VDR silent vitamin D derivatives as SREBP inhibitors and their pharmaceutical use

Abstract

Provided are vitamin D3 derivatives of formula (I), pharmaceutical compositions thereof, and pharmaceutical or medical uses thereof for treating metabolic disease, liver disease, obesity, diabetes, cardiovascular disease, or cancer in patients in need of such treatment.

Description

[Technical Field]

[0001] Cross-reference of related applications

[0001] This application is a non-provisional U.S. application claiming the benefits of U.S. Provisional Application No. 63 / 080,010 filed September 17, 2020, the entire contents of which are incorporated herein by reference.

[0002]

[0002] To provide novel vitamin D3 derivatives and their pharmaceutical or medical uses in subjects requiring this treatment for the treatment of diseases selected from metabolic diseases, liver diseases, diabetes, cancer, obesity and cardiovascular diseases. [Background technology]

[0003]

[0003] The basic function of vitamin D3 and its metabolites is to maintain calcium and phosphorus homeostasis in animals. This activity is achieved by the direct binding of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], a hydroxylated metabolite of vitamin D3, to the vitamin D receptor (VDR) (Kato, SJBiochem. 2000, 127, 717~722; Jurutka, PW; Whitfield, GK et al. Rev. Endocr. Metab. Disord. 2001, 2, 203~216). VDR is a vitamin D-specific member of the nuclear receptor family of transcription factors that regulates the expression of countless genes involved in calcium / phosphorus homeostasis (Veldurthy, V. et al. Bone Res. 2016, 4, #16041), cell differentiation and proliferation (Samuel, S. et al. Nutrition Rev. 2008, 66, S116~S124), and immune responses (White, JHRev. Endocr. Metab. Disord. 2012, 13, 21~29; Cantorna, MT et al. Am.J. Clin. Nutr. 2004, 80, 1717S~1720S; Aranow, CJ Invest. Med. 2011, 59, 881~886). Due to VDR's biological importance and the presence of 1α,25(OH)2D3 as a potent major agonist, VDR is an attractive target for drug development. Thousands of vitamin D analogues have been chemically synthesized, and clinical use has been achieved with eight synthetic VDR ligands. Examples include calcipotriol for psoriasis (Calverley, MJ Tetrahedron, 1987, 43, 4609-4619), paricalcitol for secondary hyperparathyroidism (Slatopolsky, E. et al. Am.J. Kidney Dis. 1995, 26, 852-860), and eldecalcitol for osteoporosis (Kubodera, N. Curr. Bioactive Compds. 2006, 2, 301-315).

[0004]

[0004] The majority of synthetic vitamin D analogues involve the substitution of a modified side chain on the CD ring or a functional group on the A ring, as shown below.

[0005] [ka]

[0006] However, these analogs typically retain the three hydroxyl groups or their equivalents at the C1, C3, and C25 positions, which are necessary for interaction with VDR (Rochel, N. et al. Mol. Cell 2000, 5, 173-179). In recent years, the introduction of large substituents on the CD ring side chain has resulted in VDR antagonists or partial agonists that lack the effect of increasing blood calcium levels (Nakabayashi, M. et al. J. Med. Chem. 2008, 51, 5320-5329; Kudo, T. et al. J. Med. Chem. 2014, 57, 4073-4087; Anami, Y. et al. J. Med. Chem. 2014, 57, 4351-4367). (For VDR antagonists with a large substituent on the lactam side chain DLAM, see Nakano, Y. et al. J.Med.Chem. 2006, 49, 2398-2406. For the antagonist ZK-159222 with a long alkyl side chain, see Herdick, M. et al. J.Biol.Chem. 2000, 275, 16506-16512. For antagonists with a small α,β unsaturated lactone ring on the side chain of the TEI-9647 analog, see Saito, N. et al. J.Med.Chem. 2006, 49, 7063-7075.) Also, cleavage of the vitamin D3 side chain results in a lack of blood calcium-raising effect. The discovery of an active VDR ligand in vivo was made (Plum, LA et al., Proc. Natl. Acad. Sci. USA 2004, 101, 6900-6904). However, efforts to synthesize vitamin D analogs have long focused on VDR as a pharmacological target.

[0007]

[0005] In recent years, another genomic target of vitamin D3 has emerged. The inventors have previously reported that 25-hydroxyvitamin D3 [25(OH)D3, 1, Figure 1], the major circulating form of vitamin D3, inhibits the activity of sterol regulatory element-binding proteins (SREBP), a major transcription factor family of lipid synthesis, through interaction with SCAP, a specific escort protein of SREBP (Asano, L. et al. Cell Chem. Biol. 2017, 24, 207~217). SREBP is involved in regulating lipid homeostasis and lipid metabolism in all tissues by controlling the expression of genes related to the biosynthesis and uptake of fatty acids, triglycerides, cholesterol, and phospholipids (Brown, MS; Goldstein, JL Cell 1997, 89, 331~340; Goldstein, JL et al. Cell 2006, 124, 35~46). The association of 25(OH)D3 with SCAP induces degradation of both SCAP and SREBP, thereby blocking the expression of SREBP-regulated lipid-producing genes (Asano, L. et al. CellChem. Biol. 2017, 24, 207-217). Low μM doses of 25(OH)D3 inhibit cellular lipid synthesis by limiting the expression of SREBP-responsive genes in cultured cells. This suggests that 25(OH)D3 can serve as a starting point for designing SREBP inhibitors.

[0008]

[0006] Because SREBP plays a central role in lipid metabolism, it is strongly associated with metabolic syndrome. For example, high insulin levels induced by a high-calorie diet or obesity, or high activation of SREBP, lead to triglyceride accumulation and induce fatty liver disease. In addition, high activation of SREBP increases cholesterol levels and suppresses insulin receptor substrate 2, causing hyperlipidemia, arteriosclerosis, and insulin resistance. Moreover, SREBP activation is often correlated with the ability of hepatitis viruses to cause cancer growth and fatty liver disease (JAMenendez and R. Lupu, Nat. Rev. Cancer, 2007, 7, 763~777; AJBrown, Biochem. J., 2008, 416, e15~e17). Furthermore, high SREBP1 activation contributes to other metabolic diseases and conditions, such as obesity, diabetes mellitus, dyslipidemia, fatty liver, atherosclerosis, and inflammation and fibrosis in various organs (Shimano, H. et al. 2017). The involvement of SREBP activation in multiple diseases has made such transcription factors attractive pharmaceutical targets. To date, the only known "endogenous" molecule that directly inhibits the SREBP activation pathway is sterols.

[0009]

[0007] Although no small molecule inhibitors of SREBP / SCAP have yet been approved for clinical use, SREBP is now characterized by abnormal or elevated lipid metabolism (Baenke, F. et al. 2013, 6, 1353-1363; Guo, D. et al. Curr. Pharm. Des. 2014, 20, 2619-2626; Wen, YA. et al. Cell Death & Disease 2018, 9, #265; Cheng, X. et al. Curr. Top. Med. Chem. 2018, 18, 484-493; Yin, F. et al. Cell Death & Disease 2019, 10, #672; Freed-Pastor, WA et al. Cell 2012, 148, 244-258), and fatty liver disease (Shimano, H.; Sato, R. Nature It is highly regarded as a promising drug target for cancer (Rev. Endocrinol. 2017, 13, 710-730) and cancer (DeBose-Boyd, RA; Ye, J. Trends Biochem. Sci. 2018, 43, 358-368; Rohrig, F.; Schulze, A. Nature Rev. Cancer 2016, 16, 732-749; Chen, M. et al. An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer. Nature Genet. 2018, 50, 206-218; Liu, M. et al. Transcriptional profiling reveals a common metabolic program in high-risk human neuroblastoma and mouse neuroblastoma sphere-forming cells. Cell Reports 2016, 17, 609-623). Furthermore, SREBP has been described as playing a role in several disease-related physiological processes that are not directly related to lipid homeostasis, including innate immunity (Im, SS. Cell Metab. 2011, 13, 540-549) and viral infection (Yuan, S. Nature Commun. 2019, 10, 120).Some notable synthetic SREBP inhibitors include fatostatin and its drug-like derivative FGH10019 (Kamisuki, S. et al. Chem. Biol. 2009, 16, 882-892; Kamisuki, S. et al. J. Med. Chem. 2011, 54, 4923-4927), and these are widely used as pharmacological tools to investigate the role of SREBP / SCAP in disease conditions (Kusnadi, A. et al. Immunity 2019, 51, 241-257; Guo, C. et al. Immunity 2018, 49, 842-856; Bertolio, R. et al. Nature Commun. 2019, 10, 1326; Syafruddin, SE et al. Nature Commun. 2019, 10, 1152; Talebi, A. et al. Nature Commun. 2018, 9, 2500; Nguyen, Van T.M. et al. Nature Commun. 2015, 6, 10044; van der Kant, R. et al. Cell Stem Cell 2019, 24, 363-375; Chen, M. et al. Nature Genet. 2018, 50, 206-218; Liu, M. et al. Cell Reports 2016, 17, 609-623). None of these experimental SREBP inhibitors have yet reached clinical approval.

[0010]

[0008] To provide SREBP inhibitors that have little or no VDR activity, the synthesis and biological evaluation of vitamin D3 analogs in which the C1 and / or C3 positions of the A ring are substituted have been reported to date (WO2016 / 103722). Among these, compound 3

[0011] [ka] Compound 3 selectively inhibited SREBP / SCAP in cultured cells without inducing VDR activity (Nagata, A. ACS Chem. Biol. 2019, 14, 2851~2858). However, the usefulness of compound 3 in vivo was limited due to residual serum calcium-elevating activity at high doses and low bioavailability.

[0012]

[0009] What is needed is a structurally different novel chemical skeleton with potentially different pharmacological properties in order to meet the specific requirements of the target disease state. [Overview of the Initiative] [Problems that the invention aims to solve]

[0013]

[0010] The present invention aims to provide synthetic vitamin D analogues that are SREBP inhibitors that may have very weak or negligible improvements in VDR activity and / or drug-like properties. Compounds disclosed herein in which the structure of the A ring of 25(OH)D3 is completely substituted are SREBP(plural). Certain compounds also have very weak or negligible VDR activity. Furthermore, the present invention aims to make the compounds provided useful in the treatment of diseases such as metabolic diseases including non-alcoholic steatohepatitis (NASH), liver diseases including fatty liver disease, diabetes, cancer, obesity, and cardiovascular diseases. [Means for solving the problem]

[0014]

[0011] In one embodiment, the following general formula (I):

[0015] [ka] Compounds thereof, or stereoisomers thereof, mixtures of stereoisomers thereof, and / or pharmaceutically acceptable salts thereof The double bond from a to b is either in an E configuration or a Z configuration. R 1 However, hydrogen;

[0016] [ka] (R a and R bwhich, together with the carbon to which they are attached, form an unsubstituted C5-C7-cycloalkyl group); -CH2-S-(heteroaryl); -CH2-(1,3-dioxo-isoindolin-2-yl);

[0017]

Chemical formula

[0018]

Chemical formula

[0019] [ka] Alternatively, the present invention provides a compound of formula (I) that is not this stereoisomer, a mixture of this stereoisomer, and / or this pharmaceutically acceptable salt, or this stereoisomer, a mixture of this stereoisomer, and / or this pharmaceutically acceptable salt.

[0020]

[0012] In another embodiment, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

[0021]

[0013] In another embodiment, a method is provided for treating a disease selected from metabolic diseases including non-alcoholic steatohepatitis; liver diseases including fatty liver disease; obesity; diabetes; cardiovascular disease; hyperlipidemia (including hypertriglyceridemia and hypercholesterolemia); or cancer (including prostate cancer, liver cancer, bile duct cancer, bone cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, hematological cancers (including lymphoma and leukemia), kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the skin, cutaneous melanoma and uveal melanoma) in a subject, comprising the steps of administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need, or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier as an active ingredient to a subject in need.

[0022]

[0014] In another embodiment, a method for inhibiting SREBP in a subject is provided, comprising the steps of administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need, or administering a therapeutically effective amount of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier as an active ingredient to a subject in need.

[0023]

[0015] In another aspect, provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of metabolic diseases including non-alcoholic steatohepatitis; liver diseases including fatty liver disease; diabetes; hyperlipidemia (including hypertriglyceridemia and hypercholesterolemia); cancer (including prostate cancer, liver cancer, bile duct cancer, bone cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, blood cancer (including lymphoma and leukemia), kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, head and neck squamous cell carcinoma, squamous skin cancer, cutaneous melanoma and uveal melanoma); obesity or cardiovascular diseases.

[0024]

[0016] In another aspect, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of metabolic diseases including non-alcoholic steatohepatitis; liver diseases including fatty liver disease; diabetes; hyperlipidemia (including hypertriglyceridemia and hypercholesterolemia); cancer (including prostate cancer, liver cancer, bile duct cancer, bone cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, blood cancer (including lymphoma and leukemia), kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, head and neck squamous cell carcinoma, squamous skin cancer, cutaneous melanoma and uveal melanoma); obesity; hyperlipidemia (including hypertriglyceridemia and hypercholesterolemia); or cardiovascular diseases.

[0025]

[0017] In another aspect, the following formula:

[0026]

Chemical formula

[0027]

Chem.

[0028]

[0018] In yet another aspect, R 1 is

[0029]

Chem.

[0030]

Chem.

[0031]

Chem.

Brief Description of the Drawings

[0032] [Figure 1]

[0019] It is a diagram showing the effects of Compounds 10 - 33 on SREBP activation. [Figure 2]

[0020] It is a diagram showing the effects of Compounds 10 - 33 on VDR activation. [Figure 3]

[0021] It is a diagram showing the effects of Compounds 38 - 41 and Compounds 46 - 51 on SREBP activation. [Figure 4]

[0022] This figure shows the effects of 25(OH)D3(1) and compounds 38-41 and 46-51 on VDR activation. [Figure 5A]

[0023] This figure shows the short-term in vivo evaluation of the compounds disclosed herein. It is an experimental protocol for a short-term screening system to evaluate the inhibitory effect of synthetic compounds on SREBP activation. [Figure 5B] This figure shows the short-term in vivo evaluation of the compounds disclosed herein. The relative mRNA levels of SREBP-responsive genes were determined by real-time PCR in the livers of mice that had free access to a normal diet or that had been fasted and re-fed a special diet (mean ± SEM, n=3 per group), *p<0.05. [Figure 5C] This figure shows the short-term in vivo evaluation of the compounds disclosed herein. The expression levels of SREBP-responsive genes were determined by real-time PCR in the livers of mice treated with the compounds indicated by each number (10 mg / kg) according to the protocol illustrated in Figure 5A. [Figure 5D] This figure shows the short-term in vivo evaluation of the compounds disclosed herein. The vehicle, serum calcium levels in mice treated with the compound indicated by each number or with 25(OH)D3 (mean ± SEM, n=3 per group), *p<0.05. [Figure 5E] This figure shows the short-term in vivo evaluation of the compounds disclosed herein. The relative mRNA levels of SREBP-responsive genes were determined by real-time PCR in the livers of mice treated as shown in the figure. [Figure 5F] This figure shows the short-term in vivo evaluation of the compounds disclosed herein. It is a Western blot analysis of SCAP protein in the liver of mice treated as shown in the figure. [Figure 6A]FIG.

[0024] Inhibition of SREBP and SCAP by KK-052(50). Effects of 25(OH)D3 and KK-052 on the ability of endogenous SREBP to activate the transcription of the luciferase reporter gene (where in the right panel, the line labeled with circles is 25(OH)D3 and the line labeled with squares is KK-052). [Figure 6B] FIG. Inhibition of SREBP and SCAP by KK-052(50). Western blot analysis of endogenous SREBP-2 and endogenous SCAP. Treatment with 25(OH)D3 and KK-052 decreased the protein levels of both the precursor and mature forms of SREBP-2, as well as the protein level of SCAP (CHO-K1 cells were treated with the compounds in lipid-free medium for 24 hours). [Figure 6C] FIG. Inhibition of SREBP and SCAP by KK-052(50). Western blot analysis of SCAP. CHO-K1 cells expressing FLAG-tagged SCAP were treated with the compounds in lipid-free medium for 24 hours, and immunoblotting was performed with an anti-FLAG antibody. [Figure 7A]

[0025] FIG. Long-term efficacy and safety data of KK-052 for the treatment of fatty liver using ob / ob mice. ​​​​​​​​​​​​​​​​​​​

[0026] The term "C" used in this specification 1-4 The term "alkoxy" is defined herein as R is C 1-4 This refers to the alkyl -OR group.

[0034]

[0027] As used herein, the term "alkyl" refers in some embodiments to a linear or branched hydrocarbon group having 1 to 12 carbon atoms, in some embodiments to 1 to 6 carbon atoms, and in some embodiments to 1 to 4 carbon atoms. In some embodiments, the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0035]

[0028] As used herein, the term "cycloalkyl" refers to a saturated aliphatic monocyclic hydrocarbon ring having 3 to 10 carbon atoms, in some embodiments having 5 to 7 carbon atoms, and in some embodiments having 3 to 6 carbon atoms. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0036]

[0029] As used herein, the term “aryl” refers to a monovalent group of a monocyclic or bicyclic aromatic hydrocarbon ring having 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl.

[0037]

[0030] In this specification, the terms "halogen" or "halo" refer to fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.

[0038]

[0031] "Halo-C" used in this specification 1-4 The term "alkyl" refers to a C molecule substituted with at least one independently selected halo (in some embodiments, 1-5, 1-4, 1-3, 1-2, 1, 2, 3, 4, or 5) 1-4 This refers to an alkyl group.

[0039]

[0032] "Halo-C" used in this specification1-4 The term "alkoxy" is defined herein as R being halo-C 1-4 This refers to the alkyl -OR group.

[0040]

[0033] The term "C" used in this specification 1-4 The term "alkoxycarbonyl" is defined herein as R being C 1-4 This refers to the alkoxy -C(O)R group.

[0041]

[0034] As used herein, the term “heteroaryl” refers to a monocyclic or bicyclic monovalent aromatic cyclic group having 5 to 10 ring atoms, where at least one (in some embodiments, 1, 2, 3, or 4) atoms is a heteroatom independently selected from nitrogen, oxygen, and sulfur, and the remaining atoms are carbon atoms. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl group. In some embodiments, the heteroaryl is pyrrolyl, furanyl, thienyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyrazinyl, pyridadinyl, triazolyl, tetrazolyl. In some embodiments, the heteroaryl is thienyl or pyridyl.

[0042]

[0035] The term “hydroxy-C1-C6-alkyl” as used herein refers to a C1-C6-alkyl group substituted with one, two, or three hydroxyl groups (in some embodiments, one hydroxyl group) as defined herein. In some embodiments, the hydroxy-C1-C6-alkyl group is 3-hydroxypropyl, 4-hydroxybutyl, or 5-hydroxypentyl.

[0043]

[0036] The optionally substituted aryls and optionally substituted heteroaryls are halogens, halo-C 1-4 Alkyl, -S-(halo-C) 1-4 Alkyl), C1-4 Alkoxy, Halo-C 1-4 Alkoxy, nitro, cyano, C 1-4 Alkoxycarbonyl and C 6-10 The above aryl and heteroaryl compounds refer to those which can be optionally substituted with at least one identical or distinct group (in some embodiments, 1 to 4 groups, 1 to 3 groups, 1 to 2 groups, 4 groups, 3 groups, 2 groups, or 1 group) selected from the group consisting of aryls (where the aryl is not further substituted). In some embodiments, the optionally substituted aryl and heteroaryl compounds are aryl and heteroaryl compounds substituted with 1 to 4 identical or distinct groups independently selected from the group consisting of chloro, fluoro, bromo, methyl, methoxy, trifluoromethyl, methoxycarbonyl, trifluoromethoxy, nitro, cyano, -S-CF3, and phenyl.

[0044]

[0037] All embodiments disclosed herein, unless otherwise specified in detail, include any stereoisomer or mixture of such stereoisomers and / or pharmaceutically acceptable salts thereof.

[0045]

[0038] Compounds of formula (I) may have a chiral center. Compounds of formula (I) containing asymmetrically substituted atoms may be isolated in optically active or racemic forms. Individual stereoisomers of the compound may be prepared synthetically from commercially available starting materials containing a chiral center, or by separation after preparation of a mixture of enantiomer products, e.g., separation or recrystallization after conversion to a diastereomer mixture, chromatographic techniques, direct separation of enantiomers on a chiral chromatography column, or any other suitable method known in the art. All chiral, diastereomers, chiral or diastereomer forms, and all mixtures in racemic forms are within the scope of this disclosure unless a specific stereochemical or isomeric form is specified in detail. It will also be understood by those skilled in the art that when a compound is represented as an (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity, and vice versa.

[0046]

[0039] Compounds of a particular formula (I) may exist as tautomers and / or geometric isomers. All possible tautomers, as well as cis and trans isomers, in their individual forms and mixtures thereof, are within the scope of this disclosure. In addition, as used herein, the term alkyl includes all possible isomeric forms of the alkyl groups described herein, although only a few examples are given. Furthermore, in cases of substitution with cyclic groups such as aryl, heteroaryl, and heterocyclyl, all positional isomers are included, although only a few examples are given.

[0047]

[0040] The following embodiments are provided.

[0048]

[0041] Embodiment 1: Provides a compound of formula (I) as described in the summary of the invention.

[0049]

[0042] Embodiment 1A: Formula (IP)

[0050] [ka] Compounds thereof, or stereoisomers thereof, mixtures of stereoisomers thereof, and / or pharmaceutically acceptable salts thereof The double bond from a to b is either in an E configuration or a Z configuration. R 1 However, hydrogen;

[0051] [ka] (R a and R b However, these, together with the carbon they bond to, form an unsubstituted C5-C7 cycloalkyl group);-CH2-S-(heteroaryl);-CH2-(1,3-dioxoisoindorin-2-yl);

[0052] [ka] (ortho-carbonyl);-CH2-NH-(phenyl);or

[0053] [ka] And, R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b However, hydrogen and halo are selected independently, If either X or Y is CR 5 The other is CH, or one of X and Y is CR 5 And the other is N, R 5 However, hydrogen; C1-C6-alkyl; hydroxy-C1-C6-alkyl; 1, 2 or 3 R 5a An aryl substituted by choice in the base; or 1, 2, or 3 R 5a A 5- or 6-member heteroaryl that has been optionally substituted in the base, Each R 5a However, they are independently hydrogen or halo, Here, each phenyl and heteroaryl group is independently a halogen, halo-C 1-4 Alkyl, -S-(halo-C) 1-4 Alkyl), C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, nitro, cyano, and C 1-4 It is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from the group consisting of alkoxycarbonyl groups. However, the compound

[0054] [ka] Alternatively, the present invention provides a compound of formula (IP) that is not this stereoisomer, a mixture of this stereoisomer, and / or this pharmaceutically acceptable salt, or this stereoisomer, a mixture of this stereoisomer, and / or this pharmaceutically acceptable salt.

[0055]

[0043] Embodiment 1B: The double bond from a to b is in an E configuration or a Z configuration, R 1 Is it hydrogen, or R 1 but

[0056] [ka] (R a and R b However, these together with the carbon they bond to form an unsubstituted C5-C7 cycloalkyl group.) 1 However, halogen, Halo-C 1-4 Alkyl, -S-(halo-C) 1-4 Alkyl), C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, nitro, cyano, and C 1-4 -CH2-S-(heteroaryl) is a heteroaryl in which the heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from the group consisting of alkoxycarbonyls, or R 1 Is it -CH2-(1,3-dioxoisoindorin-2-yl), or R 1 but

[0057] [ka] (ortho-carboranil) or R 1 However, halogen, Halo-C 1-4 Alkyl, -S-(halo-C) 1-4 Alkyl), C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, nitro, cyano, and C 1-4-CH2-NH-(phenyl) optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of alkoxycarbonyl, or R 1 is

[0058]

Chemical formula

[0059]

Chemical formula

[0060]

[0044] Embodiment 2: R 1 is hydrogen, -CH2-S-(heteroaryl), -CH2-(1,3-dioxo-isoindolin-2-yl),

[0061] [ka] , -CH2-NH-(phenyl) or

[0062] [ka] And, R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b However, hydrogen and halo are selected independently, If either X or Y is CR 5 The other is CH, or one of X and Y is CR 5 And the other is N, R 5 However, hydrogen; C1-C6-alkyl; hydroxy-C1-C6-alkyl; 1, 2 or 3 R 5a An aryl substituted by choice in the base; or 1, 2, or 3 R 5a A 5- or 6-member heteroaryl that has been optionally substituted in the base, Each R 5a However, they are independently hydrogen, alkyl, haloalkyl or halo, Here, each phenyl and heteroaryl group is independently a halogen, halo-C 1-4 Alkyl, -S-(halo-C) 1-4 Alkyl), C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, nitro, cyano, and C 1-4 The compounds of Embodiments 1, 1A, or 1B are provided, which are optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from the group consisting of alkoxycarbonyls. In some or any embodiments of Item 2, the phenyl and heteroaryl groups are unsubstituted.

[0063]

[0045] Embodiment 3A: One R 5a It is hydrogen, and the other R 5a The present invention provides compounds of Embodiments 1, 1B, or 2, or stereoisomers thereof, mixtures of these stereoisomers, and / or pharmaceutically acceptable salts thereof, wherein the element is independently hydrogen, alkyl, haloalkyl, or halo.

[0064]

[0046] Embodiment 3B: Two R 5a Each of these is hydrogen, and the third R 5a The present invention provides compounds of Embodiment 1, 1B, or 2, which are alkyl, haloalkyl, or halo, or stereoisomers thereof, mixtures of these stereoisomers, and / or pharmaceutically acceptable salts thereof.

[0065]

[0047] Embodiment 3C: One R 5a is hydrogen, and the other two R 5a The present invention provides compounds of Embodiments 1, 1B, or 2, or stereoisomers thereof, mixtures of these stereoisomers, and / or pharmaceutically acceptable salts thereof, wherein the element is independently alkyl, haloalkyl, or halo.

[0066]

[0048] Embodiment 3D: Two R 5a Each of these is hydrogen, and the third R 5a The present invention provides compounds of Embodiments 1, 1A, 1B, or 2, or stereoisomers thereof, mixtures of these stereoisomers, and / or pharmaceutically acceptable salts thereof, wherein the compound is a halo.

[0067]

[0049] Embodiment 3E: Two R 5a Each of these is hydrogen, and the third R 5a The present invention provides compounds of Embodiments 1, 1A, 1B, or 2, or stereoisomers thereof, mixtures of these stereoisomers, and / or pharmaceutically acceptable salts thereof, wherein the compound is a halo.

[0068]

[0050] Embodiment 4: A compound according to formula (I) is, formula (Ia):

[0069] [ka] The present invention provides a compound according to any one of Embodiments 1 to 3E, or a stereoisomer thereof, a mixture of these stereoisomers, and / or a pharmaceutically acceptable salt thereof.

[0070]

[0051] Embodiment 5: R 1 but,

[0071] [ka] The present invention provides a compound according to any one of Embodiments 1 to 4, or a stereoisomer thereof, a mixture of these stereoisomers, and / or a pharmaceutically acceptable salt thereof.

[0072]

[0052] Embodiment 6: One of X and Y is CR 5 The present invention provides a compound according to any one of Embodiments 1 to 5, wherein the other is CH, or a stereoisomer thereof, a mixture of these stereoisomers, and / or a pharmaceutically acceptable salt thereof.

[0073]

[0053] Embodiment 7: X is CR 5 The present invention provides a compound according to any one of Embodiments 1 to 6, wherein Y is CH, or a stereoisomer thereof, a mixture of these stereoisomers, and / or a pharmaceutically acceptable salt thereof.

[0074]

[0054] Embodiment 8: One of X and Y is CR 5 The present invention provides a compound according to any one of Embodiments 1 to 5, wherein the other is N, or a stereoisomer thereof, a mixture of the stereoisomers thereof, and / or a pharmaceutically acceptable salt thereof.

[0075]

[0055] Embodiment 9: X is CR 5 The present invention provides a compound according to any one of embodiments 1 to 5 and 8, wherein Y is N, or a stereoisomer thereof, a mixture of these stereoisomers, and / or a pharmaceutically acceptable salt thereof.

[0076]

[0056] Embodiment 10: Y is CR 5 The present invention provides a compound according to any one of embodiments 1 to 5 and 8, wherein X is N, or a stereoisomer thereof, a mixture of these stereoisomers, and / or a pharmaceutically acceptable salt thereof.

[0077]

[0057] Embodiment 11: R 5 However, C1-C6-alkyl; 1, 2 or 3 R 5a Phenyl group optionally substituted with a R group; or 1, 2, or 3 R groups 5a The present invention provides a compound according to any one of Embodiments 1 to 10, which is a five-membered heteroaryl optionally substituted with a group, or a stereoisomer thereof, a mixture of such stereoisomers, and / or a pharmaceutically acceptable salt thereof.

[0078]

[0058] Embodiment 12: R 5 However, 1, 2, or 3 R 5a An aryl that is optionally substituted in the base; or 1, 2, or 3 R 5a The present invention provides a compound according to any one of Embodiments 1 to 11, which is a five-membered heteroaryl optionally substituted with a group, or a stereoisomer thereof, a mixture of such stereoisomers, and / or a pharmaceutically acceptable salt thereof.

[0079]

[0059] Embodiment 13: R 5 However, 1, 2 or 3 R 5a The present invention provides a compound according to any one of Embodiments 1 to 12, wherein the phenyl group is optionally substituted with a phenyl group, or a stereoisomer thereof, a mixture of these stereoisomers, and / or a pharmaceutically acceptable salt thereof.

[0080]

[0060] Embodiment 14: R 5 However, 1, 2 or 3 R 5aThe present invention provides a compound according to any one of Embodiments 1 to 12, which is a five-membered heteroaryl optionally substituted with a group, or a stereoisomer thereof, a mixture of such stereoisomers, and / or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 However, 1, 2 or 3 R 5a The present invention provides a compound according to any one of Embodiments 1 to 12, which is a six-membered heteroaryl optionally substituted with a group, or a stereoisomer thereof, a mixture of such stereoisomers, and / or a pharmaceutically acceptable salt thereof.

[0081]

[0061] Embodiment 15: R 2a and R 2b The present invention provides a compound according to any one of Embodiments 1 to 14, or a stereoisomer thereof, a mixture of such stereoisomers, and / or a pharmaceutically acceptable salt thereof, wherein the element is independently hydrogen or fluoro.

[0082]

[0062] Embodiment 16: R 2a and R 2b The present invention provides a compound according to any one of Embodiments 1 to 14, or a stereoisomer thereof, a mixture of these stereoisomers, and / or a pharmaceutically acceptable salt thereof, wherein is independently a halo.

[0083]

[0063] Embodiment 17:R 2a and R 2b The present invention provides a compound according to any one of Embodiments 1 to 14, wherein each of the elements is fluoro, or a stereoisomer thereof, a mixture of the stereoisomers thereof, and / or a pharmaceutically acceptable salt thereof.

[0084]

[0064] Embodiment 18: R 2a and R 2b The present invention provides a compound according to any one of Embodiments 1 to 14, wherein each of the elements is hydrogen, or a stereoisomer thereof, a mixture of the stereoisomers thereof, and / or a pharmaceutically acceptable salt thereof.

[0085]

[0065] Embodiment 19:R 3 , R3a , R 3b , R 4 , R 4a and R 4b The present invention provides a compound according to any one of Embodiments 1 to 18, wherein each of the elements is hydrogen, or a stereoisomer thereof, a mixture of the stereoisomers thereof, and / or a pharmaceutically acceptable salt thereof.

[0086]

[0066] Embodiment 20:R 3 , R 3a , R 3b , R 4 , R 4a and R 4b The present invention provides a compound according to any one of Embodiments 1 to 18, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof, wherein each of the elements is independently a halo.

[0087]

[0067] Embodiment 21:R 3 , R 3a , R 3b , R 4 , R 4a and R 4b The present invention provides a compound according to any one of Embodiments 1 to 18, wherein each of the elements is fluoro, or a stereoisomer thereof, a mixture of the stereoisomers thereof, and / or a pharmaceutically acceptable salt thereof.

[0088]

[0068] Embodiment 22: Provides a compound according to any one of Embodiments 1 to 21, or a stereoisomer thereof, a mixture of these stereoisomers, and / or a pharmaceutically acceptable salt thereof, wherein the bond from a to b is in the E configuration.

[0089]

[0069] Embodiment 22a:R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b At least one of them is a halo (or, in some embodiments, a fluoro), or R 2a , R 2b , R3 , R 3a , R 3b , R 4 , R 4a and R 4b At least two of them are independently halo (or fluoro in some embodiments), or R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b At least three of these are independently halo (or fluoro in some embodiments), or R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b At least four of them are independently halo (or fluoro in some embodiments), or R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b At least five of these are independently halo (or fluoro in some embodiments), or R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b The present invention provides a compound according to any one of Embodiments 1 to 14, wherein at least six of are independently halos (and in some embodiments, fluoros). In one embodiment, R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b One of them is a halo (or fluoro in some embodiments), or R 2a , R 2b , R 3 , R 3a, R 3b , R 4 , R 4a and R 4b Two of these are independently halo (or fluoro in some embodiments), or R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b Three of these are independently halo (or fluoro in some embodiments), or R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b Four of these are independently halo (or fluoro in some embodiments), or R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b Five of these are independently halo (or fluoro in some embodiments), or R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b The present invention provides a compound according to any one of items 1 to 13, wherein six of the elements are independently halos (or fluoros in some embodiments).

[0090]

[0070] Embodiment 23: Provided are the compounds of Embodiment 1, or stereoisomers thereof, mixtures of stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, selected from the group consisting of the following:

[0091] [Table 1-1]

[0092] [Table 1-2]

[0093] [Table 1-3]

[0094] [Table 1-4]

[0095] [Table 1-5]

[0096] [Table 1-6]

[0097] [Table 1-7]

[0098]

[0071] Embodiment 24: A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of Embodiments 1 to 23 or a stereoisomer thereof, a mixture of the stereoisomers, and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0099]

[0072] Embodiment 25: A method for inhibiting SREBP in a subject is provided, comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 23, or a therapeutically effective amount of a pharmaceutical composition described in Embodiment 24, to a subject in need thereof.

[0100]

[0073] Embodiment 26: A method for treating metabolic diseases, liver diseases, obesity, diabetes, cardiovascular diseases, hyperlipidemia, or cancer in a subject, comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 23, or a therapeutically effective amount of a pharmaceutical composition described in Embodiment 24, to a subject in need thereof.

[0101]

[0074] Embodiment 27: Provides the use of a compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 23, or a pharmaceutical composition described in Embodiment 24, in the manufacture of a pharmaceutical for the treatment of metabolic diseases, liver diseases, obesity, diabetes, cardiovascular diseases, hyperlipidemia, or cancer.

[0102]

[0075] Embodiment 28: Provides a compound according to any one of Embodiments 1 to 23 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 24, for use in the treatment of metabolic diseases, liver diseases, obesity, diabetes, cardiovascular diseases, hyperlipidemia, or cancer.

[0103]

[0076] Embodiment 29: Provides the method or use of any one of Embodiments 26-28, wherein the cancer is selected from prostate cancer, liver cancer, bile duct cancer, bone cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, hematological cancer (including lymphoma and leukemia), kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, head and neck squamous cell carcinoma, squamous cell carcinoma, cutaneous melanoma and uveal melanoma. In one embodiment of Embodiment 30, provides the method or use of any one of Embodiments 26-28, wherein the cancer is selected from prostate cancer, liver cancer, breast cancer, cutaneous melanoma and uveal melanoma.

[0104]

[0077] Embodiment 30: Provides the method of Embodiment 26 or the use described in Embodiments 27 and 28, wherein the disease is obesity, non-alcoholic steatohepatitis (NASH), fatty liver disease, or cancer.

[0105]

[0078] Embodiment 31: In any one of embodiments 26, 27, and 28, the disease is hypertriglyceridemia. In any one of embodiments 26, 27, and 28, the disease is hypercholesterolemia.

[0106]

[0079] Embodiment 32: Provides a compound according to any one of Embodiments 1 to 23 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 24, for therapeutic use.

[0107]

[0080] The term "pharmaceutically acceptable salt" as used herein refers to any salt that is known in the art and does not have excessive toxicity. In particular, a pharmaceutically acceptable salt may include an inorganic acid, an organic acid, an inorganic base, or a salt having an organic base. Examples of such inorganic acids include hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. Examples of such organic acids include acetic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid, citric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, malic acid, succinic acid, and tartaric acid. Examples of such inorganic bases include lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc. Examples of such organic bases include arginine and lysine. In some or any embodiment, a pharmaceutically acceptable salt is a salt having an inorganic acid, in particular a hydrochloride salt.

[0108]

[0081] The pharmaceutically acceptable carriers used herein include a variety of conventional organic or inorganic carrier materials, and in some embodiments, substances commonly used in the art in the preparation of solid formulations, such as excipients, disintegrants, binders, flow promoters and lubricants, and substances commonly used in the art in the preparation of liquid formulations, such as solvents, solubilizers, suspending agents, isotonic agents, buffers and analgesics. Additives commonly used in the art, such as preservatives, antioxidants, colorants and sweeteners, may be added to the pharmaceutical compositions disclosed herein as needed.

[0109]

[0082] The compound of formula (I) can be administered orally or parenterally in a therapeutically effective dose to mammals, such as mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, monkeys, and humans. The therapeutically effective dose of the compound of formula (I) may vary depending on the subject, disease, dosage form, route of administration, etc., but the therapeutically effective dose of the compound of formula (I) generally ranges from about 0.01 mg to about 0.1 mg to about 1 g to about 10 g per day, and can be administered in one or more divided doses.

[0110]

[0083] To avoid misunderstanding, it is confirmed throughout the above summary and its entirety that, with respect to the various characteristics of compounds, methods, uses, and compositions, all combinations of general priorities and choices for those characteristics can be proposed in the usual manner, as long as they are combinatorial, interchangeable, and discussed in the same context.

[0111] Preparation of the compounds disclosed herein

[0084] Methods for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof are illustrated below, but are not limited to these examples. For example, the following scheme illustrates an exemplary preparation method for the exemplary compounds disclosed herein. The compounds obtained in each step may be isolated or purified by known methods, including distillation, recrystallization, column chromatography, etc., as needed, or they may be used in the next step without isolation or purification.

[0112]

[0085] 1 H and 13 ¹³C NMR spectra were recorded using JEOL AL-400NMR (400 MHz) and ECP-600NMR (600 MHz) spectrometers. 1 The 1H NMR spectrum was referenced using (CH3)4Si (δ 0.00 ppm) as an internal standard. 13¹³C NMR spectra were referenced using deuterated solvents (δ 77.0 ppm for CDCl3 and 49.3 ppm for CD3OD). IR spectra were recorded using a JASCO FT-IR-800 Fourier transform infrared spectrometer. High-resolution mass spectra were obtained by electrospray ionization (ESI) using a SHIMADZU LCMS-IT-TOF mass spectrometer. Optical rotation was measured using a JASCO DIP-370 digital polarimeter. Column chromatography was performed on silica gel 60N (Kanto Chemical Co., Inc., 100–210 μm) or silica gel 60 (Merck, 0.040–0.063 mm). Preparative thin-layer chromatography was performed on silica gel 60F254 (Merck, 0.5 mm). All experiments were performed under anhydrous conditions and in an argon atmosphere unless otherwise specified.

[0113]

[0086] The compound of formula (I) can be prepared using the following general scheme. General Scheme 1

[0114] [ka] General Scheme 2

[0115] [ka] Scheme 3

[0116] [ka] General Scheme 4

[0117] [ka] General Scheme 5

[0118] [ka] [Examples]

[0119] Example of synthesis Example 1 (1R,3aR,7aR)-7a-methyl-1-{(2R)-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}octahydro-4H-inden-4-one(6)

[0120] [ka]

[0121]

[0087] Sigueiro, R.; Otero, R.; Gonzalez-Berdullas, P.; Loureiro, J.; Mourino, A.; Maestro, MAA new approach to 19-nor-A-ring phosphine oxide for the convergent synthesis of 19-nor-calcitriol.J.Steroid Please refer to Biochem.Mol.Biol.2017, 173, 86-88.

[0122] (6R)-2-methyl-6-[(1R,3aS,7aR)-7a-methyl-4-methyleneoctahydro-1H-inden-1-yl]heptan-2-ol (10KK-023)

[0123] [ka]

[0124]

[0088] To a suspension of methyltriphenylphosphonium bromide (90.5 mg, 0.253 mmol) in THF (2 mL), n-BuLi (146 μL, 1.65 M in hexane, 0.241 mmol) was added at -78°C, and the mixture was stirred at the same temperature for 15 minutes and then at 0°C for 20 minutes. To the mixture, 8-ketoCD ring (6) (50.0 mg, 0.127 mmol) in THF (2 mL) was added, and the mixture was stirred at the same temperature for 1 hour. After quenching the reaction with H2O and saturated aqueous solution NH4Cl at 0°C, the mixture was extracted twice with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The resulting residue was used in the next reaction without further purification.

[0125]

[0089] Tetrabutylammonium fluoride (381 μL, 1 M in THF, 0.381 mmol) was added to the solution of the crude residue in THF (5 mL). The mixture was stirred at room temperature for 24 hours. After quenching the reaction at room temperature with H2O and saturated aqueous solution NH4Cl, the mixture was extracted three times with toluene, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:toluene = 5:1) to obtain 10KK-023 as a colorless oil (9.6 mg, 27%, 2 steps).

[0126]

[0090] 10 KK-023:[α] D 27 +63.5 (c 0.754, CHCl3); IR (undiluted) 3360, 1649, 1469, 1378, 1148, 885 cm -1 ; 1 H NMR(400MHz,CDCl3)δ0.56(s,3H), 0.94(d,J=6.4Hz,3H), 1.02~1.09(m,1H), 1.21~1.64(m,1H) , 1.84~2.01(m,4H), 2.26(dd,J=4.1,13.3Hz,1H), 4.46(d,J=1.8Hz,1H), 4.72(d,J=1.8Hz,1H); 13C NMR(100MHz,CDCl3)δ11.7, 18.8, 20.8, 22.2, 23.7, 27.7, 29.2, 29.4, 35.4, 36.1, 36.4, 40.2, 44.4, 45.1, 55.3, 56.3, 71.1, 105.0, 149.6;HRMS(ESI + )C 19 H 33 [M-OH] + The calculated value is 261.2577, and the measured value is 261.2577.

[0127] Example 2 2-[(1R,3aS,7aR,E)-7a-methyl-1-{(2R)-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}octahydro-4H-indene-4-ylidene]ethane-1-ol(8)

[0128] [ka]

[0129]

[0091] Ono, K.; Yoshida, A.; Saito, N.; Fujishima, T.; Honzawa, S.; Suhara, Y.; Kishimoto, S.; Sugiura, T.; Waku, K.; Takayama, H.; Kittaka, A. Please refer to potency in induction of differentiation on HL-60cells.J.Org.Chem.2003,68,7407~7415.

[0130] (6R)-6-[(1R,3aS,7aR,E)-4-(2-hydroxyethylidene)-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(11KK-025)

[0131] [ka]

[0132]

[0092] Asano, L.; Watanabe, M.; Ryoden, Y.; Usuda, K.; Yamaguchi, T.; Khambu, B.; Takashima, M.; Sato, S.; Sakai, J.; Nagasawa, K.; Uesugi, M. Vitamin D metabolite,25-hydroxyvitamin D, regulates lipid metabolism by inducing degradation of Please refer to SREBP / SCAP.Cell Chem.Biol.2017,24,207~217.

[0133] Example 3 (6R)-6-{(1R,3aS,7aR,E)-4-[2-(benzo[d]thiazole-2-ylthio)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-methylheptan-2-ol(15KK-026)

[0134] [ka]

[0135]

[0093] To a solution of 2-mercaptobenzothiazole (29.7 mg, 0.178 mmol), Ph3P (29.9 mg, 0.114 mmol), and 8 (30.7 mg, 0.073 mmol) in CH2Cl2 (10 mL), diisopropyl azodicarboxylate (60 μL, 1.9 M in toluene, 0.114 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 2 hours. After quenching the reaction with H2O at 0°C, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was roughly purified on silica gel by flash column chromatography (hexane:siRNA = 10:1) to obtain crude sulfide.

[0136]

[0094] Tetrabutylammonium fluoride (111 μL, 1 M in THF, 0.111 mmol) was added to the above crude sulfide solution in THF (5 mL). The mixture was stirred at room temperature for 21 hours. After quenching the reaction at room temperature with H2O and saturated aqueous solution NH4Cl, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:ethyl acetate = 5:1) to obtain 15KK-026 as a colorless oil (16.1 mg, 50%, 2 steps).

[0137]

[0095] 15 KK-026:[α] D 27 +77.3(c 1.24,CHCl3); IR (undiluted) 3390, 1457, 1427, 1377, 1238, 996, 756 cm -1 ; 1 H NMR (400MHz, CDCl3) δ0.49(s,3H), 0.93(d,J=6.4Hz,3H), 1.00~1.08(m,1H), 1.21~1.7 3(m,21H), 1.81~2.00(m,3H), 1.81~2.00(m,3H), 2.74~2.78(m,1H), 4.02(dd,J=7.1,1 2.4Hz,1H), 4.13(dd,J=7.8,12.8Hz,1H), 5.20(t,J=8.0Hz,1H), 7.28(td,J=1.4,8.2H) z,1H), 7.41(td,J=1.4,7.8Hz,1H), 7.75(dd,J=1.4,7.8Hz,1H), 7.86(d,J=7.8Hz,1H); 13 C NMR (100MHz, CDCl3) δ11.7, 18.8, 20.8, 22.1, 23.5, 27.6, 28.8, 29.2, 29.3, 31.3, 36.0, 36.3, 40.3, 44 .4,45.6,55.7,56.4,71.1,113.1,120.9,121.4,124.1,126.0,135.2,146.1,153.3,167.2;HRMS(ESI + )C 27 H 40 NOS2[M+H] + The calculated value is 458.2546, and the measured value is 458.2578.

[0138] Example 4 2-(2-{(1R,3aS,7aR,E)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-4H-indene-4-ylidene}ethyl)isoindoline-1,3-dione (16KK-027)

[0139] [ka]

[0140]

[0096] To a solution of phthalimide (69.6 mg, 0.473 mmol), Ph3P (29.9 mg, 0.473 mmol), and 8 (100.0 mg, 0.237 mmol) in THF (5 mL), diisopropyl azodicarboxylate (249 μL, 1.9 M in toluene, 0.473 mmol) was added at 0°C, and the mixture was stirred at room temperature for 10 minutes. After quenching the reaction with H2O, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was roughly purified on silica gel by flash column chromatography (hexane:ethyl acetate = 6:1) to obtain the crude phthalimide product.

[0141]

[0097] p-toluenesulfonic acid monohydrate (113.1 mg, 0.595 mmol) was added to the above crude phthalimide solution in MeOH (10 mL). The mixture was stirred at room temperature under air for 30 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (ethyl acetate only) to obtain 16KK-027 as a colorless oil (57.8 mg, 56%, 2 steps).

[0142]

[0098] 16 KK-027:[α] D 27+44.7 (c 0.98, CHCl3); IR (undiluted) 3394, 1715, 1394, 1088, 941, 724 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.49(s,3H), 0.92(d,J=6.6Hz,3H), 0.99~1.05(m,1H), 1.17~1.64(m,19H), 1.66~1.71(m,2H), 1.80~1.86(m,1H), 1.92(t ,J=9.6Hz,1H), 1.92(dt,J=3.0,11.4Hz,1H), 2.91~2.95(m,1H), 4.27~4 .37(m,2H), 5.20(t,J=7.2Hz,1H), 7.67~7.70(m,H), 7.81~7.84(m,2H); 13 C NMR(100MHz,CDCl3)δ11.8, 18.8, 20.8, 22.1, 23.4, 27.6, 28.8, 29.2, 29.3, 35.1, 36.0, 36. 3,40.3,44.4,45.4,55.6,56.4,71.1,113.7,123.1,132.3,133.7,144.5,168.1;HRMS(ESI + )C 28 H 39 NO3Na[M+Na] + The calculated value is 460.2822, and the measured value is 460.2850.

[0143] Example 5 2-({2-[(1R,3aS,7aR,E)-7a-methyl-1-{(2R)-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}octahydro-4H-indene-4-ylidene]ethyl}sulfonyl)benzo[d]thiazole(A)

[0144] [ka]

[0145] 3-Deoxy-25-hydroxy-19-norvitamin D3 (14KK-024)

[0146] [ka]

[0147]

[0099] LHMDS (332 μL, 1.0 M THF solution, 0.332 mmol) was added to a solution of CD ring sulfone A (99.1 mg, 0.164 mmol) in THF (2 mL) at -78°C. After stirring for 30 minutes, a solution of cyclohexanone (48.8 mg, 50 μL, 0.497 mmol) was added to the reaction mixture, and the mixture was stirred at -78°C for 30 minutes. After quenching the reaction with H2O at the same temperature, the mixture was extracted three times with ELISA, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane only) to obtain a crude coupling product (41.5 mg), which was used in the next reaction without further purification. Tetrabutylammonium fluoride (497 μL, 1 M THF solution, 0.497 mmol) was added to the solution of the crude coupling product (41.5 mg) in THF (5 mL), and the mixture was stirred at room temperature for 24 hours. After quenching the reaction with H2O and saturated aqueous solution NH4Cl at room temperature, the mixture was extracted three times with HCl, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:HCl = 5:1) to obtain 14KK-024 as a colorless oil (30.9 mg, 50%, 2 steps).

[0148]

[0100] 14 KK-024:[α] D 27 +64.3(c 2.06,CHCl3); IR (undiluted) 3368, 1445, 1376, 1215, 1148, 863, 759 cm -1 ; 1H NMR(600MHz,CDCl3)δ0.55(s,3H), 0.94(d,J=7.2Hz,3H), 1.03~1.08(m,1H), 1.20~1.67(m,23H), 1.86~1.92(m,1H), 1.9 7~2.01(m,2H), 2.13~2.24(m,3H), 2.33~2.35(m,1H), 2.78~2.82(m,1H), 5.84(d,J=12.0Hz,1H), 6.06(d,J=12.0Hz,1H); 13 C NMR (150MHz, CDCl3) δ12.1, 198.8, 20.8, 22.3, 23.4, 26.9, 27.6, 27.7, 28.6, 28.7, 28.9, 29.2, 2 9.3,36.1,36.4,37.6,40.6,44.4,45.6,56.3,56.5,71.1,115.7,117.3,140.4,140.6;HRMS(ESI - )C 26 H 43 O[MH] - The calculated value is 371.3308, and the measured value is 371.3310.

[0149] Example 6 (6R)-2-methyl-6-[(1R,3aS,7aR,E)-7a-methyl-4-(propa-2-in-1-ylidene)octahydro-1H-inden-1-yl]heptan-2-ol (13KK-030)

[0150] [ka]

[0151]

[0101] To a solution of 8 (522.4 mg, 1.24 mmol) in CH2Cl2 (10 mL), 4-methylmorpholine N-oxide (290.5 mg, 2.48 mmol) and a 4 Å molecular sieve (100 mg) were added and cooled to 0°C. TPAP (130.3 mg, 0.37 mmol) was added to the mixture and stirred at 0°C for 1 hour. The reaction product was diluted with an excess of Et2O. The mixture was filtered through Celite and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:siRNA = 10:1) to obtain crude aldehyde (439.2 mg), which was used in the next reaction without further purification. To a solution of trimethylsilyldiazomethane (71 μL, 2.0 M in diethyl ether, 0.143 mmol) in THF (2 mL), n-BuLi (82 μL, 1.65 M in hexane, 0.135 mmol) was added at -78°C and the mixture was stirred at the same temperature for 15 minutes. To this mixture, the above crude CD ring aldehyde (30 mg) in THF (2 mL) was added and the mixture was stirred at the same temperature for 30 minutes. After quenching the reaction with H2O and saturated aqueous solution NH4Cl at -78°C, the mixture was extracted twice with ethylethanol, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:ethylethanol = 50:1) to obtain crude CD ring alkyne (22.2 mg).

[0152]

[0102] p-toluenesulfonic acid monohydrate (27.0 mg, 0.142 mmol) was added to a solution of crude CD ring alkyne (30.0 mg) in MeOH (3 mL). The mixture was stirred at room temperature under air for 10 minutes. After quenching the reaction with H2O and saturated aqueous NaHCO3 at room temperature, the mixture was extracted three times with toluene, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:toluene = 4:1) to obtain 13KK-030 as a colorless oil (19.7 mg, 58%, 3 steps).

[0153]

[0103] 13 KK-030:[α] D 27+147.1(c 1.52,CHCl3); IR (undiluted) 3381, 3310, 2360, 2341, 1627, 1470, 1378, 1214, 1149, 911, 735 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.55(s,3H), 0.93(d,J=6.0Hz,3H), 1.02~1.08(m,1H), 1.18~1.63(m,17H), 1.67~1. 72(m,1H), 1.75~1.80(m,1H), 1.84~1.93(m,1H), 2.00~2.04(m,1H), 2.96~2.99(m,2H), 5.05~5.06(m,1H); 13 C NMR (150MHz, CDCl3) δ11.9, 18.7, 20.8, 21.9, 23.3, 27.6, 29.2, 29.4, 31.4, 36. 0, 36.3, 40.0, 44.4, 46.3, 55.7, 56.4, 71.1, 79.3, 81.6, 99.3, 157.9;HRMS(ESI + )C 21 H 32 [M-OH] + The calculated value is 285.2577, and the measured value is 285.2571.

[0154] Example 7 (R)-6-[(1R,3aS,7aR,E)-4-(ortho-carboranylmethylidene)-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol (17KK-031)

[0155] [ka]

[0156]

[0104] To a solution of 8 (522.4 mg, 1.24 mmol) in CH2Cl2 (10 mL), 4-methylmorpholine N-oxide (290.5 mg, 2.48 mmol) and a 4 Å molecular sieve (100 mg) were added and cooled to 0°C. TPAP (130.3 mg, 0.37 mmol) was added to the mixture and stirred at 0°C for 1 hour. The reaction product was diluted with an excess of Et2O. The mixture was filtered through Celite and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:siRNA = 10:1) to obtain crude aldehyde (439.2 mg), which was used in the next reaction without further purification. To a solution of trimethylsilyldiazomethane (71 μL, 2.0 M in diethyl ether, 0.143 mmol) in THF (2 mL), n-BuLi (82 μL, 1.65 M in hexane, 0.135 mmol) was added at -78°C and the mixture was stirred at the same temperature for 15 minutes. To this mixture, the above crude CD ring aldehyde (30 mg) in THF (2 mL) was added and the mixture was stirred at the same temperature for 30 minutes. After quenching the reaction with H2O and saturated aqueous solution NH4Cl at -78°C, the mixture was extracted twice with ethylethanol, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:ethylethanol = 50:1) to obtain crude CD ring alkyne (22.2 mg).

[0157]

[0105] A solution of N,N-dimethylaniline (93.2 mg, 97 μL, 0.769 mmol) and the above crude CD ring alkyne (51.1 mg) in toluene (5 mL) is prepared by adding B 10 H 14 (43.3 mg, 0.356 mmol) was added at room temperature, and the mixture was stirred at 100°C for 15 minutes. The mixture was concentrated under vacuum, and the resulting residue was purified on silica gel by flash column chromatography (hexane only - hexane: Depositphotos = 20:1), and then purified on silica gel by flash column chromatography (hexane: Depositphotos = 100:1) to obtain the crude product (20.0 mg).

[0158]

[0106] p-toluenesulfonic acid monohydrate (14.1 mg, 0.074 mmol) was added to the solution of the crude product in MeOH (3 mL). The mixture was stirred at room temperature under air for 10 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with toluene, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:toluene = 5:1) to obtain 17KK-031 as a colorless oil (13.1 mg, 16%, 4 steps).

[0159]

[0107] 17 KK-031:[α] D 27 +117.4(c 1.01,CHCl3); IR (undiluted) 3463, 2602, 2565, 1467, 1440, 1376, 1208, 1128, 1072, 1020, 931, 721 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.50(s,3H), 0.55~0.62(m,1H), 0.92~2.82(m,38H), 3.20(d,J=13.2Hz,3H), 3.64(brs,1H), 5.09(s,1H); 13 C NMR (150MHz, CDCl3) δ11.7, 18.8, 20.7, 22.1, 23.4, 27.3, 29.0, 29.4, 35.9, 3 6.3, 40.0, 44.3, 46.8, 56.3, 56.6, 62.8, 71.0, 74.0, 114.9, 150.3;HRMS(ESI - )C 21 H 43 OB 10 [MH] - The calculated value is 421.4282, and the measured value is 421.4321.

[0160] Example 8 (6R)-6-{(1R,3aS,7aR,E)-4-[2-(decylthio)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-methylheptan-2-ol(33KK-032)

[0161] [ka]

[0162]

[0108] In a solution of 11KK-025 (96.5 mg, 0.312 mmol) and pyridine (153.5 mg, 157 μL, 1.94 mmol) in CCl4 (15 mL) and CH2Cl2 (15 mL), tri-n-butylphosphine (263.0 mg, 320 μL, 1.30 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 15 minutes. After diluting the reaction product with hexane, the mixture was filtered and concentrated. The resulting residue was roughly purified on silica gel by flash column chromatography (hexane:Â=5:1) to obtain crude chloride. This crude allyl chloride was used in the next reaction without further purification. To a solution of the above crude allyl chloride, K2CO3 (61.6 mg, 0.446 mmol), and KI (37.0 mg, 0.223 mmol) in DMF (4 mL) and CH2Cl2 (15 mL), decanethiol (388.8 mg, 423 μL, 2.23 mmol) was added at room temperature under air, and the mixture was stirred at the same temperature for 190 minutes. After quenching the reaction with H2O and saturated aqueous solution NH4Cl, the mixture was extracted three times with toluene, washed with saturated brine, and dried on Na2SO4. The residue was purified on silica gel by flash column chromatography (hexane:toluene = 5:1) to obtain 33KK-032 as a colorless oil (80.8 mg, 78%, 2 steps).

[0163]

[0109] 33 KK-032:[α] D 27 +89.6(c 2.19,CHCl3); IR (undiluted) 3370, 1467, 1377, 1217, 1148 cm -1 ; 1H NMR(600MHz,CDCl3)δ0.56(s,3H), 0.88(t,J=7.2Hz,3H), 0.94(d,J=7.2Hz,3H), 1.02~1.08(m,1H), 1.21~1.68(m,37H), 1.83~2.01 (m,3H), 2.45(t,J=7.8Hz,3H), 2.572.61(m,1H), 3.15(dd,J=7.8,13.2Hz,1H), 3.24(dd,J=8.4,13.2Hz,1H), 5.02(t,J=8.4Hz,1H); 13 C NMR (150MHz, CDCl3) δ11.8, 14.1, 18.8, 20.8, 22.2, 22.7, 23.5, 27.6, 28.5, 28.6, 29.0, 29.2, 29.3, 29. 3,29.5,29.5,29.7,31.0,31.9,36.1,36.4,40.4,44.4,45.1,55.7,56.5,71.1,116.4,142.3;HRMS(ESI + )C 30 H 56 O3SNa[M+Na] + The calculated value is 487.3944, and the measured value is 487.3965.

[0164] Examples 9 and 10 (6R)-6-{(1R,3aS,7aR,E)-4-[2-(2H-tetrazole-2-yl)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-methylheptan-2-ol(22KK-029)

[0165] [ka] (6R)-6-{(1R,3aS,7aR,E)-4-[2-(1H-tetrazole-1-yl)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-methylheptan-2-ol(21KK-028)

[0166] [ka]

[0167]

[0110] To a solution of 1H-tetrazole (45.4 mg, 0.649 mmol), Ph3P (206.4 mg, 9.72 mmol), and 11KK-025 (100 mg, 0.324 mmol) in THF (5 mL), diisopropyl azodicarboxylate (512 μL, 1.9 M in toluene, 9.72 mmol) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. After quenching the reaction with H2O at 0°C, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:ethyl acetate = 2: 1-ethyl acetate only) to obtain the low-polarity product 22KK-029 (43.2 mg, 37%) and the high-polarity product 21KK-028 (38.8 mg, 33%) as colorless oils, respectively.

[0168]

[0111] 22 KK-029:[α] D 27 +53.6 (c 1.31, CHCl3); IR (undiluted) 3427, 1468, 1454, 1376, 1282, 1027, 911, 736 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.50(s,3H), 0.92(d,J=6.6Hz,3H), 1.01~1.06(m,1H), 1.20~2.02(m,24H), 2.77~2.80(m,1H), 5.23~5.32(m,3H), 8.47(s,1H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.8, 20.8, 22.0, 23.3, 27.5, 28.0, 29.2, 29.4, 36.0 , 36.3, 40.1, 44.3, 45.8, 50.1, 55.6, 56.4, 71.0, 111.4, 148.1, 152.8;HRMS(ESI + )C 21 H 36 N4ONa[M+Na] + The calculated value is 383.2781, and the measured value is 383.2793.

[0169]

[0112] 21 KK-028:[α] D 27+64.5 (c 0.62, CHCl3); IR (undiluted) 3400, 1468, 1445, 1376, 1162, 1101, 912, 734, 661 cm -1 ; 1 H NMR (400MHz, CDCl3) δ0.55(s,3H), 0.94(d,J=6.4Hz,3H), 1.01~1.09(m,1H), 1.20~1.61(m,18H), 1.72~1.82(m,2H) ), 1.86~1.94(m,1H), 2.01~2.08(m,3H), 2.65~2.70(m,1H), 5.03~5.12(m,1H), 5.23(t,J=7.3Hz,1H), 8.53(s,1H); 13 C NMR (100MHz, CDCl3) δ11.9, 18.8, 20.8, 22.1, 23.3, 27.5, 28.9, 29.2, 29.4, 36.0 , 36.3, 40.0, 44.3, 45.3, 45.8, 55.6, 56.4, 71.1, 110.9, 151.8, 149.4;HRMS(ESI + )C 21 H 36 N4ONa[M+Na] + The calculated value is 383.2781, and the measured value is 383.2789.

[0170] Examples 11 and 12 (6R)-2-methyl-6-{(1R,3aS,7aR,E)-7a-methyl-4-[2-(5-phenyl-2H-tetrazole-2-yl)ethylidene]octahydro-1H-inden-1-yl}heptan-2-ol(23KK-039)

[0171] [ka] (6R)-2-methyl-6-{(1R,3aS,7aR,E)-7a-methyl-4-[2-(5-phenyl-1H-tetrazole-1-yl)ethylidene]octahydro-1H-inden-1-yl}heptan-2-ol(24KK-045)

[0172] [ka]

[0113] Diisopropyl azodicarboxylate (1.12 mL, 1.9 M in toluene, 2.13 mmol) was added at 0°C to a solution of 5-phenyl-1H-tetrazole (311.3 mg, 2.13 mmol), Ph3P (372.5 mg, 1.42 mmol), and 8 (305.3 mg, 0.722 mmol) in THF (10 mL), and the mixture was stirred at the same temperature for 3 hours. After quenching the reaction with H2O at 0°C, the mixture was extracted three times with RINKAN, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was roughly purified on silica gel by flash column chromatography (hexane:RINKAN = 3:1) to obtain crude products (low-polarity and high-polarity products).

[0173]

[0114] p-toluenesulfonic acid monohydrate (285.3 mg, 1.50 mmol) was added to the solution of the above low-polarity crude product in MeOH (10 mL). The mixture was stirred at room temperature under air for 40 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with toluene, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:toluene = 1:1) to obtain 23KK-039 (187.8 mg, 60%) as a colorless oil.

[0174]

[0115] 23 KK-039:[α] D 27 +41.2(c 1.33,CHCl3); IR (undiluted) 3419, 1467, 1450, 1378, 1216, 761, 694 cm -1 ; 1 H NMR (400MHz, CDCl3) δ0.54(s,3H), 0.94(d,J=6.4Hz,3H), 1.00~1.10(m,1H), 1.19~2.0 5(m,24H), 2.83~2.86(m,1H), 5.29~5.36(m,3H), 7.43~7.52(m,3H), 8.12~8.15(m,2H); 13C NMR (100MHz, CDCl3) δ11.8, 18.8, 20.8, 22.0, 23.4, 27.6, 29.1, 29.2, 29.4, 36.0, 36.3, 40.2, 4 4.4,45.9,50.2,55.7,56.5,71.1,111.6,126.8,127.6,128.8,130.1,148.0,165.0;HRMS(ESI + )C 27 H 40 N4ONa[M+Na] + The calculated value is 459.3094, and the measured value is 459.3079.

[0175]

[0116] p-toluenesulfonic acid monohydrate (190.2 mg, 1.0 mmol) was added to the solution of the above highly polar crude product in MeOH (10 mL). The mixture was stirred at room temperature under air for 40 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with siRNA, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 1:1) to obtain 24KK-045 (48.4 mg, 15%) as a colorless oil.

[0176]

[0117] 24 KK-045:[α] D 27 +67.2(c 0.09,CHCl3); IR (undiluted) 3425, 1471, 1377, 1219, 758, 698 cm -1 ; 1H NMR (400MHz, CDCl3) δ0.46(s,3H), 0.92(d,J=6.4Hz,3H), 1.00~1.07(m,1H), 1.21~1.72(m,21H) , 1.82~2.01(m,3H), 2.51~2.56(m,1H), 5.07~5.17(m,3H), 7.52~7.60(m,3H), 7.68~7.71(m,2H); 13C NMR (100MHz, CDCl3) δ11.8, 18.8, 20.8, 22.1, 23.1, 27.5, 28.9, 29.2, 29.4, 36.0, 36.3, 40.0, 4 4.3,45.6,45.7,55.52,56.4,71.1,112.9,124.2,128.8,129.1,131.1,146.5,154.1;HRMS(ESI + )C 27 H 40 N4ONa[M+Na] + The calculated value is 459.3094, and the measured value is 459.3093.

[0177] Example 13 (6R)-6-{(1R,3aS,7aR,E)-4-[2-(decylamino)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}2-methylheptan-2-ol(32KK-040)

[0178] [ka]

[0179]

[0118] PDC (222.5 mg, 0.591 mmol) was added to a solution of 8 (100.0 mg, 0.237 mmol) in CH2Cl2 (4 mL) at room temperature, and the mixture was stirred at the same temperature under air for 4 hours. The solution was diluted with Et2O and concentrated by filtration through a Celite pad. Anhydrous MgSO4 (1 g) was added to a solution of the crude aldehyde obtained above and 1-aminodecane (184.6 mg, 233 μL, 1.19 mmol) in CH2Cl2 (5 mL) at room temperature under air. The mixture was stirred for 1 hour and refluxed for 1 hour. After quenching the reaction with H2O, the mixture was extracted three times with ELISA, dried over Na2SO4, filtered and concentrated. The obtained crude imine was used in the next reaction without further purification. NaBH4 (26.9 mg, 0.711 mmol) was added to a solution of the crude imine in MeOH (10 mL) at 0°C. The mixture was stirred at the same temperature under air for 45 minutes. After quenching the reaction with H2O and saturated aqueous solution NH4Cl, the mixture was extracted three times with ELISA, dried over Na2SO4, filtered, and concentrated. The resulting crude amine was used in the next reaction without further purification.

[0180]

[0119] p-toluenesulfonic acid monohydrate (225.4 mg, 1.19 mmol) was added to the above crude amine solution in MeOH (10 mL). The mixture was stirred at room temperature under air for 20 minutes. The reaction was quenched with 3 M NaOH aqueous solution and stirred for 15 minutes. The mixture was extracted four times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (siRNA:MeOH = 7:1, 1% Et3N) to obtain 32KK-040 as a colorless oil (64.5 mg, 61%, 4 steps).

[0181]

[0120] 32 KK-040:[α] D 27 +54.0 (c 1.38, CHCl3); IR (undiluted) 3358, 1467, 1215 cm -1 ; 1H NMR (600MHz, CDCl3) δ0.53(s,3H), 0.86(t,J=6.9Hz,3H), 0.92(d,J=6.6Hz,3H), 1.06~1.6 5(m,39H), 1.80~1.98(m,3H), 2.53~2.61(m,3H), 3.23~3.29(m,2H), 5.02(t,J=6.9Hz,1H); 13 C NMR (150MHz, CDCl3) δ11.8, 14.1, 18.8, 20.8, 22.2, 22.6, 23.4, 27.4, 27.6, 28.7, 29.1, 29.3, 29.3, 29. 5、29.5、29.9、31.9、36.1、36.4、40.4、44.4、45.1、46.2、49.3、55.6、56.5、70.9、118.4、141.6;HRMS(ESI + )C 30 H 58 ON[M+H] + The calculated value is 448.4513, and the measured value is 448.4550.

[0182] Example 14 (6R)-6-{(1R,3aS,7aR,E)-4-[2-(tert-butylamino)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-methylheptan-2-ol(12)

[0183] [ka]

[0184]

[0121] PDC (127.9 mg, 0.34 mmol) was added to a solution of 8 (99.5 mg, 0.225 mmol) in CH2Cl2 (4 mL) and DMF (0.5 mL) at room temperature, and the mixture was stirred at the same temperature under air for 2 hours. The solution was diluted with Et2O and concentrated by filtration through a Celite pad. Anhydrous MgSO4 (1 g) was added to a solution of the crude aldehyde obtained above and tert-butylamine (99.4 mg, 143 μL, 1.36 mmol) in CH2Cl2 (5 mL) at room temperature under air. The mixture was stirred for 70 minutes and refluxed overnight. After quenching the reaction with H2O, the mixture was extracted three times with ELISA, dried over Na2SO4, filtered and concentrated. The obtained crude imine was used in the next reaction without further purification. To a solution of the crude imine described above in MeOH (3 mL), NaBH4 (5.1 mg, 0.136 mmol) was added at 0°C. The mixture was stirred at the same temperature under air for 1 hour. After quenching the reaction with H2O and saturated aqueous solution NH4Cl, the mixture was extracted three times with ELISA, dried over Na2SO4, filtered, and concentrated. The resulting crude amine was used in the next reaction without further purification.

[0185]

[0122] p-toluenesulfonic acid monohydrate (129.3 mg, 0.68 mmol) was added to the solution of the crude amine in MeOH (10 mL). The mixture was stirred at room temperature under air for 20 minutes. After quenching the reaction with H2O, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was diluted with MeOH (3 mL) and 1 M aqueous NaOH (3 mL) and stirred for 10 minutes. H2O was added to the mixture, extracted four times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (SiO2 only, 1% Et3N) to obtain 12 as a colorless oil (76.2 mg, 93%, 4 steps).

[0186]

[0123] 12KK-041:[α] D 27+63.0 (c 0.44, CHCl3); IR (undiluted) 3365, 1470, 1377, 1363, 1215 cm -1 ; 1 H NMR(400MHz,CDCl3)δ0.54(s,3H), 0.93(d,J=6.4Hz,3H), 0.98~2.00(m,35H), 2.55~2.59(m,1H), 3 .21~3.30(m,2H), 5.08(t,J=6.7Hz,1H), 6.62~6.64(m,2H), 6.69~6.72(m,1H), 7.15~7.20(m,2H); 13 C NMR(100MHz,CDCl3)δ11.9, 18.8, 20.8, 22.2, 23.4, 27.7, 28.7, 28.8, 29.2, 29.3, 3 6.1, 36.4, 39.4, 40.4, 44.4, 45.2, 50.8, 55.7, 56.5, 71.1, 118.6, 141.5;HRMS(ESI + )C 24 H 46 ON[M+H] + The calculated value is 364.3574, and the measured value is 364.3603.

[0187] Example 15 (6R)-2-methyl-6-{(1R,3aS,7aR,E)-7a-methyl-4-[2-(phenylamino)ethylidene]octahydro-1H-inden-1-yl}heptan-2-ol(18KK-042)

[0188] [ka]

[0189]

[0124] PDC (333.8 mg, 0.887 mmol) was added to a solution of 8 (151.7 mg, 0.359 mmol) in CH2Cl2 (6 mL) at room temperature, and the mixture was stirred at the same temperature under air for 3 hours. The solution was diluted with Et2O, filtered through a Celite pad, and concentrated to obtain the crude aldehyde. To a solution of the crude aldehyde obtained above and aniline (330.6 mg, 324 μL, 3.55 mmol) in CH2Cl2 (10 mL), anhydrous MgSO4 (1 g) was added at room temperature under air. The mixture was stirred for 90 minutes and refluxed for 40 minutes. After quenching the reaction with H2O, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The obtained crude imine was used in the next reaction without further purification. NaBH4 (40.2 mg, 1.07 mmol) was added to a solution of the crude imine in MeOH (10 mL) at 0°C. The mixture was stirred at the same temperature under air for 30 minutes. After quenching the reaction with H2O and saturated aqueous solution NH4Cl, the mixture was extracted three times with ELISA, dried over Na2SO4, filtered, and concentrated. The resulting crude amine was used in the next reaction without further purification. p-toluenesulfonic acid monohydrate (2.7 g, 14.2 mmol) was added to the solution of the crude amine in MeOH (10 mL). The mixture was stirred at room temperature under air for 45 minutes. After quenching the reaction with 1 M aqueous NaOH solution, the mixture was stirred for a further 10 minutes. The mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:toluene = 10:1-3:1) to obtain 18KK-042 as a colorless oil (88.6 mg, 65%, 4 steps).

[0190]

[0125] 18 KK-042:[a] D 27 +67.9(c 1.89,CHCl3); IR (undiluted) 3368, 1603, 1505, 1469, 1377, 1318, 1248, 1216, 1151, 755, 692 cm -1 ; 1H NMR(400MHz,CDCl3)δ0.56(s,3H), 0.95(d,J=6.4Hz,3H), 1.03~1.10(m,1H), 1.18~1.72(m,22H), 1.84~2.06(m,3H), 2.65~2.69(m,1H), 3.71~3.81(m,2H), 5.01(t,J=6.6Hz,1H), 6.62~6.64(m,2H), 6.69~6.72(m,1H), 7.157.20(m,2H); 13 C NMR (100MHz, CDCl3) δ11.8, 18.8, 20.8, 22.2, 23.4, 27.6, 28.8, 29.2, 29.3, 36.1, 36.4, 40.3, 41.3, 45.2, 55.6, 56.5, 71.1, 113.0, 117.1, 117.3, 129.1, 143.0, 148.4;HRMS(ESI + )C 26 H 42 ON[M+H] + The calculated value is 384.3261, and the measured value is 384.3258.

[0191] Example 16 2-[(1R,3aS,7aR,E)-7a-methyl-1-{(2R)-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}octahydro-4H-indene-4-ylidene]acetic acid (B)

[0192] [ka]

[0193]

[0126] PDC (127.9 mg, 0.34 mmol) was added to a solution of 8 (103.9 mg, 0.246 mmol) in CH2Cl2 (4 mL) at room temperature, and the mixture was stirred at the same temperature under air for 3 hours. The solution was diluted with Et2O, filtered through Celite, and concentrated to obtain the crude aldehyde.

[0194]

[0127] To a mixture of the crude aldehyde, NaH2PO4 (74.3 mg, 0.476 mmol), 30% H2O2 in H2O (1 mL) (72 μL), and t-BuOH (3 mL), NaClO2 (24.6 mg, 0.272 mmol) was added at 0°C under air, and the mixture was stirred at the same temperature for 5 minutes and at room temperature for 4 hours. After quenching the reaction with H2O, the mixture was extracted three times with HCl, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:HCl = 2:1) to obtain B as a colorless oil (82.5 mg, 80%, 2 steps).

[0195]

[0128] B:[a] D 27 +93.9(c 1.54,CHCl3); IR (undiluted) 3048, 1686, 1638, 1459, 1416, 1268, 1212, 1045, 735 cm -1 ; 1 H NMR (400MHz, CDCl3) δ0.58(s,3H), 0.56(q,J=7.8Hz,1H), 0.92~0.99(m,13H), 1.19~1.77(m,1 9H), 1.84~1.96(m,1H), 2.01~2.04(m,1H), 2.10~2.15(m,1H), 3.82~3.88(m,1H), 5.49(s,1H); 13 C NMR (100MHz, CDCl3) δ6.8, 7.1, 12.0, 18.7, 20.8, 22.1, 24.0, 27.4, 29.8, 29.9, 30 .0, 35.9, 36.3, 40.1, 45.5, 47.4, 56.8, 57.1, 73.4, 111.3, 166.6, 172.0;HRMS(ESI + )C 28 H 46 O3SiNa[M+Na] + The calculated value is 481.3108, and the measured value is 481.3065.

[0196] Example 17 2-{(1R,3aS,7aR,E)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-4H-indene-4-ylidene}-1-(piperidine-1-yl)ethane-1-one(19)

[0197] [ka]

[0198]

[0129] Diisopropylethylamine (61.0 mg, 82 μL, 0.472 mmol) and BOP reagent (166.8 mg, 0.377 mmol) were added at 0°C to a solution of piperidine (24.1 mg, 28 μL, 0.283 mmol) and B (82.5 mg, 0.189 mmol) in DMF (3 mL), and the mixture was stirred at room temperature for 15 minutes. After quenching the reaction with H2O and saturated aqueous solution NH4Cl at room temperature, the mixture was extracted three times with SiO2, dried over Na2SO4, filtered, and concentrated to obtain the crude amide.

[0199]

[0130] p-toluenesulfonic acid monohydrate (179.4 mg, 0.943 mmol) was added to the above crude amide solution in MeOH (5 mL). The mixture was stirred at room temperature under air for 10 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with toluene, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:toluene = 2:1-1:1) to obtain 19KK-043 as a colorless oil (57.3 mg, 73%, 2 steps).

[0200]

[0131] 19 KK-043:[a] D 27 +84.8(c 0.96,CHCl3); IR (undiluted) 3374, 1610, 1444, 1255, 753 cm -1 ; 1H NMR(400MHz, CDCl3)δ0.59(s,3H), 0.93(d,J=6.4Hz,3H), 1.01~1.11(m,1H), 1.20 ~2.03(m,30H), 2.72~2.77(m,1H), 3.46~3.51(m,3H), 3.61(brs,1H), 5.51(s,1H); 13 C NMR (100MHz, CDCl3) δ12.1, 18.7, 20.7, 22.1, 23.3, 24.6, 25.8, 26.4, 27.5, 29.2, 29.3, 30.5 ,36.0,36.3,40.0,42.2,44.3,46.1,47.5,55.6,56.4,71.0,114.8,149.8,167.7;HRMS(ESI + )C 25 H 44 NO2 [M+H] + The calculated value is 390.3367, and the measured value is 390.3391.

[0201] Example 18 2-{(1R,3aS,7aR,E)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-4H-indene-4-ylidene}-1-morpholinoethane-1-one(20KK-044)

[0202] [ka]

[0203]

[0132] Diisopropylethylamine (80 μL, 0.46 mmol) and BOP reagent (162.4 mg, 0.367 mmol) were added at 0°C to a solution of morpholine (32.0 mg, 32 μL, 0.367 mmol) and B (80.2 mg, 0.184 mmol) in DMF (3 mL), and the mixture was stirred at room temperature for 21 hours. After quenching the reaction with H2O and saturated aqueous solution NH4Cl at room temperature, the mixture was extracted three times with SiO2, washed with saturated brine, dried over Na2SO4, filtered, and concentrated to obtain the crude amide.

[0204]

[0133] p-toluenesulfonic acid monohydrate (175.0 mg, 0.92 mmol) was added to the above crude amide solution in MeOH (10 mL). The mixture was stirred at room temperature under air for 20 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with ELISA, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:ELISA = 1:1) to obtain 20KK-044 as a colorless oil (65.4 mg, 91%, 2 steps).

[0205]

[0134] 20 KK-044:[α] D 27 +91.8(c 1.14,CHCl3); IR (undiluted) 3426, 1615, 1463, 1231, 1117, 851, 753 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.59(s,3H), 0.94(d,J=6.0Hz,3H), 1.03~1.11(m,1H), 1.21~1.62(m,19H), 1.69~1.71(m,1H), 1.7 6~1.81(m,1H), 1.88~1.92(m,1H), 2.01~2.06(m,2H), 2.83~2.85(m,1H), 3.52(brs,1H), 3.65~3.69(m,6H), 5.51(s,1H); 13 C NMR (150MHz, CDCl3) δ12.1, 18.7, 20.7, 22.1, 23.4, 27.4, 29.2, 29.4, 30.6, 36.0, 36.3 ,39.9,41.7,44.3,46.3,46.9,55.8,56.4,66.9,71.0,113.6,152.3,167.9;HRMS(ESI + )C 24 H 41 NO3Na[M+Na] + The calculated value is 414.2979, and the measured value is 414.2998.

[0206] Example 19 ({(6R)-6-[(1R,3aS,7aR,E)-4-(2-azidoethylidene)-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-yl}oxy)triethylsilane(9)

[0207] [ka]

[0208]

[0135] In a solution of 8 (300.0 mg, 0.71 mmol) and pyridine (337.0 mg, 344 μL, 4.26 mmol) in CCl4 (30 mL), tri-n-butylphosphine (574.6 mg, 700 μL, 2.84 mmol) was added over 5 minutes at 0°C, and the mixture was stirred at the same temperature for 15 minutes. After diluting the reaction product with hexane (50 mL), the mixture was filtered and concentrated. The resulting crude allyl chloride was used in the next reaction without further purification.

[0209]

[0136] To the above crude allyl chloride solution in DMF (15 mL), NaN3 (138.5 mg, 2.13 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. After quenching the reaction with H2O, the mixture was extracted three times with toluene, washed with saturated brine, dried on Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:toluene = 30:1) to obtain 9 as a colorless oil (273.1 mg, 86%, 2 steps).

[0210]

[0137] 9:[a] D 27 36.6 (c 1.61, CHCl3); IR (undiluted) 2095, 1380, 1235, 1045, 743 cm -1 ; 1H NMR(600MHz, CDCl3)δ0.57(q,J=8.0Hz,1H), 0.59(s,1H), 0.93(d,J=6.6Hz, 1H), 0.95(t,J=8.4Hz,1H), 0.99~1.06(m,1H), 1.19~1.55(m,20H), 1.67~1. 71(m,2H), 1.86~1.94(m,1H), 2.00~2.05(m,2H), 2.60~2.62(m,1H), 3.73(d d,J=6.6,13.2Hz,1H), 3.89(dd,J=7.8,13.8Hz,1H), 5.13(t,J=7.5Hz,1H); 13 C NMR (150MHz, CDCl3) δ6.9, 7.2, 11.9, 18.9, 20.9, 22.2, 23.9, 27.6, 28.9, 29.9, 30 .1, 36.2, 36.5, 40.4, 45.2, 45.6, 47.5, 55.9, 56.7, 73.5, 112.7, 147.2;HRMS(ESI + )C 26 H 49 N3OSi[M+Na] + The calculated value is 470.3537, and the measured value is 470.3577.

[0211] Example 20 (6R)-2-methyl-6-{(1R,3aS,7aR,E)-7a-methyl-4-[2-(4-phenyl-1H-1,2,3-triazole-1-yl)ethylidene]octahydro-1H-inden-1-yl}heptan-2-ol(25KK-034)

[0212] [ka]

[0213]

[0138] To a solution of phenylacetylene (56.9 mg, 24 μL, 0.557 mmol), diisopropylethylamine (719.9 mg, 0.97 mL, 5.57 mmol), and 9 (50.3 mg, 0.112 mmol) in THF (4 mL), CuI (21.2 mg, 0.557 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 68 hours. After quenching the reaction with H2O, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over Na2SO4, filtered, and concentrated.

[0214]

[0139] The obtained crude triazole product was used in the next reaction without further purification.

[0215]

[0140] p-toluenesulfonic acid monohydrate (106.0 mg, 0.557 mmol) was added to the above crude triazole solution in MeOH (5 mL). The mixture was stirred at room temperature under air for 15 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:ethyl acetate = 2:1) to obtain 25KK-034 as a colorless oil (12.1 mg, 25%, 2 steps).

[0216]

[0141] 25 KK-034:[α] D 27 +50.5(c 0.29,CHCl3); IR (undiluted) 3393, 1468, 1378, 1223, 766, 695 cm -1 ; 1H NMR(600MHz,CDCl3)δ0.58(s,3H), 0.95(d,J=6.0Hz,3H), 1.03~1.11(m,1H), 1.21~1.61(m,20H), 1.74~1.81(m,2H), 1.87~1.94(m,1H), 2.01~2.06 (m,2H), 2.73~2.75(m,1H), 5.04~5.10(m,2H), 5.27(t,J=7.5Hz,1H), 7.3 1~7.33(m,1H), 7.42(t,J=7.8Hz,2H), 7.70(s,1H), 7.82(d,J=7.8Hz,1H); 13 C NMR (150MHz, CDCl3) δ11.9, 18.8, 20.8, 22.1, 23.4, 27.5, 28.9, 29.2, 29.4, 36.0, 36.3, 40.1, 44.4 ,45.7,47.2,55.7,56.5,71.1,112.8,118.9,125.7,128.0,128.8,130.8,147.3,147.8;HRMS(ESI + )C 28 H 41 N3O[M+H] + The calculated value is 436.3322, and the measured value is 436.3312.

[0217] Example 21 (6R)-6-[(1R,3aS,7aR,E)-4-(2-{4-[(1,1'-biphenyl)-4-yl]-1H-1,2,3-triazole-1-yl}ethylidene)-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(31KK-035)

[0218] [ka]

[0219]

[0142] To a solution of 4-ethynylbiphenyl (99.3 mg, 0.557 mmol), diisopropylethylamine (719.9 mg, 0.97 mL, 5.57 mmol), and 9 (50.3 mg, 0.112 mmol) in THF (8 mL), CuI (106.1 mg, 0.557 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 112 hours. After quenching the reaction with H2O, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over Na2SO4, filtered, and concentrated.

[0220]

[0143] The obtained crude triazole product was used in the next reaction without further purification.

[0221]

[0144] p-toluenesulfonic acid monohydrate (106.0 mg, 0.557 mmol) was added to the above crude triazole solution in MeOH (10 mL). The mixture was stirred at room temperature under air for 20 minutes. After quenching the reaction with H2O and saturated aqueous NaHCO3 at room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:ethyl acetate = 2:1) to obtain 31KK-035 as a colorless oil (12.5 mg, 22%, 2 steps).

[0222]

[0145] 31 KK-035:[α] D 27 +41.8 (c 0.96, CHCl3); IR (undiluted) 3350, 1443, 1376, 1215, 1148, 840, 767, 699 cm -1 ; 1H NMR(600MHz,CDCl3)δ0.59(s,3H), 0.95(d,J=6.6Hz,3H), 1.041.11(m,1H), 1.22~1. 61(m,20H), 1.75~1.83(m,2H), 1.88~1.95(m,1H), 2.03~2.07(m,2H), 2.74~2.77(m,1 H), 5.06~5.13(m,2H), 5.29(t,J=7.2Hz,1H), 7.34~7.37(m,1H), 7.45(t,J=7.8Hz,2 H), 7.63(d,J=7.2Hz,2H), 7.67(d,J=9.0Hz,2H), 7.75(s,1H), 7.91(d,J=8.4Hz,1H); 13 C NMR (150MHz, CDCl3) δ11.9, 18.8, 20.8, 22.1, 23.4, 27.5, 28.9, 29.2, 29.4, 36.0, 36.3, 40.1, 44.3, 45.7, 47.3, 5 5.7,56.5,71.1,112.8,118.9,126.0,127.0,127.4,127.5,128.8,129.8,140.6,140.8,147.4,147.4;HRMS(ESI + )C 34 H 45 N3ONa[M+Na] + The calculated value is 543.3455, and the measured value is 534.3494.

[0223] Example 22 (6R)-6-{(1R,3aS,7aR,E)-4-[2-(4-butyl-1H-1,2,3-triazole-1-yl)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-methylheptan-2-ol(28KK-036)

[0224] [ka]

[0225]

[0146] To a solution of 1-hexine (9.9 mg, 13.8 μL, 0.12 mmol), diisopropylethylamine (719.9 mg, 0.97 mL, 5.57 mmol), and 9 (53.8 mg, 0.112 mmol) in THF (4 mL), CuI (106.1 mg, 0.557 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 112 hours. After quenching the reaction with H2O, the mixture was extracted three times with ethylethanol, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting crude triazole product was used in the next reaction without further purification.

[0226]

[0147] p-toluenesulfonic acid monohydrate (106.0 mg, 0.557 mmol) was added to the above crude triazole solution in MeOH (5 mL). The mixture was stirred at room temperature under air for 20 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with toluene, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:toluene = 2:1-1:1) to obtain 28KK-036 as a colorless oil (15.6 mg, 31%, 2 steps).

[0227]

[0148] 28 KK-036:[α] D 27 +57.5 (c 1.20, CHCl3); IR (undiluted) 3400, 1467, 1377, 1215, 1047, 732 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.54(s,3H), 0.91~0.94(m,6H), 1.02~1.08(m,1H), 1.191.57(m,21H), 1.61~1.66(m,2H), 1.71~1.7 7(m,2H), 1.85~1.92(m,1H), 1.98~2.04(m,2H), 2.67~2.71(m,3H), 4.94~5.01(m,2H), 5.20(t,J=7.2Hz,1H), 7.20(s,1H); 13C NMR (150MHz, CDCl3) δ11.9, 13.8, 18.8, 20.8, 22.1, 22.3, 23.4, 25.4, 27.5, 28.8, 29.2, 29.4, 31 .6,36.0,36.3,40.1,44.3,45.6,47.0,55.6,56.4,71.0,113.1,119.8,146.7,148.4;HRMS(ESI + )C 26 H 45 N3ONa[M+Na] + The calculated value is 438.3455, and the measured value is 438.3473.

[0228] Example 23 (6R)-6-[(1R,3aS,7aR,E)-4-{2-[4-(4-hydroxybutyl)-1H-1,2,3-triazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(29KK-037)

[0229] [ka]

[0230]

[0149] To a solution of 5-hexyn-1-ol (108.9 mg, 120 μL, 1.11 mmol), diisopropylethylamine (1.44 g, 1.94 mL, 11.14 mmol), and 9 (60 mg, 0.124 mmol) in THF (8 mL), CuI (212.2 mg, 1.11 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 118 hours. After quenching the reaction with H2O, the mixture was extracted three times with phenylethylamine, dried over Na2SO4, filtered, and concentrated. The resulting crude triazole product was used in the next reaction without further purification.

[0231]

[0150] p-toluenesulfonic acid monohydrate (216.0 mg, 1.11 mmol) was added to the above crude triazole solution in MeOH (20 mL). The mixture was stirred at room temperature under air for 25 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (ethyl acetate only) to obtain 29KK-037 as a colorless oil (19.2 mg, 20%, 2 steps).

[0232]

[0151] 29 KK-037:[a] D 27 +40.0 (c 1.48, CHCl3); IR (undiluted) 3363, 1468, 1378, 1216, 1052, 755 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.54(s,3H), 0.94(d,J=6.0Hz,3H), 1.02~1.08(m,1H), 1.21~1.92(m,26H), 1.98~2.04(m,2H), 2 .66~2.70(m,1H), 2.74(t,J=7.5Hz,2H), 3.67(t,J=6.3Hz,2H), 4.94~5.01(m,2H), 5.20(t,J=7.2Hz,1H), 7.23(s,1H); 13 C NMR (150MHz, CDCl3) δ11.9, 18.8, 20.8, 22.1, 23.4, 25.3, 25.6, 27.5, 28.8, 29.2, 29.4, 32.1 ,36.0,36.3,40.1,44.3,45.6,47.0,55.6,62.4,71.0,113.0,119.9,146.8,148.0;HRMS(ESI + )C 26 H 45 N3O2Na[M+Na] + The calculated value is 454.3394, and the measured value is 438.3404.

[0233] Example 24 2-{4-[1-(2-{(1R,3aS,7aR,E)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-4H-indene-4-ylidene}ethyl)-1H-1,2,3-triazole-4-yl]butyl}isoindoline-1,3-dione (30KK-038)

[0234] [ka]

[0235]

[0152] To a solution of phthalimide (11.7 mg, 0.073 mmol), Ph3P (26.0 mg, 0.10 mmol), and 29KK-037 (17.1 mg, 0.0396 mmol) in THF (3 mL), diisopropyl azodicarboxylic acid (52 μL, 1.9 M in toluene, 0.10 mmol) was added at 0°C, and the mixture was stirred at room temperature for 30 minutes. After quenching the reaction with H2O and saturated aqueous solution NH4Cl, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:ethyl acetate = 1:1) to obtain 30KK-038 as a colorless oil (12.0 mg, 54%).

[0236]

[0153] 30 KK-038:[a] D 27 +32.8(c 0.92,CHCl3); IR (undiluted) 3404, 1714, 1468, 1398, 1216, 1037, 722 cm⁻¹; 1H NMR(600MHz, CDCl3)δ0.53(s,3H), 0.93(d,J=6.6Hz,3H), 1.03~1.08(m,1H), 1 .21~1.57(m,19H), 1.71~1.76(m,6H), 1.85~1.91(m,1H), 1.98~2.04(m,2H), 2 .68~2.70(m,1H), 2.76(t,J=6.9Hz,2H), 3.71(t,J=6.6Hz,2H), 4.93~5.01(m, 2H), 5.20(t,J=7.2Hz,1H), 7.25(s,1H), 7.69~7.72(m,2H), 7.81~7.84(m,2H); 13 C NMR (150MHz, CDCl3) δ11.9, 18.8, 20.8, 22.1, 23.4, 25.1, 26.7, 27.5, 28.1, 28.8, 29.2, 29.4, 36.0, 36.3, 37.6 ,40.1,44.4,45.6,47.1,55.6,56.4,71.1,113.0,120.1,123.2,132.1,133.9,146.9,147.5,168.4;HRMS(ESI + )C 34 H 48 N4O3Na[M+Na] + The calculated value is 583.3619, and the measured value is 583.3622.

[0237] Example 25 (6R)-2-methyl-6-[(1R,3aS,7aR,E)-7a-methyl-4-{2-[4-(pyridine-2-yl)-1H-1,2,3-triazole-1-yl]ethylidene}octahydro-1H-inden-1-yl]heptan-2-ol(26KK-046)

[0238] [ka]

[0239]

[0154] A mixture of 2-ethinylpyridine (38.6 mg, 38 μL, 0.374 mmol), sodium L-ascorbate (38.3 mg, 0.193 mmol), 2,6-lutidine (39.0 mg, 43 μL, 0.364 mmol), and 9 (83.8 mg, 0.187 mmol) was added to t-BuOH (3 mL) and H2O (3 mL). CuSO4·5H2O (5.2 mg, 0.021 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 24 hours. After quenching the reaction with H2O, the mixture was extracted three times with RINKAN, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting crude triazole product was used in the next reaction without further purification.

[0240]

[0155] p-toluenesulfonic acid monohydrate (182.8 mg, 0.961 mmol) was added to the above crude triazole solution in MeOH (10 mL). The mixture was stirred at room temperature under air for 20 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with siRNA, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:siRNA = 1:1) to obtain 26KK-046 as a colorless oil (60.3 mg, 74%, 2 steps).

[0241]

[0156] 26 KK-046:[a] D 27 +55.2 (c 1.08, CHCl3); IR (undiluted) 3410, 1600, 1471, 1420, 1337, 1200, 1044, 782, 793 cm -1 ; 1H NMR(600MHz, CDCl3)δ0.55(s,3H), 0.93(d,J=6.0Hz,3H), 1.02~1.10(m,1H), 1.2 0~1.60(m,19H), 1.71~1.80(m,2H), 1.85~1.92(m,1H), 1.99~2.46(m,2H), 2.71~ 2.74(m,1H), 5.04~5.10(m,2H), 5.26(t,J=7.5Hz,1H), 7.20~7.22(m,1H), 7.77( td,J=1.8,7.8Hz,1H), 8.11(s,1H), 8.17(d,J=8.4Hz,1H), 8.56(d,J=4.2Hz,1H); 13 C NMR (150MHz, CDCl3) δ11.9, 18.8, 20.8, 22.1, 23.3, 27.5, 28.8, 29.2, 29.4, 36.0, 36.3, 40.1, 44.3, 45 .6,47.3,55.6,56.4,71.0,112.6,120.2,121.3,122.7,137.0,147.5,148.2,149.2,150.4;HRMS + )C 27 H 40 N4ONa[M+Na] + The calculated value is 459.3094, and the measured value is 459.3103.

[0242] Example 26 (6R)-2-methyl-6-[(1R,3aS,7aR,E)-7a-methyl-4-{2-[4-(thiophen-2-yl)-1H-1,2,3-triazole-1-yl]ethylidene}octahydro-1H-inden-1-yl]heptan-2-ol(27KK-047)

[0243] [ka]

[0244]

[0157] A mixture of 2-ethinylthiophene (39.4 mg, 36 μL, 0.364 mmol), sodium L-ascorbate (37.8 mg, 0.191 mmol), 2,6-lutidine (39.0 mg, 42 μL, 0.364 mmol), and 9 (81.6 mg, 0.182 mmol) was added to t-BuOH (3 mL) and H2O (3 mL). CuSO4·5H2O (4.2 mg, 0.017 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 22 hours. After quenching the reaction with H2O, the mixture was extracted three times with ELISA, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting crude triazole product was used in the next reaction without further purification.

[0245]

[0158] p-toluenesulfonic acid monohydrate (179.2 mg, 0.942 mmol) was added to the above crude triazole solution in MeOH (10 mL). The mixture was stirred at room temperature under air for 20 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with siRNA, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:siRNA = 2:1) to obtain 27KK-047 as a colorless oil (53.5 mg, 67%, 2 steps).

[0246]

[0159] 27 KK-047:[α] D 27 +47.2(c 1.35,EtOH);IR (undiluted) 3418, 1665, 1468, 1420, 1376, 1044, 761cm -1 ; 1H NMR (600MHz, CDCl3) δ0.57(s,3H), 0.95(d,J=6.4Hz,3H), 1.20~1.10(m,1H), 1.22~2.06(m,24H), 2.70~2.74(m,1H), 5.04~5.10( m,2H), 5.25(t,J=7.6Hz,1H), 7.07(dd,J=3.7,4.9Hz,1H), 7.29(dd,J=1.4,5.0Hz,1H), 7.37(dd,J=1.4,3.7Hz,1H), 7.61(s,1H); 13 C NMR (150MHz, CDCl3) δ11.9, 18.8, 20.8, 22.1, 23.4, 27.5, 28.9, 29.2, 29.4, 36.0, 36.3, 40.1, 44.3 ,45.7,47.3,55.7,56.5,71.1,112,7,118.4,124.0,124.9,127.6,133.2,142.8,147.5;HRMS(ESI + )C 26 H 39 N3OSNa[M+Na] + The calculated value is 464.2706, and the measured value is 464.2731.

[0247] Reference Example 1 Hexafluoro side chain (1R,3aR,7aR)-7a-methyl-1-[(2R)-7,7,7-trifluoro-6-(methoxymethoxy)-6-(trifluoromethyl)heptan-2-yl]octahydro-4H-inden-4-one(35)

[0248] [ka]

[0249]

[0160] See Ikeda, M.; Matsumura, H.; Sawada, N.; Hashimoto, K.; Tanaka, T.; Noguchi, T.; Hayashi, M. Synthesis and biological evaluations of C-23-modified 26,26,26,27,27,27-F6-vitamin D3 analogues. Bioorg. Med. Chem. 2000, 8, 1809~1817.

[0250]

[0161] See Kawagoe, F.; Sugiyama, T.; Uesugi, M.; Kittaka, A. Recent developments for introducing a hexafluoroisopropanol unit into the vitamin D side chain. J. Steroid Biochem. Mol. Biol. 2018, 177, 250-254.

[0251] Example 27 2-{(1R,3aS,7aR,E)-7a-methyl-1-[(2R)-7,7,7-trifluoro-6-(methoxymethoxy)-6-(trifluoromethyl)heptan-2-yl]octahydro-4H-inden-4-ylidene}ethane-1-ol(36)

[0252] [ka]

[0253]

[0162] To a suspension of NaH (277.2 mg, 60% in liquid paraffin, 6.93 mmol) in THF (5 mL), (EtO)2P(O)CH2CO2Et (1.75 g, 1.56 mL, 7.79 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. Ketone 35 (374.6 mg, 0.866 mmol) was dissolved in THF (5 mL), and the solution was added to the mixture at the same temperature. After stirring at room temperature for 64 hours, the reaction mixture was quenched at room temperature with H2O and saturated aqueous solution NH4Cl. The mixture was extracted three times with ethyl, washed with saturated brine, dried on Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:ethyl = 10:1) to obtain crude ethyl ester (418.2 mg) as a colorless oil.

[0254]

[0163] To a solution of the above crude ethyl ester (418.2 mg, 0.832 mmol) in THF (10 mL), DIBAL-H (2.5 mL, 1.00 M toluene solution, 2.5 mmol) was added at -78°C, and the mixture was stirred at room temperature for 20 minutes. After quenching the reaction with H2O and saturated aqueous potassium sodium tartrate at room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:ethyl acetate = 3:1) to obtain alcohol 36 as a colorless oil (364.7 mg, 95%, 2 steps).

[0255]

[0164] 36:[a] D 27 +72.2(c 1.37,CHCl3); IR (undiluted) 3343, 1471, 1284, 1217, 1145, 1049, 937 cm -1 ; 1H NMR(600MHz,CDCl3)δ0.55(s,3H), 0.94(d,J=6.6Hz,3H), 1.03~1.11(m,1H), 1.25~1.67(m,20H), 1.83~2.04(m,5H) , 2.11(dd,J=4.2,11.4Hz,1H), 3.46(s,3H), 4.17~4.23(m,2H), 4.91(dd,J=6.9,9.6Hz,2H), 5.22(t,J=6.9Hz,1H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.7, 19.0, 22.2, 23.5, 27.6, 28.7, 28.8, 35.9, 36.4, 40.3, 45.3, 55 .6, 56.4, 56.6, 58.7, 80.2 (septet, J=28.7Hz), 92.8, 119.3, 123.0 (q, J=288.6Hz), 143.6:HRMS (ESI + )C 22 H 34 O3F6[M+Na] + The calculated value is 483.2304, and the measured value is 483.2326.

[0256] (1R,3aS,7aR,E)-4-(2-azidoethylidene)-7a-methyl-1-[(2R)-7,7,7-trifluoro-6-(methoxymethoxy)-6-(trifluoromethyl)heptan-2-yl]octahydro-1H-indene(37)

[0257] [ka]

[0258]

[0165] Tri-n-butylphosphine (509 μL, 2.04 mmol) was added over 5 minutes at 0°C to a solution of CD ring 36 (187.8 mg, 0.408 mmol) and pyridine (99 μL, 1.22 mmol) in CCl4 (20 mL), and the mixture was stirred at the same temperature for 10 minutes. The reaction product was diluted with hexane, and the mixture was filtered and concentrated. Hexane was added to the resulting residue, and the mixture was filtered through Celite and concentrated. The resulting crude allyl chloride was used in the next reaction without further purification.

[0259]

[0166] To the above crude allyl chloride solution in DMF (25 mL), NaN3 (79.5 mg, 1.22 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. After quenching the reaction with H2O, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried on Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:ethyl acetate = 50:1) to obtain azide 37 as a colorless oil (162.3 mg, 82%, 2 steps).

[0260]

[0167] 37:[a] D 27 +36.3 (c 0.208, CHCl3); IR (undiluted) 2100, 1468, 1284, 1217, 1161, 1049 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.59(s,3H), 0.94(d,J=6.6Hz,3H), 1.05~1.11(m,1H), 1.261.71(m,10H), 1.85~2.04(m,5H), 2.60~2.6 4(m,1H), 3.46(s,3H), 3.73(dd,J=7.2,13.8Hz,2H), 3.89(dd,J=8.4,13.8Hz,2H), 4.90~4.93(m,2H), 5.13(t,J=7.5Hz,1H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.7, 18.9, 22.1, 23.8, 27.5, 28.8, 35.9, 36.3, 40.2, 45.1, 47.4, 55.7, 56.4, 56.5, 80.2 (septet, J=28.0Hz), 92.8, 112.8, 123.0 (q, J=288.6Hz), 147.0; + )C 22 H 34 N3O2F6[M+H] + The calculated value is 486.2550, and the measured value is 486.2555.

[0261] Example 28 (6R)-1,1,1-trifluoro-6-{(1R,3aS,7aR,E)-7a-methyl-4-[2-(4-phenyl-1H-1,2,3-triazole-1-yl)ethylidene]octahydro-1H-inden-1-yl}-2-(trifluoromethyl)heptan-2-ol (38KK-050)

[0262] [ka]

[0263]

[0168] To a solution of ethynylbenzene (20 μL, 0.186 mmol), 2,6-lutidine (29 μL, 0.248 mmol), sodium ascorbate (24.6 mg, 0.124 mmol), and CD ring 37 (60.0 mg, 0.124 mmol) in tBuOH (3 mL) and H2O (3 mL), CuSO4·5H2O (3.1 mg, 0.012 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 25 hours. After quenching the reaction with H2O, the mixture was extracted three times with RINKAN, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting crude triazole product was used in the next reaction without further purification.

[0264]

[0169] Methanesulfonic acid (0.4 mL) was added to the solution of the crude product in MeOH (20 mL). The mixture was stirred at room temperature under air for 9 hours. After quenching the reaction at room temperature with H2O and saturated aqueous solution NaHCO3, the mixture was extracted three times with toluene, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:toluene = 2:1) to obtain 38KK-050 (37.1 mg, 55%) as a colorless oil.

[0265]

[0170] 38 KK-050:[a] D 27 +22.3(c 0.24,CHCl3); IR (undiluted) 3143, 1468, 1225, 763 cm -1 ; 1H NMR (600MHz, CDCl3) δ0.56(s,3H), 0.93(d,J=6.6Hz,3H), 1.04~1.11(m,1H), 1.21~2.04(m,17H), 2.72~2.75(m,1H), 4.21(brs ,1H), 5.03~5.09(m,2H), 5.25(t,J=7.2Hz,1H), 7.32~7.34(m,1H), 7.42(t,J=7.8Hz,2H), 7.70(s,1H), 7.80(d,J=7.2Hz,1H); 13 C NMR (150MHz, CDCl3) δ11.9, 18.5, 18.7, 22.1, 23.4, 27.5, 28.8, 30.9, 35.8, 36.1, 40.0, 45.7, 47.3, 55.6, 56.3, HRMS (ESI + )C 28 H 36 N3OF6[M+H] + The calculated value is 544.2757, and the measured value is 544.2787.

[0266] Example 29 (6R)-1,1,1-trifluoro-6-[(1R,3aS,7aR,E)-4-{2-[4-(4-fluorophenyl)-1H-1,2,3-triazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-(trifluoromethyl)heptan-2-ol (39KK-056)

[0267] [ka]

[0268]

[0171] To a solution of 1-ethynyl-4-fluorobenzene (17.1 mg, 0.142 mmol), 2,6-lutidine (16 μL, 0.142 mmol), sodium ascorbate (17.8 mg, 0.090 mmol), and CD ring 37 (34.5 mg, 0.071 mmol) in tBuOH (3 mL) and H2O (3 mL), CuSO4·5H2O (3.3 mg, 0.013 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 63 hours. After quenching the reaction with H2O, the mixture was extracted three times with RINKAN, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting crude triazole product was used in the next reaction without further purification.

[0269]

[0172] Methanesulfonic acid (0.2 mL) was added to the solution of the crude product in MeOH (10 mL). The mixture was stirred at room temperature under air for 20 hours. After quenching the reaction with H2O and saturated aqueous solution NaHCO3 at room temperature, the mixture was extracted three times with siRNA, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 1:1) to obtain 39KK-056 (27.8 mg, 70%) as a colorless oil.

[0270]

[0173] 39 KK-056:[α] D 27 +41.3(c 2.14,CHCl3); IR (undiluted) 3147, 1498, 1470, 1228, 843, 760 cm -1 ; 1 H NMR (600MHz, CDCl3) δ0.56(s,3H), 0.93(d,J=6.6Hz,3H), 1.04~1.11(m,1H), 1.22~2.04(m,17H), 2.71~2 .74(m,1H), 5.01~5.09(m,2H), 5.24(t,J=7.5Hz,1H), 7.09~7.12(m,2H), 7.66(s,1H), 7.76~7.78(m,2H); 13C NMR (150MHz, CDCl3) δ11.9, 18.5, 18.7, 22.1, 23.4, 27.5, 28.8, 31.0, 35.8, 36.1, 40.0, 45.7, 47.4, 55.6, 56.3, 76.3 (septet, J=28.8Hz) , 112.8, 115.8(d,J=21.6Hz), 118.8, 123.3(q,J=284.4Hz), 126.7, 127.5(d,J=8.6Hz), 146.9, 147.4, 162.7(d,J=245.6Hz) + )C 28 H 34 N3OF7Na[M+Na] + The calculated value is 584.2482, and the measured value is 584.2477.

[0271] Examples 30 and 31 (6R)-1,1,1-trifluoro-6-{(1R,3aS,7aR,E)-7a-methyl-4-[2-(5-phenyl-2H-tetrazole-2-yl)ethylidene]octahydro-1H-inden-1-yl}2-(trifluoromethyl)heptan-2-ol(40KK-048)

[0272] [ka] (6R)-1,1,1-trifluoro-6-{(1R,3aS,7aR,E)-7a-methyl-4-[2-(5-phenyl-1H-tetrazole-1-yl)ethylidene]octahydro-1H-inden-1-yl}2-(trifluoromethyl)heptan-2-ol(41KK-049)

[0273] [ka]

[0274]

[0174] To a solution of 5-phenyl-1H-tetrazole (166.6 mg, 1.14 mmol), Ph3P (199.3 mg, 0.76 mmol), and CD ring 36 (175.0 mg, 0.38 mmol) in THF (5 mL), diisopropyl azodicarboxylate (600 μL, 1.9 M in toluene, 1.14 mmol) was added at 0°C, and the mixture was stirred for 1 hour. After quenching the reaction with H2O at 0°C, the mixture was extracted three times with toluene, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was roughly purified on silica gel by flash column chromatography (hexane:toluene = 4:1) to obtain the crude product (low-polarity and high-polarity products) as a colorless oil.

[0275]

[0175] Methanesulfonic acid (0.4 mL) was added to the solution of the above low-polarity crude product in MeOH (20 mL). The mixture was stirred at room temperature under air for 6 hours. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with siRNA, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:siRNA = 10:1) to obtain 40KK-048 (87.2 mg, 42%) as a colorless oil.

[0276]

[0176] 40 KK-048:[α] D 27 +33.8(c 0.68,CHCl3); IR (undiluted) 3205, 1471, 1452, 1228, 1176, 734 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.54(s,3H), 0.94(d,J=6.6Hz,3H), 1.04~1.11(m,1H), 1.23~2.03(m,17H) ), 2.83~2.86(m,1H), 3.13(brs,1H), 5.28~5.45(m,3H), 7.44~7.50(m,3H), 8.13~8.15(m,2H); 13C NMR (150MHz, CDCl3) δ11.8, 18.5, 18.7, 22.0, 23.3, 27.5, 29.1, 30.8, 35.8, 36.1, 40.1, 45.9, 50.2, 55.6, 56 .3, 76.2 (septet, J=28.7Hz), 111.7, 123.2 (q, J=284.4Hz), 126.8, 127.6, 128.8, 130.2, 147.9, 165.0; HRMS (ESI - )C 28 H 35 N4O3F6[M+HCOO] - The calculated value is 589.2619, and the measured value is 589.2594.

[0277]

[0177] Methanesulfonic acid (0.4 mL) was added to the solution of the above highly polar crude product in MeOH (20 mL). The mixture was stirred at room temperature under air for 8 hours. After quenching the reaction at room temperature with H2O and saturated aqueous solution NaHCO3, the mixture was extracted three times with siRNA, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 2:1) to obtain 41KK-049 (35.7 mg, 17%) as a colorless oil.

[0278]

[0178] 41 KK-049:[α] D 27 +40.5(c 0.19,CHCl3); IR (undiluted) 3227, 1475, 1225, 759 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.44(s,3H), 0.92(d,J=6.0Hz,3H), 1.03~1.10(m,1H), 1.20~1.99(m,17H) ), 2.51~2.55(m,1H), 3.85(brs,1H), 5.06~5.17(m,3H), 7.53~7.59(m,3H), 7.67~7.68(m,2H); 13C NMR (150MHz, CDCl3) δ11.8, 18.4, 18.6, 22.0, 23.1, 27.4, 28.9, 30.9, 35.8, 36.1, 40.0, 45.6, 45.7, 55.4, 56 .2, 76.3 (septet, J=28.8Hz), 112.8, 123.3 (q, J=284.4Hz), 124.0, 128.8, 129.2, 131.2, 146.5, 154.1; HRMS (ESI - )C 28 H 35 N4O3F6[M+HCOO] - The calculated value is 589.2619, and the measured value is 589.2582.

[0279] Reference Example 2 24,24-difluorinated side chain (1R,3aR,7aR)-1-{(2R)-5,5-difluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-one(43)

[0280] [ka]

[0281]

[0179] See Flores, A.; Massarelli, I.; Thoden, JB; Plum, LA; DeLuca, HF; A methylene group on C-2 of 24,24-difluoro-19-nor-1α,25-dihydroxyvitamin D3 markedly increases bone calcium mobilization in vivo. J.Med.Chem. 2015, 58, 9731~9741.

[0282]

[0180] Kawagoe,F.;Mototani,S.;Yasuda,K.;Nagasawa,K.;Uesugi,M.;Sakaki,T.;Kittaka,A.Introduction of fluorine atoms to vitamin D3 side-chain and synthesis of24,24-difluoro-25-hydroxyvitamin D3.J.Steroid See Biochem.Mol.Biol.2019,195,#105477.

[0283] (E)-2-(1-{(2R)-5,5-difluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene)ethane-1-ol(44)

[0284] [ka]

[0285]

[0181] To a suspension of NaH (315.1 mg, 60% in liquid paraffin, 7.90 mmol) in THF (5 mL), (EtO)2P(O)CH2CO2Et (1.90 g, 1.7 mL, 8.46 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. Ketone 43 (331.1 mg, 0.769 mmol) was dissolved in THF, and the solution was added to the mixture at the same temperature. After stirring at room temperature for 72 hours, the reaction mixture was quenched at room temperature with H2O and saturated aqueous solution NH4Cl. The mixture was extracted three times with ethyl acetate, washed with saturated brine, dried on Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:ethyl acetate = 10:1) to obtain crude ethyl ester (343.7 mg) as a colorless oil.

[0286]

[0182] To a solution of the above ethyl ester (343.7 mg) in THF (10 mL), DIBAL-H (4.1 mL, 1.0 M toluene solution, 4.1 mmol) was added at -78°C, and the mixture was stirred at room temperature for 40 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous potassium sodium tartrate, the mixture was extracted three times with SiO2, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:SiO2 = 7:1) to obtain alcohol 44 as a colorless oil (278.8 mg, 79%, 2 steps).

[0287]

[0183] 44:[α] D 27 +42.6 (c 0.68, CHCl3); IR (undiluted) 3330, 1458, 1384, 1198, 1162, 1054, 738 cm -1 ; 1 H NMR(600MHz, CDCl3)δ0.56(s,3H), 0.60(q,J=7.8Hz,6H), 0.93~0.96(m,12H), 1 .24~2.05(m,23H), 2.61~2.64(m,1H), 4.17~4.23(m,2H), 5.22(t,J=6.9Hz,1H); 13 C NMR (150MHz, CDCl3) δ6.6, 6.9, 11.8, 18.6, 22.1, 23.5, 24.3, 24.6, 26.8, 27.0 (t, J=24.5Hz), 27.4, 28.7 , 35.7, 40.3, 45.3, 55.6, 56.3, 58.7, 75.6(t,J=28.7Hz), 119.3, 125.3(t,J=247.1Hz), 143.7;HRMS(ESI + )C 26 H 48 O2F2SiNa[M+Na] + The calculated value is 481.3284, and the measured value is 481.3254.

[0288] ({(6R)-6-[(1R,3aS,7aR,E)-4-(2-azidoethylidene)-7a-methyloctahydro-1H-inden-1-yl]-3,3-difluoro-2-methylheptan-2-yl}oxy)triethylsilane(45)

[0289] [ka]

[0290]

[0184] In a solution of 44 (133.0 mg, 0.29 mmol) and pyridine (70 μL, 0.87 mmol) in CCl4 (10 mL), tri-n-butylphosphine (362 μL, 1.45 mmol) was added over 10 minutes at 0°C, and the mixture was stirred at the same temperature for 10 minutes. The reaction product was diluted with hexane, and the mixture was filtered and concentrated. Hexane was added to the resulting residue, and the mixture was filtered and concentrated. The obtained crude allyl chloride was used in the next reaction without further purification.

[0291]

[0185] To the above crude allyl chloride solution in DMF (15 mL), NaN3 (57.2 mg, 0.88 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. After quenching the reaction with H2O, the mixture was extracted three times with toluene, washed with saturated brine, dried on Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:toluene = 50:1) to obtain azide 45 as a colorless oil (114.1 mg, 81%, 2 steps).

[0292]

[0186] 45:[α] D 27 +35.3 (c 2.43, CHCl3); IR (undiluted) 2104, 1464, 1380, 1240, 1197, 1161, 1057, 734 cm -1 ; 1H NMR (400MHz, CDCl3) δ0.57~0.63(m,9H), 0.93(m,12H), 1.24~2.02(m,23H), 3.7 3(dd,J=7.3,13.3Hz,1H), 3.90(dd,J=8.3,13.3Hz,1H), 5.13(t,J=7.6Hz,1H); 13 C NMR (100MHz, CDCl3) δ6.6, 6.9, 11.8, 22.1, 23.8, 24.3, 26.8, 27.0 (t, J=24.8Hz), 27.4, 28.8, 35.7 , 40.2, 45.1, 47.4, 55.8, 56.3, 75.6(t,J=28.1Hz), 112.7, 125.3(t,J=247.9Hz), 147.1;HRMS(ESI + )C 26 H 48 N3OF2Si[M+H] + The calculated value is 484.3529, and the measured value is 484.3518.

[0293] Example 32 (6R)-3,3-difluoro-2-methyl-6-{(1R,3aS,7aR,E)-7a-methyl-4-[2-(4-phenyl-1H-1,2,3-triazole-1-yl)ethylidene]octahydro-1H-inden-1-yl}heptan-2-ol(46KK-053)

[0294] [ka]

[0295]

[0187] To a mixture of phenylacetylene (20 μL, 0.186 mmol), 2,6-lutidine (29 μL, 0.248 mmol), sodium ascorbate (33.1 mg, 0.167 mmol), and 24,24-difluoro-CD ring 45 (60 mg, 0.124 mmol) in tBuOH (3 mL) and H2O (3 mL), CuSO4·5H2O (3.2 mg, 0.013 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 22 hours. After quenching the reaction with H2O, the mixture was extracted three times with ELISA, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting crude triazole product was used in the next reaction without further purification.

[0296]

[0188] p-toluenesulfonic acid monohydrate (190.2 mg, 1.0 mmol) was added to the solution of the crude triazole product in MeOH (10 mL). The mixture was stirred at room temperature under air for 1 hour. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with siRNA, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 1:1) to obtain 46KK-053 as a colorless oil (24.7 mg, 47%, 2 steps).

[0297]

[0189] 46 KK-053:[α] D 27 +48.3 (c 0.45, CHCl3); IR (undiluted) 3378, 1470, 1380, 1177, 1017, 767, 696 cm -1 ; 1 H NMR (400MHz, CDCl3) δ0.59(s,3H), 0.96(d,J=6.4Hz,3H), 1.25~2.07(m,23H), 2.72~2.77(m,1H), 5.03~5.12( m,2H), 5.28(t,J=7.3Hz,1H), 7.32(tt,J=0.9,7.3Hz,1H), 7.40~7.44(m,2H), 7.70(s,1H), 7.81~7.83(m,2H); 13C NMR(100MHz,CDCl3)δ11.9, 18.6, 22.0, 23.3, 23.5, 26.7, 27.3, 27.3(t,J=26.7Hz), 28.8, 35.6, 40.0, 45.6, 47.2, 55. 6, 56.1, 73.3(t,J=27.7Hz), 112.9, 118.9, 125.5(t,J=246.0Hz), 125.6, 128.0, 128.7, 130.7, 147.1, 147.7;HRMS(ESI + )C 28 H 39 N3OF2Na[M+Na] + The calculated value is 494.2953, and the measured value is 494.2941.

[0298] Example 32 (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[4-(4-fluorophenyl)-1H-1,2,3-triazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(47KK-057)

[0299] [ka]

[0300]

[0190] To a solution of 4-fluorophenylacetylene (23.3 mg, 0.194 mmol), 2,6-lutidine (21 μL, 0.182 mmol), sodium ascorbate (30.5 mg, 0.154 mmol), and 24,24-difluoro-CD ring 45 (44.0 mg, 0.091 mmol) in tBuOH (3 mL) and H2O (2 mL), CuSO4·5H2O (4.5 mg, 0.018 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 74 hours and 30 minutes. After quenching the reaction with H2O, the mixture was extracted three times with ELISA, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting crude triazole product was used in the next reaction without further purification.

[0301]

[0191] p-toluenesulfonic acid monohydrate (190.2 mg, 1.0 mmol) was added to the solution of the crude triazole product in MeOH (10 mL). The mixture was stirred at room temperature under air for 1 hour. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with siRNA, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 1:1) to obtain 47KK-057 as a colorless oil (30.8 mg, 69%, 2 steps).

[0302]

[0192] 47 KK-057:[α] D 27 +44.2(c 2.37,CHCl3); IR (undiluted) 3393, 1498, 1380, 1230, 1177, 1016, 843, 759 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.58(s,3H), 0.95(d,J=6.6Hz,3H), 1.252.05(m,23H), 2.73~2.75(m,1H) , 5.03~5.10(m,2H), 5.27(t,J=7.2Hz,1H), 7.08~7.12(m,2H), 7.66(s,1H), 7.77~7.80(m,2H); 13 C NMR (150MHz, CDCl3) δ11.9, 18.6, 22.1, 23.4, 23.6, 26.8, 27.4, 27.4(t,J=27.3Hz), 28.8, 35.6, 40.0, 45.7, 47.3, 55.6, 56.2, 73.3(t,J=27 HRMS(ESI + )C 28 H 38 N3OF3Na[M+Na] + The calculated value is 512.2859, and the measured value is 512.2880.

[0303] Examples 32 and 33 (6R)-3,3-difluoro-2-methyl-6-{(1R,3aS,7aR,E)-7a-methyl-4-[2-(5-phenyl-2H-tetrazole-2-yl)ethylidene]octahydro-1H-inden-1-yl}heptan-2-ol(48KK-051)

[0304] [ka] (6R)-3,3-difluoro-2-methyl-6-{(1R,3aS,7aR,E)-7a-methyl-4-[2-(5-phenyl-1H-tetrazole-1-yl)ethylidene]octahydro-1H-inden-1-yl}heptan-2-ol(50KK-052)

[0305] [ka]

[0306]

[0193] To a solution of 5-phenyl-1H-tetrazole (126.7 mg, 0.867 mmol), Ph3P (152.3 mg, 0.581 mmol), and 24,24-difluoro-CD ring 44 (132.0 mg, 0.288 mmol) in THF (5 mL), diisopropyl azodicarboxylate (454 μL, 1.9 M in toluene, 0.863 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 45 minutes. After quenching the reaction with H2O at 0°C, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was roughly purified on silica gel by flash column chromatography (hexane:siRNA = 4:1) to obtain the crude product (low-polarity and high-polarity products) as a colorless oil.

[0307]

[0194] p-toluenesulfonic acid monohydrate (190.2 mg, 1.0 mmol) was added to the solution of the above low-polarity crude product in MeOH (10 mL). The mixture was stirred at room temperature under air for 1 hour. After quenching the reaction at room temperature with H2O and saturated aqueous solution NaHCO3, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel by flash column chromatography (hexane:siRNA = 3:1) to obtain 48KK-051 (65.4 mg, 48%) as a colorless oil.

[0308]

[0195] 48 KK-051:[α] D 27 +38.1(c 0.54,CHCl3); IR (undiluted) 3445, 1468, 1450, 1381, 1177, 1017, 736, 695 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.55(s,3H), 0.94(d,J=6.6Hz,3H), 1.272.04(m,23H), 2.84 (dd,J=3.9,15.9Hz,1H), 5.25~5.35(m,3H), 7.43~7.49(m,3H), 8.13~8.15(m,2H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.6, 22.0, 23.3, 23.5, 26.7, 27.4(t,J=25.1Hz), 27.4, 29.0, 35.6, 40.1, 45.8, 50.1, HRMS (ESI + )C 27 H 38 N4OF2Na[M+Na] + The calculated value is 495.2906, and the measured value is 495.2891.

[0309]

[0196] p-toluenesulfonic acid monohydrate (190.8 mg, 1.0 mmol) was added to the solution of the above highly polar crude product in MeOH (10 mL). The mixture was stirred at room temperature under air for 1 hour. After quenching the reaction at room temperature with H2O and saturated aqueous solution NaHCO3, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 1:1) to obtain 50KK-052 (16.3 mg, 12%) as a colorless oil.

[0310]

[0197] 50 KK-052:[α] D 27 +46.6(c 1.28,CHCl3); IR (undiluted) 3408, 1471, 1381, 1177, 1017, 698 cm -1 ; 1 H NMR(400MHz, CDCl3)δ0.46(s,3H), 0.93(d,J=6.4Hz,3H), 1.26~2.08(m,23H) , 2.53~2.57(m,1H), 5.04~5.17(m,3H), 7.52~7.60(m,3H), 7.68~7.70(m,2H); 13 C NMR (100MHz, CDCl3) δ11.8, 18.6, 22.0, 23.1, 23.6, 26.7, 27.3, 27.3 (t, J=24.8Hz), 28.9, 35.6, 40.0, 45.6, 45.7, HRMS (ESI + )C 27 H 38 N4OF2Na[M+Na] + The calculated value is 495.2906, and the measured value is 495.2908.

[0311] Examples 34 and 35 (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(4-fluorophenyl)-2H-tetrazole-2-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(49KK-061)

[0312] [ka] (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(4-fluorophenyl)-1H-tetrazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(51KK-062)

[0313] [ka]

[0314]

[0198] To a solution of 5-(4-fluorophenyl)-1H-tetrazole (75.8 mg, 0.462 mmol), Ph3P (79.4 mg, 0.303 mmol), and 24,24-difluoro-CD ring 44 (69.4 mg, 0.151 mmol) in CH2Cl2 (3 mL), diisopropyl azodicarboxylate (239 μL, 1.9 M in toluene, 0.454 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 2 hours. After quenching the reaction with H2O at 0°C, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was roughly purified on silica gel by flash column chromatography (hexane:siRNA = 4:1) to obtain crude products (low-polarity and high-polarity products).

[0315]

[0199] p-toluenesulfonic acid monohydrate (96.9 mg, 0.509 mmol) was added to the solution of the above low-polarity crude product in MeOH (5 mL) and CH2Cl2 (5 mL). The mixture was stirred at room temperature under air for 150 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with toluene, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:toluene = 3:1) to obtain 49KK-061 (37.9 mg, 51%) as a colorless oil.

[0316]

[0200] 49 KK-061:[α] D 27 +39.0 (c 2.92, CHCl3); IR (undiluted) 3430, 1464, 1380, 1177, 1043, 848, 763 cm -1 ; 1 H NMR(600MHz, CDCl3)δ0.55(s,3H), 0.95(d,J=7.2Hz,3H), 1.26~2.04(m,23H), 2.84 (dd,J=4.2,13.2Hz,1H), 5.21~5.34(m,3H), 7.14~7.18(m,2H), 8.11~8.14(m,2H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.6, 22.0, 23.3, 23.6, 26.8, 27.4(t,J=24.5Hz), 27.4, 29.0, 35.6, 40.1, 45.8, 50.2, 55.6, 56.1, 73.3(t,J HRMS (ESI + )C 27 H 37 N4OF3Na[M+Na] + The calculated value is 513.2812, and the measured value is 513.2812.

[0317]

[0201] p-toluenesulfonic acid monohydrate (94.6 mg, 0.497 mmol) was added to the solution of the above highly polar crude product in MeOH (5 mL). The mixture was stirred at room temperature under air for 120 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with siRNA, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 1:1) to obtain 51KK-062 (16.9 mg, 23%) as a colorless oil.

[0318]

[0202] 51 KK-062:[α] D 27 +45.2(c 1.30,CHCl3); IR (undiluted) 3399, 1479, 1384, 1240, 1176, 1017, 851, 698 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.47(s,3H), 0.93(d,J=6.6Hz,3H), 1.242.01(m,23H), 2.54~2.57(m,1H), 5.05~5.15(m,3H), 7.23~7.25(m,2H), 7.69~7.72(m,2H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.6, 22.0, 23.1, 23.6, 26.7, 27.3, 27.4(t,J=24.5Hz), 28.9, 35.6, 39.9, 45.6, 45.7, 55.5, 56.1, 73.3(t,J=26.6H HRMS (ESI + )C 27 H 37 N4OF3Na[M+Na] + The calculated value is 513.2812, and the measured value is 513.2816.

[0319] Examples 36 and 37 (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(4-methylphenyl)-2H-tetrazole-2-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(52)

[0320] [ka] (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(4-methylphenyl)-1H-tetrazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(53)

[0321] [ka]

[0322]

[0203] To a solution of 5-(4-methylphenyl)-1H-tetrazole (29.5 mg, 0.184 mmol), Ph3P (52.7 mg, 0.201 mmol), and 24,24-difluoro-CD ring (44) (42.4 mg, 0.092 mmol) in CH2Cl2 (3 mL), diisopropyl azodicarboxylate (88 μL, 1.9 M in toluene, 0.166 mmol) was added at 0°C, and the mixture was stirred at 0°C for 5 minutes, then at room temperature for 40 minutes. The mixture was concentrated under vacuum. The resulting residue was crudely purified on silica gel by flash column chromatography (hexane:siRNA = 5:1-3:1) to obtain crude products (low-polarity and high-polarity products).

[0323]

[0204] p-toluenesulfonic acid monohydrate (109.6 mg, 0.576 mmol) was added to the solution of the above low-polarity crude product in MeOH (5 mL) and CH2Cl2 (2 mL). The mixture was stirred at room temperature under air for 1 hour. p-toluenesulfonic acid monohydrate (109.6 mg, 0.576 mmol) was added to the mixture and stirred for a further 30 minutes at the same temperature. After quenching the reaction with H2O and saturated aqueous solution NaHCO3 at room temperature, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:Â=3:1) to obtain 52 (13.5 mg, 30%) as colorless oil.

[0324]

[0205] 52:[α] D 27 +35.9 (c 1.04, CHCl3); IR (undiluted) 3442, 1464, 1380, 1176, 1041, 1017, 830, 754 cm -1 ; 1 H NMR (600MHz, CDCl3) δ0.54(s,3H), 0.94(d,J=6.6Hz,3H), 1.25~2.04(m,23H), 2.41(s,3 H), 2.83~2.85(m,1H), 5.21~5.35(m,3H), 7.28(d,J=7.8Hz,2H), 8.02(d,J=7.8Hz,2H); 13 C NMR(150MHz,CDCl3)δ11.8, 18.6, 21.5, 22.0, 23.3, 23.6, 26.8, 27.4(t,J=24.4Hz), 27.4, 29.1, 35.6, 40.1, 45.8, 50. HRMS (ESI + )C 28 H 40 N4OF2Na[M+Na] + The calculated value is 509.3062, and the measured value is 509.3075.

[0325]

[0206] p-toluenesulfonic acid monohydrate (203.6 mg, 1.07 mmol) was added to the solution of the above highly polar crude product in MeOH (5 mL) and CH2Cl2 (2 mL). The mixture was stirred at room temperature under air for 70 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 1:1) to obtain 53 (12.7 mg, 28%) as colorless oil.

[0326]

[0207] 53:[α] D 27 +41.3 (c 0.98, CHCl3); IR (undiluted) 3418, 1479, 1380, 1176, 1013, 826, 759 cm -1 ; 1 H NMR (600MHz, CDCl3) δ0.48(s,3H), 0.94(d,J=7.2Hz,3H), 1.24~2.01(m,23H), 2.45(s,3 H), 2.56~2.58(m,1H), 5.04~5.15(m,3H), 7.34(d,J=7.2Hz,2H), 7.59(d,J=7.2Hz,2H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.6, 21.5, 22.1, 23.1, 23.6, 26.7, 27.3, 27.4(t,J=24.5Hz), 28.9, 35.6, 40.0, 45.6, 45. 6, 55.5, 56.1, 73.3(t,J=27.3Hz), 113.1, 121.2, 125.4(t,J=245.6Hz), 128.7, 129.8, 141.6, 146.2, 154.1;HRMS(ESI + )C 28 H 40 N4OF2Na[M+Na] + The calculated value is 509.3062, and the measured value is 509.3079.

[0327] Examples 38 and 39 (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(4-trifluoromethylphenyl)-2H-tetrazole-2-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(54)

[0328] [ka] (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(4-trifluoromethylphenyl)-1H-tetrazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(55)

[0329] [ka]

[0330]

[0208] To a solution of 5-(4-trifluoromethylphenyl)-1H-tetrazole (61.5 mg, 0.287 mmol), Ph3P (72.2 mg, 0.275 mmol), and 24,24-difluoro-CD ring (44) (60.1 mg, 0.131 mmol) in CH2Cl2 (8 mL), diisopropyl azodicarboxylate (124 μL, 1.9 M in toluene, 0.235 mmol) was added at 0°C, and the mixture was stirred at 0°C for 70 minutes. The mixture was concentrated under vacuum, and the resulting residue was crudely purified on silica gel by flash column chromatography (hexane:siRNA = 4:1) to obtain crude products (low-polarity and high-polarity products).

[0331]

[0209] p-toluenesulfonic acid monohydrate (386.8 mg, 2.03 mmol) was added to the solution of the above low-polarity crude product in MeOH (5 mL) and CH2Cl2 (2 mL). The mixture was stirred at room temperature under air for 35 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous solution NaHCO3, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:Â=3:1) to obtain 54 (41.4 mg, 58%) as a white powder.

[0332]

[0210] 54:[α] D 27 +35.2(c 3.17,CHCl3); IR (undiluted) 3431, 1471, 1324, 1173, 1133, 1066, 858 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.55(s,3H), 0.95(d,J=6.0Hz,3H), 1.26~2.05(m,23H), 2. 83~2.86(m,1H), 5.27~5.35(m,3H), 7.74(d,J=8.1Hz,2H), 8.26(d,J=8.1Hz,2H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.6, 22.0, 23.4, 23.56, 26.8, 27.4, 27.4(t,J=24.4Hz), 29.1, 35.6, 40.1, 45.9, 50.3, 55.6, 56.1, 73.3( HRMS (ESI) - )C 28 H 37 N4OF5Cl[M+Cl] - The calculated value is 575.2582, and the measured value is 575.2577.

[0333]

[0211] p-toluenesulfonic acid monohydrate (411.7 mg, 2.05 mmol) was added to the solution of the above highly polar crude product in MeOH (5 mL) and CH2Cl2 (6 mL). The mixture was stirred at room temperature under air for 60 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous solution NaHCO3, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 1:1) to obtain 55 (15.1 mg, 21%) as a white powder.

[0334]

[0212] 55:[α] D 27 +40.8(c 1.16,CHCl3); IR (undiluted) 3522, 1459, 1328, 1173, 1129, 1073, 858 cm -1 ; 1 H NMR(400MHz,CDCl3)δ0.45(s,3H), 0.93(d,J=6.4Hz,3H), 1.22~2.10(m,23H), 2. 53~2.57(m,1H), 5.04~5.20(m,3H), 7.82(d,J=8.7Hz,2H), 7.85(d,J=8.2Hz,2H); 13 C NMR (100MHz, CDCl3) δ11.8, 18.6, 22.0, 23.4, 23.55, 26.7, 27.3, 27.3(t,J=24.8Hz), 28.9, 35.6, 39.9, 45.6, 45.9, 55.5, 56.1, 73.3( HRMS (ESI) - )C 28 H 37 N4OF5Cl[M+Cl] - The calculated value is 575.2582, and the measured value is 575.2590.

[0335] Examples 40 and 41 (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(4-chlorophenyl)-2H-tetrazole-2-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(56)

[0336] [ka] (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(4-chlorophenyl)-1H-tetrazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(57)

[0337] [ka]

[0338]

[0213] To a solution of 5-(4-chlorophenyl)-1H-tetrazole (44.7 mg, 0.248 mmol), Ph3P (67.6 mg, 0.258 mmol), and 24,24-difluoro-CD ring (44) (49.8 mg, 0.109 mmol) in CH2Cl2 (8 mL), diisopropyl azodicarboxylate (103 μL, 1.9 M in toluene, 0.196 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 110 minutes. The mixture was concentrated under vacuum, and the resulting residue was roughly purified on silica gel by flash column chromatography (hexane:siRNA = 5:1) to obtain crude products (low-polarity and high-polarity products).

[0339]

[0214] p-toluenesulfonic acid monohydrate (435.3 mg, 2.29 mmol) was added to the solution of the above low-polarity crude product in MeOH (5 mL) and CH2Cl2 (5 mL). The mixture was stirred at room temperature under air for 1 hour. After quenching the reaction at room temperature with H2O and saturated aqueous solution NaHCO3, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:Â=3:1) to obtain 56 (31.4 mg, 57%) as colorless oil.

[0340]

[0215] 56:[α] D 27 +41.4(c 2.42,CHCl3); IR (undiluted) 3414, 1456, 1326, 1175, 1093, 1017, 841, 759 cm -1 ; 1 H NMR(400MHz, CDCl3)δ0.54(s,3H), 0.94(d,J=6.4Hz,3H), 1.23~2.05(m,23H), 2.81~ 2.85(m,1H), 5.20~5.35(m,3H), 7.45(dt,2.3,8.2Hz,2H), 8.07(dt,2.3,8.7Hz,2H); 13 C NMR(100MHz,CDCl3)δ11.8, 18.6, 22.0, 23.3, 23.5, 26.7, 27.4(t,J=24.8Hz), 29.0, 35.6, 40.1, 45.8, 50.2, 55. 6, 56.1, 73.3(t,J=27.2Hz), 111.6, 125.5(t,J=246.0Hz), 126.1, 128.0, 129.1, 136.1, 148.0, 164.1;HRMS(ESI + )C 27 H 37 N4OF2ClNa[M+Na] + The calculated value is 529.2516, and the measured value is 529.2531.

[0341]

[0216] p-toluenesulfonic acid monohydrate (389.5 mg, 2.05 mmol) was added to the solution of the above highly polar crude product in MeOH (5 mL) and CH2Cl2 (5 mL). The mixture was stirred at room temperature under air for 85 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous solution NaHCO3, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:Â=1:1) to obtain 57 (15.3 mg, 28%) as colorless oil.

[0342]

[0217] 57:[α] D 27 +43.0 (c 1.18, CHCl3); IR (undiluted) 3423, 1471, 1380, 1174, 1093, 1013, 838, 739 cm -1 ; 1 H NMR (400MHz, CDCl3) δ0.47(s,3H), 0.93(d,J=6.4Hz,3H), 1.24~2.05(m,23H), 2.54~2. 58(m,1H), 5.03~5.18(m,3H), 7.53(dt,J=2.1,8.2Hz,2H), 7.65(dt,J=2.1,8.7Hz,2H); 13 C NMR (100MHz, CDCl3) δ11.8, 18.6, 22.0, 23.1, 23.5, 26.7, 27.3, 27.3 (t, J=24.3Hz), 28.9, 35.6, 39.9, 45.6, 45.8, HRMS (ESI + )C 27 H 37 N4OF2ClNa[M+Na] + The calculated value is 529.2516, and the measured value is 529.2510.

[0343] Examples 42 and 43 (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(3-methylphenyl)-2H-tetrazole-2-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(58)

[0344] [ka] (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(3-methylphenyl)-1H-tetrazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(59)

[0345] [ka]

[0346]

[0218] To a solution of 5-(3-methylphenyl)-1H-tetrazole (28.6 mg, 0.179 mmol), Ph3P (47.8 mg, 0.182 mmol), and 24,24-difluoro-CD ring (44) (51.4 mg, 0.112 mmol) in CH2Cl2 (8 mL), diisopropyl azodicarboxylate (83 μL, 1.9 M in toluene, 0.157 mmol) was added at 0°C, and the mixture was stirred at 0°C for 5 minutes, then at room temperature for 20 minutes. Diisopropyl azodicarboxylate (83 μL, 1.9 M in toluene, 0.157 mmol) and Ph3P (83.7 mg, 0.319 mmol) were added to the mixture, and the mixture was stirred at room temperature for 40 minutes. The mixture was concentrated under vacuum, and the resulting residue was roughly purified on a preparative silica gel TLC plate (hexane:Â=3:1) to obtain crude products (low-polarity and high-polarity products).

[0347]

[0219] p-toluenesulfonic acid monohydrate (584.6 mg, 3.07 mmol) was added to the solution of the above low-polarity crude product in MeOH (10 mL) and CH2Cl2 (5 mL). The mixture was stirred at room temperature under air for 90 minutes. After quenching the reaction with H2O and saturated aqueous solution NaHCO3 at room temperature, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:Â=2:1) ​​to obtain 58 (38.1 mg, 70%) as colorless oil.

[0348]

[0220] 58:[α] D 27 +23.1(c 2.93,CHCl3); IR (undiluted) 3423, 1471, 1380, 1180, 1017, 858, 754 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.55(s,3H), 0.95(d,J=6.0Hz,3H), 1.26~2.06(m,23H), 2.43(s,3H), 2.83~2.86(m, 1H), 5.22~5.35(m,3H), 7.27(d,J=7.8Hz,1H), 7.37(t,J=7.8Hz,2H), 7.93(d,J=7.8Hz,1H), 7.97(s,1H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.6, 21.4, 22.0, 23.3, 23.6, 26.8, 27.4(t,J=24.4Hz), 27.4, 29.0, 35.6, 40.1, 45.8, 50.2, 55.6 HRMS (ESI + )C 28 H 40 N4OF2Na[M+Na] + The calculated value is 509.3062, and the measured value is 509.3068.

[0349]

[0221] p-toluenesulfonic acid monohydrate (376.1 mg, 1.98 mmol) was added to the solution of the above highly polar crude product in MeOH (10 mL) and CH2Cl2 (5 mL). The mixture was stirred at room temperature under air for 60 minutes. After quenching the reaction with H2O and saturated aqueous solution NaHCO3 at room temperature, the mixture was extracted three times with CH2Cl2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 1:2) to obtain 59 (11.0 mg, 20%) as colorless oil.

[0350]

[0222] 59:[α] D 27 +44.6 (c 0.85, CHCl3); IR (undiluted) 3411, 1475, 1380, 1180, 1125, 1021, 918, 854, 739 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.46(s,3H), 0.93(d,J=6.0Hz,3H), 1.24~1.99(m,23H), 2.43(s,3H), 2.53~2.56(m, 1H), 5.04~5.16(m,3H), 7.38(d,J=7.8Hz,1H), 7.42(t,J=7.8Hz,1H), 7.45(d,J=7.8Hz,1H), 7.51(s,1H); 13 C NMR(150MHz,CDCl3)δ11.8, 18.6, 21.4, 22.0, 23.1, 23.6, 26.7, 27.3, 27.3(t,J=24.5Hz), 28.9, 35.6, 40.0, 45.5, 45. 6, 55.5, 56.1, 73.3(t,J=27.2Hz), 113.0, 124.1, 125.4(t,J=246.3Hz), 128.9, 129.5, 139.2, 146.2, 154.2;HRMS(ESI + )C 28 H 40 N4OF2Na[M+Na] + The calculated value is 509.3062, and the measured value is 509.3039.

[0351] Examples 44 and 45 (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(3,5-dichlorophenyl)-2H-tetrazole-2-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(60)

[0352] [ka] (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(3,5-dichlorophenyl)-1H-tetrazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(61)

[0353] [ka]

[0354]

[0223] To a solution of 5-(3,5-dichlorophenyl)-1H-tetrazole (40.8 mg, 0.190 mmol), Ph3P (47.6 mg, 0.181 mmol), and 24,24-difluoro-CD ring (44) (40.8 mg, 0.089 mmol) in CH2Cl2 (4 mL), diisopropyl azodicarboxylate (138 μL, 1.9 M in toluene, 0.262 mmol) was added at 0°C, and the mixture was stirred at 0°C for 35 minutes, then at room temperature for 25 minutes. The mixture was concentrated under vacuum, and the resulting residue was roughly purified on a preparative silica gel TLC plate (hexane:Ã=3:1) to obtain crude products (low-polarity and high-polarity products).

[0355]

[0224] p-toluenesulfonic acid monohydrate (200.3 mg, 1.05 mmol) was added to the solution of the above low-polarity crude product in MeOH (10 mL) and CH2Cl2 (5 mL). The mixture was stirred at room temperature under air for 2 hours. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with siRNA, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 1:1), and then re-purified on a preparative silica gel TLC plate (hexane:siRNA = 2:1) to obtain 60 (27.6 mg, 57%) as colorless oil.

[0356]

[0225] 60:[α] D 27 +33.8(c 2.12,CHCl3); IR (undiluted) 3439, 1571, 1515, 1444, 1399, 1173, 1017, 862, 735 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.55(s,3H), 0.95(d,J=6.0Hz,3H), 1.24~2.05(m,23H), 2. 81~2.84(m,1H), 5.25~5.34(m,3H), 7.45(t,J=2.4Hz,1H), 8.07(d,J=2.4Hz,2H); 13 C NMR(150MHz,CDCl3)δ11.8, 18.6, 22.0, 23.3, 23.6, 26.8, 27.4(t,J=24.4Hz), 27.4, 29.0, 35.6, 40.1, 45.9, 50.4, HRMS (ESI - )C 28 H 37 N4O3F2Cl2[M+HCOO] - The calculated value is 585.2216, and the measured value is 585.2215.

[0357]

[0226] p-toluenesulfonic acid monohydrate (580.1 mg, 3.05 mmol) was added to the solution of the above highly polar crude product in MeOH (20 mL). The mixture was stirred at room temperature under air for 1 hour. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with toluene, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:toluene = 1:1), and then re-purified on a preparative silica gel TLC plate (hexane:toluene = 1:1) to obtain 61 (15.0 mg, 31%) as colorless oil.

[0358]

[0227] 61:[α] D 27 +30.1(c 1.15,CHCl3); IR (undiluted) 3435, 1567, 1527, 1451, 1380, 1176, 1013, 905, 866, 727 cm -1 ; 1 H NMR(600MHz,CDCl3)δ0.55(s,3H), 0.95(d,J=6.0Hz,3H), 1.24~2.05(m,23H), 2. 81~2.84(m,1H), 5.25~5.34(m,3H), 7.45(t,J=2.4Hz,1H), 8.07(d,J=2.4Hz,2H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.6, 22.0, 23.1, 23.7, 26.7, 27.3, 27.3 (t, J=24.4Hz), 28.9, 35.6, 39.9, 45.6, 46.1, HRMS (ESI - )C 28 H 37 N4O3F2Cl2[M+HCOO] - The calculated value is 585.2216, and the measured value is 585.2221.

[0359] Examples 46 and 47 (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(3-fluorophenyl)-2H-tetrazole-2-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(62)

[0360] [ka] (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(3-fluorophenyl)-1H-tetrazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(63)

[0361] [ka]

[0362]

[0228] To a solution of 5-(3-fluorophenyl)-1H-tetrazole (36.4 mg, 0.222 mmol), Ph3P (58.9 mg, 0.225 mmol), and 24,24-difluoro-CD ring (44) (52.9 mg, 0.115 mmol) in CH2Cl2 (8 mL), diisopropyl azodicarboxylate (103 μL, 1.9 M in toluene, 0.196 mmol) was added at 0°C, and the mixture was stirred at 0°C for 20 minutes. The mixture was concentrated under vacuum, and the resulting residue was crudely purified on silica gel by flash column chromatography (hexane:Â=5:1-2:1) to obtain crude products (low-polarity and high-polarity products).

[0363]

[0229] p-toluenesulfonic acid monohydrate (123.3 mg, 0.65 mmol) was added to the solution of the above low-polarity crude product in MeOH (10 mL). The mixture was stirred at room temperature under air for 1 hour. After quenching the reaction with H2O and saturated aqueous NaHCO3 at room temperature, the mixture was extracted three times with toluene, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:toluene = 2:1) to obtain 62 (34.8 mg, 62%) as colorless oil.

[0364]

[0230] 62:[α] D 27 +38.9(c 2.68,CHCl3); IR (undiluted) 3439, 1471, 1380, 1225, 1176, 1021, 763 cm -1 ; 1 H NMR (600MHz, CDCl3) δ0.54(s,3H), 0.94(d,J=6.0Hz,3H), 1.24~2.04(m,23H), 2.83~2.85(m,1H), 5.28~5.37 (m,3H), 7.22(dd,J=8.4,10.2Hz,1H), 7.27(t,J=7.5Hz,3H), 7.24~7.46(m,1H), 8.12(td,J=1.8,7.8Hz,3H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.6, 22.0, 23.3, 23.5, 26.8, 27.3(t,J=24.5Hz), 27.3, 2 9.0, 35.6, 40.1, 45.8, 50.2, 55.6, 56.1, 73.3(t,J=27.3Hz), 111.5, 113.8(d,J=24.5 Hz), 117.0(d,J=21.5Hz), 122.4(d,J=2.9Hz), 125.5(t,J=246.3Hz), 129.6(d,J=8.7 Hz), 130.5(d,J=8.6Hz), 148.1, 163.0(d,J=244.2Hz), 164.0(d,J=3.0Hz) + )C 27 H 37 N4OF3Na[M+Na] + The calculated value is 513.2812, and the measured value is 513.2817.

[0365]

[0231] p-toluenesulfonic acid monohydrate (211.9 mg, 1.11 mmol) was added to the solution of the above highly polar crude product in MeOH (10 mL). The mixture was stirred at room temperature under air for 40 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with dimethyl acetate, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:dimethyl = 1:1) to obtain 63 (10.2 mg, 18%) as colorless oil.

[0366]

[0232] 63:[α] D 27 +66.9 (c 0.79, CHCl3); IR (undiluted) 3411, 1475, 1384, 1204, 1176, 1017, 739 cm -1 ; 1 H NMR (600MHz, CDCl3) δ0.54(s,3H), 0.94(d,J=6.0Hz,3H), 1.24~2.04(m,23H), 2.83~2.85(m,1H), 5.28~5.37 (m,3H), 7.22(dd,J=8.4,10.2Hz,1H), 7.27(t,J=7.5Hz,3H), 7.24~7.46(m,1H), 8.12(td,J=1.8,7.8Hz,3H); 13 C NMR (150MHz, CDCl3) δ11.8, 18.6, 22.0, 23.0, 23.6, 26.7, 27.3, 27.3 (t, J=24.5Hz) , 27.3, 28.9, 35.6, 39.9, 45.6, 45.9, 55.5, 56.1, 73.3(t,J=26.6Hz), 112.7, 116.1( d,J=23.0Hz), 118.3(d,J=21.6Hz), 124.6(d,J=4.4Hz), 125.4(t,J=245.6Hz), 126 .1(d,J=8.6Hz), 131.0(d,J=8.6Hz), 146.7, 153.0, 162.7(d,J=247.1Hz);HRMS(ESI + )C 27 H 37 N4OF3Na[M+Na] +The calculated value is 513.2812, and the measured value is 513.2821.

[0367] Examples 48 and 49 (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(2-chlorophenyl)-2H-tetrazole-2-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(64)

[0368] [ka] (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(2-chlorophenyl)-1H-tetrazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(65)

[0369] [ka]

[0370]

[0233] To a solution of 5-(2-chlorophenyl)-1H-tetrazole (39.9 mg, 0.221 mmol), Ph3P (58.2 mg, 0.222 mmol), and 24,24-difluoro-CD ring (44) (51.7 mg, 0.113 mmol) in CH2Cl2 (8 mL), diisopropyl azodicarboxylate (103 μL, 1.9 M in toluene, 0.196 mmol) was added at 0°C, and the mixture was stirred at 0°C for 35 minutes. The mixture was concentrated under vacuum, and the resulting residue was crudely purified on silica gel by flash column chromatography (hexane:Â=5:1) to obtain crude products (low-polarity and high-polarity products).

[0371]

[0234] p-toluenesulfonic acid monohydrate (573.2 mg, 3.01 mmol) was added to the solution of the above low-polarity crude product in MeOH (20 mL). The mixture was stirred at room temperature under air for 5 hours. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with siRNA, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 3:1) to obtain 64 (22.7 mg, 40%) as colorless oil.

[0372]

[0235] 64:[α] D 27 +37.7(c 1.75,CHCl3); IR (undiluted) 3435, 1446, 1380, 1176, 1125, 1073, 1038, 754 cm -1 ; 1 H NMR (400MHz, CDCl3) δ0.54(s,3H), 0.94(d,J=6.4Hz,3H), 1.24~2.05(m,23H), 2.83~2. 87(m,1H), 5.29~5.39(m,3H), 7.35~7.42(m,2H), 7.52~7.54(m,1H), 7.91~7.96(m,1H); 13 C NMR(100MHz,CDCl3)δ11.8, 18.6, 22.0, 23.4, 23.6, 26.8, 27.4(t,J=24.8Hz), 27.4, 29.0, 35.6, 40.1, 45.8, 50.3, 55.6, 5 HRMS (ESI + )C 27 H 37 N4OF2ClNa[M+Na] + The calculated value is 529.2516, and the measured value is 529.2519.

[0373]

[0236] p-toluenesulfonic acid monohydrate (580.7 mg, 3.05 mmol) was added to the solution of the above highly polar crude product in MeOH (20 mL). The mixture was stirred at room temperature under air for 90 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous NaHCO3, the mixture was extracted three times with siRNA, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:siRNA = 1:1) to obtain 65 (20.7 mg, 36%) as colorless oil.

[0374]

[0237] 65:[α] D 27 +29.4(c 1.59,CHCl3); IR (undiluted) 3407, 1459, 1380, 1176, 1125, 1073, 1020, 767 cm -1 ; 1 H NMR(400MHz, CDCl3)δ0.40(s,3H), 0.91(d,J=6.9Hz,3H), 1.18~2.02(m,23H) , 2.36~2.40(m,1H), 4.91~5.06(m,3H), 7.40~7.45(m,2H), 7.51~7.58(m,2H); 13 C NMR (100MHz, CDCl3) δ11.8, 18.6, 21.9, 23.1, 23.5, 26.7, 27.2, 27.3 (t, J=24.8Hz), 28.5, 35.6, 40.0, 45.4, 55.4, 56.0 , 73.3(t,J=26.7Hz), 112.0, 124.4, 125.4(t,J=246.0Hz), 127.2, 130.1, 131.9, 132.5, 133.9, 147.1, 152.2;HRMS(ESI + )C 27 H 37 N4OF2ClNa[M+Na] + The calculated value is 529.2516, and the measured value is 529.2531.

[0375] Examples 50 and 51 (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(2-fluorophenyl)-2H-tetrazole-2-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(66)

[0376] [ka] (6R)-3,3-difluoro-6-[(1R,3aS,7aR,E)-4-{2-[5-(2-fluorophenyl)-1H-tetrazole-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl]-2-methylheptan-2-ol(67)

[0377] [ka]

[0378]

[0238] To a solution of 5-(2-fluorophenyl)-1H-tetrazole (36.5 mg, 0.222 mmol), Ph3P (59.2 mg, 0.226 mmol), and 24,24-difluoro-CD ring (44) (51.4 mg, 0.112 mmol) in CH2Cl2 (8 mL), diisopropyl azodicarboxylate (103 μL, 1.9 M in toluene, 0.196 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. The mixture was concentrated under vacuum, and the resulting residue was crudely purified on silica gel by flash column chromatography (hexane: Depositphotos = 5:1-2:1) to obtain crude products (low-polarity and high-polarity products).

[0379] p-toluenesulfonic acid monohydrate (585.7 mg, 3.08 mmol) was added to the solution of the above low-polarity crude product in MeOH (20 mL). The mixture was stirred at room temperature under air for 105 minutes. After quenching the reaction at room temperature with H2O and saturated aqueous solution NaHCO3, the mixture was extracted three times with toluene, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:toluene = 2:1) to obtain 66 (30.8 mg, 56%) as colorless oil.

[0380] 66:[α] D 27 +36.7(c 2.37,CHCl3); IR (undiluted) 3435, 1479, 1376, 1228, 1180, 1037, 754 cm -1 ; 1 H NMR (600MHz, CDCl3) δ0.54(s,3H), 0.94(d,J=6.0Hz,3H), 1.24~2.04(m,23H), 2.83~2.85(m,1H), 5.28~5.37 (m,3H), 7.22(dd,J=8.4,10.2Hz,1H), 7.27(t,J=7.5Hz,3H), 7.24~7.46(m,1H), 8.12(td,J=1.8,7.8Hz,3H); 13 C NMR(150MHz,CDCl3)δ11.8, 18.6, 22.0, 23.3, 23.6, 26.8, 27.3(t,J=24.5Hz), 27. 4, 29.1, 35.6, 40.1, 45.8, 50.3, 55.6, 56.1, 73.3(t,J=27.3Hz), 111.6, 115.8(d, J=11.4Hz), 116.6(d,J=20.1Hz), 124.4(d,J=4.2Hz), 125.5(t,J=246.3Hz), 129. 9, 131.1(d,J=8.7Hz), 148.0, 160.1(d,J=254.3Hz), 161.2(d,J=4.4Hz);HRMS(ESI + )C 27 H 37 N4OF3[M+Na] + The calculated value is 513.2812, and the measured value is 513.2797.

[0381] p-toluenesulfonic acid monohydrate (619.1 mg, 3.25 mmol) was added to the solution of the above highly polar crude product in MeOH (20 mL). The mixture was stirred at room temperature under air for 1 hour. After quenching the reaction with H2O and saturated aqueous NaHCO3 at room temperature, the mixture was extracted three times with toluene, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on a preparative silica gel TLC plate (hexane:toluene = 1:1) to obtain 67 (21.6 mg, 39%) as colorless oil.

[0382] 67:[α] D 27 +38.0 (c 1.66, CHCl3); IR (undiluted) 3423, 1479, 1384, 1217, 1173, 1021, 774, 739 cm -1 ; 1 H NMR(400MHz,CDCl3)δ0.36(s,3H), 0.90(d,J=6.4Hz,3H), 1.20~2.06(m,23H), 2.47~2.52(m ,1H), 4.98~5.12(m,3H), 7.24~7.29(m,1H), 7.33(td,J=1.8,7.4Hz,1H), 7.56~7.62(m,1H); 13 C NMR(100MHz,CDCl3)δ11.7, 18.6, 21.9, 23.1, 23.5, 26.7, 27.3, 27.3(t,J=24.3 Hz), 28.6, 35.6, 40.0, 45.5, 45.6, 45.7, 55.4, 56.0, 73.3(t,J=27.2Hz), 112.1, 112.9(d,J=14.3Hz), 116.3(d,J=21.0Hz), 125.0(d,J=2.9Hz), 125.4(t,J=246. HRMS (ESI + )C 27 H 37 N4OF3Na[M+Na] + The calculated value is 513.2812, and the measured value is 513.2825.

[0383] Biological examples Biological Examples 1a and 1b Luciferase reporter assay and VDR reporter assay

[0239] Cell culture: CHO-K1 cells were maintained at 37°C in medium A (a 1:1 mixture of Ham's F-12 medium and DMEM, supplemented with 100 units / mL penicillin, 100 μg / mL streptomycin sulfate, and 5% [v / v] fetal bovine serum) in a humidified 5% CO2 incubator.

[0384]

[0240] CHO-K1 cells 8 x 10 per well 3 Cells were seeded in medium A in a 96-well plate and incubated for 24 hours. In the SREBP reporter assay, cells were co-transfected with the SRE-1 driven luciferase reporter plasmid (pSRE-Luc) and the actin promoter driven 13-galactosidase expression plasmid (pAc-13-gal) in a 20:1 ratio using FuGENE HD Transfection Reagent (Promega) according to the manufacturer's protocol.

[0385]

[0241] In the VDR reporter assay, Cignal Vitamin D Receptor Reporter (QIAGEN) was transfected instead of pSRE-Luc.

[0386]

[0242] After 20 hours, the culture medium was replaced with medium B containing the specific test compound (a 1:1 mixture of Ham's F-12 medium and DMEM, with 100 units / mL penicillin, 100 μg / mL streptomycin sulfate, 5% [v / v] lipid-depleted serum, 50 μM compactin (Tokyo Chemical Industry), and 50 μM lithium mevalonate (Sigma-Aldrich) added). After 24 hours of incubation, cells in each well were lysed with 100 μL of 1×Reporter Lysis Buffer (Promega), and luciferase and 13-gal activity were measured using a fixed volume of 50 μL. Luciferase activity was measured using the Steady-Glo Luciferase Assay System (Promega), and 13-gal activity was measured using the 13-Galactosidase Enzyme Assay System (Promega). Luciferase activity was normalized to 13-gal activity.

[0387]

[0243] In the SREBP reporter assay, the assay was performed using a single concentration (5 μM) of the compound in lipid-free medium, and 25(OH)D3 was found to exhibit substantial inhibitory activity. CHO-K1 cells were treated with 5 μM of the compound in lipid-free medium. The same experiment using 25(OH)D3(1) was performed as a control. Values ​​are mean ± SD. The results are shown in Figures 1 and 3.

[0388]

[0244] In the VDR assay, CHO-K1 cells were treated with 5 μM of the compound in lipid-free medium. The same experiment using 25(OH)D3(1) was performed as a control. Values ​​are mean ± SD. The results are shown in Figures 2 and 4.

[0389] Biological Example 2 In vivo short-term model

[0245] To rapidly and simultaneously investigate these SREBP inhibitory activities and VDR-derived serum calcium-raising activities in vivo, a short-term in vivo screening system was established in mice. Referring to previous reports (Horton, JD et al. Proc. Natl. Acad. Sci. USA 1998, 95, 5987~5992), mice were fasted for 48 hours, and then fed a special diet (a low-fat, high-carbohydrate diet lacking vitamin D) for 48 hours before sacrifice. Further details are shown in Figure 5A.

[0390]

[0246] In this system, 14 compounds (23-27, 38-41, 46, and 48-51) could be evaluated in vivo for 4 days, and they all showed equally good and excellent SREBP selectivity in cultured cells.

[0391]

[0247] C57BL / 6 and ob / ob mice were purchased from CLEA Japan and Charles River Japan, Inc., respectively. Animal experiments were conducted at the University of Tokyo and Charles River Laboratories. A low-fat, high-carbohydrate diet lacking vitamin D was specially prepared by Research Diets, Inc. The compounds disclosed herein and 25(OH)D3 were dissolved in ethanol / Tween 20 (9:1) to obtain stock solutions, which were then diluted 10-fold with PBS immediately before administration to mice.

[0392]

[0248] The compound or vehicle control at a dose of 10 mg / kg was administered intraperitoneally once every 24 hours during fasting and refeeding.

[0393]

[0249] After slaughter, mouse livers were fixed in 10% neutral buffered formalin, embedded in paraffin, and thinned, then stained with H&E. Liver fat was extracted with chloroform / methanol (2:1 v / v), and TG and cholesterol levels were measured using Triglyceride Reagent Set (Pointe Scientific) and Cholesterol E (Wako), respectively. Serum levels of ALT, TG, glucose, cholesterol, and calcium were measured at SRL Inc. (Tokyo). All experiments were authorized by the Animal Ethics Committees of the University of Tokyo and Charles River Laboratories Japan and were conducted in accordance with the Care and Use of Laboratory Animals guidelines.

[0394]

[0250] The relative mRNA levels of SREBP-responsive genes were determined by real-time PCR in the livers of mice that had free access to a normal diet or that had been fasted and then re-fed a special diet (mean ± SEM, n=3 per group), *p<0.05. The expression levels of SREBP-responsive genes were significantly elevated in the livers of mice that had been fasted and re-fed a special diet compared to control mice that had free access to a normal diet (Figure 5B).

[0395]

[0251] The expression levels of SREBP-responsive genes were determined by real-time PCR in the livers of mice treated with the compounds indicated by each number (10 mg / kg), according to the protocol illustrated in Figure 5A. The data are expressed as relative expression to the mean value of the livers of vehicle-treated mice (mean ± SEM, n=3 per group), *p<0.05 (Figure 5C).

[0396]

[0252] Serum calcium levels were determined in mice treated with vehicle, compound, or 25(OH)D3 (mean ± SEM, n=3 per group), *p<0.05 (Figure 5D).

[0397]

[0253] The relative mRNA levels of SREBP-responsive genes were determined by real-time PCR in the livers of mice treated as shown in the figure. Data are mean ± SEM (feeding mice, n=3; others, n=6), *p<0.05 (Figure 5E).

[0398]

[0254] Western blot analysis of SCAP protein was obtained from the livers of mice that underwent the treatment shown in the figure (Figure 5F).

[0399] Biological Example 3 Long-term model in vivo

[0255] To analyze the long-term efficacy and safety of KK-052(50) for the treatment of fatty liver disease, leptin-deficient ob / ob mice that spontaneously exhibit fatty liver disease, whose development depends on novel lipid biosynthesis mediated by SREBP, were used (Moon et al. Cell Metab. 2012, 15, 240-246). Six-week-old ob / ob mice were treated with 10 mg / kg of KK-052, 10 mg / kg of 25(OH)D3, or a vehicle control five times a week for four weeks (Figure 7A). All ob / ob mice treated with 25(OH)D3 became ill due to hypercalcemia and were euthanized after one week, while ob / ob mice treated with KK-052 remained healthy until the end of the experiment.

[0400]

[0256] The body weight of ob / ob mice was measured, and the data is shown as mean ± SEM (25(OH)D3, n=5; others, n=8), *p<0.05 (Figure 7B).

[0401]

[0257] Figure 7C shows H&E stained images (scale bar, 100 μm) of the liver of KK-052 or vehicle-treated ob / ob mice.

[0402]

[0258] Liver TG and cholesterol levels were measured in KK-052 or vehicle-treated ob / ob mice (mean ± SEM), *p<0.05 (Figure 7D).

[0403]

[0259] Serum levels of ALT, TG, total cholesterol, glucose, and calcium were measured in KK-052 or vehicle-treated ob / ob mice (mean ± SEM), *p<0.05 (Figure 7E).

[0404] Analysis of the results

[0260] Surprisingly, the applicant discovered 14-epi-25(OH)D3(4): in the process of screening their in-house collection of vitamin D analogs.

[0405] [ka] (Maynard, DF et al. J.Med.Chem. 1994, 37, 2387-2393; and Sawada, D. et al. Tetrahedron 2010, 66, 5407-5423) revealed that the expression of the SREBP-responsive luciferase reporter (Im, SS. et al. Cell Metab. 2011, 13, 540-549) was suppressed to a level comparable to that of 25(OH)D3 (data not presented). The 14-epi isomer of 25(OH)D3 tends to isomerize to this previtamin form via [1,7] sigmatropic hydrogen transfer, and has been shown to exhibit low affinity for VDR and a significant decrease in its effect on increasing blood calcium (Maynard, DF et al. J.Med.Chem. 1994, 37, 2387-2393). The applicants' observations revealed that, surprisingly, the 25-hydroxyCD ring may be more important than the A ring in SREBP inhibitory activity, and that the entire hydroxylated A ring, which is essential for VDR activity, may be substituted with a functional group occupying an equivalent volume to the A ring, as represented by the compound of formula (I).

[0406]

[0261] The ability of compounds 10-33 to inhibit the expression of SREBP-responsive reporter genes, whose luciferase expression is regulated by SREBP, in CHO-K1 cells was evaluated. Compounds 10-13, which contain relatively small substituents at the C7 position, were generally inactive (Figure 1). On the other hand, analogues with relatively large cyclic substituents (compounds 14-18 and 21-29) exhibited SREBP inhibitory activity equivalent to that of 25(OH)D3, although the amides 19 and 20 had little effect. Surprisingly, the inhibitory activity decreased when further expanded substituents were introduced (compounds 30-33) (Figure 1).

[0407]

[0262] Substitution of the 25(OH)D3A ring with an unnatural structure resulted in an overall decrease in the ability to stimulate VDR. This is most likely due to the deficiency of two hydroxyl groups important for VDR interaction (Figure 2). Compounds 21, 22, 26, and 29 showed detectable VDR activity, albeit weakly. The azole nitrogen of compounds 21, 22, and 26, as well as the hydroxyl group of compound 29, may mimic the hydroxyl group of 1α,25(OH)D3 that forms hydrogen bonds with the ligand-binding pocket of VDR.

[0408]

[0263] Compounds 23-25 ​​showed superior selectivity for SREBP compared to VDR. However, as shown after Figure 5, compounds 23-25 ​​failed to demonstrate clear SREBP inhibitory activity in vivo, which was likely due to low bioavailability. Numerous attempts have been made in the literature to increase the metabolic stability of vitamin D analogs against CYP24A1, the major inactivating enzyme of 25(OH)D3 and 1α,25(OH)2D3 (Sakaki, T. et al. Eur. J. Biochem. 2000, 267, 6158-6165; Yasuda, K. J Steroid Biochem. Mol. Biol. 2013, 133, 84-92; and St-Arnaud, R. CYP24A1: Structure, Function, and Physiological Role. In Vitamin D3 rd(ed.; Feldman, D., Pike, JW, Adams, JS, Eds.; Academic Press: London, 2011, pp43~56). One notable technique used in the production of clinically used vitamin D analogues is the introduction of a fluorine atom into the CD ring side chain (Stern, PH et al. Mol. Pharmacol. 1981, 20, 460~462; Tanaka, Y. et al. Arch. Biochem. Biophys. 1984, 229, 348~354; Stern, PH et al. J. Pharmacol. Exp. Ther. 1984, 229, 9~13).

[0409]

[0264] Compared to parent compounds 23-25, the introduction of fluorine atoms, as in compounds 38-41 and 46-51, did not adversely affect SREBP inhibitory activity. In general, the introduction of fluorine atoms did not show any effect on VDR activation. Surprisingly, compounds 39, 47, 49, and 51, in which the para position of the benzene group was fluorinated, all maintained SREBP inhibitory activity and lacked VDR activity (Figures 3 and 4).

[0410]

[0265] As expected, administration of the same amount of 25(OH)D3 resulted in a significant increase in serum calcium levels after 4 days, highlighting the effectiveness of the in vivo model described in Biological Example 2 in estimating the in vivo serum calcium-raising effect of the test compound (Figure 5D). Four fluorinated compounds (38, 39, 49, and 50) significantly suppressed the expression of two representative SREBP-responsive genes, ACC1 and FASN, compared to the vehicle control. However, 38 and 39 also resulted in increased serum calcium levels, demonstrating that such compounds or their metabolites act on VDR in vivo under test conditions (Figure 5C, D).

[0411]

[0266] These results encourage a re-evaluation of the effects of compounds 49 and 50, both of which reduced the elevation of three SREBP-responsive genes, ACC1, FASN, and SCD1, and did not cause a detectable increase in serum calcium levels. Repeated experiments with an increased number of mice highlighted that 50 (KK-052) significantly reduced the elevation of four SREBP-responsive genes in a reproducible manner (Figure 5E). SCAP protein expression levels in the liver increased after fasting and refeeding of a special diet. Consistent with reports of SCAP degradation activity by 25(OH)D3, the elevation of hepatic SCAP expression was resolved by treatment with 50 (KK-052) (Figure 5F). Therefore, 50 (KK-052) was further investigated.

[0412]

[0267] The effects of KK-052(50) on SREBP and SCAP were investigated by gene reporter assay and Western blot analysis. Similar to the screening results shown in Figure 3, KK-052 inhibited the activation of the reporter gene in a concentration-dependent manner, comparable to that of 25(OH)D3 (Figure 6A, where values ​​are mean ± SD). Nonlinear regression analysis showed a sigmoid dose response, with similar IC for both metabolites. 50 The values ​​were observed (Figure 6A, right panel). The inhibitory activity of KK-052, although its effect was not very clear at a concentration of 1 μM, may be due to its ability to reduce the levels of both the precursor and mature forms of endogenous SREBP and endogenous SCAP, similar to the action of 25(OH)D3 (Asano, L. et al. Cell Chem. Biol. 2017, 24, 207~217) (Figure 6B, here, immunoblotting was performed with anti-SREBP-2 or anti-SCAP antibody, and cells were treated with the compound in lipid-free medium for 24 hours). Western blot analysis using CHO-K1 cells expressing FLAG-tagged SCAP further revealed the degradation of SCAP by vitamin D metabolites (Figure 6C, here, cells were treated with the compound in lipid-free medium for 24 hours). Overall, these results were consistent with the action of KK-052 in vivo.

[0413]

[0268] Treatment with KK-052 according to the protocol of Biological Example 3 resulted in a slight but significant reduction in body weight gain in ob / ob mice (Figure 7B). Histological examination of the livers of vehicle-treated ob / ob mice revealed marked hepatic steatopathies, and these symptoms were attenuated by treatment with KK-052 (Figure 7C). Furthermore, liver triglyceride (TG) and cholesterol levels were significantly lower in KK-052-treated ob / ob mice compared to vehicle-treated ob / ob mice (Figure 7D). Importantly, treatment with KK-052 significantly reduced serum levels of alanine aminotransferase (ALT), a marker of liver damage, as well as TG and glucose (Figure 7E). There was no detectable difference in serum calcium levels between the KK-052-treated group and the vehicle-treated group. In summary, KK-052 reduces the development of fatty liver in ob / ob mice without inducing hypercalcemia.

[0414]

[0269] Remarkably, the substitution of the A ring of 25-hydroxyvitamin D3 with a completely non-natural substance led to the discovery of a VDR silent SREBP inhibitor and the development of KK-052(50). KK-052 is the first vitamin D-based SREBP inhibitor demonstrated to reduce hepatic lipid accumulation in mice without increasing blood calcium levels. [Industrial applicability]

[0415]

[0270] Compounds of formula (I) or pharmaceutically acceptable salts thereof may be useful in the treatment of metabolic disorders including non-alcoholic steatohepatitis (NASH), liver diseases including fatty liver, diabetes, cancer, obesity and cardiovascular diseases.

Claims

1. The following general formula (I): 【Chemistry 1】 Compounds thereof, or stereoisomers thereof, mixtures of stereoisomers and / or pharmaceutically acceptable salts, R 1 Is it hydrogen? The double bond from a to b is in an E configuration or a Z configuration, R 1 but, 【Chemistry 2】 (R a and R b However, together with the carbon atoms to which these are bonded, they form an unsubstituted C 5 -C 7 - Forms a cycloalkyl group); - CH 2 -S- (heteroaryl); -CH 2 - (1,3-dioxoisoindorin-2-yl); 【Transformation 3】 (ortho-carboranyl); -CH 2 -NH-(phenyl); or 【Chemistry 4】 And, R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b However, hydrogen and halo are selected independently, One of X and Y is CR 5 The other is CH, or one of X and Y is CR 5 The other is a program, R 5 However, hydrogen; C 1 -C 6 -Alkyl;Hydroxy-C 1 -C 6 - Alkyl; 1, 2, or 3 R 5a Arials substituted by choice in the base; or 1, 2, or 3 R 5a A 5- or 6-membered heteroaryl substituted with a base by arbitrary selection, Each R 5a However, they are independently hydrogen, alkyl, haloalkyl or halo, Here, each phenyl and heteroaryl group independently acts as a halogen, halo-C. 1-4 Alkyl, -S- (halo-C) 1-4 Alkyl), C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, nitro, cyano, and C 1-4 It is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from the group consisting of alkoxycarbonyl groups. However, the compound 【Transformation 5】 ;or 【Transformation 6】 A compound of formula (I), or a stereoisomer, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof, that is not a compound of formula (I), or a stereoisomer, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

2. R 1 Is it hydrogen? The double bond from a to b is in an E configuration or a Z configuration, R 1 but, 【Transformation 7】 (R a and R b However, together with the carbon atoms to which these are bonded, they form an unsubstituted C 5 -C 7 - Forms a cycloalkyl group); - CH 2 -S- (heteroaryl); -CH 2 - (1,3-dioxoisoindorin-2-yl); 【Transformation 8】 (ortho-carbonyl); -CH 2 -NH-(phenyl); or 【Chemistry 9】 And, R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b However, hydrogen and halo are selected independently, One of X and Y is CR 5 The other is CH, or one of X and Y is CR 5 The other is a program, R 5 However, hydrogen; C 1 -C 6 -Alkyl;Hydroxy-C 1 -C 6 - Alkyl; 1, 2, or 3 R 5a Arials substituted by choice in the base; or 1, 2, or 3 R 5a A 5- or 6-member heteroaryl that has been optionally substituted in the base, Each R 5a However, they are independently hydrogen or halo, Here, each phenyl and heteroaryl group independently acts as a halogen, halo-C. 1-4 Alkyl, -S- (halo-C) 1-4 Alkyl), C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, nitro, cyano, and C 1-4 It is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from the group consisting of alkoxycarbonyl groups. However, the compound 【Chemistry 10】 ;or 【Chemistry 11】 The compound according to claim 1, which is not any of the compounds, or any of their stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts, or a stereoisomer, mixture of stereoisomers, and / or a pharmaceutically acceptable salt.

3. R 1 Is it hydrogen? The double bond from a to b is in an E configuration or a Z configuration, R 1 but 【Chemistry 12】 (R a and R b However, together with the carbon atoms to which these are bonded, they form an unsubstituted C 5 -C 7 - Forms a cycloalkyl group) or R 1 However, halogen, halo-C 1-4 Alkyl, -S- (halo-C) 1-4 Alkyl), C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, nitro, cyano, and C 1-4 The heteroaryl group is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from the group consisting of alkoxycarbonyl groups -CH 2 -S- (heteroaryl), or R 1 ga-CH 2 -(1,3-dioxo-isoindorin-2-yl), or R 1 but 【Chemistry 13】 (ortho-carboranil) or R 1 However, halogen, halo-C 1-4 Alkyl, -S- (halo-C) 1-4 Alkyl), C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, nitro, cyano, and C 1-4 The phenyl group is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from the group consisting of alkoxycarbonyl groups -CH 2 -NH-(phenyl) or R 1 but 【Chemistry 14】 And, R 2a 、R 2b 、R 3 、R 3a 、R 3b 、R 4 、R 4a and R 4b are independently selected from hydrogen and halo, One of X and Y is CR 5 and the other is CH, or one of X and Y is CR 5 and the other is N R 5 However, hydrogen; C 1 -C 6 -Alkyl;Hydroxy-C 1 -C 6 - Alkyl; 1, 2, or 3 R 5a Arials substituted by choice in the base; or 1, 2, or 3 R 5a A 5- or 6-member heteroaryl that has been optionally substituted in the base, Each R 5a However, they are independently hydrogen, alkyl, haloalkyl or halo, However, the compound 【Chemistry 15】 ;or 【Chemistry 16】 The compound according to claim 1, which is not any of the compounds, or any of their stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts, or a stereoisomer, mixture of stereoisomers, and / or a pharmaceutically acceptable salt.

4. R 1 However, hydrogen, -CH 2 -S- (heteroaryl), -CH 2 - (1,3-dioxoisoindorin-2-yl), 【Chemistry 17】 ien-CH 2 -NH- (phenyl) or [Chemistry 18] And, R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , R 4a and R 4b However, hydrogen and halo are selected independently, One of X and Y is CR 5 The other is CH, or one of X and Y is CR 5 The other is N, R 5 However, hydrogen; C 1 -C 6 -Alkyl;Hydroxy-C 1 -C 6 - Alkyl; 1, 2, or 3 R 5a Arials substituted by choice in the base; or 1, 2, or 3 R 5a A 5- or 6-member heteroaryl that has been optionally substituted in the base, Each R 5a However, they are independently hydrogen, alkyl, haloalkyl or halo, Here, each phenyl and heteroaryl group independently acts as a halogen, halo-C. 1-4 Alkyl, -S- (halo-C) 1-4 Alkyl), C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, nitro, cyano, and C 1-4 It is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from the group consisting of alkoxycarbonyl groups. However, the compound 【Chemistry 19】 The compound according to claim 1 or 2, which is neither the compound, nor any stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

5. One R 5a It is hydrogen, and the other R 5a A compound according to any one of claims 1, 3, and 4, wherein the element is independently hydrogen, alkyl, haloalkyl, or halo, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

6. Two R's 5a Each of these is hydrogen, and the third R 5a The compound according to any one of claims 1, 3, or 4, wherein the compound is alkyl, haloalkyl, or halo, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

7. One R 5a is hydrogen, and the other two R 5a A compound according to any one of claims 1, 3, or 4, wherein the elements are independently alkyl, haloalkyl, or halo, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

8. Two R's 5a Each of these is hydrogen, and the third R 5a A compound according to any one of claims 1 to 6, wherein the compound is a halo, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

9. One R 5a is hydrogen, and the other two R 5a A compound according to any one of claims 1 to 5 and 7, wherein is independently a halo, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

10. The compound according to formula (I) is given by formula (Ia): 【Chemistry 20】 A compound according to any one of claims 1 to 9, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

11. R 1 but, 【Chemistry 21】 The compound according to any one of claims 1 to 10, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

12. One of X and Y is CR 5 A compound according to any one of claims 1 to 11, wherein the other is CH, or a stereoisomer thereof, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof.

13. X is CR 5 A compound according to any one of claims 1 to 12, wherein Y is CH, or a stereoisomer thereof, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof.

14. One of X and Y is CR 5 A compound according to any one of claims 1 to 11, wherein the other is N, or a stereoisomer thereof, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof.

15. X is CR 5 A compound according to any one of claims 1 to 11 and 14, wherein Y is N, or a stereoisomer thereof, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof.

16. Y is CR 5 A compound according to any one of claims 1 to 11 and 14, wherein X is N, or a stereoisomer thereof, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof.

17. R 5 However, C 1 -C 6 - Alkyl; 1, 2, or 3 R 5a Phenyl groups optionally substituted with R groups; or 1, 2, or 3 R groups 5a A compound according to any one of claims 1 to 16, wherein the base is a five-membered heteroaryl optionally substituted with a group, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

18. R 5 However, 1, 2, or 3 R 5a An aryl that is optionally substituted in the base; or one, two, or three R 5a A compound according to any one of claims 1 to 17, wherein the base is a five-membered heteroaryl optionally substituted with a group, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

19. R 5 However, 1, 2, or 3 R 5a A compound according to any one of claims 1 to 18, wherein the phenyl group is optionally substituted with a phenyl group, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

20. R 5 However, 1, 2, or 3 R 5a A compound according to any one of claims 1 to 18, wherein the base is a five-membered heteroaryl optionally substituted with a group, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

21. R 2a and R 2b A compound according to any one of claims 1 to 20, wherein the element is independently hydrogen or fluoro, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

22. R 2a and R 2b A compound according to any one of claims 1 to 20, wherein is independently a halo, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

23. R 2a and R 2b A compound according to any one of claims 1 to 20, wherein each of the elements is fluoro, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

24. R 2a and R 2b A compound according to any one of claims 1 to 20, wherein each of the elements is hydrogen, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

25. R 3 , R 3a , R 3b , R 4 , R 4a and R 4b A compound according to any one of claims 1 to 24, wherein each of the elements is hydrogen, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

26. R 3 , R 3a , R 3b , R 4 , R 4a and R 4b A compound according to any one of claims 1 to 24, wherein each of the elements is independently a halo, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

27. R 3 , R 3a , R 3b , R 4 , R 4a and R 4b A compound according to any one of claims 1 to 24, wherein each of the elements is fluoro, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

28. A compound according to any one of claims 1 to 27, wherein the bond from a to b is in an E configuration, or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof. 【Request Item 29】 【Table 1-1】 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

30. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 29 or a stereoisomer thereof, a mixture of stereoisomers and / or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

31. A pharmaceutical composition for inhibiting SREBP in a subject, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 29 or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition for treating metabolic disorders, liver diseases, obesity, diabetes, cardiovascular diseases, hyperlipidemia (including hypertriglyceridemia and hypercholesterolemia), or cancer in a subject, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 29 or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

33. The pharmaceutical composition according to claim 32, wherein the cancer is selected from prostate cancer, liver cancer, bile duct cancer, bone cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, hematological cancer (including lymphoma and leukemia), kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the skin, cutaneous melanoma and uveal melanoma.

34. The pharmaceutical composition according to claim 32 for treating obesity, non-alcoholic steatohepatitis (NASH), fatty liver disease, or cancer.

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