Composition for preventing or treating alzheimer's disease

Abstract

The compound represented by chemical formula IA according to the present invention is useful for the prevention, alleviation, and treatment of degenerative brain diseases.

Description

Composition for the prevention or treatment of Alzheimer's disease

[0001] Cross-reference of related applications

[0002] The present application claims priority to Patent Application No. 10-2025-0004008 filed on January 10, 2025 and Patent Application No. 10-2025-0077282 filed on June 12, 2025, the entire contents of which are incorporated herein by reference.

[0003] Technology field

[0004] The present invention relates to a novel composition for the prevention or treatment of Alzheimer's disease.

[0005] Alzheimer's disease (AD) is the most common degenerative brain disease that causes dementia. It develops gradually, leading to a progressive decline in cognitive functions, including memory. It is known that various factors, such as the deposition of extracellular amyloid beta (Aβ) protein, hyperphosphorylation of tau protein, neuroinflammation, and oxidative stress, damage brain cells to the disease and contribute to its development.

[0006] Globally, there are approximately 50 million people with Alzheimer's disease, accounting for about 5% of the population aged 65 to 74, 13.1% of those aged 75 to 84, and 33.3% of those aged 85 or older. The World Health Organization (WHO) projects that this number will increase to 114 million by 2050, and with the number of global Alzheimer's patients surging due to population aging, the development of treatments is urgent.

[0007] In addition, an early Alzheimer's disease antibody treatment targeting amyloid beta (Aβ), one of the major causative agents of Alzheimer's disease, was launched in Korea following Japan and the United States in 2024, but it is showing safety issues as it causes side effects such as edema or microtubule hemorrhage during the process of removing amyloid beta (Aβ) plaques in blood vessels, and these side effects are also closely related to neuroinflammation.

[0008] Meanwhile, WO 2011053048 A2 discloses the use of SAC-1004, one of the compounds presented in the present invention, for the treatment of vascular leakage disease, but it is not known for its use in the treatment of Alzheimer's disease.

[0009] Accordingly, the inventors intend to present in this specification a low-molecular-weight compound having an effect of improving BBB (Blood-Brain Barrier) dysfunction and neuroinflammation, which are the etiologies of Alzheimer's disease.

[0010] The present invention provides a compound for the prevention, alleviation, or treatment of degenerative brain diseases.

[0011] In order to solve the above problem,

[0012] The present invention provides a pharmaceutical composition for the prevention, alleviation, or treatment of degenerative brain diseases comprising, as active ingredients, a compound represented by the following chemical formula IA, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof.

[0013]

[0014] In the equation,

[0015] Y is -C(=O)(R 1 ) or -P(=O)(R 2 )(R 3 );

[0016] R 1 to R 3 C each independently 1-6 Alkyl;

[0017] X is H or C 1-6 Alkyl;

[0018] R is -C n Alkylene-LMR 4 is,

[0019] n is an integer from 0 to 10;

[0020] L is C(=O) or CH2;

[0021] M is O or N(R5 );

[0022] R 4 C that is unsubstituted or substituted with one or more halogens 1-6 Alkyl, 3-10-membered cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, -C(=O)(R 6 ) or -S(=O)2(R 7 );

[0023] R 5 is H or C 1-6 Alkyl;

[0024] R 6 and R 7 C each independently 1-6 It is an alkyl.

[0025] The compound according to the present invention exhibits an improvement effect on cognitive and memory abilities through object recognition experiments and underwater maze experiments, and also exhibits an improvement effect on blood-brain barrier (BBB) ​​dysfunction and neuroinflammation, which are pathogenic factors of degenerative brain diseases; therefore, it is useful for the prevention, alleviation, or treatment of degenerative brain diseases.

[0026] Figure 1 shows the excellent object recognition ability improvement effect of some examples of compounds according to the present invention (*: p<0.05: G1 vs G2). Compounds A, B, and C represent the compounds of Synthesis Examples 1-10, 1-26, and 2-3, respectively.

[0027] FIG. 2 shows the excellent memory ability improvement effect of some examples of compounds according to the present invention (*: p<0.05: G1 vs G2; #: p<0.05: G2 vs All groups). Compound A, B, and C represent the compounds of Synthesis Example 1-10, Synthesis Example 1-26, and Synthesis Example 2-3, respectively.

[0028] Figures 3a and 3b show the accumulation of amyloid beta (Aβ) plaques in the hippocampus when treated with some examples of compounds according to the present invention (***: p<0.001: G1 vs G2; #: p<0.05, ##: p<0.01, ###: p<0.001: G2 vs All groups). Compounds A, B, and C represent the compounds of Synthesis Examples 1-10, 1-26, and 2-3, respectively.

[0029] FIGS. 3c and 3d are figures confirming the accumulation of amyloid beta (Aβ) plaques in the cerebral cortex (PFC) when some examples of compounds according to the present invention were treated (***: p<0.001: G1 vs G2; #: p<0.05, ##: p<0.01, ###: p<0.001: G2 vs All groups). Compound A, B, and C represent the compounds of Synthesis Examples 1-10, 1-26, and 2-3, respectively.

[0030] Figures 4a and 4b show the expression levels of ZO-1 when some examples of compounds according to the present invention are treated (**: p<0.01: G1 vs G2; ##: p<0.01: G2 vs All groups). Compounds A, B, and C represent the compounds of Synthesis Examples 1-10, 1-26, and 2-3, respectively.

[0031] FIGS. 4c and 4d are figures confirming the expression level of Claudin5 when treated with some examples of compounds according to the present invention (*: p<0.05: G1 vs G2; #: p<0.05: G2 vs All groups). Compound A, B, and C represent the compounds of Synthesis Examples 1-10, 1-26, and 2-3, respectively.

[0032] Figures 5a and 5b show the amount of RAGE expression when some examples of compounds according to the present invention are treated (***: p<0.01: G1 vs G2; ##: p<0.01, ###: p<0.001: G2 vs All groups). Compounds A, B, and C represent the compounds of Synthesis Examples 1-10, 1-26, and 2-3, respectively.

[0033] FIGS. 6a to 6d are figures showing the GFAP expression levels when some examples of compounds according to the present invention were treated (***: p<0.01: G1 vs G2; #: p<0.05, ###: p<0.001: G2 vs All groups). Compound A, B, and C represent the compounds of Synthesis Examples 1-10, 1-26, and 2-3, respectively.

[0034] Figures 7a and 7b show the expression levels of Iba1 when some examples of compounds according to the present invention were treated (***: p<0.01: G1 vs G2; ###: p<0.001: G2 vs All groups). Compounds A, B, and C represent the compounds of Synthesis Examples 1-10, 1-26, and 2-3, respectively.

[0035] This specification presents a compound represented by the following chemical formula IA as a novel therapeutic agent for degenerative brain diseases.

[0036]

[0037] Y is independently -C(=O)(R 1 ) and -P(=O)(R 2 )(R 3 It can be selected from ). The two Ys may be the same or different.

[0038] R 1 to R 3 C each independently 1-6 It is an alkyl.

[0039] X is H and C 1-6It can be selected from alkyls.

[0040] R is -C n Alkylene-LMR 4 It is displayed as.

[0041] n can be selected from integers 0 to 10, integers 0 to 9, integers 0 to 8, integers 0 to 7, integers 0 to 6, integers 0 to 5, integers 0 to 4, and integers 0 to 3.

[0042] L can be selected from C(=O) and CH2.

[0043] M is O and N(R 5 It can be selected from ).

[0044] R 4 C that is unsubstituted or substituted with one or more halogens 1-6 Alkyl, 3-10-membered cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, -C(=O)(R 6 ) and -S(=O)2(R 7 It can be selected from ).

[0045] R 5 is H and C 1-6 It can be selected from alkyls.

[0046] R 6 and R 7 C each independently 1-6 It is an alkyl.

[0047] Here,

[0048] C 1-6 Alkyl is C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 It can be changed to one selected from alkyl and C1alkyl;

[0049] The 3-10-membered cycloalkyl can be changed to a 3-7-membered cycloalkyl, a 3-6-membered cycloalkyl, or a 9-10-membered cycloalkyl;

[0050] 5-10 yuan heteroaryls can be changed to 5-6 yuan heteroaryls and 9-10 yuan heteroaryls;

[0051] The 3-10-membered heterocycloalkyl can be changed to a 5-10-membered heterocycloalkyl, a 5-6-membered heterocycloalkyl, or a 9-10-membered heterocycloalkyl;

[0052] C 3-12 Alkyl is C 5-12 Alkyl, C 6-12 alkyl, or C 6-10 It can be changed to an alkyl.

[0053]

[0054] In this specification, the terms "alkylene" or "alkyl" comprise straight-chain or branched-chain saturated hydrocarbon residues unless otherwise specified. For example, "C 1-6 "Alkyl" refers to an alkyl group with a skeleton of 1 to 6 carbons. Specifically, C 1-6 Alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, etc., and C6 alkyl is a fully saturated hydrocarbon having six carbons, including structural isomers. Alkyl refers to a monovalent substituent, and alkylene refers to a divalent substituent.

[0055] The term “cycloalkyl” means a cyclic hydrocarbon residue forming a ring as a saturated hydrocarbon residue, unless otherwise specified, and “C 3-10“Cycloalkyl or 3-10-membered cycloalkyl” refers to a cyclic hydrocarbon residue containing 3 to 10 carbon atoms as ring atoms. It includes both single rings, bicyclic rings containing 2 or 3 rings, and tricyclic rings, wherein these 2 or 3 rings may be bridged, fused, or spiral cycloalkyls. 3-10-membered cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl, etc.

[0056] The term “heterocycloalkyl” means a monovalent saturated residue comprising one to three rings containing one or more heteroatoms selected from N, O, or S (e.g., 1-5, 1-4, 1-3, 1-2, 1) unless otherwise specified. It may be a single ring, a bicyclic or tricyclic ring comprising two or three rings, wherein these two or three rings may be bridged, fused, or spiral heterocycloalkyls. In the case of multiple rings, the heteroatoms may be present in all rings or in some rings. Where the type of heteroatom is specifically limited, it means that only heteroatoms selected from said heteroatom are included.

[0057] “3-10-membered heterocycloalkyl” refers to a heterocycloalkyl in which the ring consists of 3-10 atoms.

[0058] The term “aryl” refers to an aromatic radical formed by the fusion of a single ring or two or three hydrocarbon aromatic rings, and 6-10 aryls refer to aromatic ring compounds containing 6-10 carbons, including phenyl or naphthyl.

[0059] The term “heteroaryl” means an aromatic radical having one or more aromatic rings (the remaining ring atoms are C) containing one or more heteroatoms selected from N, O, or S as ring atoms (e.g., 1-5, 1-4, 1-3, 1-2, 1) unless otherwise specified, or an aromatic radical formed by the fusion of two or three rings. Where the type of heteroatom is specifically limited, it means that the ring atoms include heteroatoms selected only from those heteroatoms. In the case of multiple rings, heteroatoms may be present in all rings or in some rings. Where the type of heteroatom is specifically limited, it means that only heteroatoms selected only from those heteroatoms are included. “Primary heteroaryl” means a heteroaryl having 5-10 ring atoms.

[0060] The term “halogen” refers to halogen atoms such as F, Cl, Br, and I, and when one or more halogens are substituted, the substituted halogen atoms may be selected within the range of 1-5, 1-4, 1-3, 1-2, or 1.

[0061] The compound represented by the formula IA according to the present invention includes its stereoisomer, its solvate, its hydrate, and its pharmaceutically acceptable salt.

[0062] Unless specifically limited in this specification, and unless contradictory, the term "compound" refers to all compounds represented by the formula IA, and may be used to include stereoisomers thereof, solvates thereof, hydrates thereof, and pharmaceutically acceptable salts thereof.

[0063] The term “stereoisomer” includes R or S isomers (or DL ​​isomers) produced by having an asymmetric carbon or heteroatom (P, S, Si, N, etc.) center, enantiomers or diastereomers that can be produced by having two or more asymmetric atomic centers, geometric isomers (trans, cis), etc.

[0064] The term "hydrate" refers to a compound of the present invention or a salt thereof containing stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces. A hydrate of the compound represented by Formula 1 of the present invention may contain stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces. The hydrate may contain at least one equivalent, preferably one to five equivalents, of water. Such a hydrate may be prepared by crystallizing the compound represented by Formula 1 of the present invention, its isomers, or pharmaceutically acceptable salts thereof from water or a solvent containing water.

[0065] The term "solvate" means a compound of the present invention or a salt thereof comprising stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. Preferred solvents thereof include volatile, non-toxic, and / or solvents suitable for administration to humans.

[0066] The term “pharmaceuticalally acceptable salt” means a salt that is pharmaceutically acceptable as a salt formed by ionic bonding with a compound containing a carboxylic acid or amine functional group.

[0067] The compound represented by the formula IA of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromide, hydroiodide, nitrous acid, phosphoric acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., non-toxic organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. These types of pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chloride, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, malieates, butyne-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, and phthalates. Includes terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

[0068] The acid addition salt according to the present invention can be prepared by conventional methods, for example, by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or an inorganic acid to produce a precipitate, filtering and drying it, or by vacuum distilling the solvent and excess acid, drying it, and crystallizing it under an organic solvent.

[0069] In addition, pharmaceutically acceptable metal salts can be produced using a base. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to produce sodium, potassium, or calcium salts as the metal salts. In addition, the corresponding salts are obtained by reacting the alkali metal or alkaline earth metal salt with a suitable base salt (e.g., silver nitrate).

[0070]

[0071] In the present invention, specific examples of the compound represented by the chemical formula IA are not particularly limited, but may be specifically selected from the following examples.

[0072] The first embodiment is in the above chemical formula IA,

[0073] Y is -C(=O)(R 1 ) or -P(=O)(R 2 )(R 3 );

[0074] R 1 to R 3 C each independently 1-6 Alkyl;

[0075] X is H or C 1-6 Alkyl;

[0076] R is -C n Alkylene-LMR 4 is,

[0077] n is an integer from 0 to 10;

[0078] L is C(=O) or CH2;

[0079] M is O or N(R 5 );

[0080] R 4 C that is unsubstituted or substituted with one or more halogens 1-6 Alkyl, 3-10-membered cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, -C(=O)(R 6 ) or -S(=O)2(R 7 );

[0081] R 5 is H or C 1-6 Alkyl;

[0082] R 6 and R 7 C each independently 1-6 It is an alkyl.

[0083] As another embodiment of the first embodiment, n may be selected from integers 0 to 9, integers 0 to 8, integers 0 to 7, integers 0 to 6, integers 0 to 5, integers 0 to 4, and integers 0 to 3.

[0084] As another embodiment of the first embodiment, L may be C(=O) or L may be CH2.

[0085] As another embodiment of the first embodiment, when L is C(=O), M is N(R 5 ), when L is C(=O), M is O, or when L is CH2, M is O.

[0086] As another embodiment of the first embodiment, C 1-6 Alkyl is C 1-5 Alkyl C 1-4 Alkyl C 1-3 Alkyl C 1-2 It can be changed to alkyl or methyl.

[0087] Another embodiment of the first embodiment is in M ​​of the first embodiment,

[0088] M is O, S, or N(R 5 ); M is O; or M is N(R 5 It can be.

[0089] As another embodiment of the first embodiment,

[0090] The heteroaryl or heterocycloalkyl comprises a heteroatom selected from O, N and S, or comprises a heteroatom selected from O and N, or comprises an N atom. The heteroatoms included herein are 1 to 3 or 1 to 2.

[0091]

[0092] A second embodiment is in the above formula IA,

[0093] Pharmaceutical composition according to claim 1:

[0094] Y is -C(=O)(R 1 ) or -P(=O)(R 2 )(R 3 );

[0095] R 1 to R 3 C each independently 1-6 Alkyl;

[0096] X is H or C 1-6 Alkyl;

[0097] R is -C n Alkylene-LMR 4 is,

[0098] n is an integer from 0 to 10;

[0099] L is CH2;

[0100] M is O;

[0101] R 4 C that is unsubstituted or substituted with one or more halogens 1-6 Alkyl, 3-10-membered cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, -C(=O)(R 6 ) or -S(=O)2(R 7 ); and

[0102] R 6 and R 7 C each independently 1-6 It is an alkyl.

[0103] As another embodiment of the second embodiment, n may be selected from integers 0 to 9, integers 0 to 8, integers 0 to 7, integers 0 to 6, integers 0 to 5, integers 0 to 4, and integers 0 to 3.

[0104] As another embodiment of the second embodiment, C 1-6 Alkyl is C 1-5 Alkyl C 1-4 Alkyl C 1-3 Alkyl C 1-2 It can be changed to alkyl or methyl.

[0105] As another embodiment of the second embodiment,

[0106] The heteroaryl or heterocycloalkyl comprises a heteroatom selected from O, N and S, or comprises a heteroatom selected from O and N, or comprises an N atom. The heteroatoms included herein are 1 to 3 or 1 to 2.

[0107] As another embodiment of the second embodiment, R 4 is unsubstituted C 1-6 It is an alkyl.

[0108] As another embodiment of the second embodiment, R 4 is unsubstituted C 1-6 When it is alkyl, X is C 1-6 It can be an alkyl.

[0109]

[0110] A third embodiment is in the above formula IA,

[0111] Y is -C(=O)(R 1 ) or -P(=O)(R 2 )(R 3 );

[0112] R 1 to R 3C each independently 1-6 Alkyl;

[0113] X is H or C 1-6 Alkyl;

[0114] R is -C n Alkylene-LMR 4 is,

[0115] n is an integer from 0 to 10;

[0116] L is C(=O);

[0117] M is O;

[0118] R 4 C that is unsubstituted or substituted with one or more halogens 1-6 Alkyl, 3-10-membered cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, -C(=O)(R 6 ) or -S(=O)2(R 7 ); and

[0119] R 6 and R 7 C each independently 1-6 It is an alkyl.

[0120] As another embodiment of the third embodiment, n may be selected from integers 0 to 9, integers 0 to 8, integers 0 to 7, integers 0 to 6, integers 0 to 5, integers 0 to 4, and integers 0 to 3.

[0121] As another embodiment of the third embodiment, C 1-6 Alkyl is C 1-5 Alkyl C 1-4 Alkyl C 1-3 Alkyl C 1-2 It can be changed to alkyl or methyl.

[0122] As another embodiment of the third embodiment,

[0123] The heteroaryl or heterocycloalkyl comprises a heteroatom selected from O, N and S, or comprises a heteroatom selected from O and N, or comprises an N atom. The heteroatoms included herein are 1 to 3 or 1 to 2.

[0124] As another embodiment of the third embodiment, R 4 is unsubstituted C 1-6 It is an alkyl.

[0125] As another embodiment of the third embodiment, R 4 is unsubstituted C 1-6 When it is alkyl, X is C 1-6 It can be an alkyl.

[0126]

[0127] The compound of Chemical Formula 1 above may be selected from compounds of the following structures.

[0128]

[0129]

[0130]

[0131]

[0132]

[0133] Compounds according to the present invention (including stereoisomers thereof, hydrates thereof, solvates thereof, and pharmaceutically acceptable salts thereof) may be administered in various oral and parenteral formulations during clinical administration. When formulating, they are prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid formulations are prepared by mixing at least one excipient, e.g., starch, calcium carbonate, sucrose or lactose, gelatin, etc., with one or more compounds. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, and syrups; in addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspension agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleates.

[0134]

[0135] A pharmaceutical composition having a compound according to the present invention (including stereoisomers thereof, hydrates thereof, solvates thereof, and pharmaceutically acceptable salts thereof) as an active ingredient may be administered parenterally, and parenteral administration is by a method of injecting subcutaneously, intravenously, intramuscularly, or intrathoracically.

[0136] At this time, in order to formulate a parenteral administration formulation, a compound (including its stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts thereof) may be mixed with water with a stabilizer or buffer to prepare a solution or suspension, and may be prepared in an ampoule or vial unit dosage form. The composition may be sterile and / or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification promoters, salts and / or buffers for osmotic pressure regulation, and other therapeutically useful substances, and may be formulated according to conventional mixing, granulation, or coating methods.

[0137]

[0138] Oral dosage forms include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc., and these dosage forms contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine) and lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and, in some cases, disintegrants or boiling mixtures such as starch, agar, alginic acid or its sodium salts and / or absorbents, coloring agents, flavoring agents, and sweeteners.

[0139]

[0140] In the present invention, the compound (including its stereoisomers, its hydrates, its solvates, and its pharmaceutically acceptable salts) is administered in an effective amount, and an effective amount means containing it in a dose range that produces an effect of prevention, improvement, or treatment; the dose range may vary depending on the severity and formulation, and the frequency of application may also vary depending on the age, weight, and constitution of the subject. In one embodiment of the present invention, the compound of Formula 1 in the pharmaceutical composition of the present invention may be included, for example, at 0.001 mg / kg or more, preferably at 0.1 mg / kg or more, 1 mg / kg or more, 10 mg / kg or more, 100 mg / kg or more, or 250 mg / kg or more, and may be included within an amount that does not exhibit fatal toxicity. For example, it may be selected from a range of 10 g / kg or less, or 1 g / kg or less. The quantitative upper limit of the compound (including its stereoisomers, its hydrates, its solvates, and its pharmaceutically acceptable salts) included in the pharmaceutical composition of the present invention may be selected by a person skilled in the art within an appropriate range.

[0141]

[0142] In another aspect, the present invention provides a pharmaceutical composition containing as an active ingredient a compound represented by the formula IA (including stereoisomers thereof, solvates thereof, hydrates thereof, or pharmaceutically acceptable salts thereof).

[0143] The above pharmaceutical composition may further include pharmaceutically acceptable additives.

[0144] In another aspect, the present invention provides a pharmaceutical composition for the prevention, alleviation, or treatment of degenerative brain diseases containing, as an active ingredient, a compound represented by the formula IA (including stereoisomers thereof, solvates thereof, hydrates thereof, or pharmaceutically acceptable salts thereof).

[0145] In another aspect, the present invention provides a health functional food composition for the prevention, alleviation, or improvement of degenerative brain diseases, comprising as an active ingredient a compound represented by the formula IA (including stereoisomers thereof, solvates thereof, hydrates thereof, or pharmaceutically acceptable salts thereof).

[0146] In another aspect, the present invention provides a method for treating a degenerative brain disease comprising the step of administering a compound represented by the formula IA (including stereoisomers thereof, solvates thereof, hydrates thereof, or pharmaceutically acceptable salts thereof) to a subject in need.

[0147] In another aspect, the present invention provides the use of a compound represented by the formula IA (including stereoisomers thereof, solvates thereof, hydrates thereof, or pharmaceutically acceptable salts thereof) for the preparation of a drug for the prevention, alleviation, or treatment of degenerative brain diseases.

[0148] In this specification, the degenerative brain disease includes Alzheimer's disease, Parkinson's disease, stroke, Huntington's disease, or amyotrophic lateral sclerosis.

[0149]

[0150] The method for preparing the compound of chemical formula IA of the present invention is described below.

[0151] [Reaction Equation A]

[0152]

[0153] A compound of chemical formula IA can be prepared according to reaction formula A.

[0154] A compound with chemical formula IA-1 is coupled with a glutaryl derivative to be prepared as a compound of chemical formula IA.

[0155] In the above reaction scheme 1, X, Y, and R follow the definitions of the aforementioned chemical formula IA.

[0156] The coupling reaction of glutal can be carried out under known conditions and can be carried out using an organic solvent in the presence of a catalyst.

[0157] As a catalyst, the reaction catalyst may be selected from the group consisting of cation perfluoro-1-alkylsulfonate (wherein the cation is lithium, sodium, potassium, or cesium, and the alkyl is a single-chain or branched-chain perfluorinated C1-10 alkyl), (s)-camphorsulfonic acid, iodine, Amberlyst 15, and borontrifluoride etherate, or a mixture thereof, but is not limited thereto. In one embodiment of the present invention, a mixture of lithium nonafluoro-1-butylsulfonate (Li-NFBS) and (s)-camphorsulfonic acid was used, but this is merely an example and is not limited thereto.

[0158] In this specification, it can be performed according to general method 4 described below.

[0159] The compound according to the above chemical formula IA can be prepared stepwise according to the following reaction scheme A-1 depending on the Y substituent.

[0160] [Reaction Equation A-1]

[0161]

[0162] In reaction equation A-1, Ya is independently -C(=O)(R 1 ), Yc are each independently -P(=O)(R 2 )(R 3 Represents ) and R 1 to R 3C each independently 1-6 It is an alkyl, and Hal represents a halogen.

[0163] The preparation of a compound of formula IAa from formula IB is carried out as shown in reaction scheme 1 above, and

[0164] The preparation of a compound of formula IAb from formula IAa is a deprotection reaction of a glucal substituent, and can be carried out according to general method 3a or general method 3b described below in this specification.

[0165] The deprotection step of this stage is a deprotection reaction of a conventional ester functional group to an alcohol functional group carried out in the presence of an acid catalyst, and is possible under conditions other than general manufacturing method 3a or 3b.

[0166] The preparation of a compound with the formula IAc from a compound with the formula IAb is a phosphoryl esterification reaction and can be carried out using an organic solvent in the presence of a base, for example, a tertiary amine.

[0167] Compounds with chemical formula IC can be provided as starting materials for a deprotection reaction for the preparation of compounds with chemical formula IB.

[0168]

[0169] Furthermore, IC compounds can be obtained through the well-known Wittig reaction as shown in the reaction scheme below. Meanwhile, depending on the type of R substituent, additional substituent modifications may be formed after the Wittig reaction.

[0170]

[0171] The preparation of a compound according to the present invention is described exemplarily below through specific synthesis examples.

[0172] All of the following examples are exemplary and can be performed by a person skilled in the art with modifications within the obvious scope by referring to the examples in order to produce other compounds falling within the scope of the compounds according to the present invention.

[0173]

[0174] Example 1:

[0175] Example 1-1. Preparation of Chemical Formula IA-1 Compound

[0176] Synthesis Example A1: Preparation of 1-((3S,5R,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-one

[0177]

[0178] Epipregnanolon (530.0 mg, 3.14 mmol) was added to 30 mL of dichloromethane and 3 mL of tetrahydrofuran (THF) at room temperature, and 303.6 μL (3.33 mmol) of 3,4-dihydro-2H-pyran was added. 15.8 mg (0.08 mmol) of p-toluenesulfonic acid monohydrate was dissolved in 0.08 mL of tetrahydrofuran (THF), added dropwise, and stirred at room temperature for 1 hour. The reaction was terminated by adding water to the reaction mixture at room temperature, washed twice with dichloromethane and brine, dried and filtered with anhydrous sodium sulfate, and then subjected to vacuum distillation. The resulting residue was subjected to silica gel column chromatography to obtain target compound A1 (275.0 mg, 41%).

[0179] 1H NMR (500 MHz, CDCl3) δ4.65 - 4.62 (m, 1H), 3.97 - 3.93 (m, 1H), 3.93 - 3.83 (m, 1H), 3.51 - 3.42 (m, 1H), 2.52 (t, J = 8.9 Hz, 1H), 2.10 (s, 4H), 2.03 - 1.96 (m, 1H), 1.93 - 1.82(m, 3H), 1.81 - 1.59 (m, 5H), 1.59 - 1.48 (m, 8H), 1.47 (d, J = 1.3 Hz, 2H), 1.46 - 1.26 (m, 7H), 1.26 - 1.20 (m, 1H), 1.20 - 1.15 (m, 2H), 1.15 - 1.01 (m, 1H), 0.93 (d, J = 0.8 Hz, 3H), 0.59 (s, 3H).

[0180] Synthetic Example A2:

[0181]

[0182] The following compounds were prepared in the same manner.

[0183]

[0184]

[0185] The intermediate compound A26 was prepared as shown in Reaction Scheme 1-1 below.

[0186] [Reaction Equation 1-1]

[0187]

[0188] Step 1 :

[0189] Synthesis Example A3: (E)-5-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hex-4-enic acid

[0190] General procedure 5

[0191] A starting material prepared in the same manner as Synthesis Example A1 was prepared and the reaction was carried out.

[0192] 3-carboxypropyltriphenylphosphonium bromide (16.07 g, 37.44 mmol) was dissolved in 374 mL of toluene, and then potassium t-pentoxide (1.7 M in toluene, 44.1 mL, 74.89 mmol) was added at room temperature. After stirring at 110℃ for 1 hour, the reaction solution was lowered to 60℃, and 1-((3S,8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (5.0 g, 12.48 mmol) was added dropwise, and the reaction solution was heated back to 110℃ and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to 40°C, washed with an aqueous solution of saturated ammonium chloride, ethyl acetate, water, and brine, dried and filtered with anhydrous sodium sulfate, and then subjected to vacuum distillation. The resulting residue was subjected to silica gel column chromatography to obtain the target compound A3 (2.54 g, 43%).

[0193] Synthesis Examples A4, A5: Synthesis Examples A4 and A5 below were prepared according to General Method 5.

[0194]

[0195] Step 2 :

[0196] Synthesis Example A7: Methyl (E)-5-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hex-4-enoate

[0197] Synthesis Example A3 (101 mg, 0.22 mmol) was dissolved in 1.5 mL of methanol / dichloromethane (1:2), and then 0.70 mL (0.43 mmol) of a 2 M trimethylsilyldiazomethane solution (in Et2O) was slowly added dropwise at 0°C. The reaction solution was stirred at room temperature for 3 hours, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain the target compound A7 (40.7 mg, 39%).

[0198] 1 H NMR (500 MHz, CDCl3) δ5.39 - 5.31 (m, 1H), 5.16 - 5.13 (m, 1H), 4.72 - 4.71 (m, 1H), 3.97 - 3.87 (m, 1H), 3.66 (s, 3H), 3.58 - 3.43 (m, 2H), 2.40 - 2.30 (m, 6H), 2.25 - 2.15 (m, 1H), 2.06 - 1.94 (m, 2H), 1.94 - 1.49 (m, 19H), 1.49 - 1.37 (m, 3H), 1.23 - 1.12 (m, 2H), 1.10 - 1.02 (m, 2H), 1.01 (s, 3H), 0.97 - 0.92 (m, 1H), 0.52 (s, 3H).

[0199] Synthetic Examples A8 and A9:

[0200] The following compound was prepared using the same method.

[0201]

[0202] Step 3:

[0203] Synthesis Example A26: Methyl (E)-5-((3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hex-4-enoate

[0204]

[0205] General Procedure 3b

[0206] Synthesis Example A7 was dissolved in 5 mL of methanol, 70.0 mg (0.14 mmol) of p-toluenesulfonic acid monohydrate was added at room temperature, and the mixture was stirred under reflux for 5 hours. After removing the solvent by vacuum distillation, the extracted organic layer was washed with brine using ethyl acetate and an aqueous solution of saturated sodium bicarbonate. Subsequently, the organic layer was dried and filtered with anhydrous sodium sulfate, followed by vacuum distillation. The residue obtained after concentration was subjected to silica gel column chromatography to obtain the target compound A26 (34.0 mg, 59%).

[0207] 1 H NMR (500 MHz, CDCl3) δ5.36 - 5.34 (m, 1H), 5.18 - 5.12 (m, 1H), 3.67 (s, 3H), 3.57 - 3.48 (m, 1H), 2.36 (d, J = 3.2 Hz, 4H), 2.33 - 2.19 (m, 2H), 2.04 - 1.95 (m, 2H), 1.89 - 1.74 (m, 4H), 1.71 - 1.37 (m, 12H), 1.20 - 1.14 (m, 2H), 1.12 - 1.03 (m, 2H), 1.01 (s, 3H), 0.98 - 0.93 (m, 1H), 0.53 (s, 3H).

[0208]

[0209] Examples 1-2:

[0210] [Reaction Equation 1-2]

[0211]

[0212] Step 1:

[0213] Synthesis Example A10: 2-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-5-methoxypent-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)tetrahydro-2H-pyran

[0214] It was manufactured according to general method 5.

[0215] 1 H NMR (500 MHz, CDCl3) δ5.35 (dd, J1= 8.1, J2= 5.6 Hz, 1H), 5.20 - 5.15 (m, 1H), 4.71 (d, J = 4.6 Hz, 1H), 3.92 (td, J1= 7.1, J2= 3.4 Hz, 1H), 3.58 - 3.45 (m, 2H), 3.38 - 3.34 (m, 5H), 2.37-2.31 (m, 3H), 2.06 - 1.95 (m, 2H), 1.93 - 1.76 (m, 5H), 1.75 - 1.40 (m, 16H), 1.23 - 1.03 (m, 4H), 1.01 (s, 3H), 0.94 (dt, J1= 11.7, J2= 5.9 Hz, 1H), 0.54 (s, 3H). MS (m / z) [M+H] + Calcd for C 30 H 49 O3 + 457.36, found 457.4

[0216] Synthesis Example A21: Prepared using the same method.

[0217] Step 2:

[0218] Synthesis Example A30: (3S,8S,9S,10R,13S,14S,17R)-17-((E)-5-methoxyphent-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-ol

[0219] General Procedure 3a

[0220] Synthesis Example A10 was dissolved in 0.15 mL of acetonitrile and 0.15 mL of tetrahydrofuran, then 0.28 mL of 6N aqueous hydrochloric acid solution was added at 0°C and stirred for 2 hours. The reaction was terminated with an aqueous solution of saturated sodium bicarbonate, and the mixture was extracted twice with ethyl acetate. The extracted organic layer was washed with brine, dried and filtered with anhydrous sodium sulfate, and then subjected to vacuum distillation. The resulting residue was subjected to silica gel column chromatography to obtain the target compound A30 (95.0 mg, 91%).

[0221] 1 H NMR (500 MHz, CDCl3) δ5.36 (dd, J1= 5.0, J2= 2.4 Hz, 1H), 5.21 - 5.15 (m, 1H), 3.55 - 3.50 (m, 1H), 3.39 - 3.34 (m, 5H), 2.36 - 2.19 (m, 4H), 2.08 - 1.94 (m, 2H), 1.89 - 1.76 (m, 4H), 1.69 - 1.41 (m, 11H), 1.22 - 1.03 (m, 4H), 1.01 (s, 3H), 0.96 (td, J1= 11.7, J2= 4.8 Hz, 1H), 0.54 (s, 3H). MS (m / z) [M+H] + Calcd for C 25 H 41 O2 + 373.30, found 373.4

[0222] Synthesis Example A34: Prepared using the same method.

[0223]

[0224] Examples 1-3:

[0225] Synthesis Example 1-3 was prepared according to the following reaction scheme 1-3.

[0226] [Reaction Equation 1-3]

[0227]

[0228] Step 1:

[0229] Synthesis Example 1-1:

[0230] General procedure 1

[0231] Synthesis Example A8 (50.0 g, 100.3 mmol) was dissolved in 150 mL of tetrahydrofuran, and then 5.7 g (150.5 mmol) of lithium aluminum hydride (LAH) was added dropwise at 0°C, followed by stirring for 2 hours at 0°C. After terminating the reaction with water, the solution was filtered through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried and filtered with anhydrous sodium sulfate, and then subjected to vacuum distillation. The residue obtained after concentration was subjected to silica gel column chromatography to obtain target compound 1-1 (44.2 g, 39%).

[0232] 1 H NMR (500 MHz, CDCl3) δ 5.35 - 5.32 (m, 1H), 5.17 - 5.14 (m, 1H), 4.71 - 4.69 (m, 1H), 3.93 - 3.88 (m, 1H), 3.65 - 3.62 (m, 2H), 3.55 - 3.45 (m, 2H), 2.60 - 2.34 (m, 1H), 2.07 - 1.96 (m, 4H), 1.86 - 1.37 (m, 25H), 1.26 - 0.93 (m, 9H), 0.52 (s, 3H)

[0233] Synthesis Examples A11 - A14: Prepared in the same manner as Synthesis Example 1-1.

[0234]

[0235] Step 2:

[0236] Synthesis Example 1-2:

[0237] General procedure 2

[0238] Synthesis Example 1-1 (24.2 g, 51.41 mmol) was dissolved in tetrahydrofuran (520 mL), and sodium hydride (NaH, 4.11 g, 102.81 mmol) was added dropwise at 0°C and stirred for 20 minutes. Iodomethane (MeI, 4.8 mL, 77.11 mmol) was slowly added dropwise to the reaction solution and stirred at 40°C. After 3 hours, an equal amount was added dropwise and stirred for another 3 hours. After terminating the reaction with water, the mixture was extracted with ethyl acetate, washed with water and brine, and the organic layer was dried and filtered with anhydrous sodium sulfate followed by vacuum distillation. The residue obtained after concentration was subjected to silica gel column chromatography to obtain the target compound Synthesis Example 1-2 (18.5 g, 39%).

[0239] 1 H NMR (500 MHz, CDCl3) δ 5.35 - 5.32 (m, 1H), 5.15 (t, J = 7.5 Hz, 1H), 4.71 - 4.69 (m, 1H), 3.93 - 3.89 (m, 1H), 3.54 - 3.45 (m, 2H), 3.36 (t, J = 5.0 Hz, 2H), 3.32 (s, 3H), 2.35 - 2.34 (m, 1H), 2.06 - 1.94 (m, 4H), 1.88 - 1.35 (m, 25H), 1.19 - 1.00 (m, 4H), 0.99 (s, 3H), 0.93 (dt, J1= 12.5 Hz, J2= 5.0 Hz, 1H), 0.52 (s, 3H)

[0240] Compounds A15 to A24 below were prepared according to the conditions of general method 2 of synthesis example 1-2, but using a reactant corresponding to the substituent instead of MeI.

[0241]

[0242] Step 3:

[0243] Synthesis Example 1-3:

[0244]

[0245] It was manufactured according to general method 3a.

[0246] Synthesis Example 1-2 (4.0 g, 8.25 mmol) was dissolved in 10 mL of acetonitrile and 10 mL of tetrahydrofuran, then 8.25 mL of 6N aqueous hydrochloric acid solution was added at 0°C and stirred for 3.5 hours. The reaction was terminated with an aqueous solution of saturated sodium bicarbonate, and the mixture was extracted twice with ethyl acetate. The extracted organic layer was washed with brine, dried and filtered with anhydrous sodium sulfate, and then subjected to vacuum distillation. The resulting residue was subjected to silica gel column chromatography to obtain target compound 1-3 (1.22 g, 37%).

[0247] 1 H NMR (500 MHz, CDCl3) δ- 5.33 (m, 1H), 5.18 - 5.15 (m, 1H), 3.55 - 3.48 (m, 1H), 3.36 (t, J = 7.5 Hz, 2H), 3.32 (s, 3H), 2.28 - 2.22 (m, 4H), 2.06 - 1.96 (m, 4H), 1.85 - 1.77 (m, 4H), 1.62 - 1.37 (m, 15H), 1.19 - 1.04 (m, 4H), 1.00 (s, 3H), 0.97 - 0.93 (m, 1H), 0.53 (s, 3H)

[0248]

[0249] The following compound was prepared according to general method 3a.

[0250]

[0251]

[0252] Synthetic Examples A25 and A28:

[0253] It was manufactured according to general method 3b.

[0254]

[0255]

[0256] Examples 1-4:

[0257] [Reaction Equation 1-4]

[0258]

[0259] As shown in the above reaction scheme, an intermediate for the compounds of Synthesis Example 1-5 was prepared using general method 5 and general method 3b.

[0260]

[0261] Examples 1-5:

[0262] [Reaction Equation 1-5]

[0263]

[0264] Synthesis Example A6: Methyl (E)-3-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)but-2-enoate

[0265] Trimethylphosphonoacetate (1.0 mL, 7.5 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL) in a dried sealed tube, then n-butyllithium (2.0 M in cyclohexane, 3.7 mL, 7.5 mmol) was added dropwise under nitrogen at -78°C and stirred for 30 minutes. 1-((3S,8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (1.0 g, 2.5 mmol) was added to anhydrous Dissolved in tetrahydrofuran (4 mL), the solution was added dropwise to the reaction solution under nitrogen at -78°C, and the reaction solution was heated to 110°C and stirred for 16 hours. Afterward, the reaction solution was cooled to room temperature, washed with 1N aqueous hydrochloric acid, ethyl acetate, water, and brine, dried and filtered with anhydrous sodium sulfate, and then subjected to vacuum distillation. The resulting residue was subjected to silica gel column chromatography to obtain the target compound A6 (275 mg, 24%).

[0266] 1 H NMR (500 MHz, CDCl3) δ5.70 (s, 1H), 5.38 - 5.32 (m, 1H), 4.72 (dd, J1= 5.0, J2= 2.7 Hz, 1H), 3.95 - 3.85 (m, 2H), 3.69 (d, J = 2.2 Hz, 3H), 3.57 - 3.44 (m, 3H), 2.38 - 2.32 (m, 2H), 2.17 (dd, J1= 10.0, J2=1.2 Hz, 5H), 2.04 - 1.95 (m, 1H), 1.92 - 1.65 (m, 11H), 1.65 - 1.39 (m, 15H), 1.31 - 0.93 (m, 10H), 0.59 (s, 3H).

[0267] Synthesis Example A27: Methyl (E)-3-((3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)but-2-enoate

[0268] It was prepared according to general method 3b and used in the preparation of synthesis examples 1-6.

[0269]

[0270] Examples 1-6. Preparation of Synthesis Examples 1-4 to 1-25:

[0271] Synthesis Example 1-10:

[0272]

[0273] General Procedure 4

[0274] Synthesized Examples 1-3 (3.03 g, 7.56 mmol) and 3.09 g (11.34 mmol) of tri-O-acetyl D-glucal were dissolved in 50 mL of anhydrous toluene and 25 mL of acetonitrile. While maintaining the temperature at 35°C, 115.7 mg (0.38 mmol) of lithium nonafluoro-1-butylsulfonate (Li-NFBS) and 17.6 mg (0.38 mmol) of (s)-camphorsulfonic acid were added, and the mixture was stirred for 5 hours. The reaction was terminated with an aqueous solution of saturated sodium bicarbonate, followed by extraction twice with ethyl acetate. The extracted organic layer was washed with brine, dried and filtered with anhydrous sodium sulfate, and then distilled under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain the target compound 1-10 (1.89 g, 41%) in the oil phase.

[0275] 1H NMR (500 MHz, CDCl3) δ96 - 5.79 (m, 2H), 5.36 - 5.33 (m, 1H), 5.29 - 5.25 (m, 1H), 5.21 - 5.15 (m, 2H), 4.28 - 4.15 (m, 3H), 3.64 - 3.52 (m, 1H), 3.36 (t, J = 5.0 Hz, 2H), 3.32 (s, 3H), 2.42 - 2.30 (m, 2H), 2.08 - 1.96 (m, 14H), 1.67 - 1.32 (m, 14H), 1.20 - 1.01 (m, 4H), 1.01 - 0.91 (m, 4H), 0.53 (s, 3H)

[0276] Synthesis Example 1-22:

[0277]

[0278] Synthesized Example 1-10 (100 mg, 0.16 mmol) was dissolved in 3 mL of methanol, 26.1 mg (0.65 mmol) of sodium hydroxide was added, and the mixture was stirred at room temperature for 15.5 hours. The reaction was terminated with an aqueous solution of saturated sodium bicarbonate, followed by extraction twice with ethyl acetate. The extracted organic layer was washed with brine, dried and filtered with anhydrous sodium sulfate, and then subjected to vacuum distillation. The resulting residue was subjected to silica gel column chromatography to obtain target compound 1-22 (51.9 mg, 60%).

[0279] 1H NMR (500 MHz, CDCl3) δ(dt, J1= 6.3 Hz, J2= 3.3 Hz, 1H), 5.74 (dt, J1= 3.3 Hz, J2= 6.2 Hz, 1H), 5.35 (d, J = 5.0 Hz, 1H), 5.16 (t, J = 7.5 Hz, 1H), 5.12 (t, J = 2.5 Hz, 1H), 4.21 (dt, J1= 8.7 Hz, J2= 1.7 Hz, 1H), 3.90 - 3.82 (m, 2H), 3.78 - 3.75 (m, 1H), 3.56 - 3.50 (m, 1H), 3.34 (t, J = 10.1 Hz, 2H), 3.32 (s, 3H), 2.39 - 2.30 (m, 2H), 2.06 - 1.74 (m, 11H), 1.67 - 1.36 (m, 13H), 1.20 - 0.91 (m, 8H), 0.53 (s, 3H)

[0280] Synthesis Example 1-24:

[0281]

[0282] Synthesized Example 1-22 (207.8 mg, 0.39 mmol) was dissolved in 5 mL of tetrahydrofuran, and then 0.27 mL of triethylamine (TEA, 1.97 mmol) and 132.6 mg of dimethylphosphinic chloride (dimethylphosphinic chloride, 1.18 mmol) were added at 0°C and stirred for 19 hours. After stopping the reaction by adding water to the reaction solution, the mixture was extracted twice with ethyl acetate. The extracted organic layer was washed with brine, dried and filtered with anhydrous sodium sulfate, and then subjected to vacuum distillation. The resulting residue was subjected to silica gel column chromatography to obtain target compound 1-24 (8.9 mg, 3%).

[0283] Synthesis Example 1-26. Preparation of CU06-1004:

[0284] The compound CU06-1004 is used as a synonym for the compound SAC-1004 and can be prepared according to known methods and is prepared in a manner similar to the synthesis example described above.

[0285]

[0286]

[0287] The structures of Synthetic Examples 1-4 to 1-25 are presented below.

[0288]

[0289]

[0290] The IUPAC names of compounds and analysis data for Synthesis Examples 1-1 to 1-25 are presented below.

[0291] 1-4-methyl (E)-5-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hex-4-enoate 1H NMR (500 MHz, CDCl3) δ5.91 - 5.79 (m, 2H), 5.36 (d, J = 5.2 Hz, 1H), 5.33 - 5.26 (m, 1H), 5.20 - 5.10 (m, 2H), 4.29 - 4.14 (m, 3H), 3.67 (s, 3H), 3.60 - 3.53 (m, 1H), 2.45 - 2.30 (m, 6H), 2.09 (d, J = 8.3 Hz, 6H), 2.04 - 1.94 (m, 2H), 1.92 - 1.83 (m, 2H), 1.81 - 1.74 (m, 2H), 1.67 - 1.50 (m, 12H), 1.47 - 1.41 (m, 2H), 1.20 - 1.14 (m, 2H), 1.11 - 0.91 (m, 6H), 0.53 (s, 3H).1-5methyl(E)-6-((3S,8S,9S,10R,13R,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hex-5-enoate 1H NMR (500 MHz, CDCl3) δ5.88 - 5.80 (m, 2H), 5.39 - 5.16 (m, 4H), 4.25 - 4.15 (m, 3H), 3.65 (s, 3H), 3.59 - 3.52 (m, 1H), 2.42 - 2.23 (m, 5H), 2.11 - 1.97(m, 9H), 1.87 - 1.73 (m, 3H), 1.69 - 1.38 (m, 11H), 1.24 - 1.16 (m, 1H), 1.07 - 0.62 (m, 7H), 0.62 (s, 3H)1-6methyl (E)-3-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)but-2-enoate 1H NMR (500 MHz, CDCl3) δ5.88 - 5.79 (m, 2H), 5.69 (s, 1H), 5.35 - 5.34 (m, 1H), 5.29 (d, J=5.0 Hz, 1H), 5.16 (s, 1H), 4.25 - 4.15 (m, 3H), 3.68 (s, 3H), 3.58 - 3.53 (m, 1H), 2.42 - 2.31 (m, 2H), 2.18 - 2.17 (m, 4H), 2.09 - 2.07 (m, 6H), 2.00 - 1.97 (m, 1H), 1.87 - 1.82 (m, 4H), 1.73 - 1.69 (m, 2H), 1.57 - 1.41 (m, 5H), 1.27 - 1.12 (m, 3H), 1.07 - 0.93 (m, 5H), 0.58 (s, 3H)1-7((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-6-methoxyhex-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.87 (dt, J1= 10.2, J2= 1.2 Hz, 1H), 5.83 - 5.80 (m, 1H), 5.37 (dd, J1= 4.9, J2= 2.5 Hz, 1H), 5.31 - 5.28 (m, 1H) 5.18 (dd, J1= 4.5, J2= 3.0 Hz, 2H), 4.24 (dd, J1= 12.1, J2= 5.9 Hz, 1H), 4.21 - 4.12 (m, 2H), 3.56 (tt, J1= 11.2, J2= 4.7 Hz, 1H), 3.37 (t, J = 6.6 Hz, 2H), 3.33 (s, 3H), 2.44 - 2.31 (m, 2H), 2.09 (d, J = 7.9 Hz, 9H), 2.05 - 1.95 (m, 2H), 1.93 - 1.83 (m, 2H), 1.83 - 1.76 (m, 2H), 1.69 - 1.59 (m, 7H), 1.59 - 1.49 (m, 5H), 1.49 - 1.38 (m, 2H), 1.23 - 1.13 (m, 2H), 1.10 - 1.02 (m, 2H), 1.01 (s, 3H), 0.99 - 0.92 (m, 1H), 0.89 - 0.80 (m, 1H), 0.55 (s, 3H).1-8((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-6-ethoxyhex-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.89 - 5.87 (m, 1H), 5.84 - 5.81 (m, 1H), 5.37 - 5.35 (m, 1H), 5.31 - 5.28 (m, 1H), 5.19 - 5.16 (m, 2H), 4.26 - 4.16 (m, 3H), 3.60 - 3.54 (m, 1H), 3.47 (q, J = 6.7Hz, 2H), 3.41 (t, J = 5.0 Hz, 2H), 2.49 - 2.32 (m, 2H), 2.10 - 2.08 (m, 7H), 2.03 - 1.97 (m, 2H), 1.90 - 1.77 (m, 4H), 1.65 - 1.41 (m, 13H), 1.22 - 1.16 (m, 5H), 1.08 - 0.92 (m, 6H), 0.54 (s, 3H). MS (m / z) [M+Na] + Calcd for C 37 H 56 O7Na + 635.40, found 635.51-10((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-methoxyhept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ- 5.85 (m, 1H), 5.82 - 5.79 (m, 1H), 5.36 - 5.34 (m, 1H), 5.29 - 5.27 (m, 1H), 5.18 - 5.15 (m, 2H), 4.24 - 4.15 (m, 3H), 3.58 - 3.52 (m, 1H), 3.36 (t, J = 5.0 Hz, 2H), 3.32 (s, 3H), 2.42 - 2.30 (m, 2H), 2.08 (s, 3H), 2.06 (s, 3H), 2.08 - 1.96 (m, 4H), 1.87 - 1.77 (m, 4H), 1.67 - 1.37 (m, 14H), 1.20 - 1.01 (m, 4H), 0.99 (s, 3H), 0.94 - 0.91 (m, 1H), 0.53 (s, 3H)1-11((2R,3R)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-methoxyhept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ6.12 - 6.09 (m, 1H), 6.01 (dd, J1= 10.1, J2= 3.1 Hz, 1H), 5.37 (dd, J1= 5.2, J2= 2.4 Hz, 1H), 5.24 - 5.20 (m, 1H), 5.20 - 5.14 (m, 1H), 5.02 (dd, J1= 5.5, J2= 2.5 Hz, 1H), 4.43 - 4.40 (m, 1H), 4.26 - 4.20 (m, 2H), 3.63 - 3.53 (m, 1H), 3.37 (t, J = 6.6 Hz, 2H), 3.33 (s, 3H), 2.45 - 2.41 (m, 1H), 2.33 (t, J = 12.5 Hz, 1H), 2.11 - 1.95 (m, 12H), 1.93 - 1.75 (m, 5H), 1.71 - 1.49 (m, 17H), 1.49 - 1.36 (m, 5H), 1.23 - 1.12 (m, 2H), 1.09 - 1.03 (m, 2H), 1.00 (s, 3H), 0.95 (td, J1= 11.7, J2= 4.8 Hz, 1H), 0.54 (s, 3H).1-12((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-8-methoxyoct-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.89 - 5.80 (m, 2H), 5.37 - 5.36 (m, 1H), 5.30 - 5.27 (m, 1H), 5.18 - 5.17 (m, 2H), 4.24 - 4.17 (m, 3H), 3.59 - 3.54 (m, 1H), 3.37 (t, J = 7.5Hz, 2H), 3.33 (s, 3H), 2.43 - 2.32 (m, 2H), 2.10 - 2.08 (m, 6H), 2.04 - 1.96 (m,4H), 1.90-1.78 (m, 4H), 1.67 - 1.51 (m, 10H), 1.45 - 1.42 (m, 2H), 1.37 - 1.35 (m, 4H), 1.21 - 1.16 (m, 2H), 1.08 - 0.92 (m, 6H), 0.54 (s, 3H). MS (m / z) [M+Na] + Calcd for C 38 H 58 O7Na + 649.42, found 649.6.1-13((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-5-methoxypent-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.89 - 5.80 (m, 2H), 5.37 - 5.35 (m, 1H), 5.31 - 5.28 (m, 1H), 5.19 - 5.16 (m, 2H), 4.26 - 4.16 (m, 3H), 3.60 - 3.53 (m, 1H), 3.39 - 3.32 (m, 5H), 2.43- 2.31 (m, 4H), 2.10 - 2.08 (m, 8H), 2.04 - 1.96 (m, 2H), 1.90 - 1.78 (m, 4H), 1.69- 0.41 (m, 8H), 1.21 - 1.15 (m, 7H), 0.98 - 0.92 (m, 1H), 0.54 (s, 3H). MS (m / z) [M+Na] + Calcd for C 35 H 52 O7Na + 607.37, found 607.51-17((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-ethoxyhept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.89 - 5.87 (m, 1H), 5.84 - 5.81 (m, 1H), 5.37 - 5.35 (m, 1H), 5.31 - 5.29 (m, 1H), 5.27 - 5.16 (m, 2H), 4.24 - 4.18 (m, 3H), 3.60 - 3.54 (m, 1H), 3.47 (q, J = 6.7Hz, 2H), 3.41 (t, J = 7.5 Hz, 2H), 2.43 - 2.32 (m, 2H), 2.10 - 2.08 (m, 7H), 2.06 - 1.98 (m, 4H), 1.90 - 1.77 (m, 5H), 1.63 - 1.53 (m, 10H), 1.45 - 1.39 (m, 4H), 1.22 - 1.15 (m, 6H), 1.08 - 1.05 (m, 2H), 1.00 (s, 3H), 0.89 - 0.92 (m, 1H), 0.54 (s, 3H). MS (m / z) [M+Na] + Calcd for C 38 H 57 O7Na + 649.42, found 649.71-18((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13R,14S,17R)-17-((E)-6-methoxyhex-1-en-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.87 - 5.85 (m, 1H), 5.82 - 5.79 (m, 1H), 5.42 - 5.33 (m, 2H), 5.29 - 5.24 (m, 2H), 5.16 (m, 1H), 4.24 - 4.14 (m, 3H), 3.58 - 3.52 (m, 1H), 3.37 - 3.34 (m, 2H), 3.31 (s, 3H), 2.42 - 2.26 (m, 3H), 2.09 - 1.97 (m, 9H), 1.89 - 1.84 (m, 2H), 1.81 - 1.34 (m, 15H), 1.09 - 0.91 (m, 6H), 0.57 (s, 3H)1-19((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(pyridine-2-yloxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ8.13 (dq, J1= 5.0, J2= 0.9 Hz, 1H), 7.54 (ddd, J1= 8.7, J2= 6.8, J3= 1.6 Hz, 1H), 6.82 (ddd, J1= 6.9, J2= 5.1, J3= 0.9 Hz, 1H), 6.71 (dt, J1= 8.3, J2= 0.9 Hz, 1H), 5.86 (d, J = 10.3 Hz, 1H), 5.81 (ddd, J1= 10.1, J2= 2.6, J3= 1.9 Hz, 1H), 5.36 - 5.35 (m, 1H), 5.28 (dd, J1= 9.5, J2=1.4 Hz, 1H), 5.20 - 5.17 (m, 2H), 4.27 (t, J = 6.6 Hz, 2H), 4.23 (q, J = 6.0 Hz, 1H), 4.19-4.15 (m, 2H), 3.57 - 3.53 (m, 1H), 2.42 - 2.38 (m, 1H), 2.36 - 2.31 (m, 1H), 2.11 (d, J = 7.2 Hz, 1H), 2.08 (s, 3H), 2.06 (s, 3H), 2.01 - 1.95 (m, 2H), 1.88 - 1.83 (m, 2H), 1.80 - 1.75 (m, 4H), 1.68 - 1.64 (m, 5H), 1.62 - 1.57 (m, 2H), 1.57 - 1.49 (m, 4H), 1.47 - 1.38 (m, 2H), 1.20 - 1.13 (m, 2H), 1.08 - 1.02 (m, 2H), 1.01 (s, 3H), 0.96 - 0.91 (m, 1H), 0.88 - 0.84 (m, 1H), 0.53 (s, 3H). MS (m / z) [M+H] + Calcd for C 41 H 58 NO7 +676.42, found 676.6.1-20((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(pyridine-3-yloxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1 H NMR (500 MHz, CDCl3) δ8.29 (d, J = 2.3 Hz, 1H), 8.19 (d, J = 3.2 Hz, 1H), 7.20 - 7.15 (m, 2H), 5.86 (d, J = 10.6 Hz, 1H), 5.80 (dt, J1= 10.2, J2= 2.2 Hz, 1H), 5.35 (d, J = 4.9 Hz, 1H), 5.28 - 5.25 (m, 2H), 5.19 - 5.16 (m, 2H), 4.22 (q, J = 6.0 Hz, 1H), 4.19 - 4.15 (m, 2H), 3.99 (t, J = 6.4 Hz, 2H), 3.58 - 3.52 (m, 1H), 2.40 (dd, J1= 13.3, J2= 3.3 Hz, 1H), 2.36 - 2.31 (m, 1H), 2.11 (t, J = 7.2 Hz, 2H), 2.08 (s, 3H), 2.07 (s, 3H), 2.04 - 1.93 (m, 2H), 1.88 - 1.83 (m, 2H), 1.81 - 1.77 (m, 4H), 1.68 - 1.58 (m, 6H), 1.55 - 1.49 (m, 2H), 1.46 - 1.37 (m, 3H), 1.20 - 1.13 (m, 2H), 1.11 - 1.01 (m, 2H), 1.00 (s, 3H), 0.94 (td, J1= 11.6, J2= 4.3 Hz, 1H), 0.53 (s, 3H). MS (m / z) [M+H] + Calcd for C 41 H 58 NO7 +676.41, found 676.5.1-21((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(pyrimidine-5-yloxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1 H NMR (500 MHz, CDCl3) δ8.82 (s, 1H), 8.38 (s, 2H), 5.88 - 5.85 (m, 1H), 5.81 (dt, J1= 10.1, J2= 2.2 Hz, 1H), 5.36 - 5.35 (m, 1H), 5.29 - 5.25 (m, 1H), 5.20 - 5.16 (m, 2H), 4.23 (q, J = 6.1 Hz, 1H), 4.19 - 4.15 (m, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.58 - 3.52 (m, 1H), 2.42 - 2.39 (m, 1H), 2.36 - 2.31 (m, 1H), 2.12 (q, J = 7.5 Hz, 2H), 2.08 (s, 3H), 2.07 (s, 3H), 2.04 - 1.95 (m, 2H), 1.91 - 1.77 (m, 7H), 1.69 - 1.58 (m, 1H), 1.55 (s, 3H), 1.52 (t, J = 7.6 Hz, 3H), 1.46 - 1.37 (m, 3H), 1.21 - 1.12 (m, 2H), 1.09 - 1.01 (m, 2H), 1.00 (s, 3H), 0.94 (td, J1=11.7, J2=4.5 Hz, 1H), 0.54 (s, 3H). MS (m / z) [M+H] + Calcd for C 40 H 57 N2O7 +677.41, found 677.5.1-22(2R,3S)-2-(hydroxymethyl)-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-methoxyhept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-3-ol 1 H NMR (500 MHz, CDCl3) δ(dt, J1 = 6.3 Hz, J2 = 3.3 Hz, 1H), 5.74 (dt, J1 = 3.3 Hz, J2 = 6.2 Hz, 1H), 5.35 (d, J = 5.0 Hz, 1H), 5.16 (t, J = 7.5 Hz, 1H), 5.12 (t, J = 2.5 Hz, 1H), 4.21 (dt, J1 = 8.7 Hz, J2 = 1.7 Hz, 1H), 3.90 - 3.82 (m, 2H), 3.78 - 3.75 (m, 1H), 3.56 - 3.50 (m, 1H), 3.34 (t, J = 10.1 Hz, 2H), 3.32 (s, 3H), 2.39 - 2.30 (m, 2H), 2.06 - 1.74 (m, 11H), 1.67 - 1.36 (m, 13H), 1.20 - 0.91 (m, 8H), 0.53 (s, 3H)1-24((2R,3S)-3-((dimethylphosphoryl)oxy)-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-methoxyhept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl dimethylphosphinate 1H NMR (500 MHz, CDCl3) δ 6.07 (d, J = 10.1 Hz, 1H), 5.80 - 5.77 (m, 1H), 5.33 - 5.32 (m, 1H), 5.17 - 5.15 (m, 2H), 4.90 - 4.86 (m, 1H), 4.25 - 4.21 (m, 1H), 4.17 - 4.13 (m, 1H), 4.08 - 4.05 (m, 1H), 3.57 - 3.51 (m, 1H), 3.36 (t, J = 7.5 Hz, 2H), 3.31 (s, 3H), 2.35 - 2.29 (m, 2H), 2.06 - 1.96 (m, 4H), 1.87 - 1.76 (m, 4H), 1.67 - 1.24 (m, 24H), 1.19 - 0.84 (m, 10H), 0.53 (s, 3H)1-25((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-isopropoxyhept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1 H NMR (500 MHz, CDCl3) δ 5.90 - 5.85 (m, 1H), 5.84 - 5.79 (m, 1H), 5.39 - 5.33 (m, 1H), 5.32 - 5.26 (m, 1H), 5.21 - 5.15 (m, 2H), 4.29 - 4.15 (m, 3H), 3.61 - 3.51 (m, 1H), 3.20 (t, J = 7.0 Hz, 2H), 2.46 - 2.30 (m, 2H), 2.10 (s, 3H), 2.08 (s, 3H), 2.07 - 1.95 (m, 4H), 1.92 -1.76 (m. 6H), 1.71 - 1.49 (m, 6H), 1.49 - 1.12 (m, 12H), 1.12 - 1.03 (m, 2H), 1.01 (s, 3H), 0.99 - 0.81 (m, 4H), 0.55 (s, 3H).

[0292]

[0293] Example 2 :

[0294] Compounds of Synthesis Examples 2-1 to 2-3 were prepared as shown in Reaction Scheme 2-1 below.

[0295] [Reaction Equation 2-1]

[0296]

[0297] Synthesis Example 2-1:

[0298] It was performed using the same method as the synthesis example 1-22 above.

[0299] Synthesis Example 2-2:

[0300] It was performed in the same manner as Synthetic Example A7 above.

[0301] Synthesis Example 2-3:

[0302] It was performed using the same method as the synthesis method of Synthesis Example 1-24.

[0303]

[0304] The names of the compounds and analysis results for Synthesis Examples 2-1 to 2-3 are presented in the table below.

[0305] 2-1(E)-6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-hydroxy-6-(hydroxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-enic acid 1H NMR (500 MHz, DMSO-d6) δ5.81 (d, J = 10.4 Hz, 1H), 5.61 - 5.59 (m, 1H), 5.30 (brs, 1H), 5.15 (t, J = 6.4 Hz, 1H), 5.05 (brs, 1H), 3.84 (d, J = 8.4 Hz, 1H), 3.64 (d, J = 10.0 Hz, 1H), 3.52 - 3.43(m, 3H), 2.43 (dd, J = 13.2, 3.6 Hz, 1H), 2.19 - 0.87 (m, 33H), 0.51(s, 3H). HRMS (m / z) [M+Na] + Calcd for 551.3349, found 551.3349.2-2-methyl (E)-6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-hydroxy-6-(hydroxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-enoate 1 H NMR (500 MHz, CDCl3) δ5.97 (d, J = 10.4 Hz, 1H), 5.77 - 5.73 (m, 1H), 5.37 (brs, 1H), 5.16 - 5.13 (m, 2H), 4.23 (t, J = 8.4 Hz, 1H), 3.91 - 3.82(m, 2H), 3.79 - 3.75(m, 1H), 3.67(s, 3H), 3.58 - 3.50(m, 1H), 2.37 - 2.29(m, 4H), 2.30 - 1.37 (m, 22H), 1.22 - 0.91(m, 8H), 0.54(s, 3H). HRMS (m / z) [M+Na] + Calcd for C 33 H 50 O6Na +565.3505, found 565.3507.2-3-methyl (E)-6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-((dimethylphosphoryl)oxy)-6-(((dimethylphosphoryl)oxy)methyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-enoate 1 H NMR (500 MHz, CDCl3) δ6.08 (d, J = 10.3 Hz, 1H), 5.80 (dt, J1= 10.2, J2= 2.2 Hz, 1H), 5.34 (d, J = 4.9 Hz, 1H), 5.15 (t, J = 7.0 Hz, 2H), 4.89 (t, J = 8.9 Hz, 1H), 4.25 (dd, J1= 9.8, J2= 6.8 Hz, 1H), 4.18 - 4.14 (m, 1H), 4.08 (dd, J1= 9.3, J23.0 Hz, 1H), 3.66 (s, 3H), 3.58 - 3.52 (m, 1H), 2.37 - 2.34 (m, 2H), 2.31 (t, J = 7.6 Hz, 2H), 2.09 - 2.04 (m, 2H), 2.02 - 1.96 (m, 2H), 1.90 - 1.83 (m, 3H), 1.81 - 1.73 (m, 3H), 1.71 - 1.63 (m, 4H), 1.62 (d, J = 6.6 Hz, 4H), 1.59 -1.52 (m, 14H), 1.49 - 1.38 (m, 2H), 1.25 (s, 1H), 1.21 - 1.15 (m, 2H), 1.09 - 1.02 (m, 2H), 1.00 (d, J = 10.0 Hz, 3H), 0.94 (td, J1= 11.6, J2= 4.7 Hz, 1H), 0.54 (s, 3H); MS (m / z) [M+H] + Calcd for C 37 H 61 O8P2 + 695.38, found 695.6

[0306]

[0307] Example 3:

[0308] Example 3-1: This was carried out according to the reaction scheme 3-1 below.

[0309] [Reaction Equation 3-1]

[0310]

[0311] In the above reaction scheme 3-1, Lv represents a leaving group and may be methanesulfonyl or p-toluenesulfonyl, but is not limited thereto.

[0312] Step 1:

[0313] Synthesis Example C1: (E)-6-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-en-1-yl methanesulfonate

[0314]

[0315] The above Synthesis Example 1-1 (3.0 g, 6.37 mmol) was dissolved in 70 mL of dimethylformamide. Then, 4.48 mL of triethylamine (TEA, 31.87 mmol) and 1.48 mL of methanesulfonyl chloride (MsCl, 19.12 mmol) were added at 0°C and stirred for 3.5 hours. After stopping the reaction by adding water, the mixture was extracted twice with ethyl acetate. The extracted organic layer was washed with brine, dried and filtered with anhydrous sodium sulfate, and then subjected to vacuum distillation. The resulting residue was subjected to silica gel column chromatography to obtain the target compound C1 (1.68 g, 48%).

[0316] 1H NMR (500 MHz, CDCl3) δ5.35 - 5.32 (m, 1H), 5.14 (t, J = 7.5 Hz, 1H), 4.71 - 4.70 (m, 1H), 4.22 (t, J = 5.0 Hz, 2H), 3.93 - 3.89 (m, 1H), 3.55 - 3.45 (m, 2H), 2.99 (s, 3H), 2.37 - 2.31 (m, 2H), 2.07 (m, J = 6.7 Hz, 2H), 2.01 - 1.95 (m, 2H), 1.88 - 1.37 (m, 24H), 1.20 - 1.12 (m, 2H), 1.09 - 1.01 (m, 2H), 1.00 (2, 3H), 0.94 (dt, J1= 15.0 Hz, J2= 5.0 Hz, 1H), 0.53 (s, 3H)

[0317] Synthesis Example C2 used p-TsCl (p-Ts;p-toluenesulfonyl) instead of MsCl (Ms:mesil) and was prepared in the same manner as C1.

[0318] Step 2:

[0319] Synthesis Example C3: 2-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(((R)-tetrahydrofuran-3-yl)oxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)tetrahydro-2H-pyran

[0320]

[0321] Synthesis Example C1 (519.1 mg, 0.95 mmol) was dissolved in dimethylformamide (9.5 mL), and sodium hydride (NaH, 90.8 mg, 2.27 mmol) was added dropwise at 0°C and stirred for 20 minutes. (R)-tetrahydrofuran-3-ol (100 mg, 1.14 mmol) was slowly added dropwise to the reaction solution and stirred at 40°C. After 16.5 hours, the reaction was terminated with water, extracted with ethyl acetate, washed with water and brine, and the organic layer was dried and filtered with anhydrous sodium sulfate followed by vacuum distillation. The residue obtained after concentration was subjected to silica gel column chromatography to obtain the target compound Synthesis Example C3 (287.6 mg, 56%).

[0322] 1 H NMR (500 MHz, CDCl3) δ5.35 - 5.33 (m, 1H), 5.17 - 5.14 (m, 1H), 4.71 - 4.70 (m, 1H), 4.08 - 4.05 (m, 1H), 3.92 - 3.86 (m, 2H), 3.81 - 3.77 (m, 3H), 3.53 - 3.46 (m, 2H), 3.42 - 3.35 (m, 2H), 2.35 - 2.31 (m, 2H), 2.06 - 1.94 (m, 6H), 1.88 - 1.36 (m, 24H), 1.19 - 1.12 (m, 2H), 1.08 - 1.02 (m, 2H), 1.00 (s, 3H), 0.94 (dt, J1= 12.5 Hz, J2= 5.0 Hz, 1H), 0.53 (s, 3H)

[0323] Synthetic Examples C4 to C15 were prepared in the same manner.

[0324] Step 3:

[0325] Synthesis Example C19: (3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(((R)-tetrahydrofuran-3-yl)oxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol

[0326]

[0327] It was manufactured according to general method 3a.

[0328] 1 H NMR (500 MHz, CDCl3) δ5.35 - 5.33 (m, 1H), 5.17 - 5.14 (m, 1H), 4.08 - 4.05 (m, 1H), 3.90 - 3.85 (m, 1H), 3.81 - 3.77 (m, 3H), 3.54 - 3.48 (m, 1H), 3.42 - 3.34 (m, 2H), 2.32 - 2.27 (m, 1H), 2.26 - 2.19 (m, 1H), 2.06 - 1.94 (m, 6H), 1.86 - 1.76 (m, 4H), 1.68 - 4.36 (m, 15H), 1.20 - 1.12 (m, 2H), 1.11 - 1.04 (m, 2H), 1.00 (s, 3H), 0.98 - 0.92 (m, 1H), 0.53 (s, 3H)

[0329] C19 to C24, C29 to C33, and C37 were manufactured in the same manner.

[0330] Step 4:

[0331] Synthetic Examples C38, 3-1 to 3-6, 3-11 to 3-15 were prepared according to General Method 4.

[0332] Synthesis Example C38: ((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(tosyloxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate

[0333]

[0334] 1 H NMR (500 MHz, CDCl3) δ7.79 (d, J = 8.3 Hz, 2H), 7.36 - 7.32 (m, 2H), 5.89 - 5.80 (m, 2H), 5.36 (d, J = 5.3 Hz, 1H), 5.32 - 5.28 (m, 1H), 5.18 (s, 1H), 5.08 (t, J = 7.0 Hz, 1H), 4.27 - 4.15 (m, 3H), 4.03 (t, J = 6.5 Hz, 2H), 3.56 (tt, J1= 10.6, J2= 4.7 Hz, 1H), 2.45 (s, 3H), 2.44 - 2.31 (m, 2H), 2.09 (d, J = 7.8 Hz, 6H), 1.98 (q, J = 7.4 Hz, 4H), 1.87 (d, J = 13.5 Hz, 2H), 1.77 (d, J = 12.7 Hz, 2H), 1.66 - 1.51 (m, 10H), 1.47 - 1.35 (m, 4H), 1.17 (td, J1= 12.4, J2= 5.9 Hz, 2H), 1.10 - 0.99 (m, 5H), 0.95 (td, J1= 11.7, J2= 4.7 Hz, 1H), 0.52 (s, 3H). MS (m / z) [M+NH4] + Calcd for C 43 H 64 O9SN + 770.40, found 770.6

[0335] Synthesis Example Synthesis Example Synthesis Example R 4C1 or C2 general method 3a, 3bC38C37C2p-Toluenesulfonyl 3a3-1C19C3((R)-Tetrahydrofuran-3-ylC13a3-2C20C4((S)-Tetrahydrofuran-3-ylC13a3-3C21C39CyclopropylC13a3-4C22C40CyclobutylC13a3-5C23C5EthylC23b3-6C24C6CF3-CH2-C23b3-11C29C11CyclohexylC23b3-12C30C12Decahydronaphthalene-2-ylC23b3-13C31C13PhenylC23a3-14C32C144-FluorphenylC23a3-15C33C15Naphthalene-2-ylC23a

[0336]

[0337] Example 3-2:

[0338] [Reaction Equation 3-2]

[0339]

[0340] In the above reaction scheme 3-2, R 5a is H, and R 5b is Me, and R 4 It is methanesulfonyl or acetyl.

[0341] Synthesis Example C7: N-((E)-6-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-en-1-yl )methanesulfonamide

[0342]

[0343] It was prepared according to general method 2, except for using methanesulfonamine.

[0344] 1H NMR (500 MHz, CDCl3) δ5.35 (t, J = 6.7 Hz, 1H), 5.14 (t, J = 7.0 Hz, 1H), 4.72 (d, J = 4.5 Hz, 1H), 4.15 (t, J = 6.2 Hz, 1H), 3.96 - 3.89 (m, 1H), 3.58 - 3.45 (m, 2H), 3.14 (q, J = 6.9 Hz, 2H), 2.96 (s, 3H), 2.36 (d, J = 7.3 Hz, 2H), 2.07 (q, J = 7.2 Hz, 2H), 2.00 (q, J = 7.6) Hz, 2H), 1.90 - 1.51 (m, 20H), 1.46 - 1.39 (m, 4H), 1.22 - 1.13 (m, 2H), 1.10 - 1.03 (m, 2H), 1.01 (s, 3H), 0.95 (td, J1= 11.7, J2= 4.7 Hz, 1H), 0.54 (s, 3H). MS (m / z) [M+H] + Calcd for C 32 H 53 NO4S + 548.37, found 548.4

[0345] Synthesis Example C25: N-((E)-6-((3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10, 11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-en-1-yl)methanesulfonamide

[0346]

[0347] It was manufactured according to general method 3a.

[0348] MS (m / z) [M+H] + Calcd for C 27 H 46 NO3S + 464.31, found 464.3

[0349] Synthesis Example 3-7: ((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(methylsulfonamido)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate

[0350] It was manufactured according to general method 4.

[0351] Synthetic Example R 4 R 5a R 5b R 5 General method 3a, 3b C7, C25, 3-7 methanesulfonyl HH3a C8, C26, 3-8 acetyl CH3CH33a C9, C27, 3-9 methanesulfonyl HH3a C10, C28, 3-10 acetyl CH3CH33a

[0352]

[0353] Example 3-3

[0354] [Reaction Equation 3-3]

[0355]

[0356] Synthesis Examples 3-20 and 3-24:

[0357] It was prepared from C38 according to general method 2 with different reactants.

[0358]

[0359] The table below shows the structures, compound names, and analysis data of Synthesis Examples 3-1 to 3-24.

[0360]

[0361]

[0362] No.NameAnalytical data3-16-(((3S,8S,9S,10R,13S,((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(((R)-tetrahydrofuran-3-yl)oxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1 H NMR (500 MHz, CDCl3) δ5.95 - 5.78 (m, 2H), 5.35 - 5.33 (m, 1H), 5.28 - 5.24 (m, 1H), 5.20 - 5.13 (m, 2H), 4.28 - 4.14 (m, 3H), 4.07 - 4.04 (m, 1H), 3.89 - 3.84 (m, 1H), 3.80 - 3.75 (m, 3H), 3.56 - 3.52 (m, 1H), 3.41 - 3.33 (m, 2H), 2.41 - 2.360 (m, 2H), 2.11 - 1.94 (m, 12H), 1.88 - 1.74 (m, 4H), 1.67 - 1.35 (m, 14H), 1.17 - 1.11 (m, 2H), 1.08 - 0.98 (m, 5H), 0.96 - 0.90 (m, 1H), 0.52 (s, 3H).3-2((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(((S)-tetrahydrofuran-3-yl)oxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.95 - 5.78 (m, 2H), 5.35 - 5.33 (m, 1H), 5.28 - 5.24 (m, 1H), 5.20 - 5.14 (m, 2H), 4.28 - 4.14 (m, 3H), 4.08 - 4.04 (m, 1H), 3.89 - 3.84 (m, 1H), 3.80 - 3.75 (m, 3H), 3.64 - 3.51 (m, 1H), 3.41 - 3.33 (m, 2H), 2.42 - 2.30 (m, 2H), 2.11 - 1.93 (m, 12H), 1.89 - 1.74 (m, 4H), 1.68 - 1.35 (m, 14H), 1.19 - 1.12 (m, 2H), 1.08 -0.98 (m, 5H), 0.97 - 0.90 (m, 1H), 0.52 (s, 3H)3-3((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-cyclopropoxyhept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.86 (dt, J1= 0.0 Hz, J2= 10.0 Hz, 1H), 5.81 (dt, J1= 8.3 Hz, J2= 1.2 Hz, 1H), 5.36 - 5.34 (m, 1H), 5.30 - 5.25 (m, 1H), 5.17 - 5.14 (m, 2H), 4.24 - 4.15 (m, 3H), 3.58 - 3.52 (m, 1H), 3.48 - 3.45 (m, 2H), 3.25 - 3.21 (m, 1H), 2.41 - 2.31 (m, 2H), 2.10 - 1.96 (m, 10H), 1.87 - 1.76 (m, 4H), 1.68 - 1.36 (m, 15H), 1.19 - 1.13 (m, 2H), 1.08 - 1.01 (m, 2H), 0.99 (s, 3H), 0.96 - 0.91 (m, 1H), 0.56 - 0.42 (m, 6H)3-4((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-cyclobutoxyhept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.96 - 5.79 (m, 2H), 5.36 - 5.33 (m, 1H), 5.29 - 5.25 (m, 1H), 5.20 - 5.15 (m, 2H), 4.28 - 4.15 (m, 3H), 3.91 - 3.85 (m, 1H), 3.65 - 3.52 (m, 1H), 3.32 - 3.28 (m, 2H), 2.42 - 2.31 (m, 2H), 2.22 - 2.15 (m, 2H), 2.10 - 1.96 (m, 10H), 194 - 1.35 (m, 16H), 1.20 - 1.13 (m, 2H), 1.08 - 0.91 (m, 6H), 0.53 (s, 3H)3-5((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-propoxyhept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1 H NMR (500 MHz, CDCl3) δ5.89 - 5.80 (m, 2H), 5.37 - 5.35 (m, 1H) 5.30 - 5.28 (m, 1H), 5.19 - 5.16 (m, 2H), 4.26 - 4.16 (m, 3H), 3.60 - 3.53 (m, 1H), 3.41 (t, J = 7.5Hz, 2H), 3.36 (t, J = 5.0Hz, 2H), 2.43 - 2.32 (m, 2H), 2.10 - 1.98 (m, 11H), 1.89 - 1.78 (m, 4H), 1.63 - 1.39 (m, 15H), 1.20 - 1.15 (m, 2H), 1.08 - 1.00 (m, 5H), 0.98 - 0.90 (m, 4H), 0.54 (s, 3H). MS (m / z) [M+Na] + Calcd for C 39 H 60 O7Na +663.43, found 663.63-6((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(2,2,2-trifluoroethoxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1 H NMR (500 MHz, CDCl3) δ5.88 - 5.80 (m, 2H), 5.37 - 5.35 (m, 1H), 5.31 - 5.28 (m, 1H), 5.18 - 5.15 (m, 2H), 4.26 - 4.16 (m, 3H), 3.83 (t, J = 8.3Hz, 2H), 3.61 - 3.41 (m, 3H), 2.43 - 2.32 (m, 2H), 2.09 - 1.98 (m, 11H), 1.89 - 1.77 (m, 4H), 1.65 - 1.40 (m, 13H), 1.21 - 1.16 (m, 2H), 1.10 - 1.02 (m, 2H), 1.01 (s, 3H), 0.98 - 0.93 (m, 1H), 0.54 (s, 3H). MS (m / z) [M+Na] + Calcd for C 38 H 55 F3O7Na + 703.39, found 703.5.3-7((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(methylsulfonamido)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.90 - 5.86 (m, 1H), 5.83 - 5.80 (m, 1H), 5.36 (d, J = 5.2 Hz, 1H), 5.32 - 5.28 (m, 1H), 5.15 (dd, J1= 15.1, J2= 7.9 Hz, 2H), 4.27 - 4.15 (m, 3H), 4.11 (s, 1H), 3.57 (td, J1= 11.3, J2= 5.6 Hz, 1H), 3.18 - 3.11 (m, 2H), 2.95 (s, 3H), 2.44 - 2.31 (m, 2H), 2.11 - 1.96 (m, 10H), 1.91 - 1.75 (m, 4H), 1.54 (s, 6H), 1.23 - 1.14 (m, 2H), 1.01 (s, 5H), 0.95 (td, J1= 11.7, J2= 4.7 Hz, 1H), 0.54 (s, 3H). MS (m / z) [M+Na] + Calcd for C 37 H 57 NO8SNa + 698.38, found 698.5.3-8((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(N-methylmethylsulfonamido)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.87 (dt, J1=10.2, J2=1.3 Hz, 1H), 5.84 - 5.80 (m, 1H), 5.39 - 5.35 (m, 1H), 5.30 (s, 3H), 5.19 - 5.13 (m, 2H), 4.27 - 4.15 (m, 3H), 3.56 (tt, J1= 11.3, J2= 4.7 Hz, 1H), 3.13 (t, J = 7.3 Hz, 2H), 2.83 (s, 3H), 2.78 (s, 3H), 2.44 - 2.30 (m, 2H), 2.09 (d, J = 7.8 Hz, 8H), 2.03 - 1.95 (m, 2H), 1.92 - 1.75 (m, 4H), 1.69 - 1.50 (m, 11H), 1.48 - 1.39 (m, 4H), 1.22 - 1.15 (m, 2H), 1.11 - 0.99 (m, 5H), 0.98 - 0.92 (m, 1H), 0.54 (s, 3H).3-9(2R,3S)-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-acetamidohept-2-en-2-yl)-10,13- Dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-2-(acetoxymethyl)-3,6-dihydro-2H-pyran-3-yl acetate 1H NMR (500 MHz, CDCl3) δ5.89 - 5.80 (m, 2H), 5.47 (s, 1H), 5.36 (dt, J1= 5.6, J2= 2.0 Hz, 1H), 5.29 (dq, J1= 9.4, J2= 1.7 Hz, 1H), 5.20 - 5.11 (m, 2H), 4.27 - 4.15 (m, 3H), 3.60 - 3.53 (m, 1H), 3.26 - 3.22 (m, 1H), 2.43 - 2.32 (m, 1H), 2.09 (dd, J1= 7.7, J2= 1.7 Hz, 7H), 2.06 - 1.98 (m, 4H), 1.97 (d, J = 1.8 Hz, 4H), 1.91 - 1.76 (m, 4H), 1.70 - 1.60 (m, 6H), 1.58 - 1.34 (m, 6H), 1.22 - 1.13 (m, 2H), 1.06 (qd, J1= 11.8, J2= 6.9 Hz, 2H), 1.00 (d, J = 1.7 Hz, 3H), 0.99 - 0.91 (m, 1H), 0.54 (d, J = 1.8 Hz, 3H). MS (m / z) [M+H] + Calcd for C 38 H 58 NO7 + 640.41, found 640.5.3-10((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(N-methylacetamido)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.90 - 5.80 (m, 2H), 5.36 (dt, J1= 4.8, J2= 2.0 Hz, 1H), 5.28 (td, J1= 9.2, J2= 1.7 Hz, 1H), 5.19 - 5.12 (m, 2H), 4.27 - 4.15 (m, 3H), 3.61 - 3.52 (m, 1H), 3.36 (t, J = 7.5 Hz, 1H), 3.28 - 3.23 (m, 1H), 2.94 (d, J = 31.9 Hz, 3H), 2.44 - 2.31 (m, 2H), 2.11 - 2.06 (m, 10H), 2.03 - 1.97 (m, 3H), 1.91 - 1.71 (m, 5H), 1.68 - 1.31 (m, 13H), 1.22 - 1.03 (m, 4H), 1.01 (s, 3H), 0.95 (d, J = 4.6 Hz, 1H), 0.54 (d, J = 2.5 Hz, 3H). MS (m / z) [M+H] + Calcd for C 39 H 60 NO7 + 654.43, found 654.5.3-11((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-(cyclohexyloxy)hept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.89 - 5.80 (m, 2H), 5.37 - 5.35 (m, 1H), 5.31 - 5.28 (m, 1H), 5.18 - 5.15 (m, 2H), 4.26 - 4.16 (m, 3H), 3.60 - 3.53 (m, 3H), 2.43 - 2.32 (m, 2H), 2.10 - 1.97 (m, 11H), 1.88 - 1.77 (m, 7H), 1.67 - 1.43 (m, 20H), 1.21 - 1.16 (m, 2H), 1.10 - 0.93 (m, 7H), 0.55 (s, 3H).3-12((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-((decahydronaphthalene-2-yl)oxy) hept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta [a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1 H NMR (500 MHz, CDCl3) δ5.89 - 5.80 (m, 2H), 5.37 - 5.35 (m, 1H), 5.31 - 5.28 (m, 1H), 5.19 - 5.16 (m, 2H), 4.26 - 4.16 (m, 3H), 3.60 - 3.53 (m, 3H), 3.46 - 3.81 (m, 3H), 2.43 - 2.35 (m, 2H), 2.10 - 1.98 (m, 11H), 1.90 - 1.77 (m, 5H), 1.69 - 1.38 (m, 21H), 1.20 - 0.15 (m, 5H), 1.09 - 0.85 (m, 8H), 0.54 (s, 3H).3-13((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-phenoxyhept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate1 H NMR (500 MHz, CDCl3) δ7.27 - 7.24 (m, 2H), 6.93 - 6.87 (m, 3H), 5.86 (d, J = 10.9 Hz, 1H), 5.81 (dt, J1= 10.2, J2= 2.3 Hz, 1H), 5.36 - 5.35 (m, 1H), 5.29 - 5.27 (m, 1H), 5.20 - 5.17 (m, 2H), 4.23 (q, J = 6.0 Hz, 1H), 4.19 - 4.15 (m, 2H), 3.95 (t, J = 6.6 Hz, 2H), 3.58 - 3.52 (m, 1H), 2.40 (dd, J1= 13.2, J2= 3.4 Hz, 1H), 2.36 - 2.31 (m, 1H), 2.11 (d, J = 7.2 Hz, 2H), 2.08 (s, 3H), 2.07 (s, 3H), 2.02 - 1.96 (m, 2H), 1.89 - 1.83 (m, 2H), 1.81 - 1.76 (m, 4H), 1.68 - 1.59 (m, 5H), 1.57 - 1.37 (m, 7H), 1.24 - 1.13 (m, 2H), 1.09 - 1.02 (m, 2H), 1.00 (s, 3H), 0.97 - 0.91 (m, 1H), 0.55 (d, J = 16.6 Hz, 3H). MS (m / z) [M+Na] + Calcd for C 42 H 58 O7Na + 697.41, found 697.53-14((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-(4-fluorophenoxy)hept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ6.97 - 6.92 (m, 2H), 6.83 - 6.79 (m, 2H), 5.86 (d, J = 10.3 Hz, 1H), 5.81 (dt, J1= 10.3, J2= 2.3 Hz, 1H), 5.36 - 5.35 (m, 1H), 5.29 - 5.27 (m, 2H), 5.19 - 5.16 (m, 2H), 4.23 (q, J = 5.9 Hz, 1H), 4.19 - 4.15 (m, 2H), 3.90 (t, J = 6.6 Hz, 2H), 3.58 - 3.52 (m, 1H), 2.42 - 2.38 (m, 1H), 2.36 - 2.31 (m, 1H), 2.10 (d, J = 7.4 Hz, 2H), 2.08 (s, 3H), 2.07 (s, 3H), 2.03 - 1.96 (m, 2H), 1.88 - 1.83 (m, 2H), 1.81 - 1.74 (m, 4H), 1.68 - 1.57 (m, 4H), 1.56 - 1.49 (m, 2H), 1.48 - 1.37 (m, 3H), 1.20 - 1.12 (m, 2H), 1.09 - 1.02 (m, 2H), 1.00 (s, 3H), 0.97 - 0.91 (m, 1H), 0.53 (s, 3H). MS (m / z) [M+Na] + Calcd for C 42 H 57 FO7Na + 715.41, found 715.5.3-15((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(naphthalene-2-yloxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ7.76 - 7.70 (m, 3H), 7.44 - 7.40 (m, 1H), 7.33 - 7.30 (m, 1H), 7.16 - 7.12 (m, 2H), 5.87 (d, J = 10.3 Hz, 1H), 5.82 (dt, J1= 10.2, J2=2.2 Hz, 1H), 5.37 - 5.36 (m, 1H), 5.31 - 5.27 (m, 1H), 5.22 (t, J = 6.9 Hz, 1H), 5.18 - 5.18 (m, 1H), 4.24 (q, J = 6.0 Hz, 1H), 4.20 - 4.16 (m, 2H), 4.09 (t, J = 6.4 Hz, 2H), 3.60 - 3.53 (m, 1H), 2.43 - 2.39 (m, 1H), 2.37 - 2.32 (m, 1H), 2.17 - 2.12 (m, 2H), 2.10 (s, 3H), 2.08 (s, 3H), 2.04 - 1.95 (m, 2H), 1.89 - 1.78 (m, 4H), 1.66 (d, J = 11.7 Hz, 2H), 1.60 (q, J = 7.5 Hz, 3H), 1.55 - 1.55 (m, 5H), 1.53 - 1.51 (m, 2H), 1.48 - 1.37 (m, 2H), 1.21 - 1.12 (m, 2H), 1.10 - 1.02 (m, 2H), 1.01 (s, 3H), 0.95 (td, J1= 11.5, J2= 4.5 Hz, 1H), 0.57 (d, J = 16.6 Hz, 3H). MS (m / z) [M+H] + Calcd for C 46 H 61 O7 +725.43, found 725.6.3-20((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(quinoline-6-yloxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1 H NMR (500 MHz, CDCl3) δ8.76 (dd, J1= 4.2, J2= 1.6 Hz, 1H), 8.01 (dd, J1= 19.6, J2= 8.7 Hz, 2H), 7.38 - 7.33 (m, 2H), 7.06 (d, J = 2.6 Hz, 1H), 5.87 (d, J = 10.9 Hz, 1H), 5.82 (dt, J1= 10.5, J2= 2.3 Hz, 1H), 5.37 - 5.35 (m, 1H), 5.30 - 5.28 (m, 1H), 5.21 (t, J = 6.9 Hz, 1H), 5.18 (s, 1H), 4.24 (q, J = 6.0 Hz, 1H), 4.20 - 4.16 (m, 2H), 4.09 (t, J = 6.4 Hz, 2H), 3.59 - 3.53 (m, 1H), 2.41 (dd, J1= 13.2, J2=3.4 Hz, 1H), 2.37 - 2.32 (m, 1H), 2.14 (q, J = 7.2 Hz, 2H), 2.09 (s, 3H), 2.08 (s, 3H), 2.04 - 1.96 (m, 2H), 1.90 - 1.77 (m, 6H), 1.69 - 1.50 (m, 10H), 1.48 - 1.37 (m, 2H), 1.21 - 1.14 (m, 2H), 1.12 - 1.04 (m, 2H), 1.01 (s, 3H), 0.95 (td, J1= 11.6, J2= 4.6 Hz, 1H), 0.86 (d, J = 3.2 Hz, 1H), 0.55 (s, 3H). MS (m / z) [M+H] + Calcd for C 45 H 60NO7726.43, found 726.7.3-24((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-(dimethylamino)hept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1 H NMR (500 MHz, CDCl3) δ5.87 (dt, J1= 10.3, J2= 1.1 Hz, 1H), 5.83 - 5.80 (m, 1H), 5.37 (dd, J1= 5.0, J2= 2.5 Hz, 1H), 5.29 (dq, J1= 9.4, J2= 1.6 Hz, 1H), 5.19 - 5.15 (m, 2H), 4.26 - 4.15 (m, 3H), 3.56 (tt, J1= 11.3, J2=4.7 Hz, 1H), 2.44 - 2.28 (m, 4H), 2.25 (s, 6H), 2.10 (s, 3H), 2.08 (s, 3H), 2.07 - 1.96 (m, 6H), 1.91 - 1.76 (m, 4H), 1.69 - 1.33 (m, 11H), 1.22 - 1.13 (m, 2H), 1.10 - 1.04 (m, 2H), 1.00 (s, 3H), 0.98 - 0.92 (m, 1H), 0.54 (s, 3H). MS (m / z) [M+H] + Calcd for C 38 H 60 NO6 + 626.43, found 626.6.

[0363]

[0364] Example 4:

[0365] [Reaction Equation 4]

[0366]

[0367] In the above reaction scheme 4-1, R is methanesulfonyl or acetyl.

[0368] Synthesis Example R5 R4 D15, D18, 4-5 HMe D16, D19, 4-6 MeMe

[0369]

[0370] Synthesis Example D15: (E)-6-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-N-methylhept-5-enamide

[0371]

[0372] 240 mg (0.5 mmol) of Synthesis Example A4 and 104 μL of triethylamine (TEA, 0.74 mmol) were dissolved in 15 mL of tetrahydrofuran. Then, 100 μL of isobutyl chloroformate (0.75 mmol) was added at 0°C and stirred for 20 minutes. Subsequently, 600 μL of methylamine solution (2 mol / L in THF, 38.5 mmol) was added dropwise and stirred at room temperature for 1 hour. The reaction was terminated with an aqueous solution of saturated ammonium chloride, followed by extraction with ethyl acetate. The mixture was then dried and filtered with anhydrous sodium sulfate, followed by vacuum distillation. The resulting residue was subjected to silica gel column chromatography to obtain the target compound D15 (220 mg, 88%).

[0373] 1H NMR (500 MHz, CDCl3) δ5.40 (brs, 1H), 5.36 (d, J = 5.7 Hz, 1H), 5.17 - 5.13 (m, 1H), 4.74 - 4.69 (m, 1H), 3.95 - 3.89 (m, 1H), 3.57 - 3.44 (m, 2H), 2.81 (d, J = 4.8 Hz, 3H), 2.36 (d, J = 7.5 Hz, 2H), 2.20 - 2.15 (m, 2H), 2.07 (dd, J1= 14.5, J2=7.2 Hz, 2H), 2.03 - 1.94 (m, 2H), 1.91 - 1.60 (m, 14H), 1.58 - 1.53 m, 5H), 1.47 - 1.40 (m, 3H), 1.20 - 1.15 (m, 2H), 1.10 - 1.02 (m, 2H), 1.01 (s, 3H), 0.98 - 0.92 (m, 1H), 0.54 (s, 3H).

[0374] Synthesis Example D16 was prepared using the same method as D15.

[0375] Synthetic Example D18 was prepared according to general method 3a.

[0376] Synthetic Examples 4-5 and 4-6 were prepared according to General Method 4.

[0377]

[0378] The structures of synthetic examples 4-5 and 4-6 are presented below.

[0379]

[0380] The table below presents the compound names and analysis results.

[0381] 4-5((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)-7-(methylamino)-7-oxohept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.90 - 5.80 (m, 2H), 5.37 (s, 1H), 5.30 (dd, J1= 9.4, J2=1.6 Hz, 1H), 5.20 - 5.13 (m, 2H), 4.28 - 4.16 (m, 3H), 3.57 (td, J1= 11.2, J2=5.6 Hz, 1H), 2.81 (d, J = 4.8 Hz, 3H), 2.44 - 2.32 (m, 2H), 2.20 - 2.14 (m, 2H), 2.12 - 2.04 (m, 10H), 2.03 - 1.96 (m, 2H), 1.83 (d, J = 46.4 Hz, 4H), 1.74 - 1.63 (m, 4H), 1.61 (s, 4H), 1.49 - 1.37 (m, 2H), 1.26 (t, J = 7.1 Hz, 2H), 1.17 (q, J = 9.0 Hz, 2H), 1.12 - 0.99 (m, 6H), 0.95 (td, J1= 11.6, J2=4.7 Hz, 1H), 0.54 (s, 3H). MS (m / z) [M+Na] + Calcd for C 37 H 55 NO7Na + 648.40, found 648.7.4-6((2R,3S)-3-acetoxy-6-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-(dimethylamino)-7-oxohept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate 1H NMR (500 MHz, CDCl3) δ5.90 - 5.80 (m, 2H), 5.36 (d, J = 4.8 Hz, 1H), 5.30 (dt, J1= 9.6, J2= 1.6 Hz, 1H), 5.18 (d, J = 6.9 Hz, 2H), 4.27 - 4.15 (m, 3H), 3.56 (td, J1= 11.0 J2=1, 5.5 Hz, 1H), 3.00 (s, 3H), 2.94 (s, 3H), 2.44 - 2.34 (m, 2H), 2.34 - 2.29 (m, 2H), 2.12 -2.07 (m, 9H), 2.04 - 1.95 (m, 2H), 1.93 - 1.76 (m, 4H), 1.73 - 1.38 (m, 12H), 1.18 (td, J1= 11.9, J2=4.4 Hz, 2H), 1.11 - 0.99 (m, 6H), 0.96 (dt, J1= 11.5, J2= 5.8 Hz, 1H), 0.54 (s, 3H). [M+H] + Calcd for C 38 H 58 NO7 + 639.41, found 640.4.

[0382]

[0383] Experimental Example 1: Confirmation of Cognitive Function Improvement Effect

[0384] 1) Preparation for animal experiments

[0385] 5xFAD transgenic (Transgenic, TG) mice (3 months, male), an Alzheimer's disease mouse model, were used, and wild-type mice of the same age were used as a control. Synthetic Examples 1-10, 2-3, and 1-26 (CU06-1004) were orally administered daily at different concentrations (5, 10, 20 mg / kg) for 6 months.

[0386] The experimental groups consisted of a total of 8 groups: 1) G1: WT (wild type) + vehicle, 2) G2: TG + vehicle, 3) G3: TG + Donepezil (1 mg / kg), 4) G4: TG + Synthetic Example 1-10 (5 mg / kg), 5) G5: TG + Synthetic Example 1-10 (10 mg / kg), 6) G6: TG + Synthetic Example 1-10 (20 mg / kg), 7) G7: TG + Synthetic Example 1-26 (CU06-1004) (10 mg / kg), and 8) G8: TG + Synthetic Example 2-3 (10 mg / kg). After administering each drug for a total of 6 months, Novel Object Recognition (NOR) and Morris Water Maze (MWM) tests were conducted to verify learning and cognitive abilities.

[0387]

[0388] 2) Novel Object Recognition (NOR) Experiment

[0389] First, a No Object Recognition (NOR) experiment was conducted to verify the difference in exploratory ability between previously viewed objects and new objects. Generally, when rodents such as mice see two identical objects, curiosity is aroused, leading them to touch both objects, and the time and frequency of exploring the two objects are similar. When one of the two objects is replaced with a new object, normal mice show greater curiosity toward the new object, increasing the time and frequency of exploration; however, if memory is impaired, they cannot distinguish the newly changed object, and the time and frequency of exploration do not increase.

[0390] As a result of this experiment, it was confirmed that cognitive function was significantly impaired, as the G2 group administered the vehicle showed a significantly lower discrimination index for exploring existing objects compared to the G1 group. On the other hand, the G5 group administered 10 mg / kg of Synthetic Example 1-10 showed a tendency for the discrimination index to increase compared to G2, confirming the possibility of improving cognitive function.

[0391]

[0392] 3) Morris Water Maze (MWM)

[0393] To evaluate spatial learning and memory, mice were trained to remember the location of a platform inside a tank for 5 days using an underwater maze measuring device. The mice found the platform location while swimming to survive without falling into the water, and through repeated training, they came to remember the platform location. On the final 6th day, it was checked whether they remembered the platform location when the platform was removed from the tank.

[0394] As a result of this experiment, it was confirmed that cognitive function was impaired in the G2 group, as the time spent around the platform location decreased significantly by about 30% compared to the G1 group. However, in the G5 group, the time spent around the platform location increased significantly by about 30% compared to the G2 group. In addition, memory in the G5 group improved to the level of the G1 group, confirming that long-term memory ability improved with the administration of Synthetic Example 1-10 (10 mg / kg).

[0395]

[0396] 4) Results

[0397] The compound (10 mg / kg) according to the present invention showed an improvement effect on cognitive and memory abilities through object recognition experiments and water maze experiments. Therefore, the compound according to the present invention can treat degenerative brain diseases such as Alzheimer's disease by protecting brain neurons despite the overexpression of amyloid beta (Aβ), which is one of the causative substances of Alzheimer's disease.

[0398]

[0399] Experimental Example 2: Analysis of Factors Associated with Neurodegenerative Diseases

[0400] 1) Immunohistological staining method

[0401] After the above behavioral experiment was completed, the mice were anesthetized, perfused with 0.9% physiological saline, and then fixed by perfusing with 4% paraformaldehyde. Subsequently, the brains were excised, post-fixed by immersing them in 4% paraformaldehyde at 4°C, and then immersed in 0.02% sodium azide (in PBS). The mouse brains were then frozen, sectioned to a thickness of 20 μm, and stored in a storage solution at 4°C. For staining, the slides were washed with PBS solution and then blocked at room temperature for 1 hour in a blocking solution containing PBS, 5% normal goat serum, and 0.3% Triton X-100. Afterward, tissue slides of the prefrontal cortex and hippocampus from the hemisphere were incubated with a primary antibody overnight at 4°C. Next, the slide was washed with PBS solution and incubated with a secondary antibody at room temperature for 1 hour. Finally, the slide was washed again with PBS solution, completely dried, and mounted using a mounting solution containing DAPI. Subsequently, the stained area was observed and photographed using a confocal microscope.

[0402]

[0403] 2) Western Blotting Analysis Method

[0404] After perfusing mouse brains with physiological saline, the brains were excised, immediately flash-frozen in liquid nitrogen, and stored at -80°C until analysis. For protein extraction, brain tissue samples were homogenized with radioimmunoprecipitation assay buffer (0.5% NP-40 buffer, 50 mM β-glycerophosphate, 0.5% NaF, 50 mM Na3VO4, 1% Triton X-100, 0.5% sodium deoxycholate, 1 M Tris-HCl, 50 mM NaCl, 5 mM EDTA) containing protease and phosphatase inhibitors, and centrifuged at 12,000g at 4°C for 15 minutes. Protein concentration was measured using the Bicinchoninic acid (BCA) method with a SMART BCA assay kit (Intron Biotechnology, Korea). Proteins were separated via 8-12% SDS-PAGE and transferred to a polyvinylidene fluoride (PVDF) membrane. The membrane was blocked in 3% bovine serum albumin (BSA) and incubated overnight at 4°C in 3% BSA containing the primary antibody. The next day, after incubating with the secondary antibody for 1 hour, protein bands were captured using a Gel Doc XR Imaging system (Bio-Rad) and quantitatively analyzed using Image J software.

[0405]

[0406] 3) Confirmation of amyloid beta (Aβ) expression levels

[0407] To determine whether the compound according to the present invention affects the accumulation of amyloid beta (Aβ) plaques, as the cognitive function improvement effect was confirmed, immunohistochemical staining was performed on the hippocampus and cerebral cortex of the brain.

[0408] First, the accumulation of amyloid beta (Aβ) plaques in the hippocampus was confirmed using 6E10 (anti-Amyloid β) antibodies. As shown in Figures 3a and 3b, the expression of 6E10 was significantly increased in the G2 group compared to the normal group G1, whereas the accumulation of amyloid beta (Aβ) plaques was significantly decreased in the G4, G5, G6, G7, and G8 groups administered Synthetic Examples 1-10, 1-26, and 2-3, respectively, compared to the G2 group administered with the vehicle.

[0409] In addition, in the cerebral cortex, the accumulation of amyloid beta (Aβ) plaques was significantly reduced in groups G4, G5, G6, and G7 administered Synthetic Examples 1-10 and 1-26 compared to group G2 administered with the vehicle. In particular, it was confirmed that the accumulation of amyloid beta (Aβ) plaques was more significantly reduced in groups G4 and G5 administered 5 and 10 mg / kg of Synthetic Example 1-10, respectively (Figs. 3c and 3d).

[0410] Therefore, through the above results, it was demonstrated that the compound according to the present invention reduces the accumulation of amyloid beta (Aβ) plaques in 5xFAD, an Alzheimer's disease transgenic model.

[0411]

[0412] 4) Confirmation of vascular endothelial junction protein expression levels

[0413] The blood-brain barrier (BBB) ​​in cerebral vascular tissue is a structure specifically present between blood vessels and brain parenchyma, where tight junctions and adherent junctions between microvascular endothelial cells play a key role in inhibiting blood leakage. Additionally, pericytes, astrocytes, neurons, and the extracellular matrix are located around these endothelial cells, further enhancing the structural stability of the BBB. Due to this structure, the BBB maintains the homeostasis of the central nervous system (CNS) by regulating not only the transport of nutrients from the blood to the brain but also the migration of immune cells. However, in neurodegenerative diseases such as Alzheimer's disease, tight junctions weaken and become damaged, leading to neuronal damage caused by the leakage of blood components and immune cells into the brain parenchyma. Therefore, to evaluate the BBB protective effect of the compound according to the present invention in a 5xFAD Alzheimer's disease model, the expression levels of the junction proteins ZO-1 and Claudin5 were checked.

[0414] Changes in the expression of junction proteins were confirmed through immunohistochemical staining and Western blot protein quantification methods. As a result, it was confirmed that the expression level of ZO-1 was significantly decreased in the G2 group, a 5xFAD model group, compared to the normal G1 group, while the expression level of ZO-1 was significantly increased in the G5 group, administered 10 mg / kg of Synthetic Example 1-10, compared to the G2 group administered with the vehicle (Figs. 4a and 4b).

[0415] In addition, changes in Claudin5 expression were significantly reduced in the 5xFAD model group G2 compared to the normal group G1, and were also significantly increased in the G6 group administered 20 mg / kg of Synthetic Examples 1-10, and in the G7 and G8 groups administered Synthetic Examples 1-26 and 2-3, respectively, when compared to the G2 group (Figs. 4c and 4d). This confirmed that the morphology of the blood vessels was also maintained normally through Laminin staining, a vascular marker.

[0416] Through the above results, it was confirmed that the compound according to the present invention is effective in treating Alzheimer's disease and suggests that it can serve as a new treatment method for Alzheimer's disease.

[0417]

[0418] 5) Confirmation of blood-brain barrier (BBB) ​​transporter expression levels

[0419] As it was confirmed that the compound according to the present invention reduces amyloid beta (Aβ) accumulation and increases the expression of junction proteins in vascular endothelial cells in an Alzheimer's disease transgenic mouse model, we sought to determine the expression level of the Advanced Glycation End-product (RAGE) receptor, which is one of the blood-brain barrier (BBB) ​​influx transporters. RAGE is a multi-ligand receptor involved in inflammatory diseases, diabetic complications, and the pathogenesis of Alzheimer's disease, and plays a role in transporting amyloid beta (Aβ) in the blood to the brain via the BBB. Through this process, oxidative stress, inflammatory responses, and reduced cerebral blood flow are induced, which can affect the progression of Alzheimer's disease.

[0420] As a result of protein quantification analysis using Western blot, the expression level of RAGE was significantly increased in the 5xFAD model group G2 compared to the normal group G1, whereas it was confirmed that the expression level of RAGE was significantly decreased in the G4, G5, and G6 groups administered 5, 10, and 20 mg / kg of Synthetic Example 1-10, and in the G7 and G8 groups administered Synthetic Example 1-26 and Synthetic Example 2-3, when compared to the G2 group administered the vehicle (Figs. 5a and 5b).

[0421]

[0422] Experimental Example 3: Confirmation of anti-neuroinflammatory effect

[0423] 1) Confirmation of inhibitory effect on astrocyte hyperactivation

[0424] To evaluate whether the reduction in amyloid beta (Aβ) accumulation by the compound according to the present invention in 5xFAD, an Alzheimer's disease transgenic mouse model, is related to an anti-neuroinflammatory effect, immunofluorescence staining and western blot analysis were performed as in Experimental Example 2 using GFAP (glial fibrillary acidic protein) antibody, an astrocyte marker.

[0425] As a result, GFAP expression was significantly increased in the 5xFAD model group G2 compared to the normal group G1, and GFAP expression was significantly decreased in the G5 and G6 groups administered 10 and 20 mg / kg of Synthetic Examples 1-10, respectively (Figs. 6a and 6b). In addition, Western blot analysis also showed that GFAP expression was significantly increased in the G2 group compared to the normal group G1, but GFAP expression was significantly decreased in all groups administered Synthetic Examples 1-10, 1-26, and 2-3 (Figs. 6c and 6d).

[0426] These results suggest that the compound according to the present invention is effective in inhibiting the overactivation of astrocytes in a neuroinflammatory state induced by Alzheimer's disease.

[0427]

[0428] 2) Confirmation of inhibitory effect on microglia hyperactivation

[0429] In the brain, microglia are macrophages responsible for immune function that maintain homeostasis of the central nervous system by phagocytizing misfolded proteins, cellular debris, and apoptotic cells. Accordingly, to evaluate the microglia-mediated anti-neuroinflammatory effect of the compound according to the present invention in 5xFAD, an Alzheimer's disease transgenic mouse model, an immunofluorescence staining method was performed as in Experimental Example 2 using the Iba1 antibody, which is a microglia activation marker.

[0430] As a result of the analysis, the expression level of Iba1 was significantly increased in the 5xFAD model group G2 compared to the normal group G1, and the expression level of Iba1 was significantly decreased in the G4, G5, and G6 groups administered 5, 10, and 20 mg / kg of Synthetic Example 1-10, the G7 group administered Synthetic Example 1-26, and the G8 group administered Synthetic Example 2-3 (Figs. 7a and 7b).

[0431] These results indicate that the compound according to the present invention can inhibit neuroinflammation by inhibiting the chronic activation of microglia in an Alzheimer's disease model.

Claims

1. A pharmaceutical composition for the prevention, alleviation, or treatment of degenerative brain diseases comprising, as an active ingredient, a compound represented by the following chemical formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: In the equation, Y is -C(=O)(R 1 ) or -P(=O)(R 2 )(R 3 ); R 1 to R 3 C each independently 1-6 Alkyl; X is H or C 1-6 Alkyl; R is -C n Alkylene-LMR 4 is, n is an integer from 0 to 10; L is C(=O) or CH2; M is O or N(R 5 ); R 4 C that is unsubstituted or substituted with one or more halogens 1-6 Alkyl, 3-10-membered cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, -C(=O)(R 6 ) or -S(=O)2(R 7 ); R 5 is H or C 1-6 alkyl; and R 6 and R 7 C each independently 1-6 It is an alkyl.

2. Pharmaceutical composition according to paragraph 1: Y is -C(=O)(R 1 ) or -P(=O)(R 2 )(R 3 ); R 1 to R 3 C each independently 1-4 Alkyl; X is H or C 1-4 Alkyl; R is -C n Alkylene-LMR 4 is, n is an integer from 0 to 5; L is C(=O) or CH2; M is O or N(R 5 ); R 4 C that is unsubstituted or substituted with one or more halogens 1-4 Alkyl, 3-10-membered cycloalkyl, unsubstituted or substituted with one or more halogens, 6-10-membered aryl, 6-10-membered heteroaryl, 5-membered heterocycloalkyl, -C(=O)(R 6 ) or -S(=O)2(R 7 ); R 5 is H or C 1-4 alkyl; and R 6 and R 7 C each independently 1-4 It is an alkyl.

3. Pharmaceutical composition according to paragraph 1: Y is -C(=O)(R 1 ) or -P(=O)(R 2 )(R 3 ); R 1 to R 3 C each independently 1-6 Alkyl; X is H or C 1-6 Alkyl; R is -C n Alkylene-LMR 4 is, n is an integer from 0 to 5; L is CH2; M is O; R 4 C that is unsubstituted or substituted with one or more halogens 1-6 Alkyl, 3-10-membered cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, -C(=O)(R 6 ) or -S(=O)2(R 7 ); and R 6 and R 7 C each independently 1-6 It is an alkyl.

4. Pharmaceutical composition according to paragraph 3: R 4 is unsubstituted C 1-6 It is an alkyl.

5. Pharmaceutical composition according to paragraph 4: X is C 1-6 It is an alkyl.

6. Pharmaceutical composition according to paragraph 1: Y is -C(=O)(R 1 ) or -P(=O)(R 2 )(R 3 ); R 1 to R 3 C each independently 1-6 Alkyl; X is H or C 1-6 Alkyl; R is -C n Alkylene-LMR 4 is, n is an integer from 0 to 5; L is C(=O); M is O; R 4 C that is unsubstituted or substituted with one or more halogens 1-6 Alkyl, 3-10-membered cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, -C(=O)(R 6 ) or -S(=O)2(R 7 ); and R 6 and R 7 C each independently 1-6 It is an alkyl.

7. Pharmaceutical composition according to paragraph 6: R 4 is unsubstituted C 1-6 It is an alkyl.

8. Pharmaceutical composition according to paragraph 7: X is C 1-6 It is an alkyl.

9. A pharmaceutical composition according to claim 1, wherein the compound is selected from the following chemical formula:

10. A pharmaceutical composition according to claim 1, wherein the degenerative brain disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, stroke, Huntington's disease, and amyotrophic lateral sclerosis.

11. A method for the prevention, alleviation, or treatment of a degenerative brain disease comprising the step of administering a compound represented by the following chemical formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a subject in need thereof: In the equation, Y is -C(=O)(R 1 ) or -P(=O)(R 2 )(R 3 ); R 1 to R 3 C each independently 1-6 Alkyl; X is H or C 1-6 Alkyl; R is -C n Alkylene-LMR 4 is, n is an integer from 0 to 10; L is C(=O) or CH2; M is O or N(R 5 ); R 4 C that is unsubstituted or substituted with one or more halogens 1-6 Alkyl, 3-10-membered cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, -C(=O)(R 6 ) or -S(=O)2(R 7 ); R 5 is H or C 1-6 alkyl; and R 6 and R 7 C each independently 1-6 It is an alkyl.

12. Compounds represented by the following chemical formula IA, stereoisomers thereof, and pharmaceutically acceptable salts thereof for the manufacture of drugs for the prevention, alleviation, or treatment of degenerative brain diseases: In the equation, Y is -C(=O)(R 1 ) or -P(=O)(R 2 )(R 3 ); R 1 to R 3 C each independently 1-6 Alkyl; X is H or C 1-6 Alkyl; R is -C n Alkylene-LMR 4 is, n is an integer from 0 to 10; L is C(=O) or CH2; M is O or N(R 5 ); R 4 C that is unsubstituted or substituted with one or more halogens 1-6 Alkyl, 3-10-membered cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, -C(=O)(R 6 ) or -S(=O)2(R 7 ); R 5 is H or C 1-6 alkyl; and R 6 and R 7 C each independently 1-6 It is an alkyl.

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