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

Abstract

The invention provides a medicine for promoting differentiation induction of oligodendrocyte precursor cells into oligodendrocytes and a medicine for promoting remyelination. A drug for use in combination with an immunomodulatory substance, the drug comprising a vitamin D derivative represented by formula (1) or a pharmaceutically acceptable salt or solvate thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a drug for promoting differentiation and induction of oligodendrocyte precursor cells into oligodendrocytes and a drug for promoting remyelination, containing a vitamin D derivative, for use 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 its side chain, including pharmaceutically acceptable salts and solvates thereof. Examples of clinically applicable drugs that promote remyelination include multiple sclerosis, neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-related myelopathy, HIV-related 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 caused by drug dependence, autism, Alzheimer's disease, Down syndrome, or ischemic stroke. Background Art

[0002] Oligodendrocytes form myelin sheaths (myelin) on the axons of nerve cells. Their main function is to increase the conduction velocity by inducing saltatory conduction. They are also related to the metabolism of nerve cells.

[0003] Demyelination and incomplete myelination have been reported in some inflammatory demyelinating diseases, neurodegenerative diseases, and psychiatric disorders. Demyelination refers to a state in which the myelin sheath is destroyed and lost, and this loss of myelin causes various neurological symptoms. Multiple sclerosis is a well-known neuroimmunological 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-related myelopathy, HIV-related leukoencephalopathy, and Krabbe disease. Furthermore, peripheral nervous system demyelinating diseases include Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, and Charcot-Marie-Tooth disease. Furthermore, demyelination is often associated with ischemic stroke, leading to subsequent functional decline. Furthermore, there are reports that even in Alzheimer's disease, a neurodegenerative disease, demyelination inhibits plastic changes in myelin sheaths, leading to a decline in cognitive function.

[0004] Furthermore, hypomyelination has been identified in the brains of patients with various mental illnesses, 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 caused by drug dependence, and its association with the disease has been suggested.

[0005] In conclusion, restoring the demyelination and hypomyelination state to normal is important in the treatment of the central nervous system or the peripheral nervous system.

[0006] In recent years, reports have suggested that 1α,25-dihydroxyvitamin D3 promotes the differentiation of oligodendrocyte precursor cells and neural stem cells into oligodendrocytes (Non-Patent Documents 1 and 2). 1α,25-dihydroxyvitamin D3 and its derivatives are known to act in two ways (Non-Patent Document 3). One is through binding to the vitamin D receptor (VDR), a nuclear receptor, to control gene expression (genomic action). The other is through binding to protein disulfideisomerase A3 (PDIA3), initiating signal transduction (non-genomic action). Currently, it is unclear whether the oligodendrocyte differentiation-inducing effects of 1α,25-dihydroxyvitamin D3 reported in Non-Patent Documents 1 and 2 are genomic or non-genomic. On the other hand, a major effect of 1α,25-dihydroxyvitamin D3 and its derivatives is their effects on calcium-phosphorus metabolism. Derivatives with strong genomic effects, generally measured by transcriptional hyperactivity, have strong calcium metabolism, increasing blood calcium levels and potentially causing hypercalcemia. Therefore, the dosage is limited, and the expected pharmacological effect may not be achieved.

[0007] Furthermore, it has been reported that the central migration of 1α,25-dihydroxyvitamin D3 is extremely low (Non-Patent Documents 4 and 5). These documents suggest that achieving sufficient concentrations of 1α,25-dihydroxyvitamin D3 in the brain requires extremely high dosages. However, high doses of 1α,25-dihydroxyvitamin D3 are difficult to administer because they can increase blood calcium levels.

[0008] Therefore, vitamin D derivatives with excellent central migration that can exert effects in the brain, and vitamin D derivatives that can decouple the myelin regeneration-promoting effect from the blood calcium-raising effect, have been desired. However, such derivatives have not been reported to date.

[0009] Drugs for treating demyelinating diseases such as multiple sclerosis include fingolimod (FTY720), interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, natalizumab, siponimod, ozanimod, ponesimod, dimethyl fumarate, and diroximel fumarate. Immunomodulatory drugs such as fumarate, cladribine, ocrelizumab, rituximab, ofatumumab, ublituximab, alemtuzumab, divozilimab, evobrutinib, orelabrutinib, tolebrutinib, remibrutinib, or fenebrutinib. Although immunomodulatory drugs have been shown to be effective in preventing relapses and suppressing symptom progression, they do not directly promote axonal remyelination.

[0010] In addition, regarding therapeutic drugs for demyelinating diseases, there are reports of combining neurotransmitter receptor modulators selected from muscarinic receptor antagonists, dopamine receptor antagonists, histamine receptor antagonists, β-adrenergic receptor modulators, and opioid receptor modulators with immunomodulatory substances (Patent Document 1). However, there are no known drugs for promoting remyelination that contain vitamin D derivatives and are used in combination with immunomodulatory substances.

[0011] Prior art literature

[0012] Patent Literature

[0013] Patent Document 1: Japanese Patent Application No. 2014-506583

[0014] Non-patent literature

[0015] Non-patent document 1: AG de la Fuente et al., Journal of Cell Biology, 2015, 211(5), 975-985

[0016] Non-patent document 2: HA Shirazi et al., Experimental and Molecular Pathology, 2015, 98(2), 240-245

[0017] Non-patent literature 3: MAZmijewski et al., Experimental Dermatology, 2020, 29, 876-884

[0018] Non-patent document 4: MR Durk et al., The Journal of Neuroscience, 2014, 34(21), 7091-7101

[0019] Non-patent document 5: ECYChow et al., The American Journal of Physiology: Endocrinology and Metabolism, 2013, 304(9), E977-989 Summary of the Invention

[0020] Problems to be solved by the invention

[0021] The present invention aims to provide a vitamin D derivative or a pharmaceutically acceptable salt or solvate thereof having excellent central migration properties for use in combination with an immunomodulatory substance as a drug for promoting differentiation and induction of oligodendrocyte precursor cells into oligodendrocytes and a drug for promoting remyelination.

[0022] Means for solving problems

[0023] The present inventors have conducted intensive studies for the above-mentioned purpose, and as a result, have completed the following invention.

[0024] That is, the present invention is a drug for promoting differentiation and induction of oligodendrocytes from oligodendrocyte precursor cells and a drug for promoting remyelination, which is used in combination with an immunomodulatory substance and contains a vitamin D derivative represented by the following formula (1) or a pharmaceutically acceptable salt or solvate.

[0025] [Chemistry 1]

[0026]

[0027] [In the formula, R represents any structure among Ra, Rb, Rc, Rd or Re in the following formula.

[0028] [Chemistry 2]

[0029]

[0030] R 1 、R 3 、R 8 and R 10Each independently represents a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted by 1 to 3 halogen atoms, a halogen atom or a hydrogen atom.

[0031] R 2 、R 4 、R 9 and R 11 Each independently represents a hydrogen atom, a hydroxyl group or a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms. (wherein, R 1 、R 3 、R 8 and R 10 When each independently represents a C1-C6 alkoxy group or a halogen atom optionally substituted by 1 to 3 halogen atoms, the R 1 、R 3 、R 8 and R 10 R substituted on the same carbon atom 2 、R 4 、R 9 and R 11 Not hydroxyl.)

[0032] 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 which is optionally substituted by 1 to 3 halogen atoms, or a C3-C6 cycloalkyl group.

[0033] 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 、R20 and R 21 、R 22 and R 23 They can be bonded to each other to form a ring structure with 3 to 5 members.

[0034] R 5 represents a hydrogen atom, optionally replaced by one -OR 501 C1-C6 alkyl substituted with 1 -OR 501 C3~C6 cycloalkyl substituted with alkyl, R 501 represents a hydrogen atom or a C1-C6 alkyl group.

[0035] R 24 represents a hydrogen atom, a C1-C3 alkyl group or a C1-C3 alkylsulfonyl group.

[0036] The stereochemistry at the 2-position of the pyrrolidine ring (Rb) may be either (R) configuration or (S) configuration.

[0037] X 1 and X 2 Each independently represents a hydrogen atom or a C1-C3 alkyl group, or X 1 and X 2 Together they form methylidene or -(CH2) m -(wherein, m is an integer from 2 to 5).

[0038] X 3 represents a CH2 group or a C=CH2 group (wherein X 1 and X 2 When forming a subunit together, X 3 is not a C=CH2 group).

[0039] n represents an integer of 1 to 3.

[0040] The stereochemistry of the hydroxyl group at position 1 may be either (R) configuration or (S) configuration.

[0041] The stereochemistry of the methyl group at position 20 may be either (R) or (S).]

[0042] Furthermore, the present invention provides a drug for promoting differentiation and induction of oligodendrocytes from oligodendrocyte precursor cells and a drug for promoting remyelination, comprising a vitamin D derivative represented by formula (1) or a pharmaceutically acceptable salt or solvate thereof and an immunomodulatory substance.

[0043] Effects of the Invention

[0044] According to the present invention, as a clinically applicable drug for promoting remyelination, a drug for treating central nervous system diseases represented by multiple sclerosis, neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-related myelopathy, HIV-related 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 caused by drug dependence, autism, Alzheimer's disease and ischemic stroke is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] [ Figure 1 Evaluation results of clinical score measurement for the combination therapy of the vitamin D derivative of the present invention and the immunomodulatory substance (fingolimod). The vertical axis represents the clinical score after administration (Day 30).

[0046] [ Figure 2 Results of blood lymphocyte count measurement for evaluating the effects of the combination therapy of the vitamin D derivative of the present invention and the immunomodulatory substance (fingolimod). The vertical axis represents the blood lymphocyte count after administration (Day 30). DETAILED DESCRIPTION

[0047] The following describes terms used individually or in combination in this specification. Unless otherwise specified, the description of each substituent is common to all parts. In addition, when any variable exists separately in any constituent element, its definition is independent in each constituent element. In addition, combinations of substituents and variables are only allowed when such combinations result in chemically stable compounds. When a substituent itself is substituted with two or more groups, these multiple groups can be present on the same carbon or different carbons, as long as a stable structure is produced.

[0048] In the present invention, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0049] In the present invention, the "C1-C6 alkyl group" refers to a monovalent saturated linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, tert-pentyl, and isohexyl.

[0050] In the present invention, "methylidene" means a =CH2 group.

[0051] In the present invention, "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms. Examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0052] In the present invention, a "C1-C6 alkoxy group" refers to a group formed of an alkyl group having 1 to 6 carbon atoms among the aforementioned "C1-C6 alkyl groups" and an oxy group. Examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a 2-methylpropoxy group, an n-pentoxy group, an isopentoxy 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 tert-butoxy group.

[0053] In the present invention, a "C1-C6 alkylsulfonyl group" refers to a group formed of the aforementioned "C1-C6 alkyl group" and a sulfonyl group. Examples thereof include a methylsulfonyl group, an ethylsulfonyl group, and an isopropylsulfonyl group.

[0054] In the above definitions, "C" in "C1" and other groups represents a carbon atom, and the number following it represents the number of carbon atoms. For example, "C1-C6" represents a group with a carbon number ranging from 1 to 6. Of course, in the present invention, if the carbon number is different, it refers to the group with that carbon number. For example, "C1-C3 alkyl" represents a group with an alkyl group defined as "C1-C6 alkyl" having 1 to 3 carbon atoms. The carbon number in other groups is handled similarly.

[0055] In the present invention, the term "C1-C6 alkyl group optionally substituted with 1-3 halogen atoms" refers to a C1-C6 alkyl group optionally having 1-3 halogen atoms at substitutable positions. When a C1-C6 alkyl group is substituted with multiple halogen atoms, the halogen atoms may be the same or different. The term "C1-C6 alkoxy group optionally substituted with 1-3 halogen atoms" has the same meaning.

[0056] In the present invention, the "vitamin D derivative" refers to a compound having a ring-opening steroid structure (ie, 4-(2-cyclohexylideneethylidene)octahydro-1H-indene).

[0057] 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 they form a methyl subunit or -(CH2) m -(wherein m is an integer from 2 to 5). Among them, X is preferably 1 and X 2 Each independently represents a hydrogen atom or a methyl group, or X 1 and X 2 Together they form the methyl subunit.

[0058] In the above formula (1), X 3 represents a CH2 or C=CH2 group (where X 1 and X 2 When forming a subunit together, X 3 is not a C=CH2 group).

[0059] As X 1 、X 2 and X 3 Preferred examples of the combination include (i) X 1 represents a hydrogen atom or a methyl group, X 2 represents a hydrogen atom, X 3 In the case of a C=CH2 group, (ii) X 1 and X 2 represents hydrogen atoms, X 3 represents a CH2 group, and (iii) X 1 and X 2 Together they form the methyl subunit, X 3 Indicates the case of a CH2 group.

[0060] In the above formula (1), n ​​represents an integer of 1 to 3.

[0061] The stereochemistry of the methyl group at position 20 in the above formula (1) may be either (R) configuration or (S) configuration.

[0062] The stereochemistry of the hydroxyl group at position 1 in the above formula (1) may be either (R) configuration or (S) configuration.

[0063] In the above formula (1), R represents the structure of Ra to Re, among which a pyrrolidine ring (Rb) and a morpholine ring (Rd) are particularly preferred.

[0064] R 1 、R 3 、R 8 and R 10 Each independently represents a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted by 1 to 3 halogen atoms, a halogen atom or a hydrogen atom. 1 、R 3 、R 8 and R 10 Preferred groups include C1-C6 alkyl groups optionally substituted with 1 to 3 fluorine atoms, C3-C6 cycloalkyl groups, C1-C6 alkoxy groups optionally substituted with 1 to 3 fluorine atoms, fluorine atoms or hydrogen atoms, and more preferred groups include methyl, ethyl, methoxy, ethoxy, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, difluoromethoxy, 2,2-difluoroethoxy, 3,3-difluoropropyl, 2,2-difluoropropyl and the like.

[0065] R 2 、R 4 、R 9 and R 11 Each independently represents a hydrogen atom, a hydroxyl group, or a C1-C3 alkyl group optionally substituted by 1-3 halogen atoms. Among them, a hydrogen atom, a hydroxyl group, or a C1-C3 alkyl group optionally substituted by 1-3 fluorine atoms is preferred, and a hydrogen atom or a hydroxyl group is more preferred. 1 、R 3 、R 8 and R 10 When each independently represents a C1-C3 alkoxy group or a halogen atom optionally substituted by 1 to 3 halogen atoms, the R 1 、R 3 、R 8 、R 10 R bonded to the same carbon atom 2 、R 4 、R 9 、R 11 In this case, it is preferably a hydrogen atom instead of a hydroxyl group.

[0066] 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 23Each independently represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, or a C3-C6 cycloalkyl group. Preferred are a hydrogen atom, a C1-C6 alkyl group optionally substituted with 1 to 3 fluorine atoms, or a C3-C6 cycloalkyl group. More preferred groups include a hydrogen atom, a methyl group, an ethyl group, and a difluoromethyl group.

[0067] In addition, 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 They can be bonded to each other to form a ring structure with 3 to 5 members. Here, the ring structure with 3 to 5 members 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 substituted carbon atom, they can form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring.

[0068] R 5 represents a hydrogen atom, optionally replaced by one -OR 501 C1-C6 alkyl substituted with 1 -OR 501 C3~C6 cycloalkyl substituted with alkyl, R 501represents a hydrogen atom or a C1 to C6 alkyl group. 5 Preferably a hydrogen atom or -C(CH3)2-OR 501 .

[0069] R 24 represents a hydrogen atom, a C1-C3 alkyl group, or a C1-C3 alkylsulfonyl group, and is particularly preferably a methylsulfonyl group.

[0070] In the present invention, among the vitamin D derivatives or pharmaceutically acceptable salts or solvates represented by formula (1), more specific examples of preferred examples include the vitamin D derivatives or pharmaceutically acceptable salts or solvates represented by formulas (1-1) and (1-2).

[0071] Vitamin D derivative represented by formula (1-1) or pharmaceutically acceptable salt or solvate

[0072] [Chemistry 3]

[0073]

[0074] [In the formula, the stereochemistry of the hydroxyl group at position 1 represents either (R) configuration or (S) configuration.

[0075] R 3 It represents a C1-C6 alkyl group optionally substituted by 1 to 3 fluorine atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted by 1 to 3 fluorine atoms, a fluorine atom or a hydrogen atom.

[0076] R 4 represents a hydrogen atom, a hydroxyl group or a C1-C3 alkyl group optionally substituted by 1-3 fluorine atoms. (wherein, R 3 When R represents a C1-C3 alkoxy group optionally substituted by 1-3 fluorine atoms or a fluorine atom, 4 Not hydroxyl.)

[0077] R 3 and R 4 They can be bonded to each other to form a ring structure with 3 to 5 members.

[0078] R 5 Indicates that one -OR is selected 501 C1-C6 alkyl substituted with alkyl radical, R 501 represents a hydrogen atom or a C1-C6 alkyl group.

[0079] In addition, R 5 The stereochemistry of represents either (R) configuration or (S) configuration.

[0080] X 1 and X 2 Each independently represents a hydrogen atom or a C1-C3 alkyl group, or X1 and X 2 Together they form a methyl subunit or -(CH2) m -(wherein m is an integer from 2 to 5).

[0081] X 3 represents a CH2 group or a C=CH2 group (wherein X 1 and X 2 When forming a subunit together, X 3 is not a C=CH2 group).

[0082] n represents an integer of 1 to 3.

[0083] The stereochemistry at position 20 in the above formula (1-1) may be either (R) or (S).]

[0084] Vitamin D derivatives or pharmaceutically acceptable salts or solvates represented by formula (1-2)

[0085] [Chemistry 4]

[0086]

[0087] [In the formula, the stereochemistry of the hydroxyl group at position 1 represents either (R) configuration or (S) configuration.

[0088] 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 or a C3-C6 cycloalkyl group which is optionally substituted by 1 to 3 halogen atoms.

[0089] R 12 and R 13 、R 14 and R 15 、R 16 and R 17 、R 18 and R 19 They can be bonded to each other to form a ring structure with 3 to 5 members.

[0090] X 1 and X 2 Each independently represents a hydrogen atom or a methyl group, or X 1 and X 2 Together they form the methyl subunit.

[0091] X 3 represents a CH2 group or a C=CH2 group (wherein X 1 and X2 When forming a subunit together, X 3 is not a C=CH2 group).

[0092] n represents an integer of 1 to 3.

[0093] The stereochemistry at position 20 in the above formula (1-2) may be either (R) or (S).]

[0094] It should be noted that the vitamin D derivatives or pharmaceutically acceptable salts or solvates represented by formula (1-1) and (1-2), R 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 in the vitamin D derivative represented by formula (1) or its pharmaceutically acceptable salt or solvate can be directly applied to the elements. That is, the preferred groups in the vitamin D derivative represented by formula (1) are also preferred groups in the vitamin D derivatives represented by formulas (1-1) and (1-2), and the elements obtained by combining the preferred constituent elements described in each of the vitamin D derivatives represented by formula (1) are also preferred in the vitamin D derivatives represented by formulas (1-1) and (1-2).

[0095] Furthermore, among the vitamin D derivatives or pharmaceutically acceptable salts or solvates represented by formulas (1-1) and (1-2), more specific examples of preferred examples include the vitamin D derivatives or pharmaceutically acceptable salts or solvates represented by the following formula (1A).

[0096] A vitamin D derivative represented by formula (1A) or a pharmaceutically acceptable salt or solvate thereof.

[0097] [Chemistry 5]

[0098]

[0099] [In the formula, R represents any structure of Rb or Rd in the following formula.

[0100] [Chemistry 6]

[0101]

[0102] R 3It represents a C1-C6 alkyl group which may be substituted by two fluorine atoms.

[0103] R 3 The stereochemistry of represents either (R) configuration or (S) configuration.

[0104] R 14 and R 15 Each independently represents a hydrogen atom or a C1-C6 alkyl group. 14 and R 15 The stereochemistry of each independently represents either (R) configuration or (S) configuration.

[0105] n represents an integer of 1 or 2.]

[0106] Preferred specific examples of the vitamin D derivative represented by formula (1) of the present invention include the compounds shown in the following table.

[0107] [Table 1-1]

[0108]

[0109] [Table 1-2]

[0110]

[0111] [Table 1-3]

[0112]

[0113] [Table 1-4]

[0114]

[0115] [Table 1-5]

[0116]

[0117] [Table 1-6]

[0118]

[0119] [Table 1-7]

[0120]

[0121] [Table 1-8]

[0122]

[0123] [Table 1-9]

[0124]

[0125] [Table 1-10]

[0126]

[0127] [Table 1-11]

[0128]

[0129] [Table 1-12]

[0130]

[0131] [Table 1-13]

[0132]

[0133] [Table 1-14]

[0134]

[0135] [Table 1-15]

[0136]

[0137] [Table 1-16]

[0138]

[0139] [Table 1-17]

[0140]

[0141] [Table 1-18]

[0142]

[0143] [Table 1-19]

[0144]

[0145] [Table 1-20]

[0146]

[0147] [Table 1-21]

[0148]

[0149] [Table 1-22]

[0150]

[0151] [Table 1-23]

[0152]

[0153] [Table 1-24]

[0154]

[0155] [Table 1-25]

[0156]

[0157] [Table 1-26]

[0158]

[0159] [Table 1-27]

[0160]

[0161] [Table 1-28]

[0162]

[0163] [Table 1-29]

[0164]

[0165] [Table 1-30]

[0166]

[0167] [Table 1-31]

[0168]

[0169] [Table 1-32]

[0170]

[0171] [Table 1-33]

[0172]

[0173] Among them, more preferred compounds include:

[0174] (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)

[0175] (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)

[0176] (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)

[0177] (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)

[0178] (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)

[0179] (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).

[0180] The vitamin D derivatives of the present invention can be converted into pharmaceutically acceptable salts thereof as needed. Examples of such salts include hydrochloride, hydrobromide, methanesulfonate, p-toluenesulfonate, acetate, trifluoroacetate, fumarate, maleate, malate, succinate, oxalate, citrate, and benzoate. Preferred salts include hydrochloride, acetate, fumarate, maleate, malate, and succinate.

[0181] Furthermore, the vitamin D derivatives of the present invention can be converted into pharmaceutically acceptable solvates thereof 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. In particular, water, methanol, ethanol, and acetonitrile are preferred solvents.

[0182] <General Synthesis Example>

[0183] The synthesis of the vitamin D derivative represented by the above formula (1) can be carried out by any method. For example, when n=1 in the above formula (1), the synthesis can be carried out according to Scheme 1. That is, compound (2) and cyclic amine compound (3) are coupled in the presence of a base, and then the hydroxyl protecting group is deprotected and purified to obtain the target compound (1).

[0184] [scheme1]

[0185] [Chemistry 7]

[0186]

[0187] (It should be noted that R 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 p-toluenesulfonyl group (OTs). In particular, an iodine atom and a p-toluenesulfonyl group are preferred leaving groups.

[0188] In addition, R in compound (2) 31 represents a protective group for a hydroxyl group. Examples of the protective group include trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), and tert-butyldiphenylsilyl (TBDPS). Among them, tert-butyldimethylsilyl (TBS) is preferred.

[0189] The cyclic amine compound (3) to be coupled with the compound (2) (step 1) may be a free form or a salt. The amount of the amine compound (3) used in this reaction may be 1 to 5 equivalents, preferably 3 to 5 equivalents. In addition, the base in this step is not particularly limited, and preferred bases include potassium carbonate, potassium bicarbonate, and cesium carbonate. The base may be added in an amount of 1 to 5 equivalents, preferably 3 to 5 equivalents. In addition, in order 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. In addition, there is no particular limitation on the solvent, and preferred solvents include N,N-dimethylformamide, N-methyl-2-pyrrolidone, etc. In addition, the reaction temperature of this coupling reaction is preferably 40°C to 70°C, and the reaction time is preferably 6 to 48 hours.

[0190] It should be noted that in step 1, purification can be performed before deprotection reaction (step 2), or deprotection reaction can be performed in bold in step 1 (step 2).

[0191] The conditions for the deprotection reaction (step 2) in the above scheme 1 are not particularly limited if they are deprotection conditions for silyl-based protecting groups, and examples include deprotection using tetrabutylammonium fluoride (TBAF) and deprotection using hydrochloric acid. Preferred conditions include adding 1 to 3 equivalents of tetrabutylammonium fluoride (TBAF) per hydroxyl group in tetrahydrofuran (THF) and stirring from room temperature to reflux temperature. In addition, another preferred condition includes adding 1 to 3 equivalents of hydrochloric acid per hydroxyl group in a solvent such as acetone or 2-butanone and stirring at room temperature. The concentration of hydrochloric acid is preferably 1M to 6M. Purification after post-treatment of this reaction can be performed by general purification methods such as silica gel column chromatography and HPLC, thereby obtaining the vitamin D derivative (1) of the present invention.

[0192] The compound of the above formula (2) can be synthesized, for example, according to the following Scheme 2.

[0193] [scheme 2]

[0194] [Chemistry 8]

[0195]

[0196] (In the above scheme 2, X 1 、X 2 and X 3 Same as the definition in the above formula (1). 30 、R 31 Same as the definition of scheme1.)

[0197] That is, compound (2) can be obtained by subjecting a phosphine oxide derivative (4) and a ketone body (5) to a coupling reaction under alkaline conditions. Preferred bases in 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 the base used is preferably 1.1 to 2 equivalents of compound 4. In addition, this reaction is preferably carried out at -78 to -0°C for 1 to 3 hours.

[0198] It should be noted that in the above formula (2), when R 30 is p-toluenesulfonyl (OTs), R 31 In the case of tert-butyldimethylsilyl (TBS), the compounds of the combinations shown in the following table are known.

[0199] [Table 2]

[0200]

[0201] In addition, when the above formula (2) is not a known compound, it can be synthesized as follows.

[0202] For example, when X 1 is methyl, X 2 is a hydrogen atom, X 3 When C=CH2, the compound (2g) can be synthesized as shown in the following Scheme 3. Specifically, the compound (6c) (CAS Registry No. 173388-39-1) and the compound (7b) (CAS Registry No. 203126-90-3) can be coupled in the presence of a Pd catalyst to obtain the compound (2g). Compound (2g) can be coupled with a cyclic amine compound (3) and deprotected in the same manner as in Scheme 1 to obtain the target vitamin D derivative (1).

[0203] [scheme3]

[0204] [Chemistry 9]

[0205]

[0206] In addition, as a different synthesis method of the vitamin D derivative represented by the above formula (1), the compound (8) is synthesized by coupling the known compound (6c) and the cyclic amine compound (3) in the presence of a base, and then coupled with the compound (9) in the presence of a Pd catalyst, followed by a deprotection reaction, thereby obtaining the vitamin D derivative represented by the above formula (1).

[0207] [scheme 4]

[0208] [Chemistry 10]

[0209]

[0210] [Here, R, X of the above scheme 1 and X 2 Same as the definition in the above formula (1). In addition, the stereochemistry at position 1 of compound (1) and compound (9) is either (R) configuration or (S) configuration.]

[0211] In the case where n=2 in the above formula (1), the synthesis can be carried out, for example, as in the following Scheme 5. That is, the primary hydroxyl group of the 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), the coupling reaction and deprotection reaction of the cyclic amine compound (3) are carried out in the same manner as in Scheme 1 to obtain the vitamin D derivative (1) of the present invention.

[0212] [scheme 5]

[0213] [Chemistry 11]

[0214]

[0215] [Here, R, X of the above scheme 1 、X 2 and X 3 Same as the definition in formula (1), R 30 and R 31 Same as the definition in scheme 1. In addition, in the vitamin D derivative (1) in this scheme, n=2.]

[0216] Alternatively, using compound (2) (n=1) of Scheme 1, a vitamin D derivative (1) with (n=2) can be synthesized as in Scheme 6 below. Specifically, compound (2) is cyanided to obtain compound (13), which is then treated with diisobutylaluminum hydride (DIBAL-H) ​​to obtain an aldehyde (14), which is then reduced to obtain an alcohol (15). Compound (15) is tosylated to obtain an OTs compound (16), which is then subjected to a coupling reaction with a cyclic amine compound (3) in the same manner as in Scheme 1, followed by deprotection to obtain the desired vitamin D derivative represented by the above formula (1). It should be noted that the cyanation, DIBAL reduction, and aldehyde reduction reactions in Scheme 6 are carried out under commonly used conditions. For example, the cyanation reaction is carried out 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°C to 100°C. Alternatively, for DIBAL reduction, 1 to 2 equivalents of diisobutylaluminum hydride (DIBAL-H) ​​are added to toluene at -78°C to 0°C and the reaction is carried out for about 0.5 to 2 hours. For aldehyde reduction, 1 to 3 equivalents of sodium tetrahydroborate are used at 0°C to room temperature for about 1 to 3 hours to obtain compound (16).

[0217] [scheme 6]

[0218] [Chemistry 12]

[0219]

[0220] [Here, R, X in the above scheme 1 、X 2 and X 3 Same as the definition in formula (1), R 30 With R 31 Same definition as scheme1.]

[0221] In addition to the above scheme, the vitamin D derivative represented by the above formula (1) can also be synthesized by using the aldehyde (14) through reductive amination with the cyclic amine compound (3) and subsequent deprotection as shown in the following scheme 7.

[0222] [scheme7]

[0223] [Chemistry 13]

[0224]

[0225] [Here, R, X in the above scheme 1 、X 2 and X 3 Same as the definition in formula (1), R 31 Same definition as scheme1.]

[0226] As the reductive amination reagent, sodium triacetoxyborohydride and sodium cyanoborohydride are preferred. The solvent is not particularly limited, but THF is a preferred solvent. Alternatively, the cyclic amine compound (3) may be used as a solvent. The reductive amination reaction is carried out, for example, by reacting 1 to 5 equivalents of the amine compound (3) with a reducing agent (1 to 3 equivalents) relative to the compound (14) in tetrahydrofuran (THF), followed by a deprotection reaction to obtain the compound (1).

[0227] When R=Rc, Re, and n=2, the synthesis is carried out, for example, as in the following scheme 8. That is, compound (2) (R 30=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 a reductive amination reaction with amine (3) to obtain compound (15), which is then deprotected to obtain the vitamin D derivative (1) of the present invention (R = Rc, Re). It should be noted that the cyanation, DIBAL reduction, and reductive amination reactions in Scheme 8 are carried out under the same conditions as those described in Schemes 6 and 7. Furthermore, the reductive amination reaction is carried out under the same conditions as those described in Scheme 7.

[0228] [scheme 8]

[0229] [Chemistry 14]

[0230]

[0231] [Here, R, X of the above scheme 1 、X 2 and X 3 Same as the definition in formula (1), R 31 Same definition as scheme1.]

[0232] The vitamin D derivative represented by formula (1) or its pharmaceutically acceptable salt or solvate has excellent central migration and further has an excellent effect of promoting the differentiation and induction of oligodendrocyte precursor cells or neural stem cells into oligodendrocytes. Due to its excellent oligodendrocyte differentiation-inducing promoting effect, the vitamin D derivative represented by formula (1) or its pharmaceutically acceptable salt or solvate is useful as a remyelination promoter.

[0233] The vitamin D derivative represented by formula (1) or a pharmaceutically acceptable salt or solvate thereof can be used clinically as a remyelination promoter, and can be used as a therapeutic agent for diseases related to demyelination or incomplete myelination, such as multiple sclerosis, neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1 related myelopathy, HIV related 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 caused by drug dependence, autism, Alzheimer's dementia and ischemic stroke.

[0234] The present invention relates to a drug for promoting differentiation induction of oligodendrocyte precursor cells to oligodendrocytes and a drug for promoting remyelination, which is used in combination with an immunomodulatory substance and contains a vitamin D derivative shown in formula (1). Immunomodulatory substances can reduce the frequency and severity of attacks or the accumulation of lesions, but it is believed that they do not promote the remyelination of damaged axons. By combining the vitamin D derivative shown in formula (1) with an immunomodulatory substance, the therapeutic effect of the immunomodulatory substance can be improved, and it is expected to further promote the effect of differentiation induction from oligodendrocyte precursor cells to oligodendrocytes.

[0235] Examples of immunomodulatory substances that can be used in combination with the vitamin D derivative represented by formula (1) include fingolimod (FTY720), interferon β-1a, interferon β-1b, glatiramer acetate, and The invention relates to an anti-cancer drug comprising the following: acetate, mitoxantrone, natalizumab, siponimod, ozanimod, ponesimod, dimethyl fumarate, diroximel fumarate, cladribine, ocrelizumab, rituximab, ofatumumab, ublituximab, alemtuzumab, divozilimab, evobrutinib, orelabrutinib, tolebrutinib, remibrutinib and fenebrutinib, with fingolimod (FTY720) being particularly preferred.

[0236] The vitamin D derivative or pharmaceutically acceptable salt or solvate shown in formula (1) for promoting differentiation induction from oligodendrocyte precursor cells to oligodendrocytes and the drug for promoting remyelination are prepared into pharmaceutical compositions using carriers, bases and excipients, and other additives commonly used in formulations. The carriers, bases and excipients used in the pharmaceutical composition may be any of solid or liquid, for example, lactose, magnesium stearate starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol and medium-chain fatty acid triglycerides, and other commonly used substances. Administration may be oral administration using tablets, pills, capsules, soft capsules, granules, powders and liquids, or any form of non-oral administration such as intravenous and intramuscular injections, suppositories, transdermal and nasal injections.

[0237] The present invention relates to a drug for promoting differentiation induction from oligodendrocyte precursor cells to oligodendrocytes and a drug for promoting remyelination, comprising a vitamin D derivative represented by formula (1) and an immunomodulatory substance. The drug comprising the vitamin D derivative represented by formula (1) and the immunomodulatory substance can be prepared into a pharmaceutical composition using conventional carriers, bases, excipients, and other additives as described above, and administered in the same manner.

[0238] In some embodiments, the present invention includes using one or both of the vitamin D derivative of formula (1) and the immunomodulatory substance in a therapeutically effective dose or an optimal dose. In some embodiments, the present invention includes using a dose (subtherapeutic dose) lower than the therapeutic dose of one or both of the vitamin D derivative of formula (1) and the immunomodulatory substance. In some embodiments, the present invention includes using a therapeutically effective dose or an optimal dose of the vitamin D derivative of formula (1) and an dose lower than the therapeutic dose of the immunomodulatory substance. In some embodiments, the present invention includes using a therapeutically effective dose or an optimal dose of the immunomodulatory substance and an dose lower than the therapeutic dose of the vitamin D derivative of formula (1).

[0239] In some embodiments, one or both of the vitamin D derivative shown in formula (1) and the immunomodulatory substance are formulated into a therapeutically effective amount or an optimal amount. In some embodiments, one or both of the vitamin D derivative shown in formula (1) and the immunomodulatory substance are formulated into an amount lower than the therapeutic amount. In some embodiments, the vitamin D derivative shown in formula (1) is formulated into a therapeutically effective amount or an optimal amount, and the immunomodulatory substance is formulated into an amount lower than the therapeutic amount. In some embodiments, the immunomodulatory substance is formulated into a therapeutically effective amount or an optimal amount, and the vitamin D derivative shown in formula (1) is formulated into an amount lower than the therapeutic amount.

[0240] In this specification, the term "therapeutically effective dose or optimal dose" refers to an amount that produces the therapeutic effect for which it is administered when administered alone. The correct dose is believed to vary depending on the purpose of treatment and is determined by a person skilled in the art using a known method (e.g., 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).

[0241] As used herein, the term "subtherapeutic dose" refers to an amount of a pharmacologically active substance that is functionally insufficient to induce the desired pharmacological effect when administered alone, or is less than the established therapeutic dose of the specific pharmacological agent (e.g., those described in references searched by those skilled in the art, such as 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, etc.), or the actual level of the pharmacologically active substance in the subject. A "subtherapeutic amount" can be defined in relative terms, i.e., as a percentage (less than 100%) of the amount of the pharmacologically active substance conventionally administered. For example, a subtherapeutic amount can be from about 1% to about 75% of the amount of the pharmacologically active substance conventionally administered. In some embodiments, a subtherapeutic amount can be about 75%, 50%, 30%, 25%, 20%, 10% or less of the amount of the pharmaceutically active substance conventionally administered.

[0242] The therapeutically effective amount of the active ingredient in the medicament of the present invention containing the vitamin D derivative represented by formula (1) varies depending on the route of administration, the patient's age, sex, and the severity of the disease, but is generally about 0.1 to 10,000 μg / day, and the frequency of administration is generally 1 to 3 times / day to 1 to 3 times / week. It is preferable to prepare a formulation to meet these conditions. However, since the administration amount varies depending on various conditions, an amount less than the above administration amount may be sufficient, and an administration amount exceeding the above range may also be required. When used in combination with an immunomodulatory substance, an amount less than the therapeutic amount may be used, 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 above administration amount.

[0243] The immunomodulatory substance used in combination with the medicament of the present invention containing the vitamin D derivative represented by formula (1) is used in a manner lower than the therapeutically effective amount or the therapeutic amount. For example, the therapeutically effective amount of benztropine is about 1 mg to about 10 mg per day, the therapeutically effective amount of fingolimod is about 0.1 mg to about 1.5 mg per day, the therapeutically effective amount of interferon beta-1a is about 30 μg per week, and the therapeutically effective amount of interferon beta-1b is about 250 μg every other day to about 500 μg every other day. The immunomodulatory substance can be used in an amount lower than the therapeutic amount, 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 conventionally administered amount. For example, fingolimod is used in an amount less than a therapeutic amount of about 0.005 mg per day to about 0.375 mg per day; interferon beta-1a can be used in an amount less than a therapeutic amount of about 0.3 μg per week to about 23 μg per week, and interferon beta-1b can be used in an amount less than a therapeutic amount of about 2 μg every other day to about 190 μg every other day.

[0244] Fingolimod (FTY720) is typically administered in a therapeutically effective amount of about 0.5 mg 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). For example, see Kappos et al., N Engl J Med 362: 387-401 (2010). Thus, in some embodiments, the subtherapeutic amount 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).

[0245] The present invention provides a method for combined use of a drug containing a vitamin D derivative represented by formula (1) and an immunomodulatory substance for promoting differentiation induction of oligodendrocyte precursor cells into oligodendrocytes or for promoting remyelination.

[0246] The drug containing the vitamin D derivative shown in formula (1) and the immunomodulatory substance can be administered together, separately, simultaneously, or at different times. When administered, the drug containing the vitamin D derivative shown in formula (1) and the immunomodulatory substance can be administered independently at a frequency of 1, 2, 3, 4 or more times per day as needed. In some embodiments, these action substances are administered once a day. In some embodiments, these action substances are administered as a mixture, for example, at the same one or more time points. One or more action substances can be administered as a sustained-release preparation.

[0247] In some embodiments, the combined administration of a drug containing a vitamin D derivative of formula (1) and an immunomodulatory substance comprises administering one active substance within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active substance. Combined administration includes administering the two active substances 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, combined administration can be achieved by preparing a co-formulation, i.e., a single pharmaceutical composition containing the two active substances (i.e., administered as a drug containing a vitamin D derivative of formula (1) and an immunomodulatory substance). In other embodiments, the active substances and / or auxiliary substances can also be linked to each other or made into a combination.

[0248] In some embodiments, one or both of a drug containing a vitamin D derivative represented by formula (1) and an immunomodulatory substance can be administered prophylactically to prevent an unwanted recurrence of symptoms of a demyelinating disease such as multiple sclerosis (e.g., to prevent or delay the recurrence of a clinical attack of multiple sclerosis), or administered therapeutically to achieve a desired alleviation of the symptoms of a demyelinating disease and to maintain the duration of such alleviation of the symptoms of a demyelinating disease.

[0249] On the other hand, the present invention provides a kit 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 caused by drug dependence, autism, Alzheimer's disease and ischemic stroke. In some embodiments, the kit comprises a drug containing a vitamin D derivative represented by formula (1) and an immunomodulatory substance.

[0250] Example

[0251] The present invention is described in more detail below with reference to examples, but the present invention is not limited thereto.

[0252] The abbreviations in the present invention are as follows:

[0253] Boc = tert-butoxycarbonyl

[0254] DAST = diethylaminosulfur trifluoride

[0255] DIBAL-H = Diisobutylaluminum hydride

[0256] DMF=N,N-dimethylformamide

[0257] LHMDS = Lithium Bis(trimethylsilyl)amide

[0258] MBP = Myelin Basic Protein (MBP)

[0259] MS4A = Molecular Sieve 4A

[0260] NMO = N-methylmorpholine-N-oxide

[0261] NMP = N-methyl-2-pyrrolidone

[0262] PTLC = Thin Layer Chromatography

[0263] TBAF = Tetrabutylammonium fluoride

[0264] TBS = tert-butyldimethylsilyl

[0265] TES = triethylsilyl

[0266] TESCl = triethylsilane

[0267] THF = Tetrahydrofuran

[0268] TPAP = Tetrapropylammonium perruthenate

[0269] Ts = p-toluenesulfonyl

[0270] TsCl = p-toluenesulfonyl chloride

[0271] In the following examples, when the compounds of the present invention were obtained by preparative HPLC, the preparation conditions were as follows:

[0272] Column: YMC-Pack ODS AM manufactured by YMC Corporation, inner diameter 3cm-30cm

[0273] Mobile phase A: 5% acetonitrile in water (with 0.1% acetic acid added)

[0274] Mobile phase B: 95% acetonitrile in water (with 0.1% acetic acid added)

[0275] Addition amount: Dissolve the crude product in 1.3 mL of methanol and inject

[0276] Liquid delivery volume: 12mL / min

[0277] UV: 265nm

[0278] Liquid delivery procedure:

[0279] 0-5 minutes: 5% solution B / 95% solution A

[0280] 5-45 minutes: Gradient to 100% Solution B over 40 minutes

[0281] 45-50 minutes: 100% Solution B

[0282] 50-55 minutes: 5-minute gradient to 5% solution B / 95% solution A

[0283] In the following examples, when the analysis was performed by HPLC / MS, the analysis conditions were as follows:

[0284] Column: Gemini C18 manufactured by Phenomenex, 3 μm, inner diameter 4.6 mm-30 mm

[0285] Mobile phase A: 5% acetonitrile in water (with 0.1% trifluoroacetic acid added)

[0286] Mobile phase B: 95% acetonitrile in water (with 0.1% trifluoroacetic acid added)

[0287] Liquid delivery rate: 1.2mL / min

[0288] UV: 254nm

[0289] Liquid delivery procedure:

[0290] 0~0.01 minutes: 2% solution B / 98% solution A

[0291] 0.01-0.3 min: gradient to 40% solution B / 60% solution A

[0292] 0.3-2.3 minutes: Gradient to 100% Solution B

[0293] 2.3 minutes to 4.2 minutes: 100% Solution B

[0294] 4.2 minutes to 4.3 minutes: Gradient to 2% Solution B / 98% Solution A

[0295] 4.3 minutes to 5.2 minutes: 2% solution B / 98% solution A

[0296] 5.2 minutes: End of analysis

[0297] [Reference Example 1]

[0298] Synthesis of (2S)-2-((1R,3aS,7aR,E)-4-((Z)-2((3S,5R)-3,5-bis((tert-butyldimethylsilyl)oxy)-2-methylenecyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (Compound (2a))

[0299] [Chemistry 15]

[0300]

[0301] In an argon atmosphere, to a THF solution [50 mL] of ((Z)-2-((3S,5R)-3,5-bis((tert-butyldimethylsilyl)oxy)-2-methylenecyclohexylidene)ethyl)diphenylphosphine oxide (compound 4a, CAS Registry No. 81522-68-1) [7.42 g, 12.7 mmol] was added LHMDS [1 M in toluene, 10 mL], and the mixture was stirred at -78°C for 1 hour. To this was added a THF solution [20 mL] of (2S)-2-((1R,3aR,7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (compound (5a), CAS Registry No. 342645-83-4) [3.6 g, 9.9 mmol], and the mixture was further stirred at the same temperature for 1 hour. The reaction mixture was warmed to room temperature and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with a mixed solvent of heptane / ethyl acetate (1 / 1). The organic phase was washed with water and then with 50% methanol in water, 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%)

[0302] 1 H-NMR(CDCl3)δ:7.79(2H,d,J=8.2Hz), 7.31(2H,d,J=8.2Hz), 6.22(1H,d,J=11.0Hz), 5.99(1H,d,J=11.0Hz), 5 .17(1H,d,J=2.0Hz),4.84(1H,d,J=2.0Hz),4.38-4.16(2H,m),3.98(1H,dd,J=9.1,3.2Hz),3.80(1H,dd,J=9.1, 6.4Hz), 2.83 (1H, d, J = 12.3Hz), 2.45 (3H, s), 2.42 (1H, d, J = 4.1Hz), 2.22 (1H, dd, J = 13.0, 7.5Hz), 1.97-1.57 (8H ,m),1.53-1.15(9H,m),0.99(3H,d,J=6.4Hz),0.87(9H,s),0.86(9H,s),0.49(3H,s),0.06(9H,s),0.04(3H,s).

[0303] [Reference Example 2]

[0304] Synthesis of (2S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((tert-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (Compound 2b)

[0305] [Chemistry 16]

[0306]

[0307] In an argon atmosphere, LHMDS [1 M toluene solution, 20 mL] was added to a THF solution [85 mL] of (2-((3R,5R)-3,5-bis((tert-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-oxooctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (compound (5a), CAS Registry No. 342645-83-4) [5.06 g, 13.9 mmol] at -78°C, and the mixture was stirred at -78°C for 2 hours. The reaction mixture was warmed to 0°C and stirred for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture at room temperature, and the mixture was extracted with a heptane / ethyl acetate (1 / 1) mixed solvent. 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 recovered and dried to obtain compound (2b) [6.40 g, 8.92 mmol]. (Yield = 64%)

[0308] 1H-NMR (CDCl3) δ: 7.79 (2H, d, J = 8.2Hz), 7.35 (2H, d, J = 8.2Hz), 6.15 (1H, d, J = 11.0Hz), 5.79 (1H, d, J = 11.4Hz), 4.12-4.0 2(2H,m),3.98(1H,dd,J=9.1,2.7Hz),3.81(1H,dd,J=9.1,6.4Hz), 2.80(1H,dd,J=12.1,3.9Hz), 2.46(3H,s),2.36(2H, dd,J=13.0,4.8Hz),2.25(1H,dd,J=14.2,2.7Hz), 2.10(1H,dd,J=12.8,8.2Hz),2.00-1.90(2H,m),1.80-1.60(6H,m),1 .55-1.16(6H,m),0.99(3H,d,J=6.4Hz),0.87(9H,s),0.85(9H,s),0.50(3H,s),0.05(3H,s),0.05(3H,s),0.04(6H,s).

[0309] [Reference Example 3]

[0310] Synthesis of (S)-2-((1R,3aS,7aR,E)-4-(2-((3S,5R)-3,5-bis((tert-butyldimethylsilyl)oxy)-4-methylenecyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (Compound 2c)

[0311] [Chemistry 17]

[0312]

[0313] To a THF solution [40 mL] of (2-((3R,5R)-3,5-bis((tert-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-oxooctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (compound (5a), CAS Reg No. 342645-83-4, 2.35 g, 6.45 mmol) was added LHMDS [1M THF solution, 8.5 mL] at -78°C under an argon atmosphere, 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 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 obtain compound (2c) (1.70 g, 2.30 mmol). (Yield = 54%)

[0314] 1 H-NMR(CDCl3)δ:7.79(2H,d,J=8.8Hz),7.35(2H,d,J=7.8Hz),6.20(1H,d,J=11.2Hz),5.82(1H,d,J=11.2Hz),4.97(1H,s),4.9 2(1H,s),4.45-4.40(2H,m),3.99(1H,dd,J=9.3,2.9Hz),3.81(1H,dd,J=9.0,6.6Hz),2.81(1H,dd,J=12.2,3.4Hz),2.54-2.42 (2H,m),2.45(3H,s),2.32(1H,dd,J=13.2,3.4Hz),2.17(1H,dd,J=12.7,8.3Hz),2.02-1.90(2H,m),1.78-1.63(4H,m),1.55-1 .15(9H,m),1.00(3H,d,J=6.3Hz),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).

[0315] [Reference Example 4]

[0316] Synthesis of (S)-2-((1R,3aS,7aR,E)-4-((Z)-2-((3S,4s,5R)-3,5-bis((tert-butyldimethylsilyl)oxy)-4-methyl-2-methylenecyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl-4-methylbenzenesulfonate (Compound 2g)

[0317] [Chemistry 18]

[0318]

[0319] Step 1

[0320] 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] was added pivaloyl chloride [0.22 mL, 1.78 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 solution, 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 obtain compound 6b [415 mg, 1.12 mmol]. (Yield = 93%)

[0321] 1 H-NMR(CDCl3)δ:5.67(1H,d,J=1.5Hz), 4.07(1H,dd,J=10.7, 3.0Hz), 3.79(1H,dd,J=10.7,7.3Hz), 2.9 5-2.85(1H,m),2.02-1.59(9H,m),1.55-1.25(7H,m),1.21(9H,s),1.03(3H,d,J=6.8Hz),0.59(3H,s).

[0322] Step 2

[0323] 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 mixed solution of toluene [4 mL] and triethylamine [4 mL], and heated and stirred at 100° C. under a nitrogen atmosphere for 3 hours. 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 subjected to silica gel column chromatography to obtain 0.82 g of a crude product containing the conjugate.

[0324] Step 3

[0325] Lithium aluminum hydride [LAH, 115 mg, 3.03 mmol] was added to a THF solution [20 mL] of the crude product obtained in Step 2 [0.82 g] at 0°C and stirred at room temperature for 1 hour. The reaction mixture was quenched with methanol at 0°C, and a 5M aqueous sodium hydroxide solution [6 mL] was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and then saturated 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.

[0326] Step 4

[0327] 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) was added p-toluenesulfonyl chloride (0.25 g, 1.3 mmol) 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 yield 2 g of the compound (0.43 g, 0.58 mmol).

[0328] 1H-NMR(CDCl3)δ:7.79(2H,d,J=7.8Hz), 7.34(2H,d,J=8.3Hz), 6.22(1H,d,J=11.2Hz), 6.01(1H,d,J=11.2Hz), 5.12(1H ,d,J=2.4Hz),4.86(1H,d,J=2.4Hz),4.20(1H,d,J=2.4Hz),3.98(1H,dd,J=9.0,2.7Hz),3.83-3.78(2H,m),2.82(1H,d, J=12.2Hz),2.51-2.45(5H,m),2.16(1H,dd,J=13.2,8.3Hz),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=6.8Hz),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).

[0329] [Example 1]

[0330] (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 (Synthesis of Compound A001)

[0331] [Chemistry 19]

[0332]

[0333] Step 1

[0334] A DMF solution [1 mL] of compound (2a) [90 mg, 0.123 mmol], 3-fluoroazetidine hydrochloride compound (3a1) [50 mg, 0.448 mmol], and K2CO3 [90 mg, 0.651 mmol] described in Reference Example 1 was heated and stirred at 60°C overnight. The reaction solution was cooled 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 a coupled product [21.0 mg, 0.0332 mmol].

[0335] Step 2

[0336] To a THF solution [1 mL] of the coupled product obtained in Step 1 (21.0 mg, 0.0332 mmol), TBAF [1 mL THF solution, 0.3 mL, 0.3 mmol] was added, and the mixture was heated and stirred at 50°C overnight. After cooling the reaction mixture 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].

[0337] 1 H-NMR (CD3OD) δ: 6.31 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.28 (1H, dd, J = 2.2, 1.2Hz), 5.2 6-5.03(1H,m),4.34(1H,t,J=5.9Hz),4.15-4.09(1H,m),3.90-3.80(2H,m),3.54-3.40(2H,m),2. 86(1H,dd,J=12.2,3.9Hz),2.71(1H,dd,J=12.2,2.9Hz),2.53-2.46(2H,m),2.25(1H,dd,J=13.4 , 6.6Hz), 2.05-1.97 (3H,m), 1.92-1.28 (14H,m), 1.00 (3H,d, J=6.8Hz), 0.59 (3H,s).LC-MS:Exact Mass=403.29(C 25 H 38 FNO2)Obs.mass=404.45(M+H),

[0338] In the following examples, each compound was synthesized in the same manner as the synthesis of Compound A001 described in Example 1. In each example, only the raw materials and the amine compounds used are described. Potassium carbonate was used as the base in the same manner as in Example 1, with the equivalent amount appropriately adjusted depending on the raw materials used under the conditions of Example 1.

[0339] [Example 2]

[0340] 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)

[0341] 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].

[0342] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7Hz), 5.91 (1H, d, J = 11.2Hz), 5.30-5.08 (1H, m), 5.05 (2H, d, J = 6.8Hz), 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=6.3Hz),0.60(3H,s).

[0343] LC-MS: Exact Mass = 403.29 (C 25 H 38 FNO2)Obs.mass=404.45(M+H),

[0344] [Example 3]

[0345] 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)

[0346] 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].

[0347] 1H-NMR (CD3OD) δ: 6.31 (1H, d, J = 10.7Hz), 6.22-5.93 (2H, m), 5.28 (1H, dd, J = 2.2, 1.2 Hz), 4.34 (1H, t, J = 5.9Hz), 4.15-4.09 (1H, m), 3.85-3.60 (4H, m), 3.20-3.08 (1H, m) ,2.86(2H,dt,J=12.2,3.0Hz),2.60-2.48(2H,m),2.25(1H,dd,J=13.4,6.6Hz),2.0 5-2.00(3H,m),1.93-1.27(13H,m),1.01(3H,d,J=6.8Hz),0.60(3H,s).LC-MS:Exact Mass=435.29(C26H39F2NO2)Obs.mass=436.45(M+H),

[0348] [Example 4]

[0349] 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)

[0350] 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].

[0351] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7Hz), 6.08 (1H, td, J = 56.5, 4.6Hz), 5.91 (1H, d, J = 11.7Hz), 5.05 (2H ,d,J=7.5Hz),4.42-4.36(2H,m),3.80(2H,q,J=8.0Hz),3.66-3.61(2H,m),3.16-3.05(1H,m),2.86(2H ,dd,J=12.2,2.4Hz), 2.66(1H,dd,J=13.2,4.4Hz), 2.57(1H,dd,J=12.2,10.2Hz), 2.48(1H,dd,J=13.2 , 3.9Hz), 2.31-2.25(2H,m),2.10-2.00(3H,m),1.70-1.31(10H,m),1.01(3H,d,J=6.3Hz),0.61(3H,s).

[0352] Exact Mass=435.29(C26H39F2NO2)Obs.mass=436.45(M+H),

[0353] [Example 5]

[0354] 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)

[0355] Compound (2 g) [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].

[0356] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 10.7Hz), 6.23-5.90 (2H, m), 5.22 (1H, d, J = 2.0Hz), 4.22 (1H,d,J=3.4Hz),3.78-3.68(3H,m),3.57(2H,dd,J=15.6,6.8Hz),3.13-3.02(1H,m),2 .88-2.78(2H,m),2.62-2.48(2H,m),2.17(1H,dd,J=13.2,8.3Hz),2.02(2H,dd,J=12.4 , 4.6Hz), 1.91-1.26 (12H, m), 1.03 (3H, d, J = 6.8Hz), 1.00 (3H, d, J = 6.3Hz), 0.58 (3H, s).

[0357] Exact Mass=435.29(C27H41F2NO2)Obs.mass=436.45(M+H)

[0358] [Example 6]

[0359] 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)

[0360] 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].

[0361] 1H-NMR (CD3OD) δ: 6.31 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.28 (1H, dd, J = 2.2, 1.2Hz), 4.34 (1H,t,J=5.9Hz),4.15-4.08(1H,m),3.95-3.85(2H,m),3.68(2H,q,J=8.5Hz),3.29-3.10(2H,m), 2.88 (2H, td, J = 12.0, 3.3Hz), 2.61 (1H, dd, J = 12.2, 10.2Hz), 2.51 (1H, dd, J = 13.7, 3.4Hz), 2.25 (1 H,dd,J=13.4,6.6Hz), 2.08-1.95(4H,m), 1.93-1.26(18H,m), 1.01(3H,d,J=6.3Hz), 0.60(3H,s).

[0362] Exact Mass=449.31(C27H41F2NO2)Obs.mass=450.50(M+H)

[0363] [Example 7]

[0364] 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)

[0365] 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].

[0366] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.92 (1H, d, J = 11.2Hz), 5.05 (2H, dd, J = 7.0, 2.0Hz), 4.4 3-4.34(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, 3.7Hz), 2.69-2.60 (2H, m), 2.48 (1H, dd, J = 13.4, 4.1Hz), 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=6.8Hz),0.61(3H,s).

[0367] Exact Mass=449.31(C27H41F2NO2)Obs.mass=450.45(M+H)

[0368] [Example 8]

[0369] 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)

[0370] Compound (2 g) [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].

[0371] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 10.7Hz), 5.22 (1H, d, J =2.0Hz), 4.22 (1H, d, J = 3.4Hz), 3.92-3.83 (2H, m), 3.75-3.61 (3H, m), 3.27-3. 12(1H,m),2.87(2H,dd,J=11.0,3.7Hz),2.63-2.55(2H,m),2.20-2.00(3H,m), 1.92-1.27(15H,m),1.03(3H,d,J=6.8Hz),1.01(3H,d,J=6.8Hz), 0.59(3H,s).

[0372] Exact Mass=463.32(C28H43F2NO2)Obs.mass=464.50(M+H)

[0373] [Example 9]

[0374] (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)

[0375] 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].

[0376] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.29 (1H, dd, J = 2.4, 1.5Hz), 4.3 5(1H,t,J=5.9Hz), 4.16-4.10(1H,m),3.62(2H,dd,J=9.3,2.9Hz), 3.25(2H,t,J=8.8Hz), 2.87(1H ,dd,J=11.5,4.1Hz),2.58(1H,dd,J=12.0,3.2Hz), 2.52(1H,dd,J=13.2,3.4Hz), 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=6.8Hz),0.59(3H,s).

[0377] Exact Mass=469.28(C26H38F3NO3)Obs.mass=470.60(M+H)

[0378] [Example 10]

[0379] 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)

[0380] 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].

[0381] 1H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2Hz), 5.89 (1H, d, J = 11.2Hz), 4.07-3.95 (2H, m), 3.62(2H,dd,J=9.3,2.9Hz),3.25(2H,t,J=9.0Hz),2.84(1H,dd,J=12.7,3.9Hz),2.6 2-2.57(2H,m),2.41(1H,dd,J=13.2,3.4Hz),2.32(1H,dd,J=11.7,9.8Hz), 2.25-2.1 1(2H,m),2.05-2.00(2H,m), 1.95-1.26(13H,m), 1.00(3H,d,J=6.3Hz), 0.59(3H,s).

[0382] Exact Mass=457.28(C25H38F3NO3)Obs.mass=458.65(M+H)

[0383] [Example 11]

[0384] 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)

[0385] 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].

[0386] Exact Mass=469.28(C26H38F3NO3)Obs.mass=470.35(M+H)

[0387] [Example 12]

[0388] 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)

[0389] 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].

[0390] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0Hz), 5.89 (1H, d, J = 11.4Hz), 4.05-3.96 (2H, m), 3. 45(3H,s),3.45(3H,dd,J=8.0,3.0Hz),3.35(4H,t,J=12.1Hz),2.83(1H,dd,J=11.7,3 .9Hz), 2.59(1H,dd,J=13.3,3.7Hz), 2.52(1H,dd,J=11.9,3.2Hz), 2.40(1H,dd,J=13. 5,3.4Hz),2.30-2.13(3H,m),2.04-1.28(17H,m),0.99(3H,d,J=6.4Hz),0.58(3H,s).

[0391] Exact Mass=471.30(C26H40F3NO3)Obs.mass=472.35(M+H)

[0392] [Example 13]

[0393] 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)

[0394] 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].

[0395] Exact Mass=4457.28(C25H38F3NO3)Obs.mass=458.25(M+H)

[0396] [Example 14]

[0397] 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)

[0398] 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].

[0399] 1 H-NMR (CD3OD) δ: 6.19 (1H, d, J = 11.0Hz), 5.87 (1H, d, J = 11.0Hz), 4.26-4.20 (1H, m), 4.05-3.93 (2H, m), 3 .88(2H,q,J=9.0Hz), 3.61(2H,q,J=7.6Hz), 2.99(1H,t,J=6.9Hz), 2.93(1H,t,J=6.9Hz), 2.81(1H,dd,J= 11.9, 4.1Hz), 2.57 (1H, dd, J = 13.3, 3.7Hz), 2.47 (1H, dd, J = 11.7, 3.0Hz), 2.39 (1H, dd, J = 13.3, 3.2Hz), 2.27(1H,dd,J=11.9,9.6Hz), 2.21-2.11(2H,m), 2.02-1.25(15H,m), 0.97(3H,d,J=6.4Hz), 0.56(3H,s).

[0400] Exact Mass=471.30(C26H40F3NO3)Obs.mass=472.25(M+H)

[0401] [Example 15]

[0402] 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)

[0403] 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].

[0404] 1 H-NMR (CD3OD) δ: 6.16 (1H, d, J = 10.7Hz), 5.85 (1H, tt, J = 3.5, 55.0Hz), 5.84 (1H, d, J = 10.7Hz) ,4.17-4,11(1H,m),4.02-3.90(2H,m),3.63-3.52(4H,m),2.92(2H,dt,J=22.9,6.8Hz),2.78( 1H,dd,J=12.0,3.7Hz), 2.54(1H,dd,J=13.2,3.4Hz), 2.44(1H,dd,J=12.2,2.9Hz), 2.36(1H,d d, J=13.2, 3.4Hz), 2.26-2.09 (3H, m), 1.99-1.24 (15H, m), 0.94 (3H, d, J=6.3Hz), 0.53 (3H, s).

[0405] Exact Mass=453.31(C26H41F2NO3)Obs.mass=454.25(M+H)

[0406] [Example 16]

[0407] 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)

[0408] 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].

[0409] 1H-NMR (CD3OD) δ: 6.24 (1H, d, J = 11.0Hz), 6.03-5.74 (2H, m), 5.03 (2H, d, J = 6.9Hz), 4.43-4.30 (2H,m),4.20-4.14(1H,m),3.68-3.55(4H,m),2.97(1H,t,J=6.9Hz),2.92(1H,t,J=6.9Hz),2. 83 (1H, dd, J = 11.9, 3.7Hz), 2.65 (1H, dd, J = 13.3, 4.6Hz), 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=6.4Hz), 0.57(3H,s).

[0410] Exact Mass=453.31(C27H41F2NO3)Obs.mass=454.25(M+H)

[0411] [Example 17]

[0412] 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)

[0413] 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].

[0414] 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7Hz), 6.04 (1H, d, J = 11.2Hz), 5.85 (1H, t t, J=55.4, 3.8Hz), 5.24 (1H, d, J=1.0Hz), 4.85 (1H, s), 4.30 (1H, t, J=5.9Hz) ,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=6.3Hz),0.53(3H,s).

[0415] Exact Mass=465.31(C27H41F2NO3)Obs.mass=466.30(M+H)

[0416] [Example 18]

[0417] 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)

[0418] 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].

[0419] 1 H-NMR (CD3OD) δ: 6.43 (1H, t, J = 75.0Hz), 6.27 (1H, d, J = 11.2Hz), 5.92 (1H, d, J = 11.2Hz), 5.06 (2H, d, J = 6.8Hz), 4.89-4.82 ( 1H, m), 4.40 (2H, ddd, J = 13.7, 7.1, 4.6Hz), 3.98 (2H, q, J = 7.5Hz), 3.50 (2H, ddd, J = 18.8, 9.5, 6.1Hz), 2.88-2.84 (1H, m), 2.8 0 (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),1.42-130(3H,m),1.02(3H,d,J=6.3Hz),0.61(3H,s).

[0420] Exact Mass=451.30(C26H39F2NO3)Obs.mass=452.40(M+H)

[0421] [Example 19]

[0422] 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)

[0423] 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].

[0424] Exact Mass=449.31(C27H41F2NO2)Obs.mass=450.25(M+H)

[0425] [Example 20]

[0426] 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)

[0427] 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].

[0428] 1 H-NMR (CD3OD) δ: 6.36 (1H, t, J = 75.0Hz), 6.21 (1H, d, J = 11.2Hz)

[0429] ),5.89(1H,d,J=11.2Hz),4.74-4.68(1H,m),4.08-3.95(2H,m),3

[0430] .65 (2H, q, J = 6.8Hz), 3.09 (1H, t, J = 6.8Hz), 3.03 (1H, t, J = 6

[0431] .8Hz), 2.83 (1H, dd, J = 12.4, 3.7 Hz), 2.59 (1H, dd, J = 13.7, 3.9

[0432] Hz), 2.49 (1H, dd, J = 11.7, 2.9Hz), 2.41 (1H, t, J = 6.6Hz), 2.29

[0433] (1H,dd,J=11.7,9.3Hz), 2.23-1.27(18H,m),0.99(3H,d,J=6.3

[0434] Hz),0.58(3H,s).

[0435] ExactMass=439.29(C25H39F2NO3)Obs.mass=440.20(M+H)

[0436] [Example 21]

[0437] 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)

[0438] 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].

[0439] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4Hz), 6.00-5.69 (2H, m), 4.06-3.95 (2H, m), 3.52 (2H, dd, J = 17.2, 7.5Hz), 2.93-2.78 (3H, m), 2.7

[0440] 3-2.65(1H,m),2.59(1H,dd,J=13.3,3.7Hz), 2.48(1H,dd,J=11

[0441] .9, 2.7Hz), 2.40 (1H, dd, J = 13.5, 3.4Hz), 2.25-1.97 (7H, m), 1.95

[0442] -1.72(3H,m),1.68-1.44(6H,m),1.38-1.23(3H,m),0.98(3H,d,J=

[0443] 6.4Hz),0.58(3H,s).

[0444] ExactMass=437.31(C26H41F2NO2)Obs.mass=438.35(M+H)

[0445] [Example 22]

[0446] 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)

[0447] 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].

[0448] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.28 (1H, dd, J = 2.4, 1.5Hz), 4.89 (1H, dd, J = 2.4, 1 .5Hz),4.34(1H,dd,J=6.3,5.4Hz),4.15-4.10(1H,m),3.55(1H,dd,J=11.0,7.6Hz),3.42-3.35(2H,m),3.09(1H,dd ,J=12.7,2.9Hz),2.99(1H,t,J=12.0Hz),2.87(1H,dd,J=12.0,3.7Hz),2.78(1H,t,J=10.0Hz),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=6.6Hz), 1.13(3H,d,J=6.3Hz), 0.63(3H,s).

[0449] Exact Mass=413.31(C27H43NO2)Obs.mass=414.45(M+H)

[0450] [Example 23]

[0451] 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)

[0452] 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].

[0453] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.92 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 5.9Hz), 4.44-4.35 (2H,m), 3.55(1H,dd,J=10.7, 7.8Hz), 3.43-3.35(2H,m), 3.10(1H,dd,J=12.7, 2.9Hz), 2.99(1H,t, J=12.0Hz), 2.89-2.75(2H,m), 2.66(1H,dd, J=13.2, 4.4Hz), 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=6.6Hz), 1.13(3H,d,J=6.3Hz), 0.64(3H,s).

[0454] Exact Mass=413.33(C27H43NO2)Obs.mass=414.45(M+H)

[0455] [Example 24]

[0456] 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)

[0457] 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].

[0458] Exact Mass=413.33(C27H43NO2)Obs.mass=414.25(M+H)

[0459] [Example 25]

[0460] 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)

[0461] 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].

[0462] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7Hz), 5.89 (1H, d, J = 10.7Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.0, 3.7Hz), 2.74-2.50 (5H, m), 2.46 -2.12(7H,m),2.07-1.47(17H,m),1.35(2H,ddd,J=23.4,10.7,2.9Hz),1.26(1H,dd,J=18.5,9.3Hz),1.05(3H,d,J=6.8Hz),0.60(3H,s).

[0463] Exact Mass=401.333(C26H43NO2)Obs.mass=402.25(M+H)

[0464] [Example 26]

[0465] 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)

[0466] 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].

[0467] Exact Mass=427.35(C28H45NO2)Obs.mass=428.25(M+H)

[0468] [Example 27]

[0469] 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)

[0470] 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].

[0471] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.4Hz), 5.91 (1H, d, J = 11.4Hz), 5.05 (2H, d, J = 6.9Hz), 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=7.6Hz),2.67(1H,dd,J=13.7,4.6Hz),2.48(1H,dd,J=13.5,3.9Hz),2.38-2.22(5H,m),2.1 2-1.92(6H,m),1.70-1.22(12H,m),1.05(3H,d,J=6.9Hz),0.90(3H,t,J=7.5Hz),0.60(3H,s).

[0472] Exact Mass=427.35(C28H45NO2)Obs.mass=428.25(M+H)

[0473] [Example 28]

[0474] 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)

[0475] 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].

[0476] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0Hz), 5.89 (1H, d, J = 11.0Hz), 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=5.9Hz),0.90(3H,t,J=7.5Hz),0.60(3H,s).

[0477] [Example 29]

[0478] 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)

[0479] 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].

[0480] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4Hz), 5.89 (1H, d, J = 11.4Hz), 4.07-3.95 (2H, m), 2.93 (1H, t, J = 8.0Hz), 2.83 (1H, dd, J = 11.9, 3.7Hz), 2.68 (1 H,t,J=7.5Hz), 2.59(1H,dd,J=13.5,3,7Hz), 2.48-2.13(6H,m), 2.10-1.20(20H,m),1.05(3H,d,J=6.9Hz), 0.90(3H,t,J=7.3Hz), 0.60(3H,s).

[0481] [Example 30]

[0482] 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)

[0483] 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].

[0484] 1 H-NMR (CD3OD) δ: 6.20 (1H, d, J = 11.0Hz), 5.87 (1H, d, J = 11.4Hz), 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, 3.2Hz), 1.04 (3H, d, J = 6.4Hz), 0.93 (1H, t, J = 7.3Hz), 0.58 (3H, s).

[0485] Exact Mass=405.30(C25H40FNO2)Obs.mass=406.30(M+H)

[0486] [Example 31]

[0487] 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)

[0488] 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].

[0489] 1H-NMR (CD3OD) δ: 6.20 (1H, d, J = 11.0Hz), 5.87 (1H, d, J = 11.0Hz), 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=6.9Hz),0.58(3H,s).

[0490] Exact Mass=405.30(C25H40FNO2)Obs.mass=406.30(M+H)

[0491] [Example 32]

[0492] 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)

[0493] 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].

[0494] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.89 (1H, td, J = 56.7, 4.7Hz), 5.28 (1H, dd, J = 2.4, 1.5Hz), 4.34 (1H, t, J=5.9Hz), 4.15-4.09(1H,m),3.21(1H,dd,J=10.5,8.5Hz),3.00-2.00(14H,m),1.90-1.27(13H,m),1.09(3H,d,J=6.3Hz),0.62(3H,s).

[0495] Exact Mass=449.31(C27H41F2NO2)Obs.mass=450.30(M+H)

[0496] [Example 33]

[0497] 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)

[0498] 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].

[0499] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.81 (1H, td, J = 57.0, 5.7Hz), 5.22 (1H, d, J = 2.0Hz), 4.88 (1H, d, J = 2.0Hz),

[0500] 4.22 (1H, d, J = 3.4Hz), 3.72 (1H, td, J = 8.2, 4.2Hz), 2.98-2.83 (2H, m), 2.76-2.52 (5H, m), 2.44 (2H, d, J = 7.3Hz), 2.17 (1H, dd, J = 13.2, 8.3Hz),

[0501] 2.07-1.93(3H,m), 1.84-1.24(11H,m),1.06(3H,d,J=6.3Hz), 1.03(3H,d,J=6.8Hz),0.59(3H,s).

[0502] Exact Mass=463.32(C28H43F2NO2)Obs.mass=464.35(M+H)

[0503] [Example 34]

[0504] 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)

[0505] 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].

[0506] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7Hz), 5.89 (1H, d, J = 10.7Hz), 5.78 (1H, td, J = 57.0, 6.0Hz), 4.06-3.95 (2H, m), 2.82 ( 2H, dd, J = 18.8, 10.0Hz), 2.66-2.50 (4H, m), 2.44-1.92 (11H, m), 1.86-1.23 (13H, m), 1.05 (3H, d, J = 6.3Hz), 0.60 (3H, s).

[0507] Exact Mass=437.31(C26H41F2NO2)Obs.mass=438.35(M+H)

[0508] [Example 35]

[0509] 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)

[0510] 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].

[0511] 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7Hz), 6.05-5.76 (2H, m), 5.05 (2H, d, J = 6 .3Hz), 4.42-4.36 (2H, m), 3.25 (1H, t, J = 9.5Hz), 3.03 (2H, t, J = 7.1Hz), 2.9 1-2.72(5H,m),2.66(1H,dd,J=13.7,4.4Hz),2.48(1H,dd,J=13.4,4.1Hz), 2.32-1.96(7H,m),1.93-1.29(10H.m),1.10(3H,d,J=6.3Hz),0.63(3H,s).

[0512] Exact Mass=449.31(C27H41F2NO2)Obs.mass=450.30(M+H)

[0513] [Example 36]

[0514] 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)

[0515] 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].

[0516] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.75 (1H, td, J = 57.0, 5.0Hz), 5.28 (1H, dd, J = 2.4, 1.5Hz), 4.89 (1H, dd, J = 2 .4, 1.0Hz), 4.34 (1H, t, J = 5.9Hz), 4.15-4.09 (1H, m), 2.86 (1H, dd, J = 12.2, 3.4Hz), 2.61-1.19 (27H, m), 1.04 (3H, d, J = 6.3Hz), 0.59 (3H, s).

[0517] Exact Mass=449.31(C27H41F2NO2)Obs.mass=450.45(M+H)

[0518] [Example 37]

[0519] 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)

[0520] 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].

[0521] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 10.7Hz), 5.75 (1H, td, J = 57.3, 5.2Hz), 5.22 (1H, d, J = 1.5Hz), 4.89 (1H, s), 4.22 (1H, d, J = 3.4Hz), 3.72 (1H, td, J = 8.1, 4.4Hz), 2.86 (1H, dd, J = 11.0, 4.0Hz), 2.63- 1.24(29H,m), 1.04(3H,d,J=7.3Hz), 1.04(3H,d,J=6.8Hz), 0.58(3H,s).

[0522] Exact Mass=463.32(C28H43F2NO2)Obs.mass=464.35(M+H)

[0523] [Example 38]

[0524] 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)

[0525] 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].

[0526] 1H-NMR (CD3OD) δ: 6.22 (1H, d, J = 10.7Hz), 5.89 (1H, d, J = 10.7Hz), 5.76 (1H, td, J = 57.0, 5.0Hz), 4.06-3.96 (2H, m), 2.84 (1H, dd, J = 12.0, 3.8Hz), 2.65-2.52 (5H, m), 2.47-1.49 (21H, m), 1.40-1.22 (4H, m), 1.05 (3H, d, J = 6.3Hz), 0.60 (3H, s).

[0527] Exact Mass=437.31(C26H41F2NO2)Obs.mass=438.3(M+H)

[0528] [Example 39]

[0529] 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)

[0530] 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].

[0531] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.77 (1H, td, J = 57.0, 5.0Hz), 5.05 (2H, d, J = 6.3Hz), 4.43-4.34 (2 H,m),2.85(1H,dd,J=12.2,3.9Hz),2.71-2.25(11H,m),2.07-1.92(4H,m),1.83-1.24(10H,m),1.05(3H,d,J=6.3Hz),0.61(3H,s).

[0532] Exact Mass=449.31(C27H41F2NO2)Obs.mass=450.45(M+H)

[0533] [Reference Example 5]

[0534] Synthesis of 3-(S)-(1,1-difluoroethyl)pyrrolidine hydrochloride (Compound 3b6)

[0535] [Chemistry 20]

[0536]

[0537] Step 1

[0538] Under the condition of cooling to -78 ℃, to a solution of oxalyl chloride [2.45mL, 28.6mmol] in dichloromethane [25mL], a solution of dimethyl sulfoxide [4.1mL, 58mmol] in dichloromethane [10mL] was added, 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 [3.84g, 19.1mmol] in dichloromethane [15mL]. The mixture was stirred at -78 ℃ for 45 minutes. Triethylamine [15mL, 92mmol] was added and stirred for a further 30 minutes at the same temperature. The reaction mixture was warmed to 0 ℃ 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 obtain tert-butyl (S)-3-formylpyrrolidine-1-carboxylate (Compound 3b2) [3.78 g, 19.0 mmol]. (Yield = 99%)

[0539] 1 H-NMR (CDCl3) δ: 9.69 (1H, J = 1.5Hz), 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).

[0540] Step 2

[0541] To a THF solution [40 mL] of tert-butyl (S)-3-formylpyrrolidine-1-carboxylate (compound 3b2) [2.00 g, 10 mmol] was added methylmagnesium bromide [1 M in THF, 15.1 mL, 15.1 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 another 1 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 tert-butyl (S)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (compound 3b3) [1.60 g, 7.41 mmol]. (Yield = 74%)

[0542] 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).

[0543] Step 3

[0544] To a dichloromethane solution [10 mL] of oxalyl chloride [1 mL, 11.7 mmol] was added a dichloromethane solution [10 mL] of dimethyl sulfoxide [1.6 mL, 23 mmol] under cooling to -78 ° C, and the mixture was stirred at the same temperature for 10 minutes. To this mixture was added a dichloromethane solution [10 mL] of tert-butyl (S)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (compound 3b3) [1.60 g, 7.41 mmol]. The mixture was stirred at -78 ° C for 45 minutes. Triethylamine [4.2 mL, 30 mmol] was added and stirred for a further 30 minutes at the same temperature. 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 obtain tert-butyl (S)-3-acetylpyrrolidine-1-carboxylate (Compound 3b4) [1.45 g, 6.80 mmol]. (Yield = 91%)

[0545] 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).

[0546] Step 4

[0547] A dichloromethane solution of tert-butyl (S)-3-acetylpyrrolidine-1-carboxylate (compound 3b4) [1.10 g, 5.16 mmol] was cooled to 0°C. DAST [0.93 mL, 2.5 mmol] was added thereto. The reaction mixture was stirred overnight and warmed to room temperature. The reaction mixture was cooled with 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 solution. 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 tert-butyl (S)-3-(1,1-difluoroethyl)pyrrolidine-1-carboxylate (compound 3b5) [0.58 g, 2.5 mmol]. (Yield = 48%)

[0548] Step 5

[0549] Next, 4 M hydrochloric acid-dioxane solution [10 mL] was added to the above-mentioned tert-butyl (S)-3-(1,1-difluoroethyl)pyrrolidine-1-carboxylate (Compound 3b5) [0.58 g, 2.5 mmol], and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain 3-(S)-(1,1-difluoroethyl)pyrrolidine hydrochloride (Compound 3b6) [354 mg, 2.06 mmol].

[0550] 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).

[0551] [Reference Example 6]

[0552] Synthesis of 3-(R)-(1,1-difluoroethyl)pyrrolidine hydrochloride (3b12)

[0553] [Chemistry 21]

[0554]

[0555] Step 1

[0556] Using tert-butyl (R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (3b7) [3.16 g, 15.7 mmol] as the starting material, the reaction was carried out in the same manner as in Step 1 of Reference Example 5 to obtain tert-butyl (R)-3-formylpyrrolidine-1-carboxylate (Compound 3b8) ​​[2.42 g, 12.1 mmol].

[0557] Step 2

[0558] Using tert-butyl (R)-3-formylpyrrolidine-1-carboxylate (Compound 3b8) ​​[2.42 g, 12.1 mmol] as the starting material, a reaction was carried out in the same manner as in Step 2 of Reference Example 5 to obtain tert-butyl (R)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (Compound 3b9) [1.64 g, 7.62 mmol].

[0559] Step 3

[0560] Using tert-butyl (R)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (Compound 3b9) [1.64 g, 7.62 mmol] as the starting material, a reaction was carried out in the same manner as in Step 3 of Reference Example 5 to obtain tert-butyl (R)-3-acetylpyrrolidine-1-carboxylate (Compound 3b10) [1.50 g, 7.03 mmol]. (Yield = 92%)

[0561] Step 4

[0562] To a dichloromethane solution [30 mL] of tert-butyl (R)-3-acetylpyrrolidine-1-carboxylate (compound 3b10) [1.50 g, 7.03 mmol] was added DAST [1.8 mL, 13.6 mmol] at 0°C and stirred at room temperature overnight. The next morning, DAST [1.8 mL, 13.6 mmol] was further added and stirred at room temperature for another day. The reaction mixture was cooled to 0°C, quenched with saturated aqueous sodium carbonate solution, 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 tert-butyl (R)-3-(1,1-difluoroethyl)pyrrolidine-1-carboxylate (compound 3b11) [0.87 g, 3.7 mmol]. (Yield = 53%)

[0563] Step 5

[0564] Using tert-butyl (R)-3-(1,1-difluoroethyl)pyrrolidine-1-carboxylate (Compound 3b11) [0.87 g, 3.7 mmol] as the starting material, the reaction was carried out 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%)

[0565] 1 H-NMR (DMSO-D6) δ: 9.60 (1H, br s),9.40(1H,brs),3,37-3.30(1H,brm),3,25-3.00(3H,brm),2,96-2.81(1H,m),2.12-2.03(1H,m),1.91-1.77(1H,m),1,66(3H,t,J=19.3Hz).

[0566] [Example 40]

[0567] 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)

[0568] 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].

[0569] 1 H-NMR (CD3OD) δ: 6,31(1H,d,J=10,7Hz), 6.09(1H,d,J=11,2Hz), 5,28(1H,dd,J=2.4,1,0Hz), 4.33(1H,d,J=5,4Hz), 4,14-4.09(1H,m),3,43(1H,dd,J =10.7,8.3Hz),3.25-2.78(8H,m),2.51(1H,dd,J=13.7,3.4Hz),2.28-1.9 7(7H,m),1.92-1.28(17H,m),1.11(3H,d,J=6.3Hz),0.63(3H,d,J=7.3Hz).

[0570] [Example 41]

[0571] 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)

[0572] 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].

[0573] 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.22 (1H, d, J = 1.5Hz). 4.89 (1 H, d, J = 1.5Hz), 4.22 (1H, d, J = 3.4Hz), 3.72 (1H, td, J = 8.2, 4.2Hz), 3.01 (1H, t, J = 9.0Hz), 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 = 6.8Hz), 1.04 (3H, d, J = 7.3Hz), 0.59 (3H, s).

[0574] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.45(M+H)

[0575] [Example 42]

[0576] 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)

[0577] 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].

[0578] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.89 (1H, d, J = 11.2Hz), 4.06-3.95 (2H, m), 2..93 (1H, t, J = 9.0Hz), 2.83 (1H, dd, J = 12 .0,3.2Hz),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=6.3Hz),0.60(3H,s).

[0579] Exact Mass=451.33(C27H43F2NO2)Obs.mass=452.45(M+H)

[0580] [Example 43]

[0581] 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)

[0582] 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].

[0583] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.92 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.3Hz), 4.43-4.34 (2H, m), 3.42 (1H, dd, J = 10.7, 8.3Hz), 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=6.8Hz),0.64(3H,s).

[0584] Exact Mass=463.33(C28H43F2NO2)Obs.mass=464.3(M+H)

[0585] [Example 44]

[0586] 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)

[0587] 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].

[0588] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.28 (1H, dd, J = 2. 2, 1.2Hz), 4.34 (1H, t, J = 5.9Hz), 4.15-4.10 (1H, m), 3.12-3.00 (2H, m), 2.94-2.75 (5H, m), 2.66 (2H, d, J = 7.3Hz), 2.51 (1H, dd, J = 13.4, 3.2Hz), 2.26 (1H, dd, J = 13.7, 6.8Hz), 2.13-1.94(5H,m), 1.90-1.23(16H,m), 1.09(3H,d,J=6.3Hz), 0.62(3H,s).

[0589] Exact Mass=463.33(C28H43F2NO2)Obs.mass=464.45(M+H)

[0590] [Example 45]

[0591] 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)

[0592] 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].

[0593] 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.22 (1H, d, J = 2.0Hz), 4.22 (1H, d, J = 3.4Hz), 3.72 (1H , td, J=8.2, 4.2Hz), 2.89-1.94 (16H, m), 1.88-1.22 (16H, m), 1.05 (6H, d, J=6.8Hz), 1.03 (6H, d, J=6.8Hz), 0.59 (3H, s).

[0594] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.5(M+H)

[0595] [Example 46]

[0596] 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)

[0597] 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].

[0598] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7Hz), 5.89 (1H, d, J = 10.7Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.0, 3.7Hz), 2.74-2.50 (5H, m), 2.46 -2.12(7H,m),2.07-1.47(17H,m),1.35(2H,ddd,J=23.4,10.7,2.9Hz),1.26(1H,dd,J=18.5,9.3Hz),1.05(3H,d,J=6.8Hz),0.60(3H,s).

[0599] Exact Mass=451.333(C27H43F2NO2)Obs.mass=452.3(M+H)

[0600] [Example 47]

[0601] 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)

[0602] 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].

[0603] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.92 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.3Hz), 4.43-4..34 (2H,m), 3.17-3.05 (2H,m), 2.99-2. 64(8H,m),2.48(1H,dd,J=13.2,3.9Hz),2.31-2.25(2H,m),2.16-1.96(5H,m),1.78-1.28(13H,m),1.10(3H,d,J=6.3Hz),0.63(3H,s).

[0604] Exact Mass=463.33(C28H43F2NO2)Obs.mass=464.5(M+H)

[0605] [Reference Example 7]

[0606] Synthesis of 3-(R)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b16)

[0607] [Chemistry 22]

[0608]

[0609] Step 1

[0610] To a solution of oxalyl chloride [0.66 mL, 7.7 mmol] in dichloromethane [10 mL] was added a solution of dimethyl sulfoxide [1.0 mL, 14 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 tert-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 stirred for a further 40 minutes at the same temperature. 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 tert-butyl-3-(R)-(2-oxoethyl)pyrrolidine-1-carboxylate (Compound 3b14) [0.85 g, 4.0 mmol]. (Yield = 86%)

[0611] Step 2

[0612] To a solution of tert-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 tert-butyl-3-(R)-(2,2-difluoroethyl)pyrrolidine-1-carboxylate (compound 3b15) [799 mg, 3.4 mmol]. (Yield = 85%)

[0613] Step 3

[0614] To tert-butyl-3-(R)-(2,2-difluoroethyl)pyrrolidine-1-carboxylate (Compound 3b15) [799 mg, 3.4 mmol] was added 4M hydrochloric acid in dioxane [6 mL] and stirred overnight at room temperature. 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%)

[0615] 1H-NMR(DMSO-d6)δ:9.88(2H,br s),5.90(1H,tt,J=55.9,3.8Hz),3.53(2H,d,J=40.5Hz),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).

[0616] [Reference Example 8]

[0617] Synthesis of 3-(S)-(2,2-difluoroethyl)pyrrolidine hydrochloride (3b20)

[0618] [Chemistry 23]

[0619]

[0620] Step 1

[0621] Using tert-butyl-3-(S)-(2-hydroxyethyl)pyrrolidine-1-carboxylate (Compound 3b17) [1.0 g, 4.64 mmol] as the starting material, the reaction was carried out in the same manner as in Step 1 of Reference Example 7 to obtain tert-butyl-3-(S)-(2-oxoethyl)pyrrolidine-1-carboxylate (Compound 3b18) [0.72 g, 3.4 mmol]. (Yield = 73%)

[0622] Step 2

[0623] Using tert-butyl-3-(S)-(2-oxoethyl)pyrrolidine-1-carboxylate (Compound 3b18) [0.72 g, 3.4 mmol] as the starting material, a reaction was carried out in the same manner as in Step 2 of Reference Example 7 to obtain tert-butyl-3-(S)-(2,2-difluoroethyl)pyrrolidine-1-carboxylate (Compound 3b19) [679 mg, 2.89 mmol]. (Yield = 62%)

[0624] Step 3

[0625] Using tert-butyl-3-(S)-(2,2-difluoroethyl)pyrrolidine-1-carboxylate (Compound 3b19) [679 mg, 2.89 mmol] as the starting material, the reaction was carried out in the same manner as in 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.)

[0626] 1H-NMR (DMSO-d6) δ: 9.86 (2H, br s), 5.91 (1H, tt, J = 55.9, 3.7Hz), 3.53 (2H, d, J = 38.5Hz), 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).

[0627] [Example 48]

[0628] 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)

[0629] 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].

[0630] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 10.7Hz), 6.12-5.81 (2H, m), 5.28 (1H, d, J = 1.0 Hz), 4.34 (1H, t, J = 5.9Hz), 4.15-4.10 (1H, m), 3.45 (1H, dd, J = 10.2, 7.8Hz), 3 .23-3.18(2H,m),2.95-2.80(3H,m),2.74(1H,t,J=10.2Hz),2.59-2.45(2H,m ), 2.30-1.90 (8H, m), 1.89-1.31 (14H, m), 1.11 (3H, d, J = 6.3Hz), 0.63 (3H, s).

[0631] Exact Mass=463.33(C28H43F2NO2)Obs.mass=464.5(M+H)

[0632] [Example 49]

[0633] 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)

[0634] 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].

[0635] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 10.7Hz), 6.09 (1H, d, J = 10.7Hz), 5.98 (1H, tt, J = 3.0, 56.0Hz), 5.29 (1 H, t, J = 1.2Hz), 4.34 (1H, t, J = 5.9Hz), 4.12 (1H, td, J = 6.5, 3.3Hz), 3.55 (1H, dd, J = 11.0, 8.1Hz), 3.41- 3.34(2H,m), 3.08-2.93(4H,m), 2.88(1H,dd,J=12.0, 3.7Hz), 2.69-2.55(1H,m), 2.51(1H,dd,J=13.7, 3.4Hz), 2.35-2.04(8H,m), 2.01-1.96(3H,m), 1.90-1.33(16H,m), 1.13(3H,d,J=6.8Hz), 0.63(3H,s).

[0636] Exact Mass=463.33(C28H43F2NO2)Obs.mass=464.5(M+H)

[0637] [Example 50]

[0638] 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)

[0639] 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].

[0640] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.88 (1H, tt, J = 56.6, 4. 6Hz), 5.22 (1H, d, J = 1.5Hz), 4.22 (1H, d, J = 3.4Hz), 3.72 (1H, td, J = 8.1, 4.2Hz), 2.94 (1H, t, J=8.3Hz), 2.86 (1H, dd, J=12.4, 4.1Hz), 2.68-2.52 (3H, m), 2.33-2.03 (9H, m), 1.98-1. 24 (20H, m), 1.05 (3H, d, J = 7.0Hz), 1.03 (3H, d, J = 6.3Hz), 0.96-0.87 (1H, m), 0.58 (3H, s).

[0641] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.3(M+H)

[0642] [Example 51]

[0643] 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)

[0644] 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].

[0645] 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 10.7Hz), 6.09 (1H, d, J = 11.2Hz), 5.87 (1H, tt, J = 5 6.6, 4.6Hz), 5.22 (1H, d, J = 1.5Hz), 4.22 (1H, d, J = 3.4Hz), 3.72 (1H, td, J = 8.1, 4. 4Hz), 2.86 (1H, dd, J = 12.4, 4.1Hz), 2.79-2.68 (2H, m), 2.59 (1H, dd, J = 13.4, 4.1H z), 2.39-1.21 (23H, m), 1.04 (3H, d, J = 6.3Hz), 1.03 (3H, d, J = 7.0Hz), 0.58 (3H, s).

[0646] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.35(M+H)

[0647] [Example 52]

[0648] 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)

[0649] 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].

[0650] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.96 (1H, tt, J = 56.5, 4.0Hz), 5.92 (1H, d, J = 11.2Hz), 5.05 (2H, d , J=5.9Hz), 4.39 (2H, ddd, J=14.3, 7.2, 4.5Hz), 3.44 (1H, dd, J=10.7, 7.8Hz), 3.24-3.12 (2H, m), 2.94-2. 82 (3H, m), 2.74 (1H, t, J = 10.2Hz), 2.66 (1H, dd, J = 13.2, 4.4Hz), 2.56 (1H, q, J = 8.1Hz), 2.48 (1H, dd, J = 13 .7, 3.9Hz), 2.34-2.17(3H,m), 2.08-1.93(5H,m), 1.83-1.28(10H,m), 1.12(3H,d,J=6.3Hz), 0.63(3H,s).

[0651] Exact Mass=463.32(C28H43F2NO2)Obs.mass=464.35(M+H)

[0652] [Example 53]

[0653] 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)

[0654] 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].

[0655] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.96 (2H, tt, J = 56.5, 4.0Hz), 5.92 (2H, d, J = 11.2Hz), 5.05 (2H ,d,J=5.9Hz),4.39(2H,ddd,J=14.4,7.1,4.4Hz),3.37(1H,dd,J=10.2,8.3Hz),3.26-3.20(1H,m),3.15 -3.05(1H,m),2.92-2.74(4H,m),2.66(1H,dd,J=13.4,4.1Hz),2.62-2.53(1H,m),2.48(1H,dd,J=13.4 , 4.1Hz), 2.32-2.19 (3H, m), 2.08-1.92 (5H, m), 1.83-1.30 (10H, m), 1.11 (3H, d, J = 6.3Hz), 0.63 (3H, s).

[0656] Exact Mass=463.32(C28H43F2NO2)Obs.mass=464.40(M+H)

[0657] [Example 54]

[0658] 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)

[0659] 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].

[0660] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.92 (1H, tt, J = 56.5, 4.2Hz), 5.89 (1H, d, J = 10.0Hz), 4.06-3.95 (2H, m), 3 .17(1H,t,J=8.3Hz),2.97-2.80(3H,m),2.61-1.91(15H,m),1.86-1.26(13H,m)1.08(3H,d,J=6.8Hz),0.61(3H,s).

[0661] Exact Mass=451.33(C27H43F2NO2)Obs.mass=452.30((M+H)

[0662] [Example 55]

[0663] 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)

[0664] 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].

[0665] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7Hz), 5.91 (1H, tt, J = 56.6, 4.0Hz), 5.89 (1H, d, J = 10.7Hz), 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=6.3Hz),0.61(3H,s).

[0666] Exact Mass=451.33(C27H43F2NO2)Obs.mass=452.25(M+H)

[0667] [Example 56]

[0668] 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)

[0669] [Chemistry 24]

[0670]

[0671] Step 1

[0672] A DMF solution [1 mL] of compound (2a) [100 mg, 0.137 mmol], triethyl[3-(trifluoromethyl)pyrrolidin-3-yl]silane (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 target compound (compound B044-TBSLP) [32.2 mg, 0.039 mmol] on the low polarity side and the target compound (compound B044-TBSMP) [35.5 mg, 0.043 mmol] on the high polarity side.

[0673] Step 2a

[0674] To a THF solution (1 mL) of compound B044-TBSLP (32.2 mg, 0.039 mmol) was added TBAF (1 M in THF, 0.5 mL, 0.5 mmol), 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 yield compound B044a (7.7 mg, 0.016 mmol).

[0675] 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2Hz), 6.04 (1H, d, J = 11.2Hz), 5.24 (1H, dd, J = 2.4, 1.5Hz), 4.30 (1H, t, J = 6.0Hz), 4.12-4.00 (1H, m), 2 .92(1H,d,J=10.7Hz),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=6.3Hz),0,55(3H,s).

[0676] Exact Mass=483.3(C27H40F3NO3)Obs.mass=484.3(M+H)

[0677] Step 2b

[0678] Compound B044-TBSMP [35.5 mg, 0.043 mmol] was treated in the same manner as in Step 2a to obtain compound B044b [10.0 mg, 0.021 mmol].

[0679] 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2Hz), 6.04 (1H, d, J = 10.7Hz), 5.24 (1H, dd, J = 2.4, 1.0Hz), 4.30 (1H, t, J = 5. 9Hz), 4.08 (1Hdt, J=10.9, 3.8Hz), 2.84-2.41 (7H, m), 2.26-1.20 (24H, m), 1.00 (3H, d, J=6.3Hz), 0.55 (3H, s).

[0680] Exact Mass=483.3(C27H40F3NO3)Obs.mmass=484.3(M+H)

[0681] [Example 57]

[0682] 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)

[0683] Using compound 2b [100 mg, 0.139 mmol] and triethyl[3-(trifluoromethyl)pyrrolidin-3-yl]silane (compound 3b21) [100.4 mg, 0.373 mmol] as starting materials, the reaction was carried out 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].

[0684] Compound B045a

[0685] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7Hz), 5.88 (1H, d, J = 11.2Hz), 4.06-3.94 (2H, m), 3.08 (1H, d, J = 11.2Hz), 2.94 (1H, q, J = 8.0Hz), 2.83 (1H, dd, J = 11.2,4.4Hz),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=6.3Hz),0.60(3H,s).

[0686] Exact Mass=471.30(C26H40F3NO3)Obs.mass=472.25(M+H)

[0687] Compound B045b

[0688] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7Hz), 5.89 (1H, d, J = 11.2Hz), 4.06-3.94 (2H, m), 2.85-2.75 (4H, m), 2.66 (1H, d d,J=15.6,7.3Hz),2.61-2.13(8H,m),2.10-1.98(2H,m),1.93-1.24(13H,m),1.06(3H,d,J=6.8Hz),0.60(3H,s).

[0689] Exact Mass=471.30(C26H40F3NO3)Obs.mass=472.25(M+H)

[0690] [Example 58]

[0691] 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)

[0692] Using compound 2c [100 mg, 0.137 mmol] and triethyl[3-(trifluoromethyl)pyrrolidin-3-yl]silane (compound 3b21) [144.3 mg, 0.536 mmol] as starting materials, the reaction was carried out 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].

[0693] Compound B046a

[0694] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.8Hz ),4,43-4.35(2H,m),3.03(1H,d,J=11.2Hz),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=6.3Hz),0.61(3H,s).ExactMass=483.3(C27H40F3NO3)Obs.mass=484.25(M+H)

[0695] Compound B046b

[0696] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 10.7Hz), 5.05 (2H ,d,J=6.8Hz),4.39(2H,ddd,J=13.9,7.1,4.6Hz),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=6.3Hz),0.61(3H,s).Exact Mass=483.3(C27H40F3NO3)Obs·mass=484.30(M+H)

[0697] [Example 59]

[0698] 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)

[0699] 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].

[0700] 1H-NMR (CD3OD) δ: 6.40 (1H, t, J = 75.0Hz), 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.29 (1H, dd, J=2.2, 1.2Hz), 4.80-4.75 (1H, m), 4.35 (1H, t, J= 5.9Hz), 4.17-4.10 (1H, m), 3.03 (1H, dd, J= 11.2, 5.9H z), 2.95-2.85 (2H,m), 2.74 (1H, dd, J=11.0, 3.2Hz), 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=6.3Hz),0.61(3H,s).

[0701] Exact Mass=465.31(C27H41F2NO3)Obs.mass=466.30(M+H)

[0702] [Example 60]

[0703] 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)

[0704] 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].

[0705] 1 H-NMR (CD3OD) δ: 6.39 (1H, t, J = 75.0Hz), 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.29 (1H, dd, J = 2.4, 1.5Hz), 4.80-4.73 (1H, m), 4. 35 (1H, t, J = 6.1Hz), 4.17-4.10 (1H, m), 2.90-1.94 (14H, m), 1.89 (3H, t, J = 5.4Hz), 1.74-1.24 (10H, m), 1.07 (3H, d, J = 6.8Hz), 0.61 (3H, s).

[0706] Exact Mass=465.31(C27H41F2NO3)Obs.mass=466.40(M+H)

[0707] [Example 61]

[0708] 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)

[0709] 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].

[0710] 1 H-NMR (CD3OD) δ: 6.39 (1H, t, J = 75.0Hz), 6.27 (1H, d, J = 11.2Hz), 5.92 (1H, d, J = 11.2Hz) ,5.06(2H,dd,J=7.0,2.0Hz),4.77-4.72(1H,m),4.40(2H,ddd,J=14.0,7.0,4.5Hz),2.9 6(1H,dd,J=11.0,6.1Hz),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=6.3Hz),0.62(3H,s).

[0711] Exact Mass=465.31(C27H41F2NO3)Obs, mass=466.40(M+H)

[0712] [Example 62]

[0713] 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)

[0714] 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].

[0715] 1 H-NMR(CD3OD)δ:6.44(1H,t,J=75,0Hz), 6,27(1H,d,J=11,2Hz), 5,92(1H,d,J=11.2Hz) ,5,06(2H,d,J=5,9Hz),4,88-4,84(1H,m),4.40(2H,ddd,J=14.3,7,2,4.5Hz),3.08(2H ,d,J=4,4Hz),3,06-2,85(3H,m),2.71-2,63(3H,m),2,49(1H,dd,J=13.4,3.7Hz),2.35 -1.98(7H,m),1.78-1.50(6H,m),1.41-1.28(3H,m),1.10(3H,d,J=6.3Hz),0.63(3H,s).

[0716] Exact Mass=465.31(C27H41F2NO3)Obs.mass=466.40(M+H)

[0717] [Example 63]

[0718] 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)

[0719] 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].

[0720] 1H-NMR (CD3OD) δ: 6.42 (1H, t, J = 75.0Hz), 6.22 (1H, d, J = 11.2Hz), 5.90 (1H, d, J = 11. 2Hz),4.84-4.79(1H,m),4.07-3.96(2H,m),3.12(1H,dd,J=11.7,6.3Hz),3.03-2. 96(1H,m),2.85(2H,dd,J=11.5,3.2Hz),2.77-2.50(4H,m),2.41(1H,dd,J=13.7,3 .4Hz),2.33-1,96(7H,m),1.91-1.27(12H,m),1.09(3H,d,J=6.8Hz),0.62(3H,s).

[0721] Exact Mass=453.31(C26H41F2NO3)Obs.mass=454.35(M+H)

[0722] [Example 64]

[0723] 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)

[0724] 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].

[0725] 1 H-NMR (CD3OD) δ: 6.43 (1H, t, J = 75.0Hz), 6.22 (1H, d, J = 11.2Hz), 5.90 (1H, d, J = 11.2Hz), 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=13.4,3.2Hz), 2.33-1.97(7H,m), 1.91-1.27(12H,m), 1.09(3H,d,J=6.8Hz), 0.62(3H,s).

[0726] Exact Mass=453.31(C26H41F2NO3)Obs.mass=454.35(M+H)

[0727] [Reference Example 9]

[0728] Synthesis of 3-(S)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (Compound 3b24)

[0729] [Chemistry 25]

[0730]

[0731] Step 1

[0732] To a THF solution [17 mL] of tert-butyl-3-(S)-hydroxypyrrolidine-1-carboxylate (compound 3b22) [1.20 g, 6.41 mmol] was added sodium hydride [60% in oil, 0.32 g, 8 mmol] at 0°C, and the mixture was stirred at 0°C for 20 minutes. To this mixture was added 2,2-difluoroethyl trifluoromethanesulfonate [1.65 g, 7.71 mmol], 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 tert-butyl-3-(S)-(2,2-difluoroethoxy)pyrrolidine-1-carboxylate (compound 3b23) [1.51 g, 6.01 mmol]. (Yield = 94%)

[0733] Step 2

[0734] To tert-butyl-3-(S)-(2,2-difluoroethoxy)pyrrolidine-1-carboxylate (Compound 3b23) [1.51 g, 6.01 mmol] was added 4 M hydrochloric acid in dioxane [15 mL] and stirred overnight at room temperature. 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%)

[0735] 1 H-NMR (DMSO-D6) δ: 9.41 (2H, s), 6.14 (1H, tt, J = 54.9, 3.7Hz), 4.34-4.27 (1H, m), 3. 72(2H,td,J=15.1,3.9Hz),3.25-3.06(4H,m),2.08-2.02(1H,m),1.97-1.87(1H,m).

[0736] [Reference Example 10]

[0737] Synthesis of 3-(R)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (Compound 3b27)

[0738] [Chemistry 26]

[0739]

[0740] Step 1

[0741] Using tert-butyl-3-(R)-hydroxypyrrolidine-1-carboxylate (Compound 3b25) [1.13 g, 6.04 mmol] as the starting material, the reaction was carried out in the same manner as in Step 1 of Reference Example 9 to obtain tert-butyl-3-(R)-(2,2-difluoroethoxy)pyrrolidine-1-carboxylate (Compound 3b26) [1.37 g, 5.45 mmol]. (Yield = 90%)

[0742] Step 2

[0743] Using tert-butyl-3-(R)-(2,2-difluoroethoxy)pyrrolidine-1-carboxylate (Compound 3b26) [1.37 g, 5.45 mmol] as the starting material, the reaction was carried out in the same manner as in Step 2 of Reference Example 9 to obtain 3-(R)-(2,2-difluoroethoxy)pyrrolidine hydrochloride (Compound 3b27) [1.04 g, 5.54 mmol]. (Yield = 92%)

[0744] 1 H-NMR (DMSO-D6) δ: 9.54 (2H, s), 6.14 (1H, tt, J = 54.9, 3.7Hz), 4.31 (1H, dd, J = 5.1, 3.2Hz ), 3.72 (2H, td, J = 15.1, 3.9Hz), 3.24-3.06 (4H, m), 2.07-2.02 (1H, m), 1.98-1.86 (1H, m).

[0745] [Example 65]

[0746] 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)

[0747] 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].

[0748] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.10 (1H, d, J = 11.2Hz), 5.94 (1H, tt, J = 55.0, 4.0Hz), 5 .29 (1H, dd, J = 2.4, 1.0Hz), 4.37-4.30 (2H, m), 4.17-4.10 (1H, m), 3.71 (2H, tdd, J = 14.5, 3.7, 2. 8Hz),3,28-3.08(4H,m),2.92-2.83(2H,m),2.76(1H,t,J=11,5Hz),2.52(1H,dd,J=13.2,3.4Hz ),2.30-2.17(2H,m),2.12-2.00(4H,m),1.91-1.29(13H,m),1.11(3H,d,J=6.3Hz),0.63(3H,s).

[0749] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.4(M+H)

[0750] [Example 66]

[0751] 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)

[0752] 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].

[0753] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.89 (1H, tt, J=55.4,4.0Hz),5.28(1H,dd,J=1.2,2.0Hz),4.89(1H,d,J=2.0Hz),4.34(1H, t,J=5.9Hz),4.16-4.10(2H,m),3.69-3.54(2H,m),2.86(1H,dd,J=12.2,3.4H z), 2.68-2.23 (8H, m), 2.13-1.21 (17H, m), 1.04 (3H, d, J = 6.3Hz), 0.59 (3H, s).

[0754] [Example 67]

[0755] 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)

[0756] 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].

[0757] 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2Hz), 5.94 (1H, tt, J = 4.0, 55.0Hz), 5.93 (1H, d, J = 11.2 Hz), 5.06(2H,d,J=5.9Hz),4.43-4.29(3H,m),3.78-3.64(2H,m),3.28-3.07(4H,m),2.87( 2H,dd,J=12.4,2.7Hz),2.76(1H,t,J=11.5Hz),2.67(1H,dd,J=13.2,4.4Hz),2.49(1H,dd, J=13.2,3.9Hz),2.33-2.04(6H,m),1.81-1.26(9H,m),1.12(3H,d,J=6.3Hz),0.64(3H,s).

[0758] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.35(M+H)

[0759] [Example 68]

[0760] 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)

[0761] 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].

[0762] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.89 (1H, tt, J = 56.0, 4.0Hz), 5.05 (2H, d, J = 8.0Hz), 4.42-4.36 (2H, m), 4.1 7-4.10(1H,m), 3.70-3.55(2H,m), 2,85(1H,dd,J=12.0, 3,7Hz), 2,69-2.24(10H,m), 2.13-1.23(15H,m), 1.05(3H,d,J=6.3Hz), 0.61(3H,s).

[0763] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.35(M+H)

[0764] [Example 69]

[0765] 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)

[0766] 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].

[0767] 1 H-NMR (CD3OD) δ: 6.22 (1H, d, J = 10.7Hz), 5.94 (1H, tt, J = 55.0, 4.0Hz), 5.91 (1H, d, J = 10.7Hz) ),4.33-4.29(1H,m),4.07-3.96(2H,m),3.71(2H,dtd,J=3.0,14.0,4.0Hz),3.29-3.05(4H,m ), 2.86 (2H, d, J = 12.2Hz), 2.75 (1H, t, J = 11.5Hz), 2.60 (1H, dd, J = 13.4, 3.7Hz), 2.42 (1H, dd ,J=13.4,3.2Hz),2.26-1.95(7H,m),1.88-1.30(11H,m),1.11(3H,d,J=6.3Hz),0.64(3H,s).

[0768] [Example 70]

[0769] 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)

[0770] 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].

[0771] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.89 (1H, tt, J = 55.0, 4.0Hz), 5.88 (1H ,d,J=11.2Hz),4.16-4.10(1H,m),4.06-3.95(2H,m),3.62(2H,tt,J=14.4,4.0H z),2.83(1H,dd,J=11.7,3.9Hz)2.68-2.56(4H,m),2.49(1H,q,J=7.8Hz),2.40( 1H, dd, J = 13.2, 3.4Hz), 2.35-1.21 (21H, m), 1.04 (3H, d, J = 6.3Hz), 0.60 (3H, s).

[0772] Exact Mass=467.32(C27H43F2NO3)Obs.mass=468.25(M+H)

[0773] [Reference Example 11]

[0774] Synthesis of 3-(S)-(3,3-difluoropropyl)pyrrolidine hydrochloride (Compound 3b32)

[0775] [Chemistry 27]

[0776]

[0777] Step 1

[0778] A pyridine solution [10 mL] of tert-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] 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 obtain tert-butyl-3-(R)-(2-(tosyloxy)ethyl)pyrrolidine-1-carboxylate (Compound 3b28) [1.46 g, 3.95 mmol]. (Yield = 81%)

[0779] Step 2

[0780] To a DMF solution [20 mL] of tert-butyl-3-(R)-(2-(tosyloxy)ethyl)pyrrolidine-1-carboxylate (compound 3b28) [1.46 g, 3.95 mmol] were added potassium cyanide [1.009 g, 15.50 mmol] and 18-crown-6 [114 mg, 0.431 mmol], 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 tert-butyl-3-(S)-(2-cyanoethyl)pyrrolidine-1-carboxylate (compound 3b29) [0.74 g, 3.3 mmol]. (Yield = 68%)

[0781] Step 3

[0782] A toluene solution [30 mL] of tert-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 the solution, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was warmed to room temperature and quenched with saturated ammonium chloride. A 2 M aqueous sodium hydroxide solution [10 mL] was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl-3-(S)-(2-oxopropyl)pyrrolidine-1-carboxylate (compound 3b30) [280 mg, 1.23 mmol]. (Yield = 37%)

[0783] Step 4

[0784] A solution of tert-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, DAST [0.60 mL, 4.55 mmol] was further added at 0°C and stirred for another day. The reaction mixture was cooled to 0°C, 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 silica gel column chromatography to give tert-butyl-3-(S)-(3,3-difluoropropyl)pyrrolidine-1-carboxylate (compound 3b31) [230.1 mg, 0.923 mmol]. (Yield = 75%)

[0785] Step 5

[0786] To tert-butyl-3-(S)-(3,3-difluoropropyl)pyrrolidine-1-carboxylate (Compound 3b31) [230.1 mg, 0.923 mmol] was added 4 M hydrochloric acid 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-(S)-(3,3-difluoropropyl)pyrrolidine hydrochloride (Compound 3b32) [173.7 mg, 0.923 mmol].

[0787] (Yield = 100%)

[0788] 1H-NMR (DMSO-D6) δ: 9.22 (2H, s), 6.07 (1H, tt, J = 56.7, 4.3Hz), 3.35-3.15 (2H, m), 3.09-3.00 (1H, m), 2. 68(1H,dd,J=11.4,8.7Hz),2.23-2.11(1H,m),2.08-1.98(1H,m),1,91-1.76(2H,m),1.56-1.39(3H,m).

[0789] [Reference Example 12]

[0790] Synthesis of 3-(R)-(3,3-difluoropropyl)pyrrolidine hydrochloride (Compound 3b37)

[0791] [Chemistry 28]

[0792]

[0793] Step 1

[0794] A pyridine solution [10 mL] of tert-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] 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 afford tert-butyl-3-(S)-(2-(tosyloxy)ethyl)pyrrolidine-1-carboxylate (Compound 3b33) [1.28 g, 3.46 mmol]. (Yield = 70%)

[0795] Step 2

[0796] To a DMF solution [20 mL] of tert-butyl-3-(S)-(2-(tosyloxy)ethyl)pyrrolidine-1-carboxylate (compound 3b33) [1.28 g, 3.46 mmol] were added potassium cyanide [618 mg, 9.49 mmol] and 18-crown-6 ether [97.2 mg, 0.368 mmol], 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 obtain tert-butyl-3-(R)-(2-cyanoethyl)pyrrolidine-1-carboxylate (compound 3b34) [0.81 g, 3.46 mmol]. (Yield = 100%)

[0797] Step 3

[0798] A toluene solution [30 mL] of tert-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 the solution, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was warmed to room temperature and quenched with saturated ammonium chloride. A 2 M aqueous sodium hydroxide solution [10 mL] was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl-3-(R)-(2-oxopropyl)pyrrolidine-1-carboxylate (compound 3b35) [447.3 mg, 1.97 mmol]. (Yield = 54%)

[0799] Step 4

[0800] A solution of tert-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, DAST [0.63 mL, 4.77 mmol] was further 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 obtain tert-butyl-3-(R)-(3,3-difluoropropyl)pyrrolidine-1-carboxylate (compound 3b36) [269.7 mg, 1.08 mmol].

[0801] Step 5

[0802] To tert-butyl-3-(R)-(3,3-difluoropropyl)pyrrolidine-1-carboxylate (Compound 3b36) [269.7 mg, 1.08 mmol] was added 4 M hydrochloric acid 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].

[0803] (Yield = 100%)

[0804] 1H-NMR (DMSO-D6) δ: 9.03 (2H, s), 6.03 (1H, tt, J = 56.8, 4.3Hz), 3.24 (1H, dd, J = 11.2, 7.8Hz), 3.19-3.13 (1H, m), 3.06-2 .98(1H,m),2.65(1H,dd,J=11.2,8.8Hz),2.18-2.10(1H,m),2.08-1.97(1H,m),1.87-1.73(2H,m),1.53-1.36(3H,m).

[0805] [Example 71]

[0806] 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)

[0807] 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].

[0808] 1 H-NMR (CD3OD) δ: 6.30 (1H, d, J = 11.4Hz), 6.07 (1H, d, J = 11.4Hz), 5.83 (1H, tt, J = 56.9, 4.4Hz), 5.27 (1H, dd, J = 2.3, 1.4Hz), 4.33 (1H, t, J = 5 .9Hz),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=6.4Hz),0.58(3H,s).

[0809] Exact Mass=477.34(C29H45F2NO2)Obs.mmass=478.25(M+H)

[0810] [Example 72]

[0811] 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)

[0812] 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].

[0813] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.85 (1H, tt, J = 56.0, 4.0Hz), 5.28 (1H, dd, J = 2.0, 1, 2Hz), 4.34 (1H, t, J = 5.9Hz), 4, 1 5-4.10(1H,m),2.86(1H,dd,J=12.0,4.6Hz),2.79-2.70(2H,m),2,51(1H,d d,J=13.4,3,2Hz), 2,40-1,24(28H,m),1.05(3H, d,J=6.8Hz), 0.59(3H,s).

[0814] [Example 73]

[0815] 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)

[0816] 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].

[0817] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.0Hz), 5.91 (1H, d, J = 11.0Hz), 5.85 (1H, t t, J=57.5, 4.0Hz), 5.05 (2H, d, J=6.4Hz), 4.42-4.35 (2H, m), 2.92 (1H, t, J= 8.5Hz),2.85(1H,dd,J=12.1,3.4Hz),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=6.4Hz),0.61(3H,s).

[0818] [Example 74]

[0819] 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)

[0820] 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].

[0821] 1 H-NMR (CD3OD) δ: 6.28 (1H, d, J = 11.2Hz), 5.93 (1H, d, J = 11.2Hz), 5.91 (2H, tt, J = 57.0, 4.0Hz) , 5.06 (2H, d, J = 5.9Hz), 4.40 (2H, ddd, J = 14.4, 7.1, 4.4Hz), 3.51 (1H, dd, J = 11.0, 8.1Hz), 3.42 -3.26 (3H, m), 3.07-2.85 (4H, m), 2.67 (1H, dd, J = 13.4, 4.1Hz), 2.49 (1H, dd, J = 13.7, 3.9Hz), 2.45-2.20 (4H, m), 2.12-1.95 (3H, m), 1.90-1.33 (15H, m), 1.14 (3H, d, J = 6.8Hz), 0.65 (3H, s).

[0822] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.40(M+H)

[0823] [Example 75]

[0824] 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)

[0825] 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].

[0826] 1 H-NMR (CD3OD) δ: 6, 21 (1H, d, J = 11.0Hz), 5, 89 (2H, d, J = 11.0Hz), 5.85 (1H, tt, J = 4.5, 57.0Hz), 4.06-3.95 (2H, m), 2.92 (1H, t, J = 8.5Hz), 2.83 (1H ,dd,J=11.7,3.9Hz),2.68-2.55(2H,m),2.52-2.45(1H,m),2.41(1H,dd, J=13.3, 3.2Hz), 2.32-1.22 (31H, m), 1.05 (3H, d, J=6.4Hz), 0, 60 (3H, s).

[0827] Exact Mass=465.34(C28H45F2NO2)Obs.mass=466.30(M+H)

[0828] [Example 76]

[0829] 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)

[0830] 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].

[0831] 1 H-NMR(CD3OD)δ:6.21(1H,d,J=11.2Hz),5.88(1H,d,J=11.2Hz),5.85(1H,tt,J=57.0,4.0Hz),4.06-3.95(2H,m),2.83(1H,d d,J=12.0,3.7Hz),2.77-2.70(2H,m),2.59(1H,dd,J=13.4,3.7Hz),2.42-1.21(31H,m),1.05(3H,d,J=6.8Hz), 0.60(3H,s).

[0832] Exact Mass=465.34(C28H45F2NO2)Obs.mass=466.35(M+H)

[0833] [Example 77]

[0834] 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)

[0835] 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].

[0836] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.28 (1H, dd, J = 1.8, 1.0Hz), 4. 89 (1H, dd, J = 1.8, 1.0Hz), 4.86-4.80 (2H, m), 4.34 (1H, t, J = 5.9Hz), 4, 14-4.05 (1H, m), 2, 86 (2H, dd,J=10.7,5.9Hz),2.81-2.75(1H,m),2.62(1H,dd,J=10.7,2.4Hz),2.51(1H,dd,J=13.2,3.4Hz ), 2.38-2.16 (6H, m), 2.07-1.87 (7H, m), 1.73-1.21 (11H, m), 1.06 (3H, t, J = 8.1Hz), 0.59 (3H, s).

[0837] Exact Mass=483.30(C27H40F3NO3)Obs.mass=484.35(M+H)

[0838] [Example 78]

[0839] 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)

[0840] 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].

[0841] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.28 (1H, dd, J = 2.4, 1.5Hz), 4.89 (1H, d d,J=2.2,1.5Hz),4.86-4.82(1H,m),4.34(1H,t,J=5.9Hz),4.15-4.09(1H,m),2.86(1H,dd,J=12.2,3.4 Hz),2.78(1H,dd,J=11.2,2.4Hz),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=5.9Hz),1.75-1.63(2H,m),1.60-1.21(8H,m),1.04(3H,d,J=6.8Hz),0.59(3H,s).

[0842] Exact Mass=483.30(C27H40F3NO3)Obs.mass=484.20(M+H)

[0843] [Example 79]

[0844] 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)

[0845] 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].

[0846] 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 7. 3Hz), 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, 4.0Hz), 2.48 (1H, dd, J = 13.4, 4.1Hz), 2.40-2.22 (7H, m), 2.07-1.90 (5H, m), 1. 60 (7H, tt, J = 24.6, 8.1Hz), 1.38-1.21 (4H, m), 1.05 (3H, d, J = 6.3Hz), 0.61 (3H, s).

[0847] Exact Mass=483.30(C27H40F3NO3)Obs.mass=484.40(M+H)

[0848] [Example 80]

[0849] 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)

[0850] 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].

[0851] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.8Hz), 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=15.9,6.6Hz),2.37-2.20(5H,m),2. 07-1.90(4H,m),1.70-1.21(10H,m),1.05(3H,d,J=6.3Hz),0.61(3H,s).

[0852] Exact Mass=483.30(C27H40F3NO3)Obs.mass=484.30(M+H)

[0853] [Example 81]

[0854] 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)

[0855] 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].

[0856] 1 H-NMR (CD3OD) δ: 6.20 (1H, d, J = 11.0Hz), 5.87 (1H, d, J = 11.0Hz), 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=6.4Hz),0.58(3H,s).

[0857] Exact Mass=471.30(C26H40F3NO3)Obs.mass=472.25(M+H)

[0858] [Example 82]

[0859] 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)

[0860] 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].

[0861] 1H-NMR (CD3OD) δ: 6.20 (1H, d, J = 11.4Hz), 5.87 (1H, d, J = 11.0Hz), 4.85-4.81 (1H, m), 4.04-3.9 3(2H,m),2.82(1H,dd,J=11.7,3.9Hz),2.78(1H,dd,J=3.0,12.0Hz),2.66-2.61(2H,m),2.57( 1H,dd,J=13.3,3.7Hz),2.46(1H,q,J=7.9Hz),2.39(1H,dd,J=13.3,3.2Hz),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=6.4Hz),0.58(3H,s).

[0862] Exact Mass=471.30(C26H40F3NO3)Obs.mass=472.25(M+H)

[0863] [Example 83]

[0864] 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)

[0865] 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].

[0866] 1 H-NMR (CD3OD) δ: 6, 32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 10.7Hz), 5.28 (1H, s), 4.34 (1H, t, J = 5.9Hz), 4.18-4.08 (2H, m), 2.86 (1H, dd, J=12.2, 3.4Hz), 2.76 (1H, q, J=8.0Hz), 2.63-2.40 (4H,m), 2.35-2.20 (4H,m), 2.07-1.25 (21H, m), 1.05 (3H,d, J=6.8Hz), 0.59 (3H,s).

[0867] Exact Mass=429.32(C27H43NO3)Obs.mass=430.30(M+H)

[0868] [Example 84]

[0869] 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)

[0870] 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].

[0871] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.88 (1H, d, J = 11.2Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 11.7, 3.9Hz), 2.77 (1H, dd, J = 16.6, 7.3Hz), 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=6.3Hz),0.59(3H,s).

[0872] Exact Mass=417.32(C26H43NO3)Obs.mass=418.30(M+H)

[0873] [Example 85]

[0874] 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)

[0875] 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].

[0876] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.8Hz), 4.42-4.3 6 (2H, m), 2.85 (1H, dd, J = 12.0, 3.7Hz), 2.77 (1H, dd, J = 16.6, 7.3Hz), 2.67 (1H, dd, J = 13.4, 4.1Hz) ,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=11.8,3.1Hz),1.33(3H,s),1.30-1.21(2H,m), 1.05(3H,d,J=6.3Hz),0.60(3H,s).

[0877] Exact Mass=429.32(C27H43NO3)Obs.mass=430.30(M+H)

[0878] [Example 86]

[0879] 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)

[0880] 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].

[0881] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.28 (1H, dd, J = 2.4, 1.5H z),4.34(1H,t,J=6.1Hz),4.16-4.05(1H,m),2.86(1H,dd,J=12.0,3.7Hz),2.75-2.53(3H, m),2.51(1H,dd,J=13.4,3.7Hz),2.38(1H,d,J=9.8Hz),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 = 6.3Hz), 0.59 (3H, s).

[0882] Exact Mass=429.32(C27H43NO3)Obs.mass=430.30(M+H)

[0883] [Example 87]

[0884] 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)

[0885] 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].

[0886] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.88 (1H, d, J = 10.7Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.2, 3.4Hz), 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=6.3Hz),0.59(3H,s).

[0887] Exact Mass=417.32(C26H43NO3)Obs.mass=418.30(M+H)

[0888] [Example 88]

[0889] 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)

[0890] 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].

[0891] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6. 8Hz), 4.42-4.36(2H,m), 2.85(1H,dd,J=12.2,3.9Hz), 2.73-2.62(3H,m), 2.58(1H , dd, J=14.6, 8.3Hz), 2.48 (1H, dd, J=13.4, 3.7Hz), 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=6.8Hz),0.60(3H,s).

[0892] Exact Mass=429.32(C27H43NO3)Obs.mass=430.25(M+H)

[0893] [Example 89]

[0894] 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)

[0895] 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].

[0896] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.8Hz), 4.42-4.36 (2H, m), 2.9 9-2.24(12H,m),2.07-1.28(16H,m),1.08-1.00(1H,m),1.05(3H,d,J=6.3Hz),0.60(3H,s),0.45-0.30(4H,m).

[0897] Exact Mass=455.34(C29H45NO3)Obs.mmass=456.35(M+H)

[0898] [Example 90]

[0899] 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)

[0900] 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].

[0901] 1 H-NMR (CD3OD) δ: 6,21 (1H, d, J = 10,7Hz), 5,89 (1H, d, J = 11.2Hz), 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=6.3Hz),0.60(3H,s).

[0902] Exact Mass=455.30(C26H40F3NO2)Obs.mass=456.30(M+H)

[0903] [Example 91]

[0904] 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)

[0905] 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].

[0906] Exact Mass=467.30(C27H40F3NO2)Obs.mass=468.35(M+H)

[0907] [Example 92]

[0908] 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)

[0909] [Chemistry 29]

[0910]

[0911] Step 1

[0912] 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-piperidinyl]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 a 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].

[0913] 1 H-NMR (CDCl3) δ: 5.65 (1H, s), 2.91-2.85 (1H, m), 2.80 (1H, d, J = 11.2Hz), 2.63 (1 H,dd,J=5.9Hz),4.15-4.06(1H,m),2.89-2.81(2H,m),2.63(1H,d,J=11.2Hz),2. 51(1H,dd,J=11.2,4.0Hz),2.37(1H,td,J=12.0,2.3Hz),2.28(1H,dd,J=12.2,3. 4Hz),2.09-1.84(8H,m),1.68-1.23(16H,m),1.00(3H,d,J=6.9Hz),0.59(3H,s).

[0914] Step 2

[0915] Compound 3c02 synthesized in step 1 [47.1 mg, 0.107 mmol], (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 the mixture was heated and stirred at 100° C. under a nitrogen atmosphere for 3 hours. The reaction solution was concentrated under reduced pressure and crudely purified by thin-layer chromatography to obtain a crude product containing compound 3c03 [73.9 mg].

[0916] Step 3

[0917] The crude product containing compound 3c03 obtained in step 2 [73.9 mg] was dissolved in acetone [1 mL], 6N hydrochloric acid [0.2 mL] was added, and the mixture was stirred at room temperature for 8 hours. The reaction solution 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 obtain compound C001 [6.3 mg, 0.013 mmol].

[0918] 1 H-NMR(CD3OD)δ: 6.32(1H,d,J=11.2Hz), 6.08(1H,d,J=11.2Hz), 5.28(1H, t, J=1.2Hz), 4.34 (1H, t, J=5.9Hz), 4.15-4.06 (1H, m), 2.89-2.81 (2H, m), 2.63(1H,d,J=11.2Hz),2.51(1H,dd,J=13.2,3.4Hz),2.41-2.23(3H,m),2 .11-2.02 (3H, m), 1.98-1.21 (19H, m), 1.03 (3H, d, J = 6.3Hz), 0.60 (3H, s).

[0919] Exact Mass=497.31(C28H42F3NO3)Obs.mass=498.4(M+H)

[0920] [Example 93]

[0921] 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)

[0922] Compound (2b) [100 mg, 0.139 mmol] and triethyl-[[4-(trifluoromethyl)-4-piperidinyl]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].

[0923] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0Hz), 5.89 (1H, d, J = 11.4Hz), 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=6.4Hz),0.60(3H,s).

[0924] Exact Mass=485.31(C27H42F3NO3)Obs.mass=486.25(M+H)

[0925] [Example 94]

[0926] 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)

[0927] 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 give Compound C003 [10.0 mg, 0.019 mmol].

[0928] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.10 (1H, d, J = 11.2Hz), 5.22 (1H, d, J = 2.0Hz), 4.22 (1H, d, J = 3.4Hz), 3.72 (1H, td, J = 8.1, 4.1Hz), 3.17 (1H, d, J = 10.2Hz), 3.00 (1H, d, J = 11.2Hz) ,2.89-2.75(2H,m),2.67(1H,d,J=12.7Hz),2.62-2.52(2H,m),2.42(1H,t,J=11.7Hz),2.19 -1.97(5H,m),1.93-1.20(13H,m),1.08(3H,d,J=6.8Hz),1.03(3H,d,J=6.8Hz),0.61(3H,s).

[0929] Exact Mass=511.33(C29H44F3NO3)Obs.mass=512.4(M+H)

[0930] [Example 95]

[0931] 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)

[0932] Compound (2c) [60.0 mg, 0.082 mmol] and triethyl-[[4-(trifluoromethyl)-4-piperidinyl]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].

[0933] 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7Hz), 5.92 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.3Hz), 4.43-4.34 (2H, m), 3.28-3.24 (1H, m), 3.10 (1H, d, J = 1 1.7Hz),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=6.3Hz),0.63(3H,s).

[0934] Exact Mass=497.31(C28H42F3NO3)Obs.mass=498.4(M+H)

[0935] [Example 96]

[0936] 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)

[0937] [Chemistry 30]

[0938]

[0939] Step 1

[0940] 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 give 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].

[0941] Step 2, Step 3

[0942] Using 3c05 [36.0 mg, 0.085 mmol], compound 7a [41.0 mg, 0.111 mmol] and tetrakistriphenylphosphine palladium (0) [12.4 mg, 0.011 mmol] as starting materials, the same treatment as in Steps 2 and 3 of Example 92 was carried out to obtain compound C007 [5.5 mg, 0.011 mmol].

[0943] 1H-NMR(CD3OD)δ: 6.32(1H,d,J=11.2Hz), 6.08(1H,d,J=11.7Hz), 5.28(1H,dd,J=2.4,1.5Hz), 4.34(1H,t,J=5.9Hz), 4.12(1H,br s), 3.04 (1H, d, J = 11.2Hz), 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 = 6.8Hz), 0.59 (3H, s).

[0944] Exact Mass=481.32(C28H42F3NO2)Obs.mass=482.4(M+H)

[0945] [Example 97]

[0946] 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)

[0947] 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].

[0948] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0Hz), 5.88 (1H, d, J = 11.4Hz), 4.06-3.95 (2 H,m),3.04(1H,d,J=11.4Hz),2.88-2.80(2H,m),2.59(1H,dd,J=13.3,3.7Hz) ,2.40(1H,dd,J=13.3,3.7Hz),2.26(1H,dd,J=12.1,3.0Hz),2.23-1.73(13H, m),1.67-1.48(8H,m),1.38-1.22(4H,m),1.02(3H,d,J=6.4Hz),0.60(3H,s).

[0949] Exact Mass=469.32(C27H42F3NO2)Obs.mass=470.30(M+H)

[0950] [Example 98]

[0951] 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)

[0952] 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].

[0953] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 5.9Hz), 4.43-4.35 (2H, m), 3.35-3.31 (1H, m), 3. 14(1H,d,J=11.7Hz),2.86(1H,dd,J=12.4,3.7Hz),2.69-2.04(12H,m),1.92-1.27(13H,m),1.07(3H,d,J=6.3Hz),0.62(3H,s).

[0954] Exact Mass=481.32(C28H42F3NO2)Obs.mass=482.4(M+H)

[0955] [Example 99]

[0956] 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)

[0957] Compound 3c05 [42.0 mg, 0.099 mmol] obtained in Step 1 of Example 96, compound 7b [50 mg, 0.131 mmol], and tetrakistriphenylphosphine 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].

[0958] 1H-NMR (DMSO-D6) δ: 6.19 (1H, d, J = 11.2Hz), 5.99 (1H, d, J = 11.2Hz), 5.17 (1H, d, J = 2.4 Hz), 4.75 (2H, dd, J = 11.7, 3.4Hz), 4.57 (1H, d, J = 4.4Hz), 4.15 (1H, t, J = 3.4Hz), 3.63 -3.59(1H,m),2.93(1H,d,J=11.2Hz),2.77(2H,t,J=12.7Hz),2.46(1H,dd,J=14.1,3 .4Hz), 2.22-1.14 (27H, m), 0.95 (3H, d, J = 5.9Hz), 0.85 (3H, d, J = 6.8Hz), 0.52 (3H, s).

[0959] Exact Mass=495.33(C29H44F3NO2)Obs.mass=496.4(M+H)

[0960] [Example 100]

[0961] 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-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound C013)

[0962] [Chemistry 31]

[0963]

[0964] Step 1

[0965] 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 give 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].

[0966] Step 2, Step 3

[0967] Using 3c08 [16.0 mg, 0.0394 mmol], compound 7a [20.0 mg, 0.0542 mmol] and tetrakistriphenylphosphine palladium (0) [10.0 mg, 0.0086 mmol] as starting materials, the same treatment as in Steps 2 and 3 of Example 92 was carried out to give compound C013 [2.5 mg, 0.0054 mmol].

[0968] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.68 (1H, td, J = 57.0, 5.0Hz), 5.28 (1H, d, J = 1.5Hz), 4.34 (1H, d, J = 5.9Hz), 4.12(1H,brs),3.05-2.82(3H,m),2.51(1H,dd,J=10.2,5.1Hz),2.28-2.22(2H,m),2.06-1.22(22H,m),1.02(3H,d,J=6.8Hz), 0.59(3H,s).

[0969] Exact Mass=463.33(C28H43F2NO2)Obs.mass=464.4(M+H)

[0970] [Example 101]

[0971] 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)

[0972] 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].

[0973] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0Hz), 5.88 (1H, d, J = 11.0Hz), 5.65 (1H, t d,J=56.8,4.3Hz),4.05-3.95(2H,m),3.02(1H,d,J=11.0Hz),2.83(2H,dd, J=12.3,3.0Hz),2.59(1H,dd,J=13.3,3.7Hz),2.40(1H,dd,J=13.3,3.2Hz) ,2.27-2.13(3H,m),2.05-1.21(22H,m),1.02(3H,d,J=6.4Hz),0.60(3H,s).

[0974] Exact Mass=451.33(C27H43F2NO2)Obs.mass=452.25(M+H)

[0975] [Example 102]

[0976] 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)

[0977] 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].

[0978] 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7Hz), 5.91 (2H, d, J = 10.7Hz), 5.76 (2H, td, J = 56.0, 5.0Hz), 5.05 (2H, d, J = 5.9Hz), 4 .42-4.36(2H,m),3.48(2H,t,J=11.5Hz), 2.88-2.00(15H,m), 1.91-1.32(13H,m),1.10(3H,d,J=6.3Hz), 0.64(3H,s).

[0979] Exact Mass=463.33(C28H43F2NO2)Obs.mass=464.40(M+H)

[0980] [Example 103]

[0981] 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)

[0982] Compound 3c08 [35.7 mg, 0.093 mmol] obtained in Step 1 of Example 100, compound 7b [50 mg, 0.131 mmol], and tetrakistriphenylphosphine 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].

[0983] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.67 (1H, td, J = 56.8, 4 .2Hz), 5.22 (1H, d, J = 1.5Hz), 4.22 (1H, d, J = 3.4Hz), 3.72 (1H, td, J = 8.2, 4.2Hz), 3.10 (1 H, d, J = 11.2Hz), 2.89 (2H, dd, J = 16.6, 11.7Hz), 2.59 (1H, dd, J = 13.4, 4.1Hz), 2.35 (1H, t, J=6.1Hz), 2.21-1.90 (7H, m), 1.86-1.26 (19H, m), 1.03 (6H, d, J=6.8Hz), 0.59 (3H, s).

[0984] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.4(M+H)

[0985] [Example 104]

[0986] 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)

[0987] 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].

[0988] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.51 (1H, t, J = 56.4Hz), 5.28 ( 1H, t, J = 1.2Hz), 4.89 (1H, d, J = 2.4Hz), 4.34 (1H, t, J = 6.0Hz), 4.16-4.09 (1H, m), 2.86 (1H, dd, J=12.2, 3.4Hz), 2.79 (1H, d, J= 10.7Hz), 2.60 (1H, d, J= 11.2Hz), 2.51 (1H, dd, J= 13.2, 3.4Hz), 2.45-2.36(1H,m),2.34-2.03(7H,m),1.98-1.27(21H,m),1.03(3H,d,J=6.3Hz),0.60(3H,s).

[0989] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.4(M+H)

[0990] [Example 105]

[0991] 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)

[0992] 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].

[0993] 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2Hz), 5.92 (1H, d, J = 11.2Hz), 5.63 (1H, t, J = 56.1Hz), 5.05 (2H, d, J = 6.3Hz), 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=6.3Hz),0.64(3H,s).

[0994] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.30(M+H)

[0995] [Example 106]

[0996] 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)

[0997] [Chemistry 32]

[0998]

[0999] Step 1

[1000] 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 give 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].

[1001] Step 2, Step 3

[1002] Using 3c11 [50.7 mg, 0.103 mmol], compound 7b [49.5 mg, 0.129 mmol] and tetrakistriphenylphosphine palladium (0) [23.0 mg, 0.020 mmol] as starting materials, the same treatment as in Steps 2 and 3 of Example 92 was carried out to obtain compound C023 [16.4 mg, 0.033 mmol].

[1003] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.51 (1H, t, J = 56.4Hz), 5.22 (1H, d, J =2.0Hz), 4.89 (1H, d, J = 2.4Hz), 4.22 (1H, d, J = 3.4Hz), 3.72 (1H, td, J = 8.2, 4.2Hz), 2.86 (1H, dd, J = 12 .0, 3.7Hz), 2.78 (1H, d, J = 11.2Hz), 2.59 (2H, dd, J = 13.2, 3.9Hz), 2.40 (1H, td, J = 11.6, 2.1Hz), 2.30 ( 1H, dd, J = 12.2, 2.4Hz), 2.19-1.20 (23H, m), 1.04 (6H, d, J = 8.0Hz), 1.03 (6H, d, J = 6.3Hz), 0.59 (3H, s).

[1004] Exact Mass=493.34(C29H45F2NO3)Obs.mass=494.40(M+H)

[1005] [Example 107]

[1006] 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)

[1007] 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].

[1008] 1H-NMR(CD3OD)δ: 6.32(1H,d,J=11.2Hz), 6.09(1H,d,J=11.2Hz), 5.28(1H,dd,J=2.4,1.5Hz ),4.35(1H,t,J=6.1Hz),4.15-4.10(1H,m),3.50-3.18(4H,m),3.10-2.92(2H,m),2.89-2.8 6(1H,m),2.77((1H,t,J=12.0Hz),2.51(1H,dd,J=13.2,3.4Hz),2.26(1H,dd,J=13.2,6.8H z),2.08-2.01(3H,m),1.95-1.30(17H,m),1.28(3H,s),1.12(3H,d,J=6.3Hz),0.64(3H,s).

[1009] Exact Mass=443.34(C28H45NO3)Obs.mass=444.40(M+H)

[1010] [Example 108]

[1011] 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)

[1012] [Chemistry 33]

[1013]

[1014] Step 1

[1015] 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 target compound (compound C030-TBSLP) [21.2 mg, 0.0292 mmol] on the low polarity side and the target compound (compound C030-TBSMP) [22.3 mg, 0.0307 mmol] on the high polarity side.

[1016] Step 2a

[1017] To a THF solution (1 mL) of compound C030-TBSLP (21.2 mg, 0.0292 mmol) was added TBAF (1 M in THF, 0.5 mL, 0.5 mmol), 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 yield compound C030a (10.3 mg, 0.0207 mmol).

[1018] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.28 (1H, t, J = 1.2Hz), 4.34(1H,t,J=5.9Hz),4.15-4.09(1H,m),3.05-2.93(1H,m),2.87(1H,dd,J=12.2,3.4H z), 2.80 (1H, d, J = 11.7Hz), 2.53-2.44 (4H, m), 2.25 (1H, dd, J = 13.2, 6.8Hz), 2.13 (2H, t , J=11.5Hz), 2.07-2.00 (4H, m), 1.94-1.24 (20H, m), 1.06 (3H, d, J=6.3Hz), 0.61 (3H, s).

[1019] Exact Mass=497.31(C28H42F3NO3)Obs.mass=498.40(M+H)

[1020] Step 2b

[1021] Compound C030-TBSMP [22.3 mg, 0.0307 mmol] was reacted in the same manner as in Step 2a to obtain compound C030b [9.7 mg, 0.019 mmol].

[1022] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.28 (1H, dd, J = 2.4, 1.5Hz), 4.34 (1H, t, J = 5.9Hz), 4.15-4.09 (1H, m), 2.98 (1H ,d,J=11.2Hz),2.87(2H,d,J=11.2Hz),2.53(2H,td,J=12.3,3.1Hz),2. 45-1.98(9H,m),1.92-1.23(18H,m),1.05(3H,d,J=6.3Hz),0.61(3H,s).

[1023] Exact Mass=497.31(C28H42F3NO3)Obs.mass=498.40(M+H)

[1024] [Example 109]

[1025] 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)

[1026] [Chemistry 34]

[1027]

[1028] Step 1

[1029] 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] was added potassium carbonate [390 mg, 2.82 mmol] at room temperature, and the reaction solution was heated and stirred at 60°C for 20 hours. After the reaction solution was cooled to room temperature, saturated brine was injected 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 the low-polarity compound 3c14-LP [65.6 mg, 0.150 mmol] and the high-polarity compound 3c14-MP [57.2 mg, 0.130 mmol] by TLC.

[1030] Steps 2a, 3a (compound C Synthesis of 031a)

[1031] Step 2a

[1032] To a mixed solution of compound 3c14-LP [29.9 mg, 0.0682 mmol] and compound 7b [38.7 mg, 0.101 mmol] obtained in step 1 in toluene [1 mL] / triethylamine [1 mL] was added tetrakis(triphenylphosphine)palladium(0) [15 mg, 0.013 mmol]. The mixture was heated and stirred at 100°C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography to obtain compound 3c15-LP [38.5 mg].

[1033] Step 3a

[1034] To a THF solution (1 mL) of compound 3c15-LP (38.5 mg, 0.052 mmol) was added TBAF (1 M in THF, 0.6 mL, 0.6 mmol), and the mixture was heated and stirred at 60°C overnight. After cooling to room temperature, the reaction mixture was added with saturated 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 to afford compound C031a (10.5 mg, 0.0205 mmol).

[1035] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 10.7Hz), 6.09 (1H, d, J = 11.2Hz), 5.22 (1H, d, J = 2.0Hz), 4.2 2 (1H, d, J = 3.4Hz), 3.72 (1H, td, J = 8.1, 4.2Hz), 2.97 (1H, d, J = 11.2Hz), 2.86 (1H, dd, J = 11. 7, 3.4Hz), 2.77 (1H, d, J = 11.7Hz), 2.59 (1H, dd, J = 13.4, 4.1Hz), 2.47-2.41 (2H, m), 2.19-2 .00 (5H, m), 1.94-1.23 (17H, m), 1.06 (3H, d, J = 6.3Hz), 1.03 (3H, d, J = 6.8Hz), 0.59 (3H, s).

[1036] Exact Mass=511.33(C29H44F3NO3)Obs.mass=512.4(M+H)

[1037] Step 2b, Step 3b (Compound C Synthesis of 031b)

[1038] 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].

[1039] 1 H-NMR(DMSO-D6)δ:6.19(1H,d,J=11.2Hz),5.99(1H,d,J=11.2Hz),5.58(1H,s),5.17(1H,d,J=2.4Hz ), 4.77 (1H, d, J = 2.9Hz), 4.75 (1H, d, J = 4.4Hz), 4.57 (1H, d, J = 3.4Hz), 4.15 (1H, t, J = 2.4Hz), 3.61 (1 H,brs),2.79(1H,dd,J=12.7,3.9Hz),2.66(1H,d,J=10.7Hz),2.46(2H,dd,J=14.9,3.7Hz),2.18(1H ,dd,J=12.2,2.9Hz), 2.11-1.13(23H,m),0.96(3H,d,J=6.3Hz), 0.85(3H,d,J=6.8Hz), 0.52(3H,s).

[1040] Exact Mass=511.33(C29H44F3NO3)Obs.mass=512.4(M+H)

[1041] [Example 110]

[1042] 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)

[1043] Using compound (2c) [110 mg, 151 mmol] and 3-(trifluoromethyl)piperidin-3-ol hydrochloride (compound 3c13) [125 mg, 0.608 mmol] as starting materials, the reaction was carried out 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].

[1044] Compound C032a

[1045] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6. 3Hz), 4.39 (2H, ddd, J = 13.9, 7.1, 4.4Hz), 3.00 (1H, d, J = 10.7Hz), 2.88-2.77 (2H, m ),2.67(1H,dd,J=13.2,4.4Hz),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=6.3Hz),0.62(3H,s).

[1046] Exact Mass=497.31(C28H42F3NO3)Obs.mass=498.40(M+H)

[1047] Compound C032b

[1048] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J=7.0Hz), 4.42-4.33 (2H, m), 3.03 (1H, d, J=11.7Hz), 2.93 (1H, d, J=11. 7Hz),2.86(1H,dd,J=12.2,3.4Hz),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=6.3Hz),0.63(3H,s).

[1049] Exact Mass=497.31(C28H42F3NO3)Obs.mass=498.40(M+H)

[1050] [Example 111]

[1051] 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)

[1052] Using compound (2a) [100 mg, 0.137 mmol] and 3-(difluoromethyl)piperidin-3-ol hydrochloride [50 mg, 0.267 mmol] as starting materials, the reaction was carried out 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].

[1053] Compound C034a

[1054] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.85 (1H, t, J = 55.9Hz), 5.29 (1H, dd, J = 2.4, 1.0Hz), 4.35 (1H, t, J = 5.9Hz), 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=6.3Hz), 0.61(3H,s).

[1055] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.45(M+H)

[1056] Compound C034b

[1057] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 10.7Hz), 6.09 (1H, d, J = 11.2Hz), 5.84 (1H, t, J = 55. 9Hz), 5.29(1H,t,J=1.2Hz), 4.35(1H,t,J=5.9Hz), 4.16-4.10(1H,m), 2.88(1H,dd , J=12.4,3.2Hz),2.67-2.40(6H,m),2.26(1H,dd,J=13.4,7.1Hz),2.15(1H,t,J=1 1.2Hz), 2.09-1.98(2H,m), 1.91-1.22(17H,m), 1.04(3H,d,J=6.3Hz), 0.61(3H,s).

[1058] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.35(M+H)

[1059] [Example 112]

[1060] 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)

[1061] Using compound (2b) [116.1 mg, 0.162 mmol] and 3-(difluoromethyl)piperidin-3-ol hydrochloride [70.0 mg, 0.373 mmol] as starting materials, the reaction was carried out 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].

[1062] Compound C035a

[1063] 1 H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2Hz), 5.89 (1H, d, J = 11.2Hz), 5.89 (1H, t, J = 56.0Hz), 4.07-3.96 (2H, m), 2.84 (1H, dd, J = 11 .5,4.1Hz),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=6.3Hz),0.60(3H,s).

[1064] Exact Mass=467.32(C27H43F2NO3)Obs.mass=468.35(M+H)

[1065] Compound C035b

[1066] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.88 (1H, d, J = 11.2Hz), 5.85 (1H, t, J = 56.0Hz), 4.06-3.94 (2H, m), 2.83 (1H, dd, J=11.5, 3.7Hz), 2.59 (1H, dd, J=13.2, 3.4Hz), 2.46-1.50 (28H, m), 1.37-1.25 (3H, m), 1.02 (3H, d, J=6.3Hz), 0.59 (3H, s).

[1067] Exact Mass=467.32(C27H43F2NO3)Obs.mass=468.35(M+H)

[1068] [Example 113]

[1069] 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)

[1070] Using compound (2c) [100 mg 0.137 mmol] and 3-(difluoromethyl)piperidin-3-ol hydrochloride [49.8 mg 329 mmol] as starting materials, the reaction was carried out 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].

[1071] Compound C036a

[1072] 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2Hz), 5.92 (1H, d, J = 11.2Hz), 5.84 (1H, t, J = 57.0Hz), 5.06 (2H, d, J = 6.3Hz), 4.40 (2H, ddd, J = 14.1, 7.1, 4.4Hz), 2.86 (1H, dd, J = 12.2, 3.4Hz), 2.80 (2H, d, J=11.7Hz), 2.68 (1H, dd, J=13.4, 4.1Hz), 2.56 (1H, dd, J=11.7, 3.2Hz), 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=6.3Hz),0.63(3H,s).

[1073] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.40(M+H)

[1074] Compound C036b

[1075] 1H-NMR (CD3OD) δ: 6.28 (1H, d, J = 10.7Hz), 5.93 (1H, d, J = 10.0Hz), 5.81 (1H, t, J = 55.0Hz), 5.06 (2H, d, J = 7.0Hz), 4.45-4.36 (2H, m), 3.01-1.99 (16H, m), 1.94-1.29 (14H, m), 1.07 (3H, d, J = 6.3Hz), 0.65 (3H, s).

[1076] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.40(M+H)

[1077] [Example 114]

[1078] 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)

[1079] 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].

[1080] Compound C037a

[1081] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.0Hz), 6.08 (1H, d, J = 11.0Hz), 5.28 (1H, s), 4.34 (1H, t, J = 5.9Hz), 4.12-4.06 (1H, m), 2.87 (1H,dd,J=12.3,3.0Hz),2.51(1H,dd,J=13.3,3.2Hz),2.28-1.21(24H,m),1.18(3H,s),1.03(3H,d,J=6.4Hz),0.59(3H,s).

[1082] Compound C037b

[1083] 1H-NMR (DMSO-D6) δ: 6.19 (1H, d, J = 11.4Hz), 5.98 (1H, d, J = 11.4Hz), 5.22 (1 H, d, J = 1.4Hz), 4.88 (1H, d, J = 5.0Hz), 4.75 (1H, d, J = 1.8Hz), 4.56 (1H, d, J = 3.7Hz), 4.25-3.95 (3H, m), 2.79 (1H, dd, J = 11.0, 4.0Hz), 2.36 (1H, d, J = 13. 7Hz),2.18-1.15(23H,m),1.11(3H,s),0.96(3H,d,J=6.4Hz),0.52(3H,s).

[1084] [Example 115]

[1085] 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)

[1086] 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].

[1087] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.88 (1H, d, J = 11.2Hz), 4.05-3.94 (2H, m), 2.83 (1H, dd, J = 12.2, 3.9Hz), 2. 59 (1H, dd, J = 13.2, 3.4Hz), 2.42-2.13 (7H, m), 2.07-1.21 (21H, m), 1.18 (3H, ss), 1.03 (3H, d, J = 6.3Hz), 0.60 (3H, s).

[1088] Exact Mass=431.34(C27H45NO3)Obs.mass=432.30(M+H)

[1089] [Example 116]

[1090] 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)

[1091] 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].

[1092] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.88 (1H, d, J = 11.2Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.2, 3.4Hz), 2.59 (1 H,dd,J=13.2,3.4Hz),2.40(1H,dd,J=13.2,3.4Hz),2.31-1.20(26H,m),1.18(3H,s),1.03(3H,d,J=6.3Hz),0.60(3H,s).

[1093] Exact Mass=431.34(C27H45NO3)Obs.mass=432.30(M+H)

[1094] [Example 117]

[1095] 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)

[1096] 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].

[1097] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.90 (1H, d, J = 11.2Hz), 5.05 (2H, d ,J=6.8Hz),4.43-4.35(2H,m),2.85(1H,dd,J=11.7,3.4Hz),2.67(1H,dd,J= 13.2,4.4Hz),2.48(1H,dd,J=13.2,3.9Hz),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=6.3Hz),0.60(3H,s).

[1098] Exact Mass=443.34(C28H45NO3)Obs.mass=444.35(M+H)

[1099] [Example 118]

[1100] 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)

[1101] 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].

[1102] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J =6.8Hz),4.42-4.36(2H,m),2.85(1H,dd,J=12.2,3.4Hz),2.67(1H,dd,J=13.2 , 4.4Hz), 2.48 (2H, dd, J = 13.4, 3.7Hz), 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=6.3Hz),0.62(3H,d,J=14.6Hz).

[1103] Exact Mass=443.34(C28H45NO3)Obs.mass=444.35(M+H)

[1104] [Example 119]

[1105] 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)

[1106] Using compound (2a) [100 mg, 0.137 mmol] and 3-ethylpiperidin-3-ol [40 mg, 0.310 mmol] as starting materials, the reaction was carried out 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].

[1107] Compound C042a

[1108] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.0Hz), 6.08 (1H, d, J = 11.0Hz), 5.28 (1H, s) ,4.34(1H,t,J=5.9Hz), 4.14-4.10(1H,m),2.86(1H,dd,J=12.6,3.0Hz), 2.5 1(2H,dd,J=13.0,3.0Hz),2.25(3H,dd,J=13.3,6.4Hz),2.10-1.85(8H,m),1 .73-1.25(15H,m), 1.03(3H,d,J=6.4Hz),0.89(3H,t,J=7.5Hz),0.59(3H,s).

[1109] Exact Mass=457.36(C29H47NO3)Obs, mass=458.25(M+H)

[1110] Compound C042b

[1111] 1H-NMR (CD3OD) δ: 6.32 (1H,d,J=11.0Hz), 6.08 (1H,d,J=11.4Hz), 5,28 (1H,s), 4.34 (1H,t,J=5,9Hz), 4.15-4,07 (1H,m), 2.86 (1H,dd,J=12. 3, 4.6Hz), 2.51 (1H, dd, J = 13.3, 3, 2Hz), 2, 42-2, 20 (5H, m), 2.07-1.20 (22H, m), 1.03 (3H, d, J = 6.4Hz), 0.90 (3H, t, J = 7.5Hz), 0.59 (3H, s).

[1112] Exact Mass=457.36(C29H47NO3)Obs.mass=458.25((M+H)

[1113] [Example 120]

[1114] 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)

[1115] Using compound (2a) [100 mg, 0.310 mmol] and 3-methoxy-3-methylpiperidine [40 mg, 0.310 mmol] as starting materials, the reaction was carried out 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].

[1116] Compound C043a

[1117] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.4Hz), 6.08 (1H, d, J = 11.0Hz), 5.28 (1H, s), 4.34 (1H, t, J = 5.9Hz), 4 .15-4.10(1H,m),3.22(3H,s),2.86(1H,dd,J=11.9,3.7Hz), 2.51(1H,dd,J=13.5,3.4Hz),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=6.4Hz),0.59(3H,s).

[1118] Exact Mass=457.36(C29H47NO3)Obs.mass=458.25(M+H)

[1119] Compound C043b

[1120] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.0Hz), 6.08 (1H, d, J = 11.4Hz), 5.28 (1H, d, J = 0.9Hz), 4.34 (1H, t, J = 5.7Hz), 4.13-4.08 (1H, m), 3.20 (3H,s ), 2.86 (1H, dd, J = 12.1, 4.3Hz), 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 = 6.4Hz), 0.59 (3H, s).

[1121] Exact Mass=457.36(C29H47NO3)Obs.mass=458.25(M+H)

[1122] [Example 121]

[1123] 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 compounds (C044a, C044b)

[1124] Using compound (2b) [100 mg, 0.139 mmol] and 3-ethylpiperidin-3-ol [40 mg, 0.310 mmol] as starting materials, the reaction was carried out 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].

[1125] Compound C044a

[1126] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0Hz), 5.88 (1H, d, J = 11.0Hz), 4.06-3.95 (2H, m), 2.84 (1H, dd, J = 12.3, 3.2Hz), 2.59 (1H, dd , J=13.3, 3.7Hz), 2.40 (1H, dd, J= 13.5, 3.4Hz), 2.29-1.20 (27H, m), 1.03 (3H, d, J= 6.4Hz), 0.89 (3H, t, J= 7.3Hz), 0.60 (3H, s).

[1127] Exact Mass=445.36(C28H47NO3)Obs.mass=446.30(M+H)

[1128] Compound C044b

[1129] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4Hz), 5.88 (1H, d, J = 11.0Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.0, 4.0Hz ), 2.59 (1H, dd, J = 14.0, 4.0Hz), 2.42-1.21 (33H, m), 1.03 (3H, d, J = 6.4Hz), 0.90 (3H, t, J = 7.3Hz), 0.60 (3H, s).

[1130] Exact Mass=445.36(C28H47NO3)Obs.mass=446.30(M+H)

[1131] [Example 122]

[1132] 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)

[1133] Using compound (2b) [100 mg, 0.139 mmol] and 3-methoxy-3-methylpiperidine [40 mg, 0.310 mmol] as starting materials, the reaction was carried out 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].

[1134] Compound C045a

[1135] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4Hz), 5.88 (1H, d, J = 11.0Hz), 4.06-3.95 (2H, m), 3.22 (3H, s), 2.83 (1H, dd, J = 12.1, 3.9Hz), 2.59 (1H, dd, J = 13.3 ,3.7Hz),2.40(2H,dd,J=13.3,3.7Hz),2.26-2.11(6H,m),2.07-1.51(17 H,m),1.37-1.19(4H,m),1.17(3H,s),1.02(3H,d,J=6.4Hz),0.59(3H,s).

[1136] Exact Mass=445.36(C28H47NO3)Obs.mass=446.30(M+H)

[1137] Compound C045b

[1138] 1 H-NMR(CD3OD)δ: 6.21(1H,d,J=11.0Hz), 5.88(1H,d,J=11.0Hz), 4.06-3.95(2H,m), 3.21(3H,s), 2.83(1H,dd,J=11.0,4.6Hz), 2,59(2H,dd ,J=13.7,3.7Hz),2.57-2.52(2H,brm),2.40(1H,dd,J=13.5,3.4Hz),2,30-1,21(26H,m),1,17(3H,s),1.04(3H,d,J=6.4Hz),0,60(3H,s).

[1139] Exact Mass=445.366(C28H47NO3)Obs.mass=446.30(M+H)

[1140] [Example 123]

[1141] 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)

[1142] Using compound (2c) [100 mg, 0.137 mmol] and 3-ethylpiperidin-3-ol [60 mg, 0.464 mmol] as starting materials, the reaction was carried out 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].

[1143] Compound C046a

[1144] 1 H-NMR (CD3OD) δ: 6,26 (1H, d, J = 10,7Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.8Hz), 4.43 -4.33(2H,m),2.85(1H,dd,J=12.2,3.4Hz),2.67(1H,dd,J=13.4,4.1Hz),2.57-2.49(1H,br m), 2.48 (1H, dd, J = 10.0, 5.0Hz), 2.31-1.88 (11H, m), 1.68-1.25 (16H, m), 1.03 (3H, d, J = 6.3Hz), 0.89 (3H, t, J = 7.6Hz), 0.60 (3H, s).

[1145] Exact Mass=457.36(C29H47NO3)Obs.mass=458.35(M+H)

[1146] Compound C046b

[1147] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J =6.8Hz), 4.45-4.35(2H,m),2.85(1H,dd,J=11.0,3.8Hz),2.67(1H,dd,J=13.2 ,4.4Hz),2.48(1H,dd,J=13.2,3.9Hz),2.42-2.25(6H,m),2.07-1.88(6H,m), 1.76-1.21(17H,m), 1.03(3H,d,J=6.3Hz), 0.90(3H,t,J=7.6Hz), 0.60(3H,s).

[1148] Exact Mass=457.36(C29H47NO3)Obs.mass=458.35(M+H)

[1149] [Example 124]

[1150] 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)

[1151] Using compound (2c) [100 mg, 0.137 mmol] and 3-methoxy-3-methylpiperidine [60 mg, 0.464 mmol] as starting materials, the reaction was carried out 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].

[1152] Compound C047a

[1153] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.90 (1H, d, J = 11.2Hz), 5.05 (2H, t, J=3.9Hz), 4.42-4.36 (2H, m), 3.22 (3H, s), 2.85 (1H, dd, J=12.0, 3.7Hz), 2.67 (1H, dd, J = 13.4, 4.1Hz), 2.48 (1H, dd, J = 13.2, 3.9Hz), 2.40-1.85 (12 H,m),1.70-1.20(15H,m),1.17(3H,s),1.03(3H,d,J=6.3Hz),0.60(3H,s).

[1154] Exact Mass=457.36(C29H47NO3)Obs.mass=458.35(M+H)

[1155] Compound C047b

[1156] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.8Hz), 4.42-4.36 (2H, m), 3.20 (3H, s), 2.85 (1H, dd, J = 12.2, 3.9H z), 2.67 (1H, dd, J = 13.2, 4.4Hz), 2.56 (1H, s), 2.48 (1H, dd, J = 13.2, 3.9H z), 2.31-1.20 (28H, m), 1.17 (3H, s), 1.04 (3H, d, J = 6.3Hz), 0.61 (3H, s).

[1157] Exact Mass=457.36(C29H47NO3)Obs.mass=458.35(M+H)

[1158] [Example 125]

[1159] 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)

[1160] 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].

[1161] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.77 (1H, td, J = 56 .7, 4.7Hz), 5.28 (1H, dd, J = 2.4, 1.5Hz), 4.34 (1H, t, J = 5.9Hz), 4.15-4.09 (1H, m), 3.05-2.70 (3H, m), 2.51 (1H, dd, J = 13.7, 3.4Hz), 2.42 (1H, d, J = 9.8Hz), 2.30-2.15 (3H,m),2.10-1.96(4H,m),1.91-1.21(18H,m),1.04(3H,d,J=6.3Hz),0.61(3H,s).

[1162] Exact Mass=463.33(C28H43F2NO2)Obs,mass=464.50(M+H)

[1163] [Example 126]

[1164] 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)

[1165] 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].

[1166] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (2H, d, J = 11.2Hz), 5.74 (2H, td, J = 56.5, 5.0Hz), 5.05 (2H, d, J = 7.3Hz), 4.45-4.35 (2 H,m),2.92-2.82(2H,m),2.69-2.61(2H,m),2.48(1H,dd,J=12.9,4.1Hz),2.31-1.21(28H,m),1.02(3H,d,J=6.3Hz), 0.61(3H,s).

[1167] Exact Mass=463.33(C28H43F2NO2)Obs.mass=464.50(M+H)

[1168] [Example 127]

[1169] 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)

[1170] 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].

[1171] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.74 (1H, td, J = 56. 8, 4.9Hz), 5.22 (1H, d, J = 2.0Hz), 4.22 (1H, d, J = 3.4Hz), 3.72 (1H, td, J = 8.2, 4.2Hz) ,2.92-2.80(2H,m),2.64-2.57(2H,m),2.27(1H,dd,J=12.2,2.9Hz),2.21-1.93(7H ,m), 1.81-1.20(17H,m), 1.03(3H,d,J=7.1Hz), 1.02(3H,d,J=6.5Hz), 0.59(3H,s).

[1172] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.50(M+H)

[1173] [Example 128]

[1174] 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)

[1175] 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].

[1176] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0Hz), 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 = 1 3.7, 3.7Hz), 2.41 (1H, dd, 13.3, 3.2Hz), 2.27-2.13 (3H, m), 2.07-1.47 (20H, m), 1.37-1.20 (3H, m), 1.02 (3H, d, J = 6.4Hz), 0.60 (3H, s).

[1177] Exact Mass=465.34(C28H45F2NO2)Obs.mass=466.25(M+H)

[1178] [Example 129]

[1179] 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)

[1180] 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].

[1181] 1 H-NMR(CD3OD)δ:5.85(1H,d,J=10.7Hz), 5.63(1H,d,J=11.2Hz), 4.82(1H,dd,J=2.4,1 .5Hz), 3.88(1H,t,J=6.1Hz), 3.70-3.60(1H,m),2.78(1H,d,J=8.3Hz), 2.57(1H,d,J=1 1.7Hz), 2.41 (1H,dd,J=12.0, 3.7Hz), 2.15(1H,dd,J=12.7, 2.9Hz), 2.05(1H,dd,J=13 .2, 3.4Hz), 1.94-1.53 ​​(9H, m), 1.46-0.80 (22H, m), 0.60 (3H, d, J = 6.8Hz), 0.16 (3H, s).

[1182] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.50(M+H)

[1183] [Example 130]

[1184] 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)

[1185] 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].

[1186] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.5Hz), 4.43-4.35 (2H, m), 3.20 (1H, d, J = 10.7Hz), 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=6.8Hz),0.63(3H,s).

[1187] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.50(M+H)

[1188] [Example 131]

[1189] 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)

[1190] Compound (2 g) [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].

[1191] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.22 (1H, d, J = 2.0H z), 4.22 (1H, d, J = 3.4Hz), 3.72 (1H, td, J = 8.1, 4.2Hz), 3.13 (1H, d, J = 9.3Hz), 2.87 (2 H, d, J = 12.2Hz), 2.59 (1H, dd, J = 13.7, 3.9Hz), 2.43 (1H, d, J = 12.2Hz), 2.31-1.98 (9 H, m), 1.89-1.17 (27H, m), 1.04 (3H, d, J = 6.3Hz), 1.04 (3H, d, J = 6.8Hz), 0.60 (3H, s).

[1192] Exact Mass=491.36(C30H47F2NO2)Obs.mass=492.55(M+H)

[1193] [Example 132]

[1194] 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)

[1195] 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].

[1196] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.8Hz), 4.43-4.35 (2H, m), 3.15 (1H, d, J = 11.7Hz), 2.98-2.83 ( 2H,m),2.67(1H,dd,J=13.4,4.1Hz),2.48(1H,dd,J=13.2,3.9Hz),2.39-1.92(9H,m),1.86-1.23(19H,m),1.04(3H,d,J=6.3Hz),0.61(3H,s).

[1197] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.45(M+H)

[1198] [Example 133]

[1199] 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)

[1200] 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].

[1201] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.99 (2H, tt, J = 57.0, 5.0Hz), 5.92 (2H, d, J = 11.0Hz), 5.05 (2H, d, J = 8.0Hz), 4.43-4.35 (2H, m), 3.43 (1H, d, J = 1 2.7Hz),2.87-2.57(6H,m),2.48(1H,dd,J=13.4,4.1Hz),2.32-2.25(2H,m) ,2.09-1.96(5H,m),1.90-1.28(16H,m),1.10(3H,d,J=6.3Hz),0.64(3H,s).

[1202] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.45(M+H)

[1203] [Example 134]

[1204] 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)

[1205] [Chemistry 35]

[1206]

[1207] Step 1

[1208] 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 give 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].

[1209] Step 2

[1210] Compound 3d01 [38 mg, 0.107 mmol] obtained in step 1, compound 7a [53.2 mg, 0.144 mmol], and tetrakistriphenylphosphine palladium (0) [15.0 mg, 0.013 mmol] were treated in the same manner as in steps 2 and 3 of Example 92 to give compound D001 [7.7 mg, 0.019 mmol].

[1211] 1 H-NMR(CD3OD)δ: 6.31(1H,d,J=11.2Hz), 6.08(1H,d,J=11.2Hz), 5.28(1H,dd,J=2.4,1.5Hz) ,4.89(1H,s),4.34(1H,t,J=5.9Hz),4.14-4.08(1H,m),3.76-3.66(5H,m),2.86(1H,dd,J=1 2.0,3.7Hz),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 = 6.0Hz), 0.60 (3H, s).

[1212] Exact Mass=415.31(C26H41NO3)Obs.mass=416.40(M+H)

[1213] [Example 135]

[1214] 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)

[1215] Compound 3d01 [38 mg, 0.107 mmol] obtained in Step 1 of Example 134, Compound 7b [55.7 mg, 0.146 mmol], and tetrakistriphenylphosphine palladium (0) [15.0 mg, 0.013 mmol] were used and treated in the same manner as in Step 2 and Step 3 of Example 92 to obtain Compound D002 [2.6 mg, 0.006 mmol].

[1216] 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.22 (1H, d, J = 2.4Hz), 4. 89(1H,s),4.22(1H,d,J=3.4Hz), 3.75-3.61(6H,m),2.87(1H,d,J=12.7Hz), 2.59(1H,dd,J =13.7, 4.4Hz), 2.54-2.46 (2H, m), 2.25 (3H, dd, J = 12.2, 2.9Hz), 2.17 (1H, dd, J = 13.4, 8.1H z), 2.06-1.21 (14H, m), 1.03 (3H, d, J = 6.6Hz), 1.03 (3H, d, J = 7.0Hz), 0.59 (3H, d, J = 7.3Hz).

[1217] Exact Mass=429.32(C27H43NO3)Obs.mass=430.40(M+H)

[1218] [Example 136]

[1219] 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)

[1220] 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].

[1221] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.88 (1H, d, J = 11.2Hz), 4.12-3.95 (2H, m), 3.72-3.61 (4H, m), 2.83 (1H, dd, J = 13.4, 3.7Hz), 2.59 (1H, d d,J=13.4,3.7Hz),2.53-2.49(2H,m),2.40(1H,dd,J=13.7,3.4Hz),2.2 8-2.13(5H,m),2.06-1.21(17H,m),1.03(3H,d,J=6.3Hz),0.59(3H,s).

[1222] Exact Mass=403.31(C25H41NO3)Obs.mass=404.30(M+H)

[1223] [Example 137]

[1224] 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)

[1225] [Chemistry 36]

[1226]

[1227] Step 1

[1228] To a dichloromethane solution [9 mL] of oxalyl chloride [0.6 mL, 7 mmol] was added a dichloromethane solution [4 mL] of dimethyl sulfoxide [1 mL, 14 mmol] under the condition of being cooled to -78 ° C, and the mixture was stirred at the same temperature for 10 minutes. To this mixture was added a dichloromethane solution [10 mL] of tert-butyl-(S)-2-(hydroxymethyl)morpholine-4-carboxylate (compound 3d03) [1.0 g, 4.6 mmol]. The mixture was stirred at -78 ° C for 45 minutes. Triethylamine [3.3 mL, 23 mmol] was added and stirred at the same temperature for another 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 tert-butyl-(S)-2-formylmorpholine-4-carboxylate (Compound 3d04) [0.72 g, 3.3 mmol]. (Yield = 73%)

[1229] Step 2

[1230] A solution of tert-butyl-(S)-2-formylmorpholine-4-carboxylate (compound 3d04) [0.72 g, 3.3 mmol] in dichloromethane [20 mL] was cooled to 0°C, and diethylaminosulfur trifluoride (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 tert-butyl-(S)-2-(difluoromethyl)morpholine-4-carboxylate (compound 3d05) [0.58 g, 2.4 mmol]. (Yield = 53%)

[1231] Step 3

[1232] To tert-butyl-(S)-2-(difluoromethyl)morpholine-4-carboxylate (Compound 3d05) [0.58 g, 2.4 mmol] was added 4 M hydrochloric acid 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%)

[1233] 1H-NMR (DMSO-D6) δ: 9.79 (2H, s), 6.13 (1H, td, J = 54.0, 3.3Hz), 4.18-4.09 (1H, m), 4.03 (1H, dd, J = 12.7, 3.9Hz), 3.85 (1H, td,J=12.4,2.4Hz), 3.27(1H,d,J=12.2Hz), 3.20(1H,d,J=13.2Hz), 2.99(1H,td,J=12.4,4.0Hz), 2.92(1H,t,J=12.0Hz).

[1234] Steps 4 and 5

[1235] 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].

[1236] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.77 (1H, td, J = 55.4, 4.2Hz), 5.28 (1H, dd, J = 2.2, 1.2Hz), 4.89 (1H, d, J = 1.5Hz), 4.34 (1H, t, J = 5.9Hz), 4.1 4-4.09 (1H, m), 3.86 (1H, d, J = 10.7Hz), 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=6.3Hz),0.60(3H,s).

[1237] Exact Mass=465.31(C27H41F2NO3)Obs.mass=466.40(M+H)

[1238] [Example 138]

[1239] 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)

[1240] [Chemistry 37]

[1241]

[1242] Step 1

[1243] Tert-butyl-(R)-2-(hydroxymethyl)morpholine-4-carboxylate (Compound 3d07) [1.00 g, 3.3 mmol] was used as the starting material and treated in the same manner as in Step 1 of Example 137 to obtain tert-butyl-(R)-2-formylmorpholine-4-carboxylate (Compound 3d08) [0.70 g, 3.3 mmol]. (Yield = 71%)

[1244] Step 2

[1245] Tert-butyl-(R)-2-formylmorpholine-4-carboxylate (Compound 3d08) [0.70 g, 3.3 mmol] was used as the starting material and treated in the same manner as in Step 2 of Example 137 to obtain tert-butyl-(R)-2-(difluoromethyl)morpholine-4-carboxylate (Compound 3d09) [0.55 g, 2.3 mmol]. (Yield = 50%)

[1246] Step 3

[1247] Tert-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 give (R)-2-(difluoromethyl)morpholine hydrochloride (Compound 3d10) [384.8 mg, 2.22 mmol].

[1248] (Yield = 96%)

[1249] 1 H-NMR (DMSO-D6) δ: 9.62 (2H, s) 6.13 (1H, td, J = 54.0, 3.3Hz), 4.11 (1H, tdd, J = 14.8, 7.6, 3.8Hz), 4.03 (1H, dd, J = 12.7, 3.9Hz), 3.83 (1H,td,J=12.4,2.4Hz),3.28(1H,d,J=12.2Hz),3.20(1H,dd,J=12.0,2.4Hz),3.00(1H,td,J=12.0,3.9Hz),2.93(1H,t,J=12.0Hz).

[1250] Steps 4 and 5

[1251] 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].

[1252] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 10.7Hz), 6.08 (1H, d, J = 11.2Hz), 5.76 (1H, td, J = 55.4, 4.2Hz), 5.28 (1H, t, J = 1.2Hz), 4.34 (1H, t, J = 6.1Hz), 4.15-4.09 (1H, m), 3.88 (1H, dt, J = 11.4, 2.6Hz), 3.78-3.69 (1H, m), 3.61 (1H, td, J = 11.2, 2.4Hz), 2.87 ( 1H,dd,J=12.2,3.4Hz), 2.71(2H,dd,J=28.8,11.2Hz), 2.51(1H,dd,J=13.7,3.4Hz), 2.31(1H,dd,J=12.2,2.9Hz), 2.25(1 H,dd,J=13.7,6.8Hz), 2.16(1H,t,J=10.7Hz), 2.07-1.99(4H,m), 1.96-1.26(14H,m), 1.04(3H,d,J=6.3Hz), 0.59(3H,s).

[1253] Exact Mass=465.31(C27H41F2NO3)Obs.mass=466.40(M+H)

[1254] [Example 139]

[1255] 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)

[1256] 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 reacted in the same manner as in Example 1 to obtain compound D007 [17.0 mg, 0.037 mmol].

[1257] 1H-NMR (DMSO-D6) δ: 6.14 (2H, d, J = 11.2Hz), 6.02 (2H, td, J = 55.0, 4.0Hz), 5.82 (1H, d, J=11.2Hz), 4.93-4.75(2H,m),4.91(2H,d,J=6.0Hz), 4.24(2H,td,J=4.0,16.0Hz),3 .83(1H,d,J=10.7Hz),3.67-3.47(2H,m),2.78(2H,d,J=10.7Hz),2.55-2.50(2H,m), 2.34 (1H, dd, J = 12.9, 3.7Hz), 2.22-1.18 (21H, m), 0.98 (3H, d, J = 6.3Hz), 0.54 (3H, s).

[1258] Exact Mass=465.31(C27H41F2NO3)Obs.mass=466.35(M+H)

[1259] [Example 140]

[1260] 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)

[1261] Compound (2c) [90 mg, 0.123 mmol] and compound (3d10) described in Example 138 [65 mg, 0.374 mmol] were used as starting materials and reacted in the same manner as in Example 1 to obtain compound D008 [17.3 mg, 0.037 mmol].

[1262] 1H-NMR (DMSO-D6) δ: 6.14 (2H, d, J = 11.2Hz), 6.01 (2H, td, J = 55.0, 4.0Hz), 5.82 (1H, d, J = 11.2Hz), 4.91 (2 H, d, J = 10.0Hz), 4.89-4.80 (1H, m), 4.28-4.21 (2H, m), 3.84 (1H, d, J = 11.2Hz), 3.74-3.65 (1H, m), 3.58- 3.45(2H,m),2.79-2.74(1H,m),2.69(1H,d,J=11.7Hz), 2.62(1H,d,J=11.2Hz),2.53(1H,d,J=6.0Hz),2 .34(1H,dd,J=13.2,3.4Hz),2.23-1.77(9H,m),1.65-1.18(10H,m),0.98(3H,d,J=6.3Hz),0.53(3H,s).

[1263] Exact Mass=465.31(C27H41F2NO3)Obs.mass=466.40(M+H)

[1264] [Example 141]

[1265] 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)

[1266] [Chemistry 38]

[1267]

[1268] Step 1

[1269] A 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] in DMF 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 crudely purified by silica gel column chromatography to obtain compound 3d12 [92.3 mg, 0.218 mmol] as a mixture of diastereomers.

[1270] Step 2

[1271] To a mixed solution of compound 3d12 [92.3 mg, 0.218 mmol] and compound 7b [90 mg, 0.235 mmol] obtained in step 1 in toluene [1 mL] / triethylamine [1 mL] was added tetrakis(triphenylphosphine)palladium(0) [25 mg, 0.021 mmol], and the mixture was heated and stirred at 100°C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was crudely purified by preparative thin-layer chromatography to obtain the low-polarity compound D009-LP [56.3 mg] and the high-polarity compound D009-MP [42.0 mg] by TLC.

[1272] D009-LP:Exact Mass=725.48(C40H70F3NO3Si2)Obs.mass=726.60(M+H)

[1273] D009-MP:Exact Mass=725.48(C40H70F3NO3Si2)Obs.mass=726.60(M+H)

[1274] Step 3a

[1275] 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 the mixture was stirred at 50°C overnight. 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 reverse-phase HPLC to yield compound D009a (16.7 mg, 0.0336 mmol).

[1276] 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.2Hz), 6.09 (1H, d, J = 11.2Hz), 5.22 (1H, d, J = 2.0Hz), 4.89 (1H, d, J = 2.0H z), 4.22 (1H, d, J = 3.4Hz), 4.05-3.96 (1H, m), 3.92 (1H, dd, J = 11.0, 3.0Hz), 3.72 (1H, td, J = 8.1, 4.4Hz), 3.6 3 (1H, td, J = 11.3, 2.3Hz), 2.87 (1H, dd, J = 11.0, 4.4Hz), 2.77 (2H, d, J = 11.7Hz), 2.59 (1H, dd, J = 13.4, 4.1Hz ), 2.32 (1H, dd, J = 12.2, 2.9Hz), 2.23-2.14 (2H, m), 2.06-1.18 (18H, m), 1.03 (6H, d, J = 7.3Hz), 0.58 (3H, s).

[1277] Exact Mass=497.31(C28H42F3NO3)Obs.mass=498.40(M+H)

[1278] Step 3b

[1279] Using D009-MP [42.0 mg] obtained in step 2 as a starting material, the compound D009b [9.1 mg, 0.018 mmol] was obtained by treating in the same manner as in step 3a.

[1280] 1 H-NMR (DMSO-D6) δ: 6.19 (1H, d, J = 10.7Hz), 5.99 (1H, d, J = 11.2Hz), 5.17 (1H, d, J = 2.4Hz), 4.77 (1H , d, J = 2.4Hz), 4.75 (1H, d, J = 4.4Hz), 4.57 (1H, d, J = 4.4Hz), 4.15 (1H, t, J = 3.7Hz), 4.10-4.00 (1H, m), 3.89 (1H, d, J = 10.2Hz), 3.66-3.55 (2H, m), 2.88 (1H, d, J = 10.2Hz), 2.79 (1H, d, J = 9.3Hz), 2.56 (2H,d,J=11.7Hz),2.25-1.16(22H,m),0.97(3H,d,J=5.9Hz), 0.85(3H,d,J=6.8Hz),0.53(3H,s).

[1281] Exact Mass=497.31(C28H42F3NO3)Obs.mass=498.40(M+H)

[1282] [Example 142]

[1283] 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)

[1284] 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].

[1285] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6.8Hz), 4.43-4.35 (2H,m),3.79(1H,dd,J=11.5,1.7Hz),3.68-3.57(2H,m),2.85(1H,dd,J=12.0,3.7Hz),2.75(1H,d , J=11.7Hz),2.69-2.61(2H,m),2.48(1H,dd,J=13.4,4.1Hz),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 = 6.3Hz), 1.03 (3H, d, J = 6.3Hz), 0.60 (3H, s).

[1286] Exact Mass=429.32(C27H43NO3)Obs.mmass=430.35(M+H)

[1287] [Example 143]

[1288] 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)

[1289] 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].

[1290] 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7Hz), 5.92 (1H, d, J = 10.7Hz), 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, 3.9Hz), 2.68 (1H, dd,J=13.7,4.4Hz),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=6.3Hz), 0.71(2H,s),0.61(3H,s),0.59-0.48(2H,m).

[1291] Exact Mass=441.32(C28H43NO3)Obs.mass=442.35(M+H)

[1292] [Example 144]

[1293] 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)

[1294] 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].

[1295] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J=7.3Hz),4.45-4.33(2H,m),3.72-3.60(2H,m),2.85(1H,dd,J=12.7,3.4Hz) ,2.67(1H,dd,J=13.2,4.4Hz), 2.48(1H,dd,J=13.2,3.9Hz),2.39-2.19(6H,m ), 2.16-1.88 (5H, m), 1.84-1.25 (18H, m), 1.04 (3H, d, J = 6.8Hz), 0.60 (3H, s).

[1296] Exact Mass=469.36(C30H47NO3)0bs.mass=470.35(M+H)

[1297] [Example 145]

[1298] 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)

[1299] 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].

[1300] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, t, J = 3.9Hz), 4.42-4.36 (2H, m), 3.73-3.59 ( 2H,m),2.85(1H,dd,J=12.0,3.7Hz),2.79(1H,d,J=11.2Hz),2.67(1H,dd,J=13.2,4.4Hz),2.62(1H,d,J=11.2Hz),2.4 8(1H,dd,J=13.7,3.9Hz),2.27(2H,td,J=12.7,6.0Hz),2.22(1H,dd,J=12.0,3.2Hz),2.16-1.89(4H,m),1.79(1H,dd, J=25.9, 15.6Hz), 1.70-1.21 (12H, m), 1.12 (3H, d, J= 5.0Hz), 1.10 (3H, d, J= 5.0Hz), 1.03 (3H, d, J= 6.3Hz), 0.60 (3H, s).

[1301] Exact Mass=443.34(C28H45NO3)Obs.mass=444.30(M+H)

[1302] [Example 146]

[1303] 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)

[1304] 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].

[1305] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 7.3Hz), 4.43-4.35 (2H, m), 3.75-3.64 (2H, m), 2.85 (1H, dd, J = 11.0 ,3.9Hz), 2.67(1H,dd,J=13.4,4.1Hz), 2.48(1H,dd,J=13.2,3.9Hz), 2.4 0-1.88(13H,m), 1.68-1.21(18H,m), 1.04(3H,d,J=6.3Hz), 0.60(3H,s).

[1306] Exact Mass=443.34(C28H45NO3)Obs.mass=444.30(M+H)

[1307] [Example 147]

[1308] 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)

[1309] 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].

[1310] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 10.7Hz), 5.05 (2H, d, J = 6.8Hz), 4.45-4.35 (2H, m), 3.75 (1H, dt, J = 1 1.4,3.3Hz),3.60(2H,ddd,J=24.4,11.2,2.4Hz),3.21(1H,dd,J=11.0,9.5Hz),2.84(2H,td,J=11.3,3.3Hz),2.67(1H,dd, J=13.2,4.4Hz),2.48(1H,dd,J=13.2,3.9Hz),2.37(1H,t,J=11.5Hz),2.31-2.25(3H,m),2.08-2.02(5H,m),1.96(1H,dd,J =11.5,8.1Hz),1.68-1.52(6H,m),1.32(4H,dt,J=32.9,10.5Hz),1.02(3H,d,J=6.3Hz),0.93(3H,d,J=6.3Hz),0.61(3H,s).

[1311] Exact Mass=429.32(C27H43NO3)Obs.mass=430.25(M+H)

[1312] [Example 148]

[1313] 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)

[1314] 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].

[1315] Exact Mass=443.34(C28H45NO3)Obs.mass=444.30(M+H)

[1316] [Example 149]

[1317] 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)

[1318] 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].

[1319] Exact Mass=443.34(C28H45NO3)Obs.mass=444.30(M+H)

[1320] [Example 150]

[1321] 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)

[1322] 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].

[1323] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.4Hz), 5.91 (1H, d, J = 11.0Hz), 5.05 (2H, d, J = 7.3Hz), 4.42-4.36 (2H, m), 3.80-3.73 (1H , m), 3.67 (1H, td, J = 11.3, 2.4Hz), 3.62-3.53 (1H, m), 2.85 (1H, dd, J = 12.1, 3.9Hz), 2.80 (1H, d, J = 11.0Hz), 2.67 (1H, dd, J=13.3, 4.1Hz), 2.56 (1H, dd, J= 11.9, 1.8Hz), 2.48 (1H, dd, J= 13.3, 4.1Hz), 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 = 5.9Hz), 1.03 (3H, d, J = 6.4Hz), 0.61 (3H, s).

[1324] Exact Mass=429.32(C27H43NO3)Obs.mass=430.40(M+H)

[1325] [Example 151]

[1326] 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)

[1327] 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].

[1328] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.88 (1H, d, J = 11.2Hz), 4.06-3.95 (2H, m), 3.79-3.67 (2H, m), 2.83 (1H, dd, J = 11.0, 3.9Hz), 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 = 6.3Hz), 0.70 (2H, s), 0.59 (3H, s), 0.57-0.49 (2H, m).

[1329] Exact Mass=429.32(C27H43NO3)Obs.mass=430.30(M+H)

[1330] [Example 152]

[1331] 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)

[1332] 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].

[1333] Exact Mass=431.34(C27H45NO3)Obs.mass=432.25(M+H)

[1334] [Example 153]

[1335] 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)

[1336] 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].

[1337] Exact Mass=431.34(C27H45NO3)Obs.mass=432.30(M+H)

[1338] [Example 154]

[1339] 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)

[1340] Compound (E001) [14.3 mg, 0.029 mmol] was obtained by reacting in the same manner as in Example 92 using 1-methylsulfonylpiperazine instead of triethyl-[[4-(trifluoromethyl)-4-piperidinyl]oxy]silane, the starting material in Step 1 of Example 92.

[1341] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 10.7Hz), 6.08 (1H, d, J = 11.2Hz), 5, 28 (1H, t, J = 1.2Hz), 4.34 (1H, t, J = 6.1Hz), 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=6.3Hz),0.60(3H,s).

[1342] Exact Mass=492.30(C27H44N204S)Obs.mass=493.40(M+H)

[1343] [Example 155]

[1344] 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)

[1345] 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].

[1346] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.0Hz), 5.91 (1H, d, J = 11.0Hz), 5.05 (2H, d, J = 7.3H z), 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=13.3,4.1Hz),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=6.4Hz), 0.61(3H,s).

[1347] Exact Mass=492.30(C27H44N204S)Obs.mass=493.25(M+H)

[1348] [Example 156]

[1349] 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, E005b)

[1350] Using compound (2a) [100 mg, 0.137 mmol] and 2-(trifluoromethyl)piperazine [50 mg, 0.324 mmol] as starting materials, the reaction was carried out 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].

[1351] Compound E005a

[1352] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.28 (1H, dd, J = 2.4, 1.5Hz), 4.34 (1H, t, J = 5.9Hz), 4.15-4.09 (1H, m), 3.43-3.37 (1 H,m), 3.00-2.95(1H,m),2.90-2.76(4H,m),2.51(1H,dd,J=13.4,3.2Hz), 2.34-1.99 (7H, m), 1.94-1.21 (15H, m), 1.02 (3H, d, J = 6.3Hz), 0.59 (3H, s).

[1353] Exact Mass=482.31(C27H41F3N202)Obs.mass=483.4(M+H)

[1354] Compound E005b

[1355] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.28 (1H, dd, J = 2.4 , 1.5Hz), 4.34(1H,t,J=5.9Hz), 4.15-4.09(1H,m), 3.35-3.30(1H,m), 2.95(2H,d,J= 11.2Hz), 2.85 (2H, td, J = 11.7, 2.9Hz), 2.63 (1H, d, J = 11.7Hz), 2.51 (1H, dd, J = 13.7 ,3.4Hz),2.33-1.97(7H,m),1.94-1.21(15H,m),1.02(3H,d,J=6.8Hz),0.60(3H,s).

[1356] Exact Mass=482.31(C27H41F3N202)Obs.mass=483.3(M+H)

[1357] [Example 157]

[1358] 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, E006b)

[1359] Using compound (2b) [100 mg, 0.139 mmol] and 2-(trifluoromethyl)piperazine [70 mg, 0.454 mmol] as starting materials, the reaction was carried out 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].

[1360] Compound E006a

[1361] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4Hz), 5.89 (1H, d, J = 11.0Hz), 4.06-3.93 (2 H,m),3.41-3.37(1H,m),2.97(1H,d,J=12.3Hz),2.86-2.74(4H,m),2.59(1H, dd,J=13.5,3.4Hz), 2.40(1H,dd,J=13.3,3.7Hz), 2.31(1H,dd,J=11.9,3.2Hz) ), 2.23-1.48 (17H, m), 1.38-1.21 (4H, m), 1.02 (3H, d, J = 6.4Hz), 0.60 (3H, s).

[1362] Exact Mass=470.31(C26H41F3N202)Obs.mass=471.25(M+H)

[1363] Compound E006b

[1364] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4Hz), 5.89 (1H, d, J = 11.0Hz), 4.06-3.93 (2 H, m), 3.36-3.30 (1H, m), 2.95 (2H, d, J = 11.9Hz), 2.85 (2H, td, J = 11.5, 2.9Hz) ,2.65-2.54(2H,m),2.40(1H,dd,J=13.3,3.7Hz),2.31(1H,dd,J=12.1,3.0Hz ), 2.23-1.49 (16H, m), 1.38-1.21 (4H, m), 1.03 (3H, d, J = 6.4Hz), 0.60 (3H, s).

[1365] Exact Mass=470.31(C26H41F3N202)Obs.mass=471.25(M+H)

[1366] [Example 158]

[1367] 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)

[1368] Using compound (6c) [264.5 mg, 0.599 mmol] and 2-(trifluoromethyl)piperazine [220.7 mg, 1.43 mmol] as starting materials, the reaction was carried out 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].

[1369] Compound E007a:

[1370] 1 H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.0Hz), 6.09 (1H, d, J = 11.0Hz), 5.22 (1H, d, J = 2.0Hz), 4. 88(1H,brs),4.22(1H,d,J=3.4Hz),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, 3.9Hz), 2.33 (1H, dd, J = 12.0, 3.2Hz), 2.19-2.01 (6H, m), 1.93-1 .42(12H,m),1.38-1.21(4H,m),1.04(3H,d,J=6.3Hz), 1.02(3H,d,J=6.4Hz),0.58(3H,s).

[1371] Compound E007b:

[1372] 1H-NMR (CD3OD) δ: 6.33 (1H, d, J = 11.0Hz), 6.09 (1H, d, J = 11.0Hz), 5.22 (1H, d, J = 2.0Hz), 4. 89(1H,brs),4.22(1H,d,J=3.4Hz),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=12.2,3.4Hz),2.17(2H,dd,J=11.2,2.9Hz),2.06-1 .97(4H,m), 1.91-1.20(13H,m), 1.04(3H,d,J=6.3Hz), 1.02(3H,d,J=6.3Hz), 0.59(3H,s).

[1373] [Example 159]

[1374] 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)

[1375] 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].

[1376] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.28 (1H, dd, J = 2.4, 1.0Hz), 4 .34(1H,t,J=5.9Hz),4.15-4.09(1H,m),3.28-3.23(3H,m),3.02(2H,q,J=7.3Hz),2.87(1H,dd, J=12.0,3.7Hz),2.65-2.55(2H,m),2.51(1H,dd,J=13.4,3.2Hz),2.39-2.30(3H,m),2.25(1H, dd, J=13.4, 6.6Hz), 2.10-1.99 (3H, m), 1.94-1.21 (17H, m), 1.03 (3H, d, J=6.3Hz), 0.59 (3H, s).

[1377] [Reference Example 13]

[1378] Synthesis of (3R)-3-((1R,3aS,7aR,E)-4-((Z)-2-((3S,5R)-3,5-bis((tert-butyldimethylsilyl)oxy)-2-methylenecyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)butyl 4-methylbenzenesulfonate (Compound 16a)

[1379] [Chemistry 39]

[1380]

[1381] Step 1

[1382] 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] was added p-toluenesulfonyl chloride [1.6 g, 8.4 mmol], and the mixture was 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 1M hydrochloric acid, and then washed with saturated sodium bicarbonate and saturated brine in that order. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude Compound 17.

[1383] Step 2

[1384] The crude compound 17 was dissolved in acetone [30 mL], 2M hydrochloric acid [10 mL, 20 mmol] was added at room temperature, and stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous 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 (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 over 2 steps = 52%)

[1385] Step 3

[1386] 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 hour. Tetrabutylammonium perruthenate (TPAP) [120 mg, 0.342 mmol] was added to the reaction mixture, and the mixture was stirred at 0°C for 1 hour. Heptane [30 mL] was added to the reaction mixture at room temperature, and the mixture was filtered through celite. The filtrate was washed sequentially with saturated aqueous ammonium chloride solution and 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 (3R)-3-((1R,3aR,7aR)-7a-methyl-4-oxooctahedral-1H-inden-1-yl)butyl 4-methylbenzenesulfonate (Compound 11) [1.15 g, 2.93 mmol]. (Yield = 84%)

[1387] 1 H-NMR (CDCl3) δ: 7.79 (2H, d, J = 7.8Hz), 7.35 (2H, d, J = 7.8Hz), 4.06-3.94 (2H, m) 245 (3H, s), 242 (1H, dd, J = 12.27.8Hz), 2.33-2.17(2H,m), 2.11-1.65(6H,m),, 1.60-0.99(9H,m), 0.91(3H,d,J=6.3Hz), 0.60(3H,s).

[1388] Step 4

[1389] To a THF solution [21 mL] of compound 4a [2.1 g, 3.6 mmol] was added LHMDS [1 M in THF, 5 mL, 5 mmol] at -78 ° C in a nitrogen atmosphere, and the reaction mixture was stirred at the same temperature for 30 minutes. To this mixture was added a THF solution [10 mL] of compound 11 [0.85 g, 2.2 mmol] obtained in step 3, and the reaction mixture was further stirred at the same temperature for 1.5 hours. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added and quenched, 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 compound 16a [1.21 g, 1.63 mmol]. (Yield = 72%)

[1390] 1H-NMR (CDCL3) δ: 7.80 (2H, d, J = 8.2Hz), 7.35 (2H, d, J = 8.2Hz), 6.23 (1H, d, J = 11.0Hz), 6.00 (1H, d, J = 11.4H z),5.18(1H,s),4.86(1H,d,J=2.3Hz),4.37(1H,dd,J=7.0,4.0Hz),4.23-4.16(1H,m),4.15-4.03(2H,m), 2.82(1H,d,J=11.9Hz),2,48-2.41(1H,m),2.45(3H,s),2.21(1H,dd,J=13.0,7.5Hz),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=6.9Hz),0.49(3H,s),0.07(3H,s),0.06(9H,s).

[1391] [Reference Example 14]

[1392] Synthesis of (3R)-3-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((tert-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)butyl 4-methylbenzenesulfonate (Compound 16b)

[1393] [Chemistry 40]

[1394]

[1395] Step 1

[1396] Potassium cyanide [2.16 g, 33.2 mmol] was added to a DMF solution [100 mL] of compound 2b [11.94 g, 16.65 mmol] and 18-crown ether-6 [0.45 g, 1.7 mmol], and the mixture was heated and stirred at 60°C for 4 hours. After cooling to room temperature, the reaction solution 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 obtain compound 13b [8.02 g, 14.0 mmol]. (Yield = 84.2%)

[1397] 1H-NMR (CDCl3) δ: 6.16 (1H, d, J = 11.4Hz), 5.82 (1H, d, J = 11.0Hz), 4.11-4.02 (2H, m ),2.82(1H,dd,J=12.3,2.7Hz),2.40-2.35(3H,m),2.30-2.22(2H,m),2.08(2H,dt ,J=23.0,7.9Hz),1.98-1.88(2H,m),1.82-1.59(6H,m),1.55-1.26(8H,m),1.18( 3H,d,J=6.4Hz), 0.87(9H,s),0.86(9H,s),0.56(3H,s),0.06(3H,s),0.05(9H,s).

[1398] Step 2

[1399] To a THF solution [120 mL] of compound 13b [8.02 g, 14.0 mmol] was added a hexane solution of diisobutylaluminum hydride (DIBAL-H) ​​[1 M, 42 mL, 42 mmol] at -10 ° C in a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution. A saturated aqueous solution of potassium sodium tartrate (Rochelle salt) was added to the mixed solution, 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 obtain compound 14b [4.93 g, 8.57 mmol]. (Yield = 61%)

[1400] 1 H-NMR (CDCl3) δ: 9.76 (1H, dd, J = 3.2, 1.4Hz), 6.16 (1H, d, J = 11.4Hz), 5.82 (1H, d, J = 11.4 Hz),4.10-4.04(2H,m),2.82(1H,dd,J=11.7,3.9Hz),2.48(1H,dd,J=15.3,3.0Hz),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=6.9Hz),0.87(9H,s),0.86(9H,s),0.59(3H,s),0.06(3H,s),0.05(6H,s).

[1401] Step 3

[1402] Compound 14b [4.92 g, 8.56 mmol] was dissolved in a mixed solution of THF [50 mL] / methanol [50 mL]. Sodium borohydride [0.65 g, 17.0 mmol] was added to the solution at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride at 0°C, injected with 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 obtain compound 15b [4.32 g, 7.49 mmol]. (Yield = 87%)

[1403] 1 H-NMR (CDCl3) δ: 6.17 (1H, d, J = 10.5Hz), 5.82 (1H, d, J = 11.0Hz), 4.12-4.03 (2H, m), 3.78- 3.60(2H,m),2.81(1H,d,J=11.9Hz),2.42-2.35(2H,m),2.26(1H,d,J=13.3Hz),2.11(1H,t , J=10.1Hz),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)

[1404] Step 4

[1405] 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 the mixture was stirred at room temperature for 2 hours. The reaction solution 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 obtain compound 16b [4.60 g, 6.29 mmol]. (Yield = 87%)

[1406] 1H-NMR (CDCl3) δ: 7.80 (2H, d, J = 8.3Hz), 7.35 (2H, d, J = 8.3Hz), 6.16 (1H, d, J = 11.2Hz), 5.80 (1H, d, J = 11.2Hz), 4.17-4.01 (4H, m), 2.85-2.7 0(1H,m),2.45(3H,s),2.41-2.23(2H,m),1.98-1.60(8H,m)1.51-1.1 8(10H,m),0.87-0.85(27H,m),0.50(3H,s)0.05(6H,s),0.055(6H,s).

[1407] [Reference Example 15]

[1408] Synthesis of (3R)-3-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((tert-butyldimethylsilyl)oxy)-4-methylenecyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)butyl 4-methylbenzenesulfonate (Compound 16c)

[1409] [Chemistry 41]

[1410]

[1411] A THF solution [15 mL] of (3R)-3-((1R,3aR,7aR)-7a-methyl-4-oxooctahedral-1H-inden-1-yl)butyl 4-methylbenzenesulfonate (Compound 11) [1.24 g, 3.28 mmol] and Compound 4c [1.3 g, 2.2 mmol] described in Step 3 of Reference Example 13 was cooled to -78°C under a nitrogen atmosphere. LHMDS [1M THF solution, 4.5 mL, 4.5 mmol] was added dropwise to the solution and 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 obtain Compound 16c [0.83 g, 1.1 mmol]. (Yield = 50%)

[1412] 1H-NMR(CDCl3)δ:7.80(2H,d,J=8.3Hz), 7.35(2H,d,J=8.8Hz), 6.21(1H,d,J=11.2Hz), 5.83(1H,d,J=11.2 Hz),4.97(1H,s),4.92(1H,s),4.43(2H,dd,J=7.6,4.1Hz),4.11-4.02(2H,m),2.81(1H,dd,J=10.0,3,8Hz ),2,55-2,45(2H,m),2,45(3H,s),2,31(1H,dd,J=13.4,3.2Hz),2.17(1H,dd,J=12.4,8.5Hz),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).

[1413] [Example 160]

[1414] 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)

[1415] 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].

[1416] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 6.00 (1H, td, J = 57.0, 5.0Hz), 5.88 (1H, d, J = 11.2Hz), 4.05 (2H, s ),4.05-3.94(2H,m),3.38(2H,t,J=8.3Hz),3.17(2H,t,J=7.3Hz), 2.91(1H,td,J=13.5,7.3Hz),2.82(1H, dd, J=12.2, 3.9Hz), 2.58 (1H, dd, J=13.7, 3.4Hz), 2.52 (1H, dd, J=10.7, 4.9Hz), 2.46-2.38 (2H, m), 2.22-2 .12(2H,m),2.06-1.90(3H,m),1.86-1.27(13H,m),1.17-1.06(1H,m),0.96(3H,d,J=6.3Hz),0.57(3H,s).

[1417] Exact Mass=437.31(C26H41F2NO2)Obs.mass=438.25(M+H)

[1418] [Example 161]

[1419] 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)

[1420] 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].

[1421] 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.06 (2H, d , J=6.8Hz), 4,43-4,37(2H,m),3,70(2H,d,J=10,7Hz),2.86(1H,dd,J=12.0, 3.7Hz),2.75-2.53(3H,m),2.49(1H,dd,J=13.2,3.9Hz),2.32-2.25(2H,m) ,2.08-1.98(2H,m),1.95-1.13(12H,m),0.98(3H,d,J=6.3Hz),0.59(3H,s).

[1422] Exact Mass=483.30(C27H40F3NO3)Obs.mass=484.25(M+H)

[1423] [Example 162]

[1424] 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)

[1425] 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].

[1426] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.88 (1H, d, J = 11.2Hz), 5.86 (1H, tt, J = 56.0, 4.5Hz), 4.06- 3.95 (2H, m), 3.49 (2H, t, J = 7.6Hz), 2.87 (2H, dt, J = 3.0, 8.0Hz), 2.83 (1H, dd, J = 13.0, 4.0Hz), 2.75-2 .63(1H,m),2.58(1H,dd,J=13.2,3.9Hz),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=9.6,6.0Hz),1.15-1.05(1H,m),0.96(3H,d,J=6,8Hz),0,57(3H,s).

[1427] Exact Mass=451.33(C27H43F2NO2)Obs.mass=452.25(M+H)

[1428] [Example 163]

[1429] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-(difluoromethoxy)azetidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A025)

[1430] 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].

[1431] 1H-NMR (CD3OD) δ: 6.38 (1H, t, J = 75.0Hz), 6.21 (1H, d, J = 10.7Hz), 5.88 (1H, d, J = 10.7Hz), 4.76-4.70 ( 1H,m), 4.06-3.95(2H,m), 3.64(2H,td,J=6.1,2.4Hz), 3.12-3.07(2H,m),2.83(1H,dd,J=11.5,4,1Hz ),2.61-2.44(3H,m),2.40(1H,dd,J=13.7,3.4Hz),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=6.3Hz),0.57(3H,s).

[1432] Exact Mass=453.31(C26H41F2NO3)Obs.mass=454.25(M+H)

[1433] [Example 164]

[1434] 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)

[1435] 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].

[1436] 1H-NMR (CD3OD) δ: 6.16 (1H, d, J = 10.7Hz), 5.85 (1H, tt, J = 3.5, 55.0Hz), 5.84 (1H, d, J = 10.7Hz) ,4.17-4.11(1H,m),4.02-3.90(2H,m),3.63-3.52(4H,m),2.92(2H,dt,J=22.9,6.8Hz),2.78( 1H, dd, J = 12.0, 3.7Hz), 2.54 (1H, dd, J = 13.2, 3.4Hz), 2.44 (1H, dd, J = 12.2, 2.9Hz), 2.36 (1H, d d,J=13.2,3.4Hz),2.26-2.09(3H,m),1.99-1.24(15H,m),0.94(3H,d,J=6.3Hz),0.53(3H,s).

[1437] [Example 165]

[1438] 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)

[1439] 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].

[1440] Exact Mass=485.31(C27H42F3NO3)Obs.mass=486.25(M+H)

[1441] [Example 166]

[1442] 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)

[1443] 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].

[1444] Exact Mass=471.30(C26H40F3NO3)Obs.mass=472.25(M+H)

[1445] [Example 167]

[1446] 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)

[1447] 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].

[1448] 1 H-NMR (CD3OD) δ: 6.24 (1H, d, J = 11.4Hz), 6.04-5.74 (2H, m), 5.03 (2H, d, J = 6.9Hz), 4.42-4.32 ( 2H,m),4.21-4.15(1H,m),3.62(2H,dd,J=14.4,3.9Hz),3.59-3.56(2H,m),2.99-2.94(2H,m),2 .83(1H,dd,J=12.3,3.7Hz),2.65(1H,dd,J=13.3,4.6Hz),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=6.4Hz),0.56(3H,s).

[1449] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.25(M+H)

[1450] [Example 168]

[1451] Synthesis of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(3-(difluoromethoxy)azetidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound A030)

[1452] 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].

[1453] 1 H-NMR (CD3OD) δ: 6.38 (1H, t, J = 75.0Hz), 6.26 (1H, d, J = 11.2Hz), 5.90 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6 .8Hz), 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, 12.6Hz),2.66(1H,dd,J=12.6,4.0Hz),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=6.3Hz), 0.58(3H,s).

[1454] Exact Mass=465.31(C27H41F2NO3)Obs.mass=466.25(M+H)

[1455] [Example 169]

[1456] 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)

[1457] 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].

[1458] 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2Hz), 6.10 (1H, td, J = 56.4, 4.2Hz), 5.92 (1H, d, J = 11.2Hz), 5.06 (2H, d, J = 6.8H z), 4.40 (2H, ddd, J = 14.3, 7.2, 4.5Hz), 3.80 (2H, t, J = 9.3Hz), 3.65 (2H, t, J = 8.1Hz), 3.17-3.09 (1H, m), 2.89 (2H, d dd, J=23.1, 11.6, 4.3Hz), 2.78 (1H, td, J=11.3, 5.2Hz), 2.68 (1H, dd, J=13.4, 4.1Hz), 2.49 (1H, dd, J=13.2, 3.9Hz) ,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=6.3Hz),0.60(3H,s).

[1459] Exact Mass=449.31(C27H41F2NO2)Obs.mass=450.40(M+H)

[1460] [Example 170]

[1461] 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)

[1462] 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].

[1463] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.88 (1H, d, J = 11.2Hz), 4.06-3.95 (2H, m), 3.43 (2H, t, J=8.1Hz), 3.12(2H, td, J=7.9, 2.1Hz), 3.04-2.93 (1H, m), 2.83 (1H, dd, J=12.0, 3.7Hz), 2.58 (1H ,dd,J=13.7,3.9Hz),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 = 6.8Hz), 0.57 (3H, s).

[1464] Exact Mass=451.33(C27H43F2NO2)Obs.mass=452.30(M+H)

[1465] [Example 171]

[1466] 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)

[1467] Compound (16b) [50 mg, 0.068 mmol] and 3-isopropylazetidin-3-ol hydrochloride [30 mg, 0.218 mmol] were used to obtain compound A034 [8.1 mg, 0.018 mmol].

[1468] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0Hz), 5.88 (1H, d, J = 11.4Hz), 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. 7Hz),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 = 6.9Hz), 0.90 (6H, d, J = 6.9Hz), 0.57 (3H, s).

[1469] Exact Mass=445.36(C28H47NO3)Obs.mass=446.30(M+H)

[1470] [Example 172]

[1471] 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)

[1472] Compound (16b) [50 mg, 0.068 mmol] and (S)-3-fluoropyrrolidine hydrochloride [30 mg, 0.239 mmol] were used to obtain compound B014 [9.0 mg, 0.021 mmol].

[1473] Exact Mass=419.32(C26H42FNO2)Obs.mass=420.30(M+H)

[1474] [Example 173]

[1475] 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)

[1476] Compound (16b) [50 mg, 0.068 mmol] and (R)-3-fluoropyrrolidine hydrochloride [30 mg, 0.239 mmol] were used to obtain compound B015 [7.9 mg, 0.019 mmol].

[1477] Exact Mass=419.32(C26H42FNO2)Obs.mass=420.30(M+H)

[1478] [Example 174]

[1479] 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)

[1480] Compound (16b) [50 mg, 0.068 mmol] and (S)-3-(difluoromethyl)pyrrolidine hydrochloride [30 mg, 0.190 mmol] were used to obtain compound B080 [12.5 mg, 0.0277 mmol].

[1481] 1 H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2Hz), 5.89 (1H, d, J = 11.2Hz), 5.81 (1H, td, J = 57.0, 5.0Hz), 4.07-3.96 (2H, m), 2.84 (1H, dd, J = 12.0, 4.0H z),2.80(1H,t,J=9.0Hz),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=6.3Hz),0.59(3H,s).

[1482] Exact Mass=451.33(C27H43F2NO2)Obs.mass=452.30(M+H)

[1483] [Example 175]

[1484] 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)

[1485] Compound (16b) [50 mg, 0.068 mmol] and (R)-3-(difluoromethyl)pyrrolidine hydrochloride [30 mg, 0.190 mmol] were used to obtain compound B081 [12.4 mg, 0.0275 mmol].

[1486] 1H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2Hz), 5.89 (1H, d, J = 11.2Hz), 5.80 (1H, td, J = 56.5, 5.0Hz), 4.07-3.96 (2H, m), 2.84 (1H, dd, J = 12.0, 3.7Hz), 2,77-2.47(8H,m),2.41(1H,dd,J=13.4,3.2Hz),2.24-2.14(2H,m),2.0 7-1.95(4H,m),1.92-1.27(15H,m),0.99(3H,d,J=6.3Hz),0.59(3H,s).

[1487] Exact Mass=451.33(C27H43F2NO2)Obs.mass=452.30(M+H)

[1488] [Example 176]

[1489] 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)

[1490] Compound (16b) [50 mg, 0.068 mmol] and (R)-3-(2,2-difluoroethyl)pyrrolidine hydrochloride [30 mg, 0.175 mmol] were used to obtain compound B082 [8.4 mg, 0.018 mmol].

[1491] 1 H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2Hz), 5.97 (1H, tt, J = 56.0, 4.0Hz), 5.90 (1H, d, J = 11.2Hz),4.07-3.95(2H,m),3.35(1H,dd,J=10.5,8.1Hz),3.18-2.83(5H,m),2.70(1 H,t,J=9.8Hz),2.60(1H,dd,J=13.4,3.7Hz), 2.56-2.48(1H,m),2.41(1H,dd,J=13.2 ,3.4Hz),2.27-1.95(9H,m),1.88-1.29(16H,m),1.01(3H,d,J=6.3Hz),0.60(3H,s).

[1492] Exact Mass=465.34(C28H45F2NO2)Obs.mass=466.35(M+H)

[1493] [Example 177]

[1494] 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)

[1495] Compound (16b) [50 mg, 0.068 mmol] and (S)-3-(1,1-difluoroethyl)pyrrolidine hydrochloride [30 mg, 0.175 mmol] were used to obtain compound B083 [9.3 mg, 0.020 mmol].

[1496] 1 H-NMR (CD3OD) δ: 6.22 (1H, d, J = 11.2Hz), 5.89 (1H, d, J = 11.2Hz), 4.07-3.96 (2H, m), 2.90 (1H, t, J = 9.3Hz), 2.86-2.39 (9H, m), 2.24-2.14(2H,m),2.07-1.46(15H,m),1.59(3H,t,J=19.0Hz),1.39-1.28(4H,m),0.99(3H,d,J=6.8Hz),0.59(3H,s).

[1497] Exact Mass=465.34(C28H45F2NO2)Obs.mass=466.35(M+H)

[1498] [Example 178]

[1499] 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)

[1500] Compound (16b) [50 mg, 0.068 mmol] and (S)-3-(difluoromethoxy)pyrrolidine hydrochloride [25 mg, 0.182 mmol] were used to obtain compound B086 [10.0 mg, 0.0214 mmol].

[1501] 1H-NMR (CD3OD) δ: 5.96 (1H, t, J = 75.0Hz), 5.79 (1H, d, J = 11.4Hz), 5.47 (1H, d, J = 11.4Hz), 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 = 6.4Hz), 0.16 (3H, s).Exact Mass=467.32(C27H43F2NO3)Obs.mass=468.30(M+H)

[1502] [Example 179]

[1503] 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)

[1504] Compound (16b) [50 mg, 0.068 mmol] and (R)-3-(difluoromethoxy)pyrrolidine hydrochloride [26.5 mg, 0.153 mmol] were used to obtain compound B087 [6.5 mg, 0.014 mmol].

[1505] 1 H-NMR (CD3OD)c: 6.38 (1H, t, J = 75.0Hz), 6.21 (1H, d, J = 11.4Hz), 5.89 (1H, d, J =11.4Hz),4.79-4.72(1H,m),4.06-3.95(2H,m),2.85-2.71(4H,m),2.59(1H, dd,J=13.3,3.7Hz), 2.48(3H,dt,J=14.2,6.5Hz), 2.41(1H,dd,J=13.5,3.4Hz ), 2.27-2.13 (3H, m), 2.06-1.26 (18H, m), 0.98 (3H, d, J = 6.4Hz), 0.58 (3H, s).

[1506] Exact Mass=467.32(C27H43F2NO3)Obs.mass=468.30(M+H)

[1507] [Example 180]

[1508] 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)

[1509] Compound (16c) [50 mg, 0.067 mmol] and (S)-3-(difluoromethoxy)pyrrolidine hydrochloride [30 mg, 0.190 mmol] were used to obtain compound B088 [12.1 mg, 0.026.1 mmol].

[1510] 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2Hz), 5.93 (1H, dt, J = 6.0, 57.0Hz), 5.92 (1H, d, J = 11. 2Hz), 5.06 (2H, d, J = 8.0Hz), 4.40 (2H, ddd, J = 13.9, 7.1, 4.4Hz), 3.23 (1H, dd, J = 11.2, 8.8 Hz), 3.10-2.80 (8H, m), 2.68 (1H, dd, J = 13.2, 4.4Hz), 2.49 (1H, dd, J = 13.7, 3.9Hz), 2.32 -2.26(2H,m),2.20-1.91(7H,m),1.82-1.33(12H,m),1.01(3H,d,J=6.8Hz),0.60(3H,s).

[1511] Exact Mass=463.33(C28H43F2NO2)Obs.mass=464.40(M+H)

[1512] [Example 181]

[1513] 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)

[1514] Compound (16c) [50 mg, 0.067 mmol] and (R)-3-(difluoromethoxy)pyrrolidine hydrochloride [33 mg, 0.209 mmol] were used to obtain compound B089 [10.0 mg, 0.0216 mmol].

[1515] 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.90 (1H, td, J = 56.0, 5.0Hz), 5.05 (2H, d, J = 7.0Hz), 4.43-4.36 (2H, m), 3.12 (1H, dd, J = 11.0, 9. 0Hz),3.04-2.71(8H,m),2.67(1H,dd,J=13.2,4.4Hz),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=6.3Hz), 0.60(3H,s).

[1516] Exact Mass=463.33(C28H43F2NO2)Obs.mass=464.45(M+H)

[1517] [Example 182]

[1518] 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)

[1519] Compound (16c) [50 mg, 0.067 mmol] and (R)-3-(2,2-difluoroethyl)pyrrolidine hydrochloride [38 mg, 0.174 mmol] were used to obtain compound B090 [8.2 mg, 0.017 mmol].

[1520] 1H-NMR (CD3OD) δ6.27 (1H, d, J = 10.7Hz), 5.97 (1H, tt, J = 56.0, 4.0Hz), 5.92 (1H, d, J = 10.7Hz), 5.06 (2H, d, J = 6. 3Hz), 4.43-4.37(2H,m),3.41(1H,dd,J=10.7,7.8Hz),3.24-3.12(2H,m),3.07(1H,td,J=12.0,4.7Hz),2.96( 1H, td, J = 11.8, 4.7Hz), 2.86 (1H, dd, J = 12.0, 3.7Hz), 2.78 (1H, t, J = 10.2Hz), 2.68 (1H, dd, J = 13.4, 4.1Hz), 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=6.3Hz),0.60(3H,s).

[1521] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.25(M+H)

[1522] [Example 183]

[1523] 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)

[1524] Compound (16c) [50 mg, 0.067 mmol] and (S)-3-(1,1-difluoroethyl)pyrrolidine hydrochloride [35 mg, 0.161 mmol] were used to obtain compound B091 [12.7 mg, 0.0166 mmol].

[1525] 1H-NMR (CD3OD) δ: 6.27 (1H, d, J = 11.2Hz), 5.92 (1H, d, J = 11.2Hz), 5.06 (2H, d, J = 6.3Hz),4.40(2H,ddd,J=14.0,7.0,4.5Hz),3.37-3.28(1H,m),3.21-2.84(7H, m),2.68(1H,dd,J=13.2,4.4Hz), 2.49(1H,dd,J=13.7,3.9Hz), 2.32-2.08(4H, m), 2.02-1.95 (2H, m), 1.87-1.33 (15H, m), 1.02 (3H, d, J = 6.3Hz), 0.60 (3H, s).

[1526] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.25(M+H)

[1527] [Example 184]

[1528] 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)

[1529] Compound (16c) [50 mg, 0.067 mmol] and (S)-3-(2,2-difluoroethyl)pyrrolidine hydrochloride [40 mg, 0.233 mmol] were used to obtain compound B092 [14.0 mg, 0.0293 mmol].

[1530] 1H-NMR (CD3OD) δ: 6.28 (1H, d, J = 11.2Hz), 5.99 (1H, tt, J = 56.0, 3.0Hz), 5.93 (1H, d, J = 11.2Hz), 5.06 (2H, d, J = 6.3Hz), 4.40 (2H, ddd, J 14.0,7.0,4.5Hz),3.49(1H,dd,J=11.0,7.6Hz),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 .4Hz), 2.62-2.54(1H,m), 2.50(1H,dd,J=13.73.9Hz), 2.33-1.99(8H,m), 1.85-1.34(12H,m), 1.02(3H,d,J=6.3Hz), 0.61(3H,s).

[1531] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.40(M+H)

[1532] [Example 185]

[1533] 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)

[1534] Compound (16c) [50 mg, 0.067 mmol] and (R)-3-(1,1-difluoroethyl)pyrrolidine hydrochloride [38 mg, 0.221 mmol] were used to obtain compound B093 [10.7 mg, 0.0224 mmol].

[1535] 1 H-NMR(CD3OD)δ: 6.27(1H,d,J=11.2Hz), 5.92(1H,d,J=11.2Hz), 5.06(2H,d,J=6.3Hz), 4.46-4.35(2H,m), 3.22-2.85(8H,m), 2.68 (1H,dd,J=13.4,4.1Hz),2.49(1H,dd,J=13.4,4.1Hz),2.33-1.97(8H,m),1.90-1.33(16H,m),1.02(3H,d,J=6.3Hz),0.60(3H,s).

[1536] Exact Mass=477.34(C29H45F2NO2)Obs.mass=478.40(M+H)

[1537] [Example 186]

[1538] 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)

[1539] Compound (16c) [50 mg, 0.067 mmol] and (R)-3-(3,3-difluoropropyl)pyrrolidine hydrochloride [35 mg, 0.189 mmol] were used to obtain compound B094 [13.1 mg, 0.0266 mmol].

[1540] 1 H-NMR (CD3OD) δ: 6.28 (1H, d, J = 11.2Hz), 5.93 (1H, d, J = 11.2Hz), 5.91 (1H, tt, J = 57.5, 4. 0Hz), 5.06 (2H, d, J = 5.9Hz), 4.40 (2H, ddd, J14.0, 7.1, 4.4Hz), 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=13.4,4.1Hz),2.50(1H,dd,J =13.73.9Hz), 2.42-1.94(8H,m),1.90-1.30(17H,m), 1.02(3H,d,J=6.3Hz),0.61(3H,s).

[1541] Exact Mass=491.36(C30H47F2NO2)Obs.mass=492.40(M+H)

[1542] [Example 187]

[1543] 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)

[1544] Compound 16a [100 mg, 0.134 mmol] was dissolved in THF [1 mL], and morpholine [0.2 mL, 2 mmol] was added. 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 the reaction mixture was cooled to room temperature, 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].

[1545] 1 H-NMR (CD3OD) δ: 6.31 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.28 (1H, t, J = 1.2Hz), 4.34 (1H, t, J = 5.9Hz), 4.1-4.08 (1H, m), 3.75 (4H, t ,J=4.6Hz),2.86(1H,dd,J=12.0,3.7Hz),2.76-2.66(6H,m),2.60(1H,td,J=11.74.9Hz),2.51(1H,dd,J=13.73.4Hz),2.25(1H,dd,J=13.2 6.8Hz),2.11-2.00(3H,m),1.90-1.28(17H,m),1.04-0.99(1H,m),0.99(3H,d,J=6.8Hz),0.58(3H,s).Exact Mass=429.32(C27H43NO3)Obs.mass=430.30(M+H)

[1546] [Example 188]

[1547] 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)

[1548] [Chemistry 42]

[1549]

[1550] Step 1

[1551] 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, and the mixture was heated and stirred at 60°C overnight. The reaction mixture was cooled, 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 following reaction without further purification.

[1552] Step 2

[1553] 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], and the mixture was heated and stirred at 60°C for 5 hours. The reaction mixture was cooled, 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].

[1554] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0Hz), 5.88 (1H, d, J = 11.4Hz), 4.06-3.95 (2H, m ), 3.69 (4H, t, J = 4.6Hz), 2.83 (1H, dd, J = 11.9, 4.1Hz), 2.59 (1H, dd, J = 13.7, 3.7Hz ),2.50-2.37(6H,m),2.33(1H,td,J=11.4,5.3Hz),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=6.4Hz), 0.58(3H, s).

[1555] Exact Mass=417.32(C26H43NO3)Obs.mass=418.35(M+H)

[1556] [Example 189]

[1557] 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)

[1558] 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].

[1559] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, dd, J = 8 .0, 1.0Hz), 4.42-4.36 (2H, m), 3.71 (4H, t, J = 4.6Hz), 2.85 (1H, dd, J = 12.0, 3.7Hz ),2.67(1H,dd,J=13.4,4.1Hz),2.58-2.37(7H,m),2.31-2.24(2H,m),2.07-1.93 (3H,m),1.49(11H,ttt,J=61.2,17.2,7.4Hz),0.99(3H,d,J=6.3Hz),0.58(3H,s).

[1560] Exact Mass=429.32(C27H43NO3)Obs.mass=430.35(M+H)

[1561] [Example 190]

[1562] 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)

[1563] 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 give Compound D025 [13.8 mg, 0.031 mmol].

[1564] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 8.0Hz), 4.45-4.33 (2H, m),3.82(1H,dd,J=10.2,3.0Hz),3.66-3.55(2H,m),2.85(1H,dd,J=12.0,3.7Hz),2.82-2.75(2H,m),2 .67 (1H, dd, J = 13.7, 4.4Hz), 2.48 (1H, dd, J = 13.7, 3.9Hz), 2.44-2.24 (4H, m), 2.08-1.93 (4H, m), 1.79 ( 1H,dd,J=11.7,10.2Hz), 1.71-1.26(11H,m), 1.11(3H,d,J=6.3Hz), 0.98(3H,d,J=6.8Hz), 0.58(3H,s).

[1565] Exact Mass=443.34(C28H45NO3)Obs.mass=444.30(M+H)

[1566] [Example 191]

[1567] 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)

[1568] 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 give Compound D026 [12.0 mg, 0.026 mmol].

[1569] 1H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7Hz), 5.90 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 6 .8Hz), 4.42-4.36 (2H, m), 3.75 (2H, t, J = 4.9Hz), 2.85 (1H, dd, J = 12.0, 3.7Hz), 2 .67(1H,dd,J=12.0,4.0Hz)2.64-2.24(9H,m),2.07-1.96(3H,m),1.70-1.27(11 H,m),0.98(3H,d,J=6.8Hz),0.77-0.70(2H,m),0.59-0.53(2H,m),0.58(3H,s).

[1570] Exact Mass=455.34(C29H45NO3)Obs.mass=456.30(M+H)

[1571] [Example 192]

[1572] 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)

[1573] 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 give Compound D027 [18.0 mg, 0.037 mmol].

[1574] 1 H-NMR (CD3OD) δ: 6.27 (1H, d, J = 10.7Hz), 5.92 (1H, d, J = 10.7Hz), 5.06 (2H, t, J=3.9Hz), 4.43-4.37(2H,m), 3.73-3.63(2H,m), 2.86(1H,dd,J=12.0,3.7Hz) ,2.67(1H,dd,J=13.4,4.1Hz),2.49(1H,dd,J=13.4,3.7Hz),2.40-2.25(8H,m ), 2.07-1.94 (3H, m), 1.81-1.18 (20H, m), 0.99 (3H, d, J = 6.3Hz), 0.59 (3H, s).

[1575] Exact Mass=483.37(C31H49NO3)Obs.mass=484.35(M+H)

[1576] [Example 193]

[1577] 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)

[1578] 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].

[1579] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.90 (1H, d, J = 11.2Hz), 5.04 (2H, d, J = 6.8Hz), 4.42-4.36(2H,m),3.69-3.63(2H,m),2.82(3H,q,J=12.0Hz), 2.66(1H,dd,J=13.2,3.9 Hz), 2.48 (1H, dd, J = 13.4, 3.7Hz), 2.43-2.24 (4H, m), 2.06-1.96 (3H, m), 1.74-1.26 (15 H, m), 1.12 (3H, d, J = 6.1Hz), 1.12 (3H, d, J = 6.0Hz), 0.98 (3H, d, J = 6.3Hz), 0.58 (3H, s).

[1580] Exact Mass=457.36(C29H47NO33)Obs.mass=458.35(M+H)

[1581] [Example 194]

[1582] 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)

[1583] 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].

[1584] 1 H-NMR(CD3OD)δ:6.26(1H,d,J=11.2Hz), 5.90(1H,d,J=11.2Hz), 5.05(2H,d,J=6.8Hz), 4.39(2H,dt ,J=15.0,4.8Hz),3.70(2H,ddd,J=21.5,12.0,4.4Hz),2.85(1H,dd,J=12.2,3.4Hz),2.66(1H,dd,J= 13.2,4.4Hz),2.48(1H,dd,J=13.2,3.9Hz),2.39-2.24(7H,m),2.16(1H,d,J=10.7Hz),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=6.3Hz),0.58(3H,s).

[1585] Exact Mass=457.36(C29H47NO3)Obs.mass=458.35(M+H)

[1586] [Example 195]

[1587] 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)

[1588] 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 give Compound D030 [11.2 mg, 0.0252 mmol].

[1589] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.88 (1H, d, J = 11.2Hz), 4.06-3.95 (2H, m), 3.75 (2H, t, J = 4.9Hz), 2.83 (1H, dd, J = 12.2, 3.4Hz), 2.61-2.31(9H,m),2.23-2.13(2H,m),2.05-1.28(18H,m),0.98(3H,d,J=6.8Hz),0.74(2H,t,J=5.6Hz),0.62-0.55(2H,m),0.57(3H,s).

[1590] Exact Mass=443.34(C28H45NO3)Obs.mass=444.35(M+H)

[1591] [Example 196]

[1592] 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)

[1593] 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 give Compound D031 [14.9 mg, 0.0336 mmol].

[1594] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 10.7Hz), 5.05 (2H, d, J = 8.0Hz), 4, 42-4 .36(2H,m),3.77(1H,dt,J=11.4,2.8Hz),3.68-3.58(2H,m),3.23(1H,dd,J=11.2,9.3Hz),2.88 -2.81(2H,m),2.77(1H,dt,J=11.9,2.7Hz),2.67(1H,dd,J=13.2,4.4Hz),2.50-2.21(6H,m),2. 08-1.93 (3H, m), 1.74-1.14 (13H, m), 1.00 (3H, d, J = 6.3Hz), 0.99 (3H, d, J = 6.0Hz), 0.58 (3H, s).

[1595] Exact Mass=443.34(C28H45NO3)Obs.mass=444.30(M+H)

[1596] [Example 197]

[1597] 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)

[1598] 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 give Compound D032 [12.3 mg, 0.027.7 mmol].

[1599] 1 H-NMR (CD3OD) 8: 6.26 (1H, d, J = 11.2Hz), 5.91 (1H, d, J = 11.2Hz), 5.05 (2H, d, J = 7. 3Hz), 4.43-4.33(2H,m), 3.83-3.76(1H,m), 3.62(2H,ddd,J=23.5,13.5,5.0Hz),3 .23(1H,dd,J=11.2,9.3Hz),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=6.3Hz),0.98(3H,d,J=8.1Hz),0.59(3H,s).

[1600] Exact Mass=443.34(C28H45NO3)Obs.mass=444.35(M+H)

[1601] [Example 198]

[1602] 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)

[1603] 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.

[1604] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 10.7Hz), 5.91 (1H, d, J = 10.7Hz), 5.77 (1H, td, J = 55.0, 4 .0Hz), 5.05 (2H, d, J = 6.8Hz), 4.43-4.33 (2H, m), 3.91 (1H, d, J = 11.7Hz), 3.75-3.62 (2H, m),2.92-2.80(2H,m),2.75(1H,dd,J=12.0,3.2Hz),2.67(1H,dd,J=13.2,4.4Hz),2.50- 2.15(7H,m),2.07-1.91(4H,m),1.68-1.21(12H,m),0.99(3H,d,J=6.8Hz),0.58(3H,s).

[1605] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.30(M+H)

[1606] [Example 199]

[1607] 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)

[1608] 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.

[1609] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.2Hz), 5.89 (1H, d, J = 11.2Hz), 5.77 (1H, td, J = 55.0, 4.0H z), 4.06-3.95 (2H, m), 3.90 (1H, d, J = 10.0Hz), 3.75-3.62 (2H, m), 2.88 (1H, d, J = 10.7Hz), 2 .83(1H,dd,J=10.7,4.0Hz),2.75(1H,dd,J=11.7,2.0Hz),2.58(1H,dd,J=13.2,3.4Hz),2. 48-2.35(3H,m), 2,23-1.91(7H,m), 1,87-1,26(14H,m), 0,98(3H,d,J=6.8Hz), 0,58(3H,s).

[1610] Exact Mass=467.32(C27H43F2NO3)Obs.mass=468.35(M+H)

[1611] [Example 200]

[1612] 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)

[1613] Compound (16a) [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 D035 [4.3 mg, 0.0090 mmol] in the same manner as in Example 1.

[1614] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.77 (1H, td, J = 55.3, 4.2Hz) , 5.28 (1H, dd, J = 2.4, 1.5Hz), 4.34 (1H, t, J = 5.9Hz), 4.14-4.09 (1H, m), 3.90 (1H, d, J = 11.7Hz) ,3.73-3.62(2H,m),2.87(2H,dd,J=10.7,5.9Hz),2.74(1H,d,J=11.7Hz),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=6.3Hz),0.57(3H,s).

[1615] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.35(M+H)

[1616] [Example 201]

[1617] 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)

[1618] 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.

[1619] 1H-NMR(CD3OD)δ:6,26(1H,d,J=11,2Hz),5.91(1H,d,J=11.2Hz),5,77(1H,td,J=55.0,4 .0Hz),5.05(2H,d,J=6,8Hz),4,44-4.34(2H,m),3.91(1H,d,J=11.2Hz),3.74-3.61(2H, m),2.84(2H,d,J=11.7Hz),2.78(1H,d,J=11.7Hz),2.67(1H,dd,J=13.2,4.4Hz),2.50- 2.24(5H,m),2.18-1.96(5H,m),1.72-1.22(13H,m),0.99(3H,d,J=6.3Hz),0.59(3H,s).

[1620] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.35(M+H)

[1621] [Example 202]

[1622] 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)

[1623] 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.

[1624] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.2Hz), 6.08 (1H, d, J = 11.2Hz), 5.77 (1H, td, J = 55.4, 4.1H z), 5.28 (1H, dd, J = 2.4, 1.5Hz), 4.34 (1H, t, J = 5.9Hz), 4.15-4.08 (1H, m), 3.91 (1H, d, J = 10 .2Hz), 3.76-3.68(1H,m),3.63(1H,td,J=11.5,2.4Hz), 2.88-2.73(4H,m),2.51(1H,dd,J= 13.4, 3.2Hz), 2.47-1.87 (14H, m), 1.61-1.36 (18H, m), 0.98 (3H, d, J = 6.3Hz), 0.56 (3H, s).

[1625] Exact Mass=479.32(C28H43F2NO3)Obs.mass=480.30(M+H)

[1626] [Example 203]

[1627] 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)

[1628] 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].

[1629] Exact Mass=457.36(C29H47NO3)Obs.mass=458.30(M+H)

[1630] [Example 204]

[1631] 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)

[1632] 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].

[1633] Exact Mass=457.36(C29H47NO3)Obs.mass=458.30(M+H)

[1634] [Example 205]

[1635] 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)

[1636] 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].

[1637] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.0Hz), 5.91 (1H, d, J = 11.4Hz), 5.05 (2H, d, J = 6.9Hz), 4.43-4.35 (2 H,m),3.82(1H,dd,J=11.7,2.1Hz),3.67-3.55(2H,m),2.88-2.81(2H,m),2.76(1H,d,J=11.9Hz),2.6 7(1H,dd,J=13.3,4.1Hz),2.48(1H,dd,J=13.5,3.9Hz),2.44-2.25(4H,m),2.10(1H,td,J=11.7,3.4H z),2.04-1.93(3H,m),1.77-1.27(12H,m),1.12(3H,d,J=6.4Hz),0.98(3H,d,J=6.4Hz),0.58(3H,s).

[1638] Exact Mass=443.34(C28H45NO3)Obs.mass=432.35(M+H)

[1639] [Example 206]

[1640] 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)

[1641] 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 give Compound D041 [30.0 mg, 0.070 mmol].

[1642] 1 H-NMR(CD3OD)δ:6.21(1H,d,J=11.0Hz),5.88(1H,d,J=11.4Hz),4.06-3.95(2H ,m),3.82(1H,dd,J=11.7,2.1Hz),3,65-3,58(2H,m),2,85-2.76(3H,m),2.59(1 H,dd,J=13.3,3,7Hz),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=6.4Hz),0.98(3H,d,J=6.4Hz), 0.58(3H,s).

[1643] Exact Mass=431.34(C27H45NO3)Obs.mass=432.35(M+H)

[1644] [Example 207]

[1645] 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)

[1646] 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 give Compound D042 [30.0 mg, 0.070 mmol].

[1647] 1H-NMR(CD3OD)δ:6.21(1H,d,J=11.0Hz),5.89(1H,d,J=11.0Hz),4.04-3.96(2H,m),3.77(1H ,d,J=11.4Hz),3.68-3.58(2H,m),3.23(1H,dd,J=11.2,9.4Hz),2.88-2.80(2H,m),2.77(1H, dt,J=12.2,3.0Hz),2.59(1H,dd,J=13.5,3.0Hz),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=6.8Hz),0.99(6H,d,J=5.7Hz),0.58(3H,s).

[1648] Exact Mass=431.34(C27H45NO3)Obs.mass=432.35(M+H)

[1649] [Example 208]

[1650] 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)

[1651] 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].

[1652] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.4Hz), 5.89 (1H, d, J = 11.0Hz), 4.06-3.93 ( 2H,m),3.78(1H,dt,J=11.4,2.7Hz), 3.68-3.55(2H,m),3.22(1H,dd,J=11.4, 9.6Hz), 2.88-2.70(3H,m),2.59(1H,dd,J=13.3,3.7Hz),2.42-2.13(6H,m),2 .06-1.21(18H,m),0.99(3H,d,J=5.0Hz),0.98(3H,t,J=3.2Hz),0.58(3H,s).

[1653] Exact Mass=431.34(C27H45NO3)Obs.mass=432.35(M+H)

[1654] [Example 209]

[1655] 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)

[1656] 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 give Compound D045 [5.6 mg, 0.013 mmol].

[1657] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.0Hz), 6.08 (1H, d, J = 11.4Hz), 5.28 (1H, s), 4.89 (1H, d, J = 1.8Hz), 4.35 (1H, t, J=5.7Hz), 4.12(1H,q,J=6.1Hz), 3.78(1H,dt,J=11.0,3.5Hz), 3.65(1H,dd,J=11.9,3.2Hz), 3.63-3.57(1H,m), 3.23(1H,dd,J=11.2,9.4Hz),2.88-2.70(3H,m),2.51(1H,dd,J=13.3,3.2Hz),2.44-2.23(4H,m),2.10-1.92(3H , m), 1.88 (2H, t, J = 5.5Hz), 1.73-1.30 (12H, m), 0.99 (3H, d, J = 6.4Hz), 0.98 (3H, d, J = 6.4Hz), 0.58 (3H, s). Exact Mass=443.34(C28H45NO3)Obs.mass=444.35(M+H)

[1658] [Example 210]

[1659] 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)

[1660] 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].

[1661] 1 H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.4Hz), 6.08 (1H, d, J = 11.4Hz), 5.28 (1H, s), 4.89 (1H, d, J=2.3Hz), 4.35 (1H, t, J=5.9Hz), 4.18-4.06 (1H, m), 3.77 (1H, d, J=11.4Hz), 3.68-3.5 5(2H,m),3.23(1H,dd,J=11.4,9.1Hz),2.95-2.70(3H,m),2.55-2.15(5H,m),2.05-1.8 3(5H,m), 1.73-1.16(12H,m), 1.00(3H,d,J=6.4Hz), 0.99(3H,d,J=6.4Hz), 0.57(3H,s).

[1662] Exact Mass=443.34(C28H45NO3)Obs.mass=444.35(M+H)

[1663] [Example 211]

[1664] 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)

[1665] 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 give Compound D047 [6.7 mg, 0.015 mmol].

[1666] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.4Hz), 6.08 (1H, d, J = 11.0Hz), 5.28 (1H, s), 4.89 (1H, d, J = 1.8Hz), 4 .34(1H,t,J=5.9Hz),4.14-4.10(1H,m),3.82(1H,dd,J=11.7,2.1Hz),3.68-3.55(2H,m),2.89-2.73(3 H,m), 2.51(1H,dd,J=13.3,3,7Hz), 2.46-2.23(3H,m),2.11(1H,td,J=11.7,3.4Hz), 2.04-1.92(3H,m) ,1.88(2H,t,J=6.0Hz), 1.78-1.25(12H,m), 1.11(3H,d,J=6,4Hz),0,98(3H,d,J=6.4Hz), 0.57(3H,s).

[1667] Exact Mass=443.34(C28H45NO3)Obs.mass=444.35(M+H)

[1668] [Example 212]

[1669] 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)

[1670] 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].

[1671] 1H-NMR (CD3OD) δ: 6.32 (1H, d, J = 11.0Hz), 6.08 (1H, d, J = 11.0Hz), 5.28 (1H, s), 4.89 (1H, d, J = 2.3Hz), 4.34 (1H ,t,J=5.9Hz),4.15-4.10(2H,m),3.82(1H,dd,J=11.7,2.1Hz),3.65-3.59(2H,m),2.87(1H,d,J=11.4Hz),2.7 9(2H,t,J=9.4Hz),2.51(1H,dd,J=13.3,3.7Hz),2.44-2.23(3H,m),2.09-1.92(4H,m),1.88(2H,t,J=5.5Hz) , 1.81 (1H, dd, J = 20.4, 9.8Hz), 1.71-1.28 (12H, m), 1.11 (3H, d, J = 5.9Hz), 0.98 (3H, d, J = 6.4Hz), 0.57 (3H, s).

[1672] Exact Mass=443.34(C28H45NO3)Obs.mass=444.35(M+H)

[1673] [Example 213]

[1674] 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)

[1675] Compound (14b) [50 mg, 0.087 mmol] and 3,3-dimethylmorpholine [0.054 mL, 0.435 mmol] were used in the same manner as in Example 188 to obtain compound D049 [9.3 mg, 0.021 mmol].

[1676] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0Hz), 5.88 (1H, d, J = 11.4Hz), 4.04-3.95 (2H, m), 3.73-3.65 ( 2H,m),2.83(1H,dd,J=12.1,3.9Hz),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 = 4.1Hz), 0.97 (3H, d, J = 6.4Hz), 0.57 (3H, s).

[1677] Exact Mass=445.36(C28H47NO3)Obs.mass=446.30(M+H)

[1678] [Example 214]

[1679] 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)

[1680] 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].

[1681] 1 H-NMR (CD3OD) δ: 6.40 (1H, d, J = 11.2Hz), 6.16 (1H, d, J = 11.2Hz), 5.36 (1H, dd, J = 2.4, 1.5Hz), 4.43 (1H, t, J = 5.9Hz), 4.22-4.15 (1H, m), 2.95 ( 1H,dd,J=9.0,4.0Hz),2.91(3H,s),2.68-2.39(7H,m),2.33(1H,dd,J=13.4,6.6Hz),2.27-1.34(19H,m), 1.06(3H,d,J=6.3Hz), 0.65(3H,s).

[1682] [Example 215]

[1683] 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)

[1684] 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 give Compound E004 [16.0 mg, 0.0316 mmol].

[1685] 1 H-NMR (CD3OD) δ: 6.26 (1H, d, J = 11.0Hz), 5.91 (1H, d, J = 11.0Hz), 5.05 (2H, d, J = 6.9Hz ), 4.43-4.35(2H,m),3.22(4H,t,J=5.0Hz),2.89-2.82(4H,m),2.83(3H,s),2.67(1H, dd,J=13.3, 4.1Hz), 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=6.4Hz),0.59(3H,s).

[1686] Exact Mass=506.32(C28H46N204S)Obs.mass=507.25(M+H)

[1687] [Reference Example 16]

[1688] Synthesis of (4R)-4-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((tert-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)pentyl 4-methylbenzenesulfonate (Compound 19b)

[1689] [Chemistry 43]

[1690]

[1691] Step 1

[1692] 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] was added DIBAL-H [1.5 M toluene solution, 10 mL] at -78°C, and the mixture was stirred for 1.5 hours. The mixture was warmed to 0°C and further stirred for 1 hour. The reaction mixture was quenched with methanol. A 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 a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography to give (4R)-4-((1R,4S,7aR)-7a-methyl-4-((triethylsilyl)oxy)octahydro-1H-inden-1-yl)pentanol [3.65 g].

[1693] Step 2

[1694] The above compound [3.65 g] obtained in step 1 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 stirred at the same temperature for 30 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, injected 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 to obtain (4R)-4-((1R,4S,7aR)-7a-methyl-4-((triethylsilyl)oxy)octahydro-1H-inden-1-yl)pentan-1-ol [2.37 g, 6.68 mmol].

[1695] Step 3

[1696] To a pyridine solution (12 mL) of the compound obtained in Step 2 (2.37 g, 6.68 mmol), p-toluenesulfonyl chloride (1.6 g, 8.4 mmol) was added, and the mixture was 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.

[1697] Step 4

[1698] The above residue obtained in step 3 was dissolved in acetone [30 mL], 2M hydrochloric acid [10 mL] was added and stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous 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 (4R)-4-((1R,4S,7aR)-4-hydroxy-7a-methyloctahydro-1H-inden-1-yl)pentyl 4-methylbenzenesulfonate [1.37 g, 3.47 mmol].

[1699] Step 5

[1700] 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], N-methylmorpholine-N-oxide monohydrate [0.67 g, 5.0 mmol], and molecular sieves 4A [1.5 g] obtained in step 4 was stirred at 0°C for 1 hour. T...

Claims

1. A drug for promoting differentiation of oligodendrocyte precursor cells into oligodendrocytes, which is used in combination with an immunomodulatory substance, and contains a vitamin D derivative represented by the following formula (1) or a pharmaceutically acceptable salt or solvate thereof, [Chemistry 1] In formula (1), R represents any structure among Ra, Rb, Rc, Rd or Re in the following formula, [Chemistry 2] R 1 , R 3 , R 8 and R 10 each independently represents a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted by 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 hydroxyl group or a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, wherein, R 1 , R 3 , R 8 and R 10 When each independently represents a C1-C6 alkoxy group or a halogen atom optionally substituted by 1 to 3 halogen atoms, the R 1 , R 3 , R 8 , R 10 R substituted on the same carbon atom 2 , R 4 , R 9 , R 11 Not hydroxyl. 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 or a C3-C6 cycloalkyl group which may be substituted by 1 to 3 halogen atoms, 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 They can bond to each other to form a ring structure with 3 to 5 members. R 5 represents a hydrogen atom, optionally replaced by one -OR 501 C1-C6 alkyl substituted with 1 -OR 501 C3-C6 cycloalkyl substituted with alkyl, R 501 represents a hydrogen atom or a C1-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) represents either the (R) configuration or the (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 they form the methyl subunit or -(CH2)- m , where m is an integer from 2 to 5, X 3 represents a CH2 group or a C=CH2 group, wherein X 1 and X 2 When they form the methyl subunit together, X 3 It is not a C=CH2 group, n represents an integer from 1 to 3, The stereochemistry of the hydroxyl group at position 1 is either (R) configuration or (S) configuration. The stereochemistry of the methyl group at position 20 may be either (R) configuration or (S) configuration.

2. A drug for promoting remyelination, which is used in combination with an immunomodulatory substance, comprising a vitamin D derivative represented by the following formula (1) or a pharmaceutically acceptable salt or solvate thereof, [Chemistry 3] In formula (1), R represents any structure of Ra, Rb, Rc, Rd or Re in the following formula, [Chemistry 4] R 1 , R 3 , R 8 and R 10 each independently represents a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted by 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 hydroxyl group or a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, wherein, R 1 , R 3 , R 8 and R 10 When each independently represents a C1-C6 alkoxy group or a halogen atom optionally substituted by 1 to 3 halogen atoms, the R 1 , R 3 , R 8 , R 10 R substituted on the same carbon atom 2 , R 4 , R 9 , R 11 Not hydroxyl. 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 or a C3-C6 cycloalkyl group which may be substituted by 1 to 3 halogen atoms, 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 They can bond to each other to form a ring structure with 3 to 5 members. R 5 represents a hydrogen atom, optionally replaced by one -OR 501 C1-C6 alkyl substituted with 1 -OR 501 C3-C6 cycloalkyl substituted with alkyl, R 501 represents a hydrogen atom or a C1-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) represents either the (R) configuration or the (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 they form the methyl subunit or -(CH2) m -, where m is an integer from 2 to 5, X 3 represents a CH2 group or a C=CH2 group, wherein X 1 and X 2 When they form the methyl subunit together, X 3 It is not a C=CH2 group, n represents an integer from 1 to 3, The stereochemistry of the hydroxyl group at position 1 may be either (R) configuration or (S) configuration. The stereochemistry of the methyl group at position 20 may be either (R) configuration or (S) configuration.

3. A drug for treating one or more diseases selected from the group consisting of multiple sclerosis, neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-related myelopathy, HIV-related leukoencephalopathy, Krabbe disease, Guillain-Barre 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 caused by drug dependence, autism, Alzheimer's dementia and ischemic stroke, which is used in combination with an immunomodulatory substance, and contains a vitamin D derivative represented by the following formula (1) or a pharmaceutically acceptable salt or solvate thereof, [Chemistry 5] In formula (1), R represents any structure of Ra, Rb, Rc, Rd or Re in the following formula, [Chemistry 6] R 1 , R 3 , R 8 and R 10 each independently represents a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted by 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 hydroxyl group or a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, wherein, R 1 , R 3 , R 8 and R 10 When each independently represents a C1-C6 alkoxy group or a halogen atom optionally substituted by 1 to 3 halogen atoms, the R 1 , R 3 , R 8 , R 10 R substituted on the same carbon atom 2 , R 4 , R 9 , R 11 Not hydroxyl. 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 or a C3-C6 cycloalkyl group which may be substituted by 1 to 3 halogen atoms, 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 They can bond to each other to form a ring structure with 3 to 5 members. R 5 represents a hydrogen atom, optionally replaced by one -OR 501 C1-C6 alkyl substituted with 1 -OR 501 C3-C6 cycloalkyl substituted with alkyl, R 501 represents a hydrogen atom or a C1-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) represents either the (R) configuration or the (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 they form the methyl subunit or -(CH2) m -, where m is an integer from 2 to 5, X 3 represents a CH2 group or a C=CH2 group, wherein X 1 and X 2 When they form the methyl subunit together, X 3 It is not a C=CH2 group, n represents an integer from 1 to 3, The stereochemistry of the hydroxyl group at position 1 is either (R) configuration or (S) configuration. The stereochemistry of the methyl group at position 20 may be either (R) configuration or (S) configuration.

4. A drug for promoting differentiation of oligodendrocyte precursor cells into oligodendrocytes, comprising a vitamin D derivative represented by the following formula (1) or a pharmaceutically acceptable salt or solvate thereof and an immunomodulatory substance, [Chemistry 7] In formula (1), R represents any structure of Ra, Rb, Rc, Rd or Re in the following formula, [Chemistry 8] R 1 , R 3 , R 8 and R 10 each independently represents a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted by 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 hydroxyl group or a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, wherein, R 1 , R 3 , R 8 and R 10 When each independently represents a C1-C6 alkoxy group or a halogen atom optionally substituted by 1 to 3 halogen atoms, the R 1 , R 3 , R 8 , R 10 R substituted on the same carbon atom 2 , R 4 , R 9 , R 11 Not hydroxyl. 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 or a C3-C6 cycloalkyl group which may be substituted by 1 to 3 halogen atoms, 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 They can bond to each other to form a ring structure with 3 to 5 members. R 5 represents a hydrogen atom, optionally replaced by one -OR 501 C1-C6 alkyl substituted with 1 -OR 501 C3-C6 cycloalkyl substituted with alkyl, R 501 represents a hydrogen atom or a C1-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) represents either the (R) configuration or the (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 they form the methyl subunit or -(CH2) m -, where m is an integer from 2 to 5, X 3 represents a CH2 group or a C=CH2 group, wherein X 1 and X 2 When they form the methyl subunit together, X 3 It is not a C=CH2 group, n represents an integer from 1 to 3, The stereochemistry of the hydroxyl group at position 1 is either (R) configuration or (S) configuration. The stereochemistry of the methyl group at position 20 may be either (R) configuration or (S) configuration.

5. A drug for promoting remyelination, comprising a vitamin D derivative represented by the following formula (1) or a pharmaceutically acceptable salt or solvate thereof and an immunomodulatory substance, [Chemistry 9] In formula (1), R represents any structure of Ra, Rb, Rc, Rd or Re in the following formula, [Chemistry 10] R 1 , R 3 , R 8 and R 10 each independently represents a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted by 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 hydroxyl group or a C1-C6 alkyl group optionally substituted by 1-3 halogen atoms, wherein R 1 , R 3 , R 8 and R 10 When each independently represents a C1-C6 alkoxy group or a halogen atom optionally substituted by 1 to 3 halogen atoms, the R 1 , R 3 , R 8 , R 10 R substituted on the same carbon atom 2 , R 4 , R 9 , R 11 Not hydroxyl. 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 or a C3-C6 cycloalkyl group which may be substituted by 1 to 3 halogen atoms, 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 They can bond to each other to form a ring structure with 3 to 5 members. R 5 represents a hydrogen atom, optionally replaced by one -OR 501 C1-C6 alkyl substituted with 1 -OR 501 C3-C6 cycloalkyl substituted with alkyl, R 501 represents a hydrogen atom or a C1-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) represents either the (R) configuration or the (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 they form the methyl subunit or -(CH2) m -, where m is an integer from 2 to 5, X 3 represents a CH2 group or a C=CH2 group, wherein X 1 and X 2 When they form the methyl subunit together, X 3 It is not a C=CH2 group, n represents an integer from 1 to 3, The stereochemistry of the hydroxyl group at position 1 may be either (R) configuration or (S) configuration. The stereochemistry of the methyl group at position 20 may be either (R) configuration or (S) configuration.

6. A drug for treating one or more diseases selected from the group consisting of multiple sclerosis, neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-related myelopathy, HIV-related leukoencephalopathy, Krabbe disease, Guillain-Barre 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 caused by drug dependence, autism, Alzheimer's dementia and ischemic stroke, comprising a vitamin D derivative represented by the following formula (1) or a pharmaceutically acceptable salt or solvate thereof, and an immunomodulatory substance, [Chemistry 11] In formula (1), R represents any structure of Ra, Rb, Rc, Rd or Re in the following formula, [Chemistry 12] R 1 , R 3 , R 8 and R 10 each independently represents a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted by 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 hydroxyl group or a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, wherein, R 1 , R 3 , R 8 and R 10 When each independently represents a C1-C6 alkoxy group or a halogen atom optionally substituted by 1 to 3 halogen atoms, the R 1 , R 3 , R 8 , R 10 R substituted on the same carbon atom 2 , R 4 , R 9 , R 11 Not hydroxyl. 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 or a C3-C6 cycloalkyl group which may be substituted by 1 to 3 halogen atoms, 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 They can bond to each other to form a ring structure with 3 to 5 members. R 5 represents a hydrogen atom, optionally replaced by one -OR 501 C1-C6 alkyl substituted with 1 -OR 501 C3-C6 cycloalkyl substituted with alkyl, R 501 represents a hydrogen atom or a C1-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) represents either the (R) configuration or the (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 they form the methyl subunit or -(CH2) m -, where m is an integer from 2 to 5, X 3 represents a CH2 group or a C=CH2 group, wherein X 1 and X 2 When they form the methyl subunit together, X 3 It is not a C=CH2 group, n represents an integer from 1 to 3, The stereochemistry of the hydroxyl group at position 1 is either (R) configuration or (S) configuration. The stereochemistry of the methyl group at position 20 may be either (R) configuration or (S) configuration.

7. The drug according to any one of claims 1 to 6, wherein In the above formula (1), R 1 , R 3 , R 8 and R 10 each independently represents a C1-C6 alkyl group optionally substituted by 1 to 3 fluorine atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted by 1 to 3 fluorine atoms, a fluorine atom or a hydrogen atom, R 2 , R 4 , R 9 and R 11 Each independently represents a hydrogen atom, a hydroxyl group or a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, wherein R 1 , R 3 , R 5 and R 7 When each independently represents a C1-C6 alkoxy group or a fluorine atom optionally substituted by 1 to 3 fluorine atoms, 1 , R 3 , R 8 and R 10 R substituted on the same carbon atom 2 , R 4 , R 9 and R 11 Not hydroxyl. R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 22 and R 23 Each independently represents a hydrogen atom or a C1-C6 alkyl group or a C3-C6 cycloalkyl group which is optionally substituted by 1 to 3 fluorine atoms, R 1 and R 2 , R 3 and R 4 , 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 22 and R 23 They can bond to each other to form a ring structure with 3 to 5 members. R 24 represents a hydrogen atom, a C1-C3 alkyl group or a C1-C3 alkylsulfonyl group, X 1 and X 2 Each independently represents a hydrogen atom or a methyl group, or X 1 and X 2 Together they form the methyl subunit, X 3 represents a CH2 group or a C=CH2 group, wherein X 1 and X 2 When they form the methyl subunit together, X 3 It is not a C=CH2 group, n represents an integer from 1 to 3, The stereochemistry of the methyl group at position 20 may be either (R) configuration or (S) configuration.

8. The drug according to any one of claims 1 to 7, wherein R stands for Rb.

9. The drug according to any one of claims 1 to 7, wherein R stands for Rd.

10. The drug according to any one of claims 1 to 9, wherein X 1 and X 2 represents a hydrogen atom, X 3 It represents a CH2 group.

11. The drug according to any one of claims 1 to 6, wherein The vitamin D derivative represented by formula (1) is represented by the following formula (1A): [Chemistry 13] In formula (1A), R represents any structure of Rb or Rd in the following formula, [Chemistry 14] R 3 represents a C1-C6 alkyl group optionally substituted by 2 fluorine atoms, R 3 The stereochemistry of represents either (R) configuration or (S) configuration, R 14 and R 15 Each independently represents a hydrogen atom or a C1-C6 alkyl group, R 14 and R 15 The stereochemistry of each independently represents either (R) configuration or (S) configuration, n represents an integer of 1 or 2.

12. The drug according to any one of claims 1 to 6, wherein The vitamin D derivative represented by formula (1) is any of the following vitamin D derivatives or pharmaceutically acceptable salts or solvates 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).

13. The drug according to any one of claims 1 to 12, wherein The immunomodulatory substances are fingolimod (FTY720), interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, natalizumab, siponimod, ozanimod, ponesimod, dimethyl fumarate, diroxiimelfumarate, cladribine, ocrelizumab, rituximab, ofatumumab, ublituximab, alemtuzumab, divozilimab, evobrutinib, orelabrutinib, tolebrutinib, remibrutinib or fenebrutinib.

14. The drug according to any one of claims 1 to 13, wherein The vitamin D derivative represented by formula (1) and the immunomodulatory substance are each contained in a therapeutically effective amount or used in a therapeutically effective amount.

15. The drug according to any one of claims 1 to 13, wherein The vitamin D derivative represented by formula (1) is contained in a therapeutically effective amount, and the immunomodulatory substance is used in an amount less than the therapeutic amount, or is contained in an amount less than the therapeutic amount.

16. The drug according to any one of claims 1 to 13, wherein The vitamin D derivative represented by formula (1) and the immunomodulatory substance are each contained in an amount less than a therapeutic amount or used in a therapeutically effective amount.

17. The drug according to any one of claims 1 to 16, wherein The preparation is for systemic administration.

18. The drug according to any one of claims 1 to 17, wherein The vitamin D derivative represented by formula (1) and the immunomodulatory substance are administered sequentially.

19. The drug according to any one of claims 1 to 17, wherein The vitamin D derivative represented by formula (1) and the immunomodulatory substance are administered simultaneously.

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