04-5.74 (2H, m), 5.03 (2H, d, J = 6.9 Hz), 4.42-4.32 (2H, m), 4.21-4.15 (1H, m), 3.62 (2H, dd, J = 14.4, 3.9 Hz), 3.59-3.56 (2H, m), 2.99-2.94 (2H, m), 2.83 (1H, dd, J = 12.3, 3.7 Hz), 2.65 (1H, dd, J = 13.3, 4.6 Hz), 2.57-2.40 (3H, m), 2.30-2.23 (2H, m), 2.05-1.85 (3H, m), 1.69-1.23 (10H, m), 1.16-1.06 (1H, m), 0.94 (3H, d, J = 6.4 Hz), 0.56 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.25 (M+H) [Example 168] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-(difluoromethoxy)azetidin-1yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A030) Compound (16c) [50 mg, 0.067 mmol] and 3-(difluoromethoxy)azetidine [30 mg, 0.244 mmol] were used as starting materials and reacted in the same manner as in Example 5 to obtain compound A030 [10.9 mg, 0.234 mmol]. 1 H-NMR (CD3OD) δ: 6.38 (1H, t, J = 75.0 Hz), 6.26 (1H, d, J = 11.2 Hz), 5.90 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.76-4.70 (1H, m), 4.43-4.35 (2H, m), 3.68-3.60 (2H, m), 3.12-3.07 (2H, m), 2.84 (1H, dd, J = 4.0, 12.6 Hz), 2.66 (1H, dd, J = 12.6, 4.0 Hz), 2.60-2.42 (3H, m), 2.31-2.24 (2H, m), 2.07-2.00 (2H, m), 1.98-1.90 (2H, m), 1.69-1.40 (7H, m), 1.38-1.25 (3H, m), 1.17-1.09 (1H, m), 0.96 (3H, d, J = 6.3 Hz), 0.58 (3H, s). Exact Mass = 465.31(C27H41F2NO3)Obs. mass = 466.25 (M+H) [Example 169] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-(difluoromethyl)azetidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A031) Compound (16c) [50 mg, 0.067 mmol] and 3-(difluoromethyl)azetidine hydrochloride [30 mg, 0.209 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound A031 [9.4 mg, 0.021 mmol]. 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2 Hz), 6.10 (1H, td, J = 56.4, 4.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.06 (2H, d, J = 6.8 Hz), 4.40 (2H, ddd, J = 14.3, 7.2, 4.5 Hz), 3.80 (2H, t, J = 9.3 Hz), 3.65 (2H, t, J = 8.1 Hz), 3.17-3.09 (1H, m), 2.89 (2H, ddd, J = 23.1, 11.6, 4.3 Hz), 2.78 (1H, td, J = 11.3, 5.2 Hz), 2.68 (1H, dd, J = 13.4, 4.1 Hz), 2.49 (1H, dd, J = 13.2, 3.9 Hz), 2.32-2.25 (2H, m), 2.11-1.97 (3H, m), 1.96-1.90 (1H, m), 1.72-1.18 (12H, m), 1.00 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 449.31(C27H41F2NO2)Obs. mass = 450.40 (M+H) [Example 170] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-(1,1-difluoroethyl)azetidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A032) Compound (16b) [100 mg, 0.137 mmol] and 3-(1,1-difluoroethyl)azetidine hydrochloride [70 mg, 0.444 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound A032 [15.5 mg, 0.0343 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.88 (1H, d, J = 11.2 Hz), 4.06-3.95 (2H, m), 3.43 (2H, t, J = 8.1 Hz), 3.12 (2H, td, J = 7.9, 2.1 Hz), 3.04-2.93 (1H, m), 2.83 (1H, dd, J = 12.0, 3.7 Hz), 2.58 (1H, dd, J = 13.7, 3.9 Hz), 2.54-2.49 (1H, m), 2.46-2.36 (2H, m), 2.23-2.13 (2H, m), 2.05-1.91 (3H, m), 1.87-1.41 (13H, m), 1.38-1.28 (3H, m), 1.16-1.03 (1H, m), 0.96 (3H, d, J = 6.8 Hz), 0.57 (3H, s). Exact Mass = 451.33(C27H43F2NO2)Obs. mass = 452.30 (M+H) [Example 171] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-hydroxy-3-isopropylazetidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A034) Compound A034 [8.1 mg, 0.018 mmol] was obtained using compound (16b) [50 mg, 0.068 mmol] and 3-isopropylazetidin-3-ol hydrochloride [30 mg, 0.218 mmol]. 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.88 (1H, d, J = 11.4 Hz), 4.06-3.95 (2H, m), 3.39 (1H, s), 3.37 (1H, s), 3.01 (1H, s), 2.99 (1H, s), 2.83 (1H, dd, J = 11.9, 3.7 Hz), 2.64-2.55 (2H, m), 2.49-2.36 (2H, m), 2.23-2.13 (2H, m), 2.05-1.29 (16H, m), 1.19-1.10 (1H, m), 0.97 (3H, d, J = 6.9 Hz), 0.90 (6H, d, J = 6.9 Hz), 0.57 (3H, s). Exact Mass = 445.36(C28H47NO3)Obs. mass = 446.30 (M+H) [Example 172] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-fluoropyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B014) Compound B014 [9.0 mg, 0.021 mmol] was obtained using compound (16b) [50 mg, 0.068 mmol] and (S)-3-fluoropyrrolidine hydrochloride [30 mg, 0.239 mmol]. Exact Mass = 419.32(C26H42FNO2)Obs. mass = 420.30 (M+H) [Example 173] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-fluoropyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B015) Compound B015 [7.9 mg, 0.019 mmol] was obtained using compound (16b) [50 mg, 0.068 mmol] and (R)-3-fluoropyrrolidine hydrochloride [30 mg, 0.239 mmol]. Exact Mass = 419.32(C26H42FNO2)Obs. mass = 420.30 (M+H) [Example 174] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(difluoromethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B080) Compound B080 [12.5 mg, 0.0277 mmol] was obtained using compound (16b) [50 mg, 0.068 mmol] and (S)-3-(difluoromethyl)pyrrolidine hydrochloride [30 mg, 0.190 mmol]. 1 H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2 Hz), 5.89 (1H, d, J = 11.2 Hz), 5.81 (1H, td, J = 57.0, 5.0 Hz), 4.07-3.96 (2H, m), 2.84 (1H, dd, J = 12.0, 4.0 Hz), 2.80 (1H, t, J = 9.0 Hz), 2.71-2.39 (8H, m), 2.24-2.14 (2H, m), 2.07-1.92 (4H, m), 1.88-1.27 (15H, m), 0.99 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 451.33(C27H43F2NO2)Obs. mass = 452.30 (M+H) [Example 175] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(difluoromethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B081) Compound B081 [12.4 mg, 0.0275 mmol] was obtained using compound (16b) [50 mg, 0.068 mmol] and (R)-3-(difluoromethyl)pyrrolidine hydrochloride [30 mg, 0.190 mmol]. 1 H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2 Hz), 5.89 (1H, d, J = 11.2 Hz), 5.80 (1H, td, J = 56.5, 5.0 Hz), 4.07-3.96 (2H, m), 2.84 (1H, dd, J = 12.0, 3.7 Hz), 2.77-2.47 (8H, m), 2.41 (1H, dd, J = 13.4, 3.2 Hz), 2.24-2.14 (2H, m), 2.07-1.95 (4H, m), 1.92-1.27 (15H, m), 0.99 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 451.33(C27H43F2NO2)Obs. mass = 452.30 (M+H) [Example 176] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B082) Compound B082 [8.4 mg, 0.018 mmol] was obtained using compound (16b) [50 mg, 0.068 mmol] and (R)-3-(2,2-difluoroethyl)pyrrolidine hydrochloride [30 mg, 0.175 mmol]. 1 H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2 Hz), 5.97 (1H, tt, J = 56.0, 4.0 Hz), 5.90 (1H, d, J = 11.2 Hz), 4.07-3.95 (2H, m), 3.35 (1H, dd, J = 10.5, 8.1 Hz), 3.18-2.83 (5H, m), 2.70 (1H, t, J = 9.8 Hz), 2.60 (1H, dd, J = 13.4, 3.7 Hz), 2.56-2.48 (1H, m), 2.41 (1H, dd, J = 13.2, 3.4 Hz), 2.27-1.95 (9H, m), 1.88-1.29 (16H, m), 1.01 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 465.34(C28H45F2NO2)Obs. mass = 466.35(M+H) [Example 177] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B083) Compound B083 [9.3 mg, 0.020 mmol] was obtained using compound (16b) [50 mg, 0.068 mmol] and (S)-3-(1,1-difluoroethyl)pyrrolidine hydrochloride [30 mg, 0.175 mmol]. 1H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2 Hz), 5.89 (1H, d, J = 11.2 Hz), 4.07-3.96 (2H, m), 2.90 (1H, t, J = 9.3 Hz), 2.86-2.39 (9H, m), 2.24-2.14 (2H, m), 2.07-1.46 (15H, m), 1.59 (3H, t, J = 19.0 Hz), 1.39-1.28 (4H, m), 0.99 (3H, d, J = 6.8 Hz), 0.59 (3H, s). Exact Mass = 465.34(C28H45F2NO2)Obs. mass = 466.35 (M+H) [Example 178] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B086) Compound B086 [10.0 mg, 0.0214 mmol] was obtained using compound (16b) [50 mg, 0.068 mmol] and (S)-3-(difluoromethoxy)pyrrolidine hydrochloride [25 mg, 0.182 mmol]. 1 H-NMR (CD3OD) δ: 5.96 (1H, t, J = 75.0 Hz), 5.79 (1H, d, J = 11.4 Hz), 5.47 (1H, d, J = 11.4 Hz), 4.35-4.30 (1H, m), 3.65-3.53 (2H, m), 2.43-2.30 (4H, m), 2.19-1.97 (5H, m), 1.86-1.70 (3H, m), 1.64-0.85 (18H, m), 0.56 (3H, d, J = 6.4 Hz), 0.16 (3H, s).Exact Mass = 467.32(C27H43F2NO3)Obs. mass = 468.30 (M+H) [Example 179] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B087) Compound B087 [6.5 mg, 0.014 mmol] was obtained using compound (16b) [50 mg, 0.068 mmol] and (R)-3-(difluoromethoxy)pyrrolidine hydrochloride [26.5 mg, 0.153 mmol]. 1 H-NMR (CD3OD) δ: 6.38 (1H, t, J = 75.0 Hz), 6.21 (1H, d, J = 11.4 Hz), 5.89 (1H, d, J = 11.4 Hz), 4.79-4.72 (1H, m), 4.06-3.95 (2H, m), 2.85-2.71 (4H, m), 2.59 (1H, dd, J = 13.3, 3.7 Hz), 2.48 (3H, dt, J = 14.2, 6.5 Hz), 2.41 (1H, dd, J = 13.5, 3.4 Hz), 2.27-2.13 (3H, m), 2.06-1.26 (18H, m), 0.98 (3H, d, J = 6.4 Hz), 0.58 (3H, s). Exact Mass = 467.32(C27H43F2NO3)Obs. mass = 468.30 (M+H) [Example 180] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(difluoromethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B088) Compound B088 [12.1 mg, 0.026.1 mmol] was obtained using compound (16c) [50 mg, 0.067 mmol] and (S)-3-(difluoromethoxy)pyrrolidine hydrochloride [30 mg, 0.190 mmol]. 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2 Hz), 5.93 (1H, dt, J = 6.0, 57.0 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.06 (2H, d, J = 8.0 Hz), 4.40 (2H, dd, J = 13.9, 7.1, 4.4 Hz), 3.23 (1H, dd, J = 11.2, 8.8 Hz), 3.10-2.80 (8H, m), 2.68 (1H, dd, J = 13.2, 4.4 Hz), 2.49 (1H, dd, J = 13.7, 3.9 Hz), 2.32-2.26 (2H, m), 2.20-1.91 (7H, m), 1.82-1.33 (12H, m), 1.01 (3H, d, J = 6.8 Hz), 0.60 (3H, s). Exact Mass = 463.33(C28H43F2NO2)Obs. mass = 464.40 (M+H) [Example 181] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(difluoromethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B089) Compound B089 [10.0 mg, 0.0216 mmol] was obtained using compound (16c) [50 mg, 0.067 mmol] and (R)-3-(difluoromethoxy)pyrrolidine hydrochloride [33 mg, 0.209 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.90 (1H, td, J = 56.0, 5.0 Hz), 5.05 (2H, d, J = 7.0 Hz), 4.43-4.36 (2H, m), 3.12 (1H, dd, J = 11.0, 9.0 Hz), 3.04-2.71 (8H, m), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.49 (1H, dd, J = 13.7, 3.9 Hz), 2.32-1.95 (7H, m), 1.92-1.32 (13H, m), 1.01 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 463.33(C28H43F2NO2)Obs. mass = 464.45 (M+H) [Example 182] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B090) Compound B090 [8.2 mg, 0.017 mmol] was obtained using compound (16c) [50 mg, 0.067 mmol] and (R)-3-(2,2-difluoroethyl)pyrrolidine hydrochloride [38 mg, 0.174 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7 Hz), 5.97 (1H, tt, J = 56.0, 4.0 Hz), 5.92 (1H, d, J = 10.7 Hz), 5.06 (2H, d, J = 6.3 Hz), 4.43-4.37 (2H, m), 3.41 (1H, dd, J = 10.7, 7.8 Hz), 3.24-3.12 (2H, m), 3.07 (1H, td, J = 12.0, 4.7 Hz), 2.96 (1H, td, J = 11.8, 4.7 Hz), 2.86 (1H, dd, J = 12.0, 3.7 Hz), 2.78 (1H, t, J = 10.2 Hz), 2.68 (1H, dd, J = 13.4, 4.1 Hz), 2.59-2.45 (2H, m), 2.33-2.20 (3H, m), 2.09-1.98 (5H, m), 1.81-1.33 (13H, m), 1.02 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.25(M+H) [Example 183] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B091) Compound B091 [12.7 mg, 0.0166 mmol] was obtained using compound (16c) [50 mg, 0.067 mmol] and (S)-3-(1,1-difluoroethyl)pyrrolidine hydrochloride [35 mg, 0.161 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.06 (2H, d, J = 6.3 Hz), 4.40 (2H, ddd, J = 14.0, 7.0, 4.5 Hz), 3.37-3.28 (1H, m), 3.21-2.84 (7H, m), 2.68 (1H, dd, J = 13.2, 4.4 Hz), 2.49 (1H, dd, J = 13.7, 3.9 Hz), 2.32-2.08 (4H, m), 2.02-1.95 (2H, m), 1.87-1.33 (15H, m), 1.02 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.25(M+H) [Example 184] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B092) Compound B092 [14.0 mg, 0.0293 mmol] was obtained using compound (16c) [50 mg, 0.067 mmol] and (S)-3-(2,2-difluoroethyl)pyrrolidine hydrochloride [40 mg, 0.233 mmol]. 1H-NMR (CD3OD) δ: 6.28 (1H, d, J = 11.2 Hz), 5.99 (1H, tt, J = 56.0, 3.0 Hz), 5.93 (1H, d, J = 11.2 Hz), 5.06 (2H, d, J = 6.3 Hz), 4.40 (2H, ddd, J 14.0, 7.0, 4.5 Hz), 3.49 (1H, dd, J = 11.0, 7.6 Hz), 3.31-3.23 (2H, m), 3.17-3.03 (2H, m), 2.95-2.80 (2H, tm), 2.68 (1H, dd, J = 13.2, 4.4 Hz), 2.62-2.54 (1H, m), 2.50 (1H, dd, J = 13.7 3.9 Hz), 2.33-1.99 (8H, m), 1.85-1.34 (12H, m), 1.02 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.40 (M+H) [Example 185] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B093) Compound B093 [10.7 mg, 0.0224 mmol] was obtained using compound (16c) [50 mg, 0.067 mmol] and (R)-3-(1,1-difluoroethyl)pyrrolidine hydrochloride [38 mg, 0.221 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2 Hz), 5.92 (1H, d, J = 11.2 Hz), 5.06 (2H, d, J = 6.3 Hz), 4.46-4.35 (2H, m), 3.22-2.85 (8H, m), 2.68 (1H, dd, J = 13.4, 4.1 Hz), 2.49 (1H, dd, J = 13.4, 4.1 Hz), 2.33-1.97 (8H, m), 1.90-1.33 (16H, m), 1.02 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 477.34(C29H45F2NO2)Obs. mass = 478.40 (M+H) [Example 186] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B094) Compound B094 [13.1 mg, 0.0266 mmol] was obtained using compound (16c) [50 mg, 0.067 mmol] and (R)-3-(3,3-difluoropropyl)pyrrolidine hydrochloride [35 mg, 0.189 mmol]. 1H-NMR (CD3OD) δ: 6.28 (1H, d, J = 11.2 Hz), 5.93 (1H, d, J = 11.2 Hz), 5.91 (1H, tt, J = 57.5, 4.0 Hz), 5.06 (2H, d, J = 5.9 Hz), 4.40 (2H, ddd, J 14.0, 7.1, 4.4 Hz), 3.47 (1H, dd, J = 11.2, 7.8 Hz), 3.31-3.25 (2H, m), 3.19-2.84 (4H, tm), 2.68 (1H, dd, J = 13.4, 4.1 Hz), 2.50 (1H, dd, J = 13.7 3.9 Hz), 2.42-1.94 (8H, m), 1.90-1.30 (17H, m), 1.02 (3H, d, J = 6.3 Hz), 0.61 (3H, s). Exact Mass = 491.36(C30H47F2NO2)Obs. mass = 492.40(M+H) [Example 187] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D022) Compound 16a (100 mg, 0.134 mmol) was dissolved in THF (1 mL), morpholine (0.2 mL, 2 mmol) was added, and the mixture was heated and stirred at 60°C overnight. The reaction mixture was cooled to 50°C, and TBAF (1 M in THF, 0.4 mL, 0.4 mmol) was added and refluxed for 4 hours. After cooling to room temperature, the reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC as in Example 1 to obtain compound D022 (17.6 mg, 0.041 mmol). 1H-NMR (CD3OD) δ: 6.31 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.28 (1H, t, J = 1.2 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.1-4.08 (1H, m), 3.75 (4H, t, J = 4.6 Hz), 2.86 (1H, dd, J = 12.0, 3.7 Hz), 2.76-2.66 (6H, m), 2.60 (1H, td, J = 11.7 4.9 Hz), 2.51 (1H, dd, J = 13.7 3.4 Hz), 2.25 (1H, dd, J = 13.2 6.8 Hz), 2.11-2.00 (3H, m), 1.90-1.28 (17H, m), 1.04-0.99 (1H, m), 0.99 (3H, d, J = 6.8 Hz), 0.58 (3H, s).Exact Mass = 429.32(C27H43NO3)Obs. mass = 430.30(M+H) [Example 188] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D023)

[0191] [ka]

[0192] ​ To a THF solution (2 mL) of compound 14b (100 mg, 0.174 mmol) described in Step 2 of Reference Example 14, morpholine (0.2 mL) and sodium triacetoxyborohydride (110 mg, 0.519 mmol) were added, followed by heating and stirring at 60°C overnight. After cooling, the reaction mixture was transferred to saturated brine and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude D023-di-OTBS (81.1 mg). The crude product was used in the next reaction without further purification. ​ To a THF solution (1 mL) of the crude D023-di-OTBS (81.1 mg) was added TBAF (1 M in THF, 0.4 mL, 0.4 mmol), followed by stirring at 60°C for 5 hours. The reaction mixture was cooled and then transferred to saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain compound D023 (22.1 mg, 0.053 mmol). 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.88 (1H, d, J = 11.4 Hz), 4.06-3.95 (2H, m), 3.69 (4H, t, J = 4.6 Hz), 2.83 (1H, dd, J = 11.9, 4.1 Hz), 2.59 (1H, dd, J = 13.7, 3.7 Hz), 2.50-2.37 (6H, m), 2.33 (1H, td, J = 11.4, 5.3 Hz), 2.23-2.13 (2H, m), 2.06-1.93 (4H, m), 1.88-1.47 (9H, m), 1.39-1.27 (4H, m), 0.98 (3H, d, J = 6.4 Hz), 0.58 (3H, s). Exact Mass = 417.32(C26H43NO3)Obs. mass = 418.35 (M+H) [Example 189] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D024) Compound (16c) [120 mg, 0.097 mmol] and morpholine [0.1 mL, 1.1 mmol] were reacted in the same manner as in Example 1 to obtain compound D024 [22.2 mg, 0.052 mmol]. 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, dd, J = 8.0, 1.0 Hz), 4.42-4.36 (2H, m), 3.71 (4H, t, J = 4.6 Hz), 2.85 (1H, dd, J = 12.0, 3.7 Hz), 2.67 (1H, dd, J = 13.4, 4.1 Hz), 2.58-2.37 (7H, m), 2.31-2.24 (2H, m), 2.07-1.93 (3H, m), 1.49 (11H, ttt, J = 61.2, 17.2, 7.4 Hz), 0.99 (3H, d, J = 6.3 Hz), 0.58 (3H, s). Exact Mass = 429.32(C27H43NO3)Obs. mass = 430.35 (M+H) [Example 190] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-2-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D025) Compound (16c) [50 mg, 0.067 mmol] and (S)-2-methylmorpholine [30 mg, 0.297 mmol] were treated in the same manner as in Example 1 to obtain compound D025 [13.8 mg, 0.031 mmol]. 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 8.0 Hz), 4.45-4.33 (2H, m), 3.82 (1H, dd, J = 10.2, 3.0 Hz), 3.66-3.55 (2H, m), 2.85 (1H, dd, J = 12.0, 3.7 Hz), 2.82-2.75 (2H, m), 2.67 (1H, dd, J = 13.7, 4.4 Hz), 2.48 (1H, dd, J = 13.7, 3.9 Hz), 2.44-2.24 (4H, m), 2.08-1.93 (4H, m), 1.79 (1H, dd, J = 11.7, 10.2 Hz), 1.71-1.26 (11H, m), 1.11 (3H, d, J = 6.3 Hz), 0.98 (3H, d, J = 6.8 Hz), 0.58 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.30 (M+H) [Example 191] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D026) Compound (16c) [50 mg, 0.067 mmol] and 4-oxa-7-azaspiro[2.5]octane [30 mg, 0.265 mmol] were treated in the same manner as in Example 1 to obtain compound D026 [12.0 mg, 0.026 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7 Hz), 5.90 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.42-4.36 (2H, m), 3.75 (2H, t, J = 4.9 Hz), 2.85 (1H, dd, J = 12.0, 3.7 Hz), 2.67 (1H, dd, J = 12.0, 4.0 Hz), 2.64-2.24 (9H, m), 2.07-1.96 (3H, m), 1.70-1.27 (11H, m), 0.98 (3H, d, J = 6.8 Hz), 0.77-0.70 (2H, m), 0.59-0.53 (2H, m), 0.58 (3H, s). Exact Mass = 455.34(C29H45NO3)Obs. mass = 456.30 (M+H) [Example 192] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(6-oxa-9-azaspiro[4.5]decan-9-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D027) Compound (16c) [50 mg, 0.067 mmol] and 6-oxa-9-azaspiro[4.5]decane [30 mg, 0.212 mmol] were treated in the same manner as in Example 1 to obtain compound D027 [18.0 mg, 0.037 mmol]. 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7 Hz), 5.92 (1H, d, J = 10.7 Hz), 5.06 (2H, t, J = 3.9 Hz), 4.43-4.37 (2H, m), 3.73-3.63 (2H, m), 2.86 (1H, dd, J = 12.0, 3.7 Hz), 2.67 (1H, dd, J = 13.4, 4.1 Hz), 2.49 (1H, dd, J = 13.4, 3.7 Hz), 2.40-2.25 (8H, m), 2.07-1.94 (3H, m), 1.81-1.18 (20H, m), 0.99 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 483.37(C31H49NO3)Obs.mass = 484.35(M+H) [Example 193] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((2S,6R)-2,6-dimethylmorpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D028) Compound (16c) [50 mg, 0.067 mmol] and (2S,6R)-2,6-dimethylmorpholine [30 mg, 0.260 mmol] were treated in the same manner as in Example 1 to obtain compound D028 [17.3 mg, 0.0378 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.90 (1H, d, J = 11.2 Hz), 5.04 (2H, d, J = 6.8 Hz), 4.42-4.36 (2H, m), 3.69-3.63 (2H, m), 2.82 (3H, q, J = 12.0 Hz), 2.66 (1H, dd, J = 13.2, 3.9 Hz), 2.48 (1H, dd, J = 13.4, 3.7 Hz), 2.43-2.24 (4H, m), 2.06-1.96 (3H, m), 1.74-1.26 (15H, m), 1.12 (3H, d, J = 6.1 Hz), 1.12 (3H, d, J = 6.0 Hz), 0.98 (3H, d, J = 6.3 Hz), 0.58 (3H, s). Exact Mass = 457.36(C29H47NO33)Obs. mass = 458.35 (M+H) [Example 194] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(2,2-dimethylmorpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D029) Compound (16c) [50 mg, 0.067 mmol] and 2,2-dimethylmorpholine [30 mg, 0.260 mmol] were treated in the same manner as in Example 1 to obtain compound D029 [13.6 mg, 0.030 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.90 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.39 (2H, dt, J = 15.0, 4.8 Hz), 3.70 (2H, dd, J = 21.5, 12.0, 4.4 Hz), 2.85 (1H, dd, J = 12.2, 3.4 Hz), 2.66 (1H, dd, J = 13.2, 4.4 Hz), 2.48 (1H, dd, J = 13.2, 3.9 Hz), 2.39-2.24 (7H, m), 2.16 (1H, d, J = 10.7 Hz), 2.08-1.92 (3H, m), 1.70-1.48 (8H, m), 1.38-1.31 (3H, m), 1.25-1.13 (8H, m), 0.98 (3H, d, J = 6.3 Hz), 0.58 (3H, s). Exact Mass = 457.36(C29H47NO3)Obs. mass = 458.35(M+H) [Example 195] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D030) Compound (16b) [50 mg, 0.068 mmol] and 4-oxa-7-azaspiro[2.5]octane [30 mg, 0.265 mmol] were treated in the same manner as in Example 1 to obtain compound D030 [11.2 mg, 0.0252 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.88 (1H, d, J = 11.2 Hz), 4.06-3.95 (2H, m), 3.75 (2H, t, J = 4.9 Hz), 2.83 (1H, dd, J = 12.2, 3.4 Hz), 2.61-2.31 (9H, m), 2.23-2.13 (2H, m), 2.05-1.28 (18H, m), 0.98 (3H, d, J = 6.8 Hz), 0.74 (2H, t, J = 5.6 Hz), 0.62-0.55 (2H, m), 0.57 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.35 (M+H) [Example 196] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((R)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D031) Compound (16c) [50 mg, 0.067 mmol] and (R)-3-methylmorpholine [30 mg, 0.297 mmol] were treated in the same manner as in Example 1 to obtain compound D031 [14.9 mg, 0.0336 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 10.7 Hz), 5.05 (2H, d, J = 8.0 Hz), 4.42-4.36 (2H, m), 3.77 (1H, dt, J = 11.4, 2.8 Hz), 3.68-3.58 (2H, m), 3.23 (1H, dd, J = 11.2, 9.3 Hz), 2.88-2.81 (2H, m), 2.77 (1H, dt, J = 11.9, 2.7 Hz), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.50-2.21 (6H, m), 2.08-1.93 (3H, m), 1.74-1.14 (13H, m), 1.00 (3H, d, J = 6.3 Hz), 0.99 (3H, d, J = 6.0 Hz), 0.58 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.30 (M+H) [Example 197] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D032) Compound (16c) [50 mg, 0.067 mmol] and (S)-3-methylmorpholine [30 mg, 0.297 mmol] were treated in the same manner as in Example 1 to obtain compound D032 [12.3 mg, 0.027.7 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.05 (2H, d, J = 7.3 Hz), 4.43-4.33 (2H, m), 3.83-3.76 (1H, m), 3.62 (2H, dd, J = 23.5, 13.5, 5.0 Hz), 3.23 (1H, dd, J = 11.2, 9.3 Hz), 2.87-2.64 (4H, m), 2.50-2.25 (6H, m), 2.07-1.91 (3H, m), 1.70-1.27 (11H, m), 1.00 (3H, d, J = 6.3 Hz), 0.98 (3H, d, J = 8.1 Hz), 0.59 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.35 (M+H) [Example 198] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-2-(difluoromethyl)morpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D033) Compound (16c) [50 mg, 0.067 mmol] and (S)-2-(difluoromethyl)morpholine hydrochloride (compound 3d06) [40 mg, 0.230 mmol] described in Step 3 of Example 1 were used to obtain compound D033 [11.4 mg, 0.0238 mmol] in the same manner as in Example 1. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7 Hz), 5.91 (1H, d, J = 10.7 Hz), 5.77 (1H, td, J = 55.0, 4.0 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.43-4.33 (2H, m), 3.91 (1H, d, J = 11.7 Hz), 3.75-3.62 (2H, m), 2.92-2.80 (2H, m), 2.75 (1H, dd, J = 12.0, 3.2 Hz), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.50-2.15 (7H, m), 2.07-1.91 (4H, m), 1.68-1.21 (12H, m), 0.99 (3H, d, J = 6.8 Hz), 0.58 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.30(M+H) [Example 199] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-2-(difluoromethyl)morpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D034) Compound (16b) [50 mg, 0.068 mmol] and (S)-2-(difluoromethyl)morpholine hydrochloride (compound 3d06) [40 mg, 0.230 mmol] described in Step 3 of Example 1 were used to obtain compound D034 [7.5 mg, 0.016 mmol] in the same manner as in Example 1. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2 Hz), 5.89 (1H, d, J = 11.2 Hz), 5.77 (1H, td, J = 55.0, 4.0 Hz), 4.06-3.95 (2H, m), 3.90 (1H, d, J = 10.0 Hz), 3.75-3.62 (2H, m), 2.88 (1H, d, J = 10.7 Hz), 2.83 (1H, dd, J = 10.7, 4.0 Hz), 2.75 (1H, dd, J = 11.7, 2.0 Hz), 2.58 (1H, dd, J = 13.2, 3.4 Hz), 2.48-2.35 (3H, m), 2.23-1.91 (7H, m), 1.87-1.26 (14H, m), 0.98 (3H, d, J = 6.8 Hz), 0.58 (3H, s). Exact Mass = 467.32(C27H43F2NO3)Obs. mass = 468.35 (M+H) [Example 200] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-2-(difluoromethyl)morpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methyloctahydro-1,3-diol (Compound D035) Compound (16a) [50 mg, 0.067 mmol] and (S)-2-(difluoromethyl)morpholine hydrochloride (compound 3d06) [40 mg, 0.230 mmol] described in Example 1 were used in Step 3 of Example 1 to obtain compound D035 [4.3 mg, 0.0090 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.77 (1H, td, J = 55.3, 4.2 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.14-4.09 (1H, m), 3.90 (1H, d, J = 11.7 Hz), 3.73-3.62 (2H, m), 2.87 (2H, dd, J = 10.7, 5.9 Hz), 2.74 (1H, d, J = 11.7 Hz), 2.53-2.34 (3H, m), 2.28-2.14 (2H, m), 2.03-1.87 (7H, m), 1.73-1.20 (16H, m), 0.98 (3H, d, J = 6.3 Hz), 0.57 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.35 (M+H) [Example 201] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-2-(difluoromethyl)morpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D036) Compound (16c) [50 mg, 0.067 mmol] and (R)-2-(difluoromethyl)morpholine hydrochloride (compound 3d10) [40 mg, 0.230 mmol] described in Step 3 of Example 1 were used to obtain compound D036 [10.3 mg, 0.0215 mmol] in the same manner as in Example 1. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2 Hz), 5.91 (1H, d, J = 11.2 Hz), 5.77 (1H, td, J = 55.0, 4.0 Hz), 5.05 (2H, d, J = 6.8 Hz), 4.44-4.34 (2H, m), 3.91 (1H, d, J = 11.2 Hz), 3.74-3.61 (2H, m), 2.84 (2H, d, J = 11.7 Hz), 2.78 (1H, d, J = 11.7 Hz), 2.67 (1H, dd, J = 13.2, 4.4 Hz), 2.50-2.24 (5H, m), 2.18-1.96 (5H, m), 1.72-1.22 (13H, m), 0.99 (3H, d, J = 6.3 Hz), 0.59 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.35(M+H) [Example 202] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-2-(difluoromethyl)morpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methyloctahydro-1,3-diol (Compound D037) Compound (16a) [50 mg, 0.067 mmol] and (R)-2-(difluoromethyl)morpholine hydrochloride (compound 3d10) [40 mg, 0.230 mmol] described in Step 3 of Example 1 were used to obtain compound D037 [2.0 mg, 0.0042 mmol] in the same manner as in Example 1. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2 Hz), 6.08 (1H, d, J = 11.2 Hz), 5.77 (1H, td, J = 55.4, 4.1 Hz), 5.28 (1H, dd, J = 2.4, 1.5 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.08 (1H, m), 3.91 (1H, d, J = 10.2 Hz), 3.76-3.68 (1H, m), 3.63 (1H, td, J = 11.5, 2.4 Hz), 2.88-2.73 (4H, m), 2.51 (1H, dd, J = 13.4, 3.2 Hz), 2.47-1.87 (14H, m), 1.61-1.36 (18H, m), 0.98 (3H, d, J = 6.3 Hz), 0.56 (3H, s). Exact Mass = 479.32(C28H43F2NO3)Obs. mass = 480.30 (M+H) [Example 203] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((2R,5S)-2,5-dimethylmorpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D038) Compound (16c) [50 mg, 0.068 mmol] and (2R,5S)-2,5-dimethylmorpholine [30 mg, 0.260 mmol] were treated in the same manner as in Example 1 to obtain compound D038 [14.2 mg, 0.031 mmol]. Exact Mass = 457.36(C29H47NO3)Obs. mass = 458.30 (M+H) [Example 204] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((2R,5R)-2,5-dimethylmorpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D039) Compound (16c) [50 mg, 0.068 mmol] and (2R,5R)-2,5-dimethylmorpholine [30 mg, 0.218 mmol] were treated in the same manner as in Example 1 to obtain compound D039 [13.8 mg, 0.030 mmol]. Exact Mass = 457.36(C29H47NO3)Obs. mass = 458.30 (M+H) [Example 205] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((R)-2-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D040) Compound (16c) [100 mg, 0.174 mmol], (R)-2-methylmorpholine [0.2 mL], and THF [2 mL] were treated in the same manner as in Example 1 to obtain compound D040 [43.7 mg, 0.101 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.0 Hz), 5.91 (1H, d, J = 11.4 Hz), 5.05 (2H, d, J = 6.9 Hz), 4.43-4.35 (2H, m), 3.82 (1H, dd, J = 11.7, 2.1 Hz), 3.67-3.55 (2H, m), 2.88-2.81 (2H, m), 2.76 (1H, d, J = 11.9 Hz), 2.67 (1H, dd, J = 13.3, 4.1 Hz), 2.48 (1H, dd, J = 13.5, 3.9 Hz), 2.44-2.25 (4H, m), 2.10 (1H, td, J = 11.7, 3.4 Hz), 2.04-1.93 (3H, m), 1.77-1.27 (12H, m), 1.12 (3H, d, J = 6.4 Hz), 0.98 (3H, d, J = 6.4 Hz), 0.58 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 432.35 (M+H) [Example 206] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-2-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D041) Compound (14b) [100 mg, 0.174 mmol], (S)-2-methylmorpholine [0.2 mL], and THF [2 mL] were treated in the same manner as in Example 188 to obtain compound D041 [30.0 mg, 0.070 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.88 (1H, d, J = 11.4 Hz), 4.06-3.95 (2H, m), 3.82 (1H, dd, J = 11.7, 2.1 Hz), 3.65-3.58 (2H, m), 2.85-2.76 (3H, m), 2.59 (1H, dd, J = 13.3, 3.7 Hz), 2.42-2.28 (3H, m), 2.23-2.13 (2H, m), 2.08-1.92 (4H, m), 1.87-1.25 (14H, m), 1.11 (3H, d, J = 6.4 Hz), 0.98 (3H, d, J = 6.4 Hz), 0.58 (3H, s). Exact Mass = 431.34(C27H45NO3)Obs. mass = 432.35(M+H) [Example 207] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((R)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D042) Compound (14b) [100 mg, 0.174 mmol], (R)-3-methylmorpholine [0.2 mL], and THF [2 mL] were treated in the same manner as in Example 188 to obtain compound D042 [30.0 mg, 0.070 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.89 (1H, d, J = 11.0 Hz), 4.04-3.96 (2H, m), 3.77 (1H, d, J = 11.4 Hz), 3.68-3.58 (2H, m), 3.23 (1H, dd, J = 11.2, 9.4 Hz), 2.88-2.80 (2H, m), 2.77 (1H, dt, J = 12.2, 3.0 Hz), 2.59 (1H, dd, J = 13.5, 3.0 Hz), 2.48-2.30 (3H, m), 2.28-2.13 (3H, m), 2.08-1.95 (4H, m), 1.88-1.17 (14H, m), 1.00 (6H, d, J = 6.8 Hz), 0.99 (6H, d, J = 5.7 Hz), 0.58 (3H, s). Exact Mass = 431.34(C27H45NO3)Obs. mass = 432.35(M+H) [Example 208] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D043) Compound (14b) [100 mg, 0.174 mmol], (S)-3-methylmorpholine [0.2 mL], and THF [2 mL] were treated in the same manner as in Example 188 to obtain compound D043 [40.9 mg, 0.095 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4 Hz), 5.89 (1H, d, J = 11.0 Hz), 4.06-3.93 (2H, m), 3.78 (1H, dt, J = 11.4, 2.7 Hz), 3.68-3.55 (2H, m), 3.22 (1H, dd, J = 11.4, 9.6 Hz), 2.88-2.70 (3H, m), 2.59 (1H, dd, J = 13.3, 3.7 Hz), 2.42-2.13 (6H, m), 2.06-1.21 (18H, m), 0.99 (3H, d, J = 5.0 Hz), 0.98 (3H, t, J = 3.2 Hz), 0.58 (3H, s). Exact Mass = 431.34(C27H45NO3)Obs. mass = 432.35(M+H) [Example 209] Synthesis of (1R,3R, Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D045) Compound (16a) [50 mg, 0.067 mmol] and (S)-3-methylmorpholine [0.023 mL, 0.202 mmol] were treated in the same manner as in Example 1 to obtain compound D045 [5.6 mg, 0.013 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.0 Hz), 6.08 (1H, d, J = 11.4 Hz), 5.28 (1H, s), 4.89 (1H, d, J = 1.8 Hz), 4.35 (1H, t, J = 5.7 Hz), 4.12 (1H, q, J = 6.1 Hz), 3.78 (1H, dt, J = 11.0, 3.5 Hz), 3.65 (1H, dd, J = 11.9, 3.2 Hz), 3.63-3.57 (1H, m), 3.23 (1H, dd, J = 11.2, 9.4 Hz), 2.88-2.70 (3H, m), 2.51 (1H, dd, J = 13.3, 3.2 Hz), 2.44-2.23 (4H, m), 2.10-1.92 (3H, m), 1.88 (2H, t, J = 5.5 Hz), 1.73-1.30 (12H, m), 0.99 (3H, d, J = 6.4 Hz), 0.98 (3H, d, J = 6.4 Hz), 0.58 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.35(M+H) [Example 210] Synthesis of (1R,3R, Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((R)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D046) Compound (16a) [50 mg, 0.067 mmol] and (R)-3-methylmorpholine [0.023 mL, 0.202 mmol] were treated in the same manner as in Example 1 to obtain compound D046 [5.5 mg, 0.012 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.4 Hz), 6.08 (1H, d, J = 11.4 Hz), 5.28 (1H, s), 4.89 (1H, d, J = 2.3 Hz), 4.35 (1H, t, J = 5.9 Hz), 4.18-4.06 (1H, m), 3.77 (1H, d, J = 11.4 Hz), 3.68-3.55 (2H, m), 3.23 (1H, dd, J = 11.4, 9.1 Hz), 2.95-2.70 (3H, m), 2.55-2.15 (5H, m), 2.05-1.83 (5H, m), 1.73-1.16 (12H, m), 1.00 (3H, d, J = 6.4 Hz), 0.99 (3H, d, J = 6.4 Hz), 0.57 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.35(M+H) [Example 211] Synthesis of (1R,3R, Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((R)-2-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D047) Compound (16a) [50 mg, 0.067 mmol] and (R)-2-methylmorpholine hydrochloride [27.8 mg, 0.202 mmol] were treated in the same manner as in Example 1 to obtain compound D047 [6.7 mg, 0.015 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.4 Hz), 6.08 (1H, d, J = 11.0 Hz), 5.28 (1H, s), 4.89 (1H, d, J = 1.8 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.14-4.10 (1H, m), 3.82 (1H, dd, J = 11.7, 2.1 Hz), 3.68-3.55 (2H, m), 2.89-2.73 (3H, m), 2.51 (1H, dd, J = 13.3, 3.7 Hz), 2.46-2.23 (3H, m), 2.11 (1H, td, J = 11.7, 3.4 Hz), 2.04-1.92 (3H, m), 1.88 (2H, t, J = 6.0 Hz), 1.78-1.25 (12H, m), 1.11 (3H, d, J = 6.4 Hz), 0.98 (3H, d, J = 6.4 Hz), 0.57 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.35(M+H) [Example 212] Synthesis of (1R,3R, Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-2-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D048) Compound (16a) [50 mg, 0.067 mmol] and (S)-2-methylmorpholine hydrochloride [0.023 mL, 0.202 mmol] were treated in the same manner as in Example 1 to obtain compound D048 [6.8 mg, 0.015 mmol]. 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.0 Hz), 6.08 (1H, d, J = 11.0 Hz), 5.28 (1H, s), 4.89 (1H, d, J = 2.3 Hz), 4.34 (1H, t, J = 5.9 Hz), 4.15-4.10 (2H, m), 3.82 (1H, dd, J = 11.7, 2.1 Hz), 3.65-3.59 (2H, m), 2.87 (1H, d, J = 11.4 Hz), 2.79 (2H, t, J = 9.4 Hz), 2.51 (1H, dd, J = 13.3, 3.7 Hz), 2.44-2.23 (3H, m), 2.09-1.92 (4H, m), 1.88 (2H, t, J = 5.5 Hz), 1.81 (1H, dd, J = 20.4, 9.8 Hz), 1.71-1.28 (12H, m), 1.11 (3H, d, J = 5.9 Hz), 0.98 (3H, d, J = 6.4 Hz), 0.57 (3H, s). Exact Mass = 443.34(C28H45NO3)Obs. mass = 444.35(M+H) [Example 213] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3,3-dimethylmorpholino)butan-2-yl)7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D049) Compound (14b) [50 mg, 0.087 mmol] and 3,3-dimethylmorpholine [0.054 mL, 0.435 mmol] were treated in the same manner as in Example 188 to obtain compound D049 [9.3 mg, 0.021 mmol]. 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.88 (1H, d, J = 11.4 Hz), 4.04-3.95 (2H, m), 3.73-3.65 (2H, m), 2.83 (1H, dd, J = 12.1, 3.9 Hz), 2.61-2.52 (3H, m), 2.42-2.37 (3H, m), 2.23-2.13 (2H, m), 2.05-2.02 (1H, m), 1.96-1.93 (1H, m), 1.86-1.81 (1H, m), 1.78-1.72 (1H, m), 1.66-1.50 (6H, m), 1.38-1.32 (3H, m), 1.19-1.16 (1H, m), 1.01 (6H, d, J = 4.1 Hz), 0.97 (3H, d, J = 6.4 Hz), 0.57 (3H, s). Exact Mass = 445.36(C28H47NO3)Obs. mass = 446.30 (M+H) [Example 214] Synthesis of (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-(4-(methylsulfonyl)piperazin-1-yl)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound E002) Compound (16a) [100 mg, 0.134 mmol] and 4-(methylsulfonyl)piperazine [67 mg, 0.408 mmol] were treated in the same manner as in Example 1 to obtain compound E002 [11.2 mg, 0.022 mmol]. 1H-NMR (CD3OD) δ: 6.40 (1H, d, J = 11.2 Hz), 6.16 (1H, d, J = 11.2 Hz), 5.36 (1H, dd, J = 2.4, 1.5 Hz), 4.43 (1H, t, J = 5.9 Hz), 4.22-4.15 (1H, m), 2.95 (1H, dd, J = 9.0, 4.0 Hz), 2.91 (3H, s), 2.68-2.39 (7H, m), 2.33 (1H, dd, J = 13.4, 6.6 Hz), 2.27-1.34 (19H, m), 1.06 (3H, d, J = 6.3 Hz), 0.65 (3H, s). [Example 215] Synthesis of (1R,3S)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-(4-(methylsulfonyl)piperazin-1-yl)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound E004) Compound (16c) [50 mg, 0.067 mmol] and 4-(methylsulfonyl)piperazine [40 mg, 0.244 mmol] were treated in the same manner as in Example 1 to obtain compound E004 [16.0 mg, 0.0316 mmol]. 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.0 Hz), 5.91 (1H, d, J = 11.0 Hz), 5.05 (2H, d, J = 6.9 Hz), 4.43-4.35 (2H, m), 3.22 (4H, t, J = 5.0 Hz), 2.89-2.82 (4H, m), 2.83 (3H, s), 2.67 (1H, dd, J = 13.3, 4.1 Hz), 2.61-2.36 (7H, m), 2.31-2.25 (2H, m), 2.09-2.00 (2H, m), 1.98-1.90 (1H, m), 1.68-1.48 (7H, m), 1.40-1.25 (4H, m), 0.99 (3H, d, J = 6.4 Hz), 0.59 (3H, s). Exact Mass = 506.32(C28H46N2O4S)Obs. mass = 507.25 (M+H) [Reference example 16] Synthesis of (4R)-4-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)pentyl 4-methylbenzenesulfonate (Compound 19b)

[0193] [ka]

[0194] ​ DIBAL-H [1.5 M toluene solution, 10 mL] was added to a toluene solution [50 mL] of (4R)-4-((1R,4S,7aR)-7a-methyl-4-((triethylsilyl)oxy)octahydro-1H-inden-1-yl)pentanenitrile [5.1 g, 15 mmol] at -78°C, and the mixture was stirred for 1.5 hours. The mixture was warmed to 0°C and stirred for an additional 1 hour. The reaction mixture was quenched with methanol. 5 M aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The organic phase was washed with brine and saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was roughly purified by silica gel column chromatography to give (4R)-4-((1R,4S,7aR)-7a-methyl-4-((triethylsilyl)oxy)octahydro-1H-inden-1-yl)pentanal [3.65 g]. ​ The above compound obtained in Step 1 (3.65 g) was dissolved in a mixed solvent of toluene (20 mL) and methanol (20 mL). Sodium tetrahydroborate (0.88 g, 23 mmol) was added at 0°C and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, poured into saturated brine, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (4R)-4-((1R,4S,7aR)-7a-methyl-4-((triethylsilyl)oxy)octahydro-1H-inden-1-yl)pentan-1-ol (2.37 g, 6.68 mmol). ​ To a pyridine solution [12 mL] of the above compound [2.37 g, 6.68 mmol] obtained in Step 2, p-toluenesulfonyl chloride [1.6 g, 8.4 mmol] was added and stirred at room temperature for 3 hours. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. ​ The residue obtained in Step 3 was dissolved in acetone [30 mL], 2M hydrochloric acid [10 mL] was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (4R)-4-((1R,4S,7aR)-4-hydroxy-7a-methyloctahydro-1H-inden-1-yl)pentyl 4-methylbenzenesulfonate [1.37 g, 3.47 mmol]. ​ A dichloromethane solution (30 mL) of (4R)-4-((1R,4S,7aR)-4-hydroxy-7a-methyloctahydro-1H-inden-1-yl)pentyl 4-methylbenzenesulfonate (1.37 g, 3.47 mmol) obtained in Step 4, N-methylmorpholine-N-oxide monohydrate (0.67 g, 5.0 mmol), and molecular sieves 4A (1.5 g) was stirred at 0°C for 1 hour. Tetrapropylammonium perruthenate (120 mg, 0.342 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with heptane and filtered through Celite. The filtrate was washed with saturated aqueous ammonium chloride and then with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (4R)-4-((1R,7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl)pentyl 4-methylbenzenesulfonate [1.15 g, 2.93 mmol]. 1 H-NMR (CDCl3) δ: 7.79 (2H, t, J = 4.1 Hz), 7.35 (2H, d, J = 7.8 Hz), 4.06-3.94 (2H, m), 2.45 (3H, s), 2.43 (1H, dd, J = 12.2, 7.8 Hz), 2.33-2.17 (2H, m), 2.11-1.65 (6H, m), 1.60-0.99 (9H, m), 0.91 (3H, d, J = 6.3 Hz), 0.60 (3H, s). ​ LHMDS (1 M THF solution, 2.6 mL, 2.6 mmol) was added to a THF solution (10 mL) of (2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethyl)diphenylphosphine oxide (Compound 4b, CAS Registry No. 139356-39-1) (0.99 g, 1.7 mmol) under an argon atmosphere at −78°C, and the mixture was stirred for 15 minutes. A THF solution (10 mL) of (4R)-4-((1R,7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl)pentyl 4-methylbenzenesulfonate (1.15 g, 2.93 mmol) obtained in Step 5 was added to the reaction mixture, and the mixture was stirred at −78°C for 1.5 hours. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (4R)-4-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)pentyl 4-methylbenzenesulfonate (Compound 19b) [0.67 g, 0.90 mmol]. 1 H-NMR (CDCl3) δ: 7.80 (2H, d, J = 8.3 Hz), 7.35 (2H, d, J = 8.8 Hz), 6.16 (1H, d, J = 10.7 Hz), 5.81 (1H, d, J = 11.2 Hz), 4.10-3.99 (4H, m), 2.80 (1H, d, J = 11.7 Hz), 2.45 (3H, s), 2.40-2.07 (4H, m), 1.96-1.61 (10H, m), 1.53-1.21 (12H, m), 1.07-1.00 (1H, m), 0.87 (9H, s), 0.86 (9H, s), 0.50 (3H, s), 0.05 (6H, s), 0.05 (6H, s). [Example 216] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-5-(3-(difluoromethoxy)azetidin-1-yl)pentan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A033) Compound 19b [50 mg, 0.067 mmol] described in Reference Example 16...

Claims

1. A compound of the following formula (1A) used in combination with an immunomodulatory substance selected from the group consisting of fingolimod (FTY720), siponimod, ozanimod, and ponesimod: 【Chemistry 1】 [In the formula, R represents either the structure of Rb or Rd in the following formula: 【Chemistry 2】 R 3 is a C substituted with two fluorine atoms; １ ~C ６ represents an alkyl group. The stereochemistry of R 3 may be either the (R) or (S) configuration. R １４ and R15 are each independently a hydrogen atom or C １ ~C ６ represents an alkyl group. The stereochemistry of R 14 and R 15 each independently represents either the (R) configuration or the (S) configuration. n represents an integer of 1 or 2. A pharmaceutical agent for promoting the induction of differentiation from oligodendrocyte precursor cells to oligodendrocytes, comprising a vitamin D derivative represented by the formula:

2. A compound of the following formula (1A) used in combination with an immunomodulatory agent selected from the group consisting of fingolimod (FTY720), siponimod, ozanimod, and ponesimod: 【Transformation 3】 [In the formula, R represents either the structure of Rb or Rd in the following formula: 【Chemistry 4】 R 3 is a C substituted with two fluorine atoms; １ ~C ６ represents an alkyl group. The stereochemistry of R 3 may be either the (R) or (S) configuration. R １４ and R15 are each independently a hydrogen atom or C １ ~C ６ represents an alkyl group. The stereochemistry of R 14 and R 15 each independently represents either the (R) configuration or the (S) configuration. n represents an integer of 1 or 2. A pharmaceutical for promoting remyelination, comprising a vitamin D derivative represented by the formula:

3. A compound of the following formula (1A) used in combination with an immunomodulatory agent selected from the group consisting of fingolimod (FTY720), siponimod, ozanimod, and ponesimod: 【Transformation 5】 [In the formula, R represents either the structure of Rb or Rd in the following formula: 【Transformation 6】 R 3 is a C substituted with two fluorine atoms; １ ~C ６ represents an alkyl group. The stereochemistry of R 3 may be either the (R) or (S) configuration. R １４ and R15 are each independently a hydrogen atom or C １ ~C ６ represents an alkyl group. The stereochemistry of R 14 and R 15 each independently represents either the (R) configuration or the (S) configuration. n represents an integer of 1 or 2. or a pharmaceutically acceptable salt or solvate thereof. a pharmaceutical for treating one or more diseases selected from the group consisting of encephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-associated myelopathy, HIV-associated leukoencephalopathy, Krabbe disease, Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, depression due to drug addiction, autism, Alzheimer's disease, and ischemic stroke.

4. The following formula (1A): 【Transformation 7】 [In the formula, R represents either the structure of Rb or Rd in the following formula: 【Transformation 8】 R 3 is a C substituted with two fluorine atoms; １ ~C ６ represents an alkyl group. The stereochemistry of R 3 may be either the (R) or (S) configuration. R １４ and R15 are each independently a hydrogen atom or C １ ~C ６ represents an alkyl group. The stereochemistry of R 14 and R 15 each independently represents either the (R) configuration or the (S) configuration. n represents an integer of 1 or 2. or a pharmaceutically acceptable salt or solvate thereof, and an immunomodulatory substance selected from the group consisting of fingolimod (FTY720), siponimod, ozanimod, and ponesimod.

5. The following formula (1A): 【Chemistry 9】 [In the formula, R represents either the structure of Rb or Rd in the following formula: 【Chemistry 10】 R 3 is a C substituted with two fluorine atoms; １ ~C ６ represents an alkyl group. The stereochemistry of R 3 may be either the (R) or (S) configuration. R １４ and R15 are each independently a hydrogen atom or C １ ~C ６ represents an alkyl group. The stereochemistry of R 14 and R 15 each independently represents either the (R) configuration or the (S) configuration. n represents an integer of 1 or 2. or a pharmaceutically acceptable salt or solvate thereof, and an immunomodulatory substance selected from the group consisting of fingolimod (FTY720), siponimod, ozanimod, and ponesimod.

6. The following formula (1A): 【Chemistry 11】 [In the formula, R represents either the structure of Rb or Rd in the following formula: 【Chemistry 12】 R 3 is a C substituted with two fluorine atoms; １ ~C ６ represents an alkyl group. The stereochemistry of R 3 may be either the (R) or (S) configuration. R １４ and R15 are each independently a hydrogen atom or C １ ~C ６ represents an alkyl group. The stereochemistry of R 14 and R 15 each independently represents either the (R) configuration or the (S) configuration. n represents an integer of 1 or 2. or a pharmaceutically acceptable salt or solvate thereof, and an immunomodulatory substance selected from the group consisting of fingolimod (FTY720), siponimod, ozanimod, and ponesimod. a pharmaceutical for treating one or more diseases selected from the group consisting of encephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-associated myelopathy, HIV-associated leukoencephalopathy, Krabbe disease, Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, depression due to drug addiction, autism, Alzheimer's disease, and ischemic stroke.

7. The medicine according to any one of claims 1 to 6, wherein the vitamin D derivative represented by formula (1) is any one of the following vitamin D derivatives, or a pharmaceutically acceptable salt or solvate thereof: (1) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B022) (2) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B026) (3) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B034) (4) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B043) (5) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D023) (6) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound G006)

8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the vitamin D derivative represented by formula (1) and the immunomodulatory substance are each contained in a therapeutically effective dose or used in a therapeutically effective dose.

9. The pharmaceutical composition according to any one of claims 1 to 6, wherein the vitamin D derivative represented by formula (1) is contained in a therapeutically effective dose, and the immunomodulatory substance is used in a subtherapeutic dose or is contained in a subtherapeutic dose.

10. The pharmaceutical composition according to any one of claims 1 to 6, wherein the vitamin D derivative represented by formula (1) and the immunomodulatory substance are each contained in a subtherapeutic dose or used in a subtherapeutic dose.

11. The pharmaceutical agent according to any one of claims 1 to 6, which is formulated for systemic administration.

12. The pharmaceutical composition according to any one of claims 1 to 6, wherein the vitamin D derivative represented by formula (1) and the immunomodulatory substance are administered sequentially.

13. The pharmaceutical composition according to any one of claims 1 to 6, wherein the vitamin D derivative represented by formula (1) and the immunomodulatory substance are administered simultaneously.

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