Novel compounds, methods of making the same, and pharmaceutical compositions

Abstract

Provides compounds represented by the following formula (1) that are useful for cancer treatment, etc. Wherein, R 1 R 3 ~R 8 Each can independently represent a hydrogen atom or an alkyl group; R 2 Represents a hydrogen atom, or -OR a Groups shown; R 9 Represents -C(O)NR e R f Groups shown; R a R e R f Each of the hydrogen atoms can be independently represented, and optionally, a heteroaryl group, heteroarylalkyl group, etc., with substituents are provided. Furthermore, a method for efficiently producing the compound is provided, as well as a pharmaceutical composition containing the compound as an active ingredient.

Description

Technical Field

[0001] This invention relates to novel compounds, methods for manufacturing the same, and pharmaceutical compositions. Background Technology

[0002] M-COPA (Methylcoprophilinamide [AMF-26]) is a compound with the following structure, known to exhibit anticancer activity.

[0003]

[0004] In recent years, it has been clearly established that M-COPA exhibits anticancer effects by inhibiting the transport of receptor-type tyrosine kinases (MET, EGFR, KIT, etc.) between the endoplasmic reticulum and the Golgi apparatus, thereby inhibiting their movement toward the Golgi apparatus or cell membrane (see, for example, non-patent literature 1-5). It is expected to be used as a next-generation molecularly targeted anticancer agent targeting the Golgi apparatus.

[0005] M-COPA was originally synthesized using natural compounds derived from Trichoderma asperata, which is difficult to synthesize in large quantities. Therefore, Patent Document 1 proposes a method for synthesizing M-COPA and its analogues without using natural substances.

[0006] A portion of the M-COPA synthesis method described in Patent Document 1 is shown below. First, compound a is cyclized and reduced via an intramolecular Diels-Alder reaction to obtain compound b, which is then oxidized to obtain compound c. Next, compound c is subjected to a Horner-Wozworth-Emmons reaction to obtain compound d, which is then hydrolyzed to obtain compound e. Compound e is then reacted with 3-aminomethylpyridine for amidation, followed by deprotection to obtain M-COPA.

[0007]

[0008] Existing technical documents

[0009] Patent documents

[0010] Patent Document 1: International Publication No. 2013 / 151161

[0011] Non-patent literature

[0012] Non-patent literature 1: Y. Ohashi et al., Cancer Res., 2016; 76(13): 3895-3903

[0013] Non-patent literature 2: Y. Hara et al., PLOS ONE, 2017; 12(4): e0175514

[0014] Non-patent literature 3: Y. Ohashi et al., Oncotarget, 2018; 9(2): 1641-1655

[0015] Non-patent literature 4: Y. Obata et al., Cancer Lett., 2018; 415(1): 1-10

[0016] Non-patent literature 5: Y. Obata et al., Cell Commun. Signal., 2019; 17(1): 114 Summary of the Invention

[0017] The problem the invention aims to solve

[0018] As mentioned above, M-COPA holds promise as a next-generation molecularly targeted anticancer agent, and it is hoped that new analogs with M-COPA as lead compounds can be developed.

[0019] Furthermore, in the synthetic method described in Patent Document 1, a large group exists at the α-position of the aldehyde group in compound c, which is used as a synthetic intermediate. This presents the problem that the hydrogen atom at the α-position undergoes epimerization, leading to a decrease in the yield of the target substance. Therefore, it is desirable to develop a new synthetic method.

[0020] The present invention is made in view of the above, and the objective is to provide a novel compound useful for cancer treatment, a method for manufacturing the novel compound with high efficiency, and a pharmaceutical composition containing the novel compound as an active ingredient.

[0021] Solution for solving the problem

[0022] The following implementation methods are included as specific means to solve the above-mentioned problems.

[0023] <1> A compound represented by the following formula (1).

[0024]

[0025] [In the formula, R] 1 R 3 ~R 8 Each can independently represent a hydrogen atom or an alkyl group. R 2 Represents a hydrogen atom, or -OR a or -NR b R c The group shown. R 9 -CH2OR d -C(O)OR d -C(O)R d -CH2NRe R f or -C(O)NR e R f The group shown. R a ~R f Each of these can independently represent a hydrogen atom, an alkyl group, an aryl group optionally with a substituent, a heteroaryl group optionally with a substituent, an arylalkyl group optionally with a substituent, or a heteroarylalkyl group optionally with a substituent.

[0026] <2> According to the compound described in <1>, wherein, in the above formula (1), R 1 R 6 Each is independently an alkyl group, R 2 For hydroxyl group, R 4 R 5 R 7 R 8 For hydrogen atoms, R 9 -C(O)OR d or -C(O)NR e R f The group shown, R d It is an arylalkyl or heteroarylalkyl group, R e For hydrogen atoms, R f It is an arylalkyl or heteroarylalkyl.

[0027] <3> A synthetic intermediate of the compound described in <1> or <2>, which is represented by the following formula (3).

[0028]

[0029] [In the formula, R] 1 R 3 ~R 8 Each can independently represent a hydrogen atom or an alkyl group. Z represents a protecting group for a hydroxyl group.

[0030] <4> A method for manufacturing a compound represented by formula (1) includes the step of manufacturing a compound represented by formula (1) from a compound represented by formula (3).

[0031]

[0032] [In the formula, R] 1 R 3 ~R 8 Each can independently represent a hydrogen atom or an alkyl group. R 2 Represents a hydrogen atom, or -OR a or -NR b R c The group shown. R 9 -CH2OR d-C(O)OR d -C(O)R d -CH2NR e R f or -C(O)NR e R f The group shown. R a ~R f Each of these can independently represent a hydrogen atom, an alkyl group, an aryl group optionally with a substituent, a heteroaryl group optionally with a substituent, an arylalkyl group optionally with a substituent, or a heteroarylalkyl group optionally with a substituent.

[0033]

[0034] [In the formula, R] 1 R 3 ~R 8 Same meaning as above. Z represents the protecting group of the hydroxyl group.

[0035] <5> The manufacturing method according to <4> includes the following steps: subjecting the compound shown in formula (6) and the compound shown in formula (5) to a Horner-Watsworth-Emmons reaction, followed by hydrolysis to produce the compound shown in formula (3).

[0036]

[0037] [In the formula, R] 1 R 3 ~R 8 Z has the same meaning as above.

[0038]

[0039] [In the formula, R] 10 R 11 Each can be used independently to represent an alkyl group.

[0040] <6> The manufacturing method according to <5> includes the following steps: cyclizing the compound shown in formula (7) by an intramolecular Diels-Alder reaction to produce the compound shown in formula (6).

[0041]

[0042] [In the formula, R] 1 R 3 ~R 8 Z has the same meaning as above.

[0043] <7> A pharmaceutical composition comprising the compound described in <1> or <2> and a pharmaceutically permissible carrier.

[0044] The effects of the invention

[0045] According to the present invention, novel compounds useful for cancer treatment, methods for manufacturing the novel compounds that can be manufactured efficiently, and pharmaceutical compositions containing the novel compounds as active ingredients can be provided. Attached Figure Description

[0046] Figure 1 This is a graph showing the cell culture curves of GIST-T1 cells in the presence of various concentrations of compounds (RS1, RS2, RS5, or M-COPA).

[0047] Figure 2 This is a graph showing the cell culture curves of GIST-R9 cells in the presence of various concentrations of compounds (RS1, RS2, RS5, or M-COPA).

[0048] Figure 3 This is a graph showing the cell culture curves of HMC-1.2 cells in the presence of various concentrations of compounds (RS1, RS2, RS5, or M-COPA). Detailed Implementation

[0049] <The compound shown in formula (1)>

[0050] The compound in this embodiment is represented by the following formula (1).

[0051]

[0052] In the above formula (1), R 1 R 3 ~R 8 Each can independently represent a hydrogen atom or an alkyl group. R 2 Represents a hydrogen atom, or -OR a or -NR b R c The group shown. R 9 -CH2OR d -C(O)OR d -C(O)R d -CH2NR e R f 、or -C(O)NR e R f The group shown. R a ~R f Each of these can independently represent a hydrogen atom, an alkyl group, an aryl group optionally with a substituent, a heteroaryl group optionally with a substituent, an arylalkyl group optionally with a substituent, or a heteroarylalkyl group optionally with a substituent.

[0053] As R1 R 3 ~R 8 The alkyl group is preferably an alkyl group having 1 to 20 carbon atoms, and more preferably an alkyl group having 1 to 6 carbon atoms. The alkyl group can be any of the following: straight-chain, branched, or cyclic. Specific examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, cyclopentyl, hexyl, and cyclohexyl.

[0054] As R 1 R 6 Each is preferably an alkyl group (especially an alkyl group having 1 to 6 carbon atoms) as R. 3 Preferably, it is a hydrogen atom or an alkyl group (especially an alkyl group having 1 to 6 carbon atoms) as R. 4 R 5 R 7 R 8 Hydrogen atoms are preferred.

[0055] As R a ~R f The alkyl group is preferably an alkyl group having 1 to 20 carbon atoms, and more preferably an alkyl group having 1 to 6 carbon atoms. The alkyl group can be any of the following: straight-chain, branched, or cyclic. Specific examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, cyclopentyl, hexyl, and cyclohexyl.

[0056] As R a ~R f The aryl group is preferably a monocyclic or polycyclic aromatic hydrocarbon group with 6 to 20 carbon atoms, and more preferably a monocyclic or polycyclic aromatic hydrocarbon group with 6 to 12 carbon atoms. Specific examples of aryl groups include phenyl, naphthyl, anthraceneyl, phenanthryl, pyrene, etc.

[0057] As R a ~R fThe heteroaryl group preferably comprises 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen atoms, and is a monocyclic or polycyclic aromatic heterocyclic group with 2 to 9 ring carbons; more preferably, it is a monocyclic aromatic heterocyclic group with 3 to 5 ring carbons. Specific examples of heteroaryl groups include pyrroleyl, pyridinyl, imidazolyl, pyrazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, thiopheneyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, indoleyl, isoydinolyl, benzimidazolyl, indoleyl, benzotriazolyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, and isoquinolinyl. The compounds include quinazinyl, cyclolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pyrrolopyridyl, imidazopyridyl, pyrazolopyridyl, pyridopyrazinyl, purine, pteridyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzooxazolyl, benzoisooxazolyl, benzooxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, thiazopyridyl, etc.

[0058] As R a ~R f The aryl alkyl group is preferably an alkyl group with 1 to 6 carbon atoms that has been substituted by the aryl group, and more preferably an alkyl group with 1 to 4 carbon atoms that has been substituted by the aryl group. Specific examples of aryl alkyl groups include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, 2-phenylpropane-2-yl, etc.

[0059] As R a ~R f The heteroaryl alkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted by the aforementioned heteroaryl group, and more preferably an alkyl group having 1 to 4 carbon atoms substituted by the aforementioned heteroaryl group. Specific examples of heteroaryl alkyl groups include pyridylmethyl, pyridylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, pyrimidinylmethyl, pyrimidinylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, and thiazolylethyl.

[0060] Examples of substituents optionally present in the aforementioned aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups include hydroxyl, alkoxy group having 1 to 4 carbon atoms, hydroxyalkyl group having 1 to 4 carbon atoms, amino group, mono- or dialkylamino group having 1 to 4 carbon atoms, alkoxycarbonyl group having 1 to 4 carbon atoms, and halogen atoms. Specific examples of substituents include hydroxyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, amino, monomethylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, chlorine atom, and fluorine atom.

[0061] As R 2 Preferred - OR a The group shown is used as R at this time. aPreferably, it contains hydrogen atoms and an alkyl group having 1 to 6 carbon atoms. R is a preferred R group. 2 Examples include hydroxyl, methoxy, and ethoxy.

[0062] As R 9 Preferred - CH2OR d -C(O)OR d or -C(O)NR e R f The indicated group, more preferably -C(O)OR d or -C(O)NR e R f The group shown. R 9 -CH2OR d When the group shown is used as R d Preferably, it contains hydrogen atoms or an alkyl group having 1 to 6 carbon atoms. As R in this case... d Specific examples include hydrogen atoms, methyl groups, etc. R 9 -C(O)OR d When the group shown is used as R d Preferably, it contains hydrogen atoms, and is an alkyl, arylalkyl, or heteroarylalkyl group having 1 to 6 carbon atoms. As R in this case... d Specific examples include hydrogen atoms, methyl groups, pyridin-3-ylmethyl, pyridin-4-ylmethyl, oxazol-4-ylmethyl, oxazol-5-ylmethyl, thiazol-2-ylmethyl, and thiazol-5-ylmethyl. R 9 -C(O)NR e R f When the group shown is used as R e Hydrogen atoms are preferred as R f Preferably, arylalkyl or heteroarylalkyl. As R in this case... f Specific examples include pyridin-3-ylmethyl, pyridin-4-ylmethyl, oxazol-4-ylmethyl, oxazol-5-ylmethyl, thiazolyl-2-ylmethyl, and thiazolyl-5-ylmethyl.

[0063] As a preferred compound among the compounds shown in formula (1) above, examples include R. 1 R 6 Each is independently an alkyl group, R 2 hydroxyl group, R 4 R 5 R 7 R 8 For hydrogen atoms, R 9 -C(O)OR d or -C(O)NR e R f The groups shown, R d It is an arylalkyl or heteroarylalkyl, R eFor hydrogen atoms, R f Compounds that are arylalkyl or heteroarylalkyl. Preferred examples of alkyl, arylalkyl, and heteroarylalkyl groups are shown above.

[0064] When the compound shown in formula (1) above has an acidic or basic functional group, the compound can be in the form of a salt. For example, when the compound shown in formula (1) above has an acidic functional group, the compound can be in the form of an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, etc.), an ammonium salt, etc. In addition, when the compound shown in formula (1) above has a basic functional group, the compound can be in the form of a salt with inorganic acids such as hydrochloric acid and phosphoric acid, or in the form of a salt with organic acids such as acetic acid, fumaric acid, and methanesulfonic acid.

[0065] <Method for manufacturing the compound shown in formula (1)>

[0066] The compound shown in formula (1) above can be manufactured, for example, through the following steps (A) to (L).

[0067] (A) Preparation of the compound of formula (20) by asymmetric alkylation

[0068] (B) The compound of formula (19) was prepared by reduction.

[0069] (C) Preparation of the compound of formula (16) by oxidation and reaction of hornol with Evans asymmetric cofactor.

[0070] (D) Prepare compound (Wynleramide) of formula (15) from compound (16).

[0071] (E) Preparation of the compound of formula (14) by hydroxyl protection

[0072] (F) Preparation of the compound of formula (11) by reduction and Wittig reaction

[0073] (G) The compound of formula (10) is produced by reduction.

[0074] (H) The compound of formula (8) is prepared by the Wittig reaction.

[0075] (I) The compound of formula (7) is produced by reduction.

[0076] (J) Preparation of the compound of formula (6) by intramolecular Diels-Alder reaction

[0077] (K) The compound of formula (3) was prepared by the Horner-Wozworth-Emmons reaction and hydrolysis.

[0078] (L) Prepare the compound of formula (1) from the compound of formula (3).

[0079] The following provides a detailed description of each step of the manufacturing method according to this embodiment. It should be noted that R in the formula... 1 ~R 9 R a ~R f Same meaning as above.

[0080] [(A) Preparation of the compound shown in formula (20) by asymmetric alkylation]

[0081]

[0082] In the above equation (22), R 12 Indicates alkyl, aryl, or arylalkyl. As R 12 The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, and more preferably an alkyl group having 1 to 4 carbon atoms. The alkyl group can be any of straight-chain, branched, or cyclic. Specific examples of alkyl groups include methyl, ethyl, isopropyl, isobutyl, and cyclohexyl. Furthermore, as R... 12 The aryl group is preferably a monocyclic or polycyclic aromatic hydrocarbon group with 6 to 20 carbon atoms, and more preferably a monocyclic or polycyclic aromatic hydrocarbon group with 6 to 12 carbon atoms. Specific examples of aryl groups include phenyl, naphthyl, anthraceneyl, phenanthryl, pyrene, etc. Furthermore, as R... 12 The aryl alkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted by the aforementioned aryl group, and more preferably an alkyl group having 1 to 4 carbon atoms substituted by the aforementioned aryl group. Specific examples of aryl alkyl groups include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, 2-phenylpropane-2-yl, etc. Among these, as R... 12 Benzyl, phenyl, and isopropyl are particularly preferred.

[0083] In the above formula (21), X represents a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.).

[0084] By reacting a base with the compound shown in formula (22) above to generate an enol, and then reacting it with the compound shown in formula (21) (halide) as an alkylating agent, the compound shown in formula (20) above (optically active isoxazoline derivative) can be produced. As a base, lithium diisopropylamino, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, etc., can be used. Furthermore, tetrabutylammonium iodide can be added as a catalyst. The reaction is carried out in an organic solvent such as tetrahydrofuran or ether. The preferred reaction temperature is approximately -78°C to room temperature. After the reaction, the target compound is recovered and purified by column chromatography or the like.

[0085] It should be noted that R in the compound shown in formula (20) above 3The stereoconfiguration of the compound is determined by R in the compound shown in formula (22) above. 12 The three-dimensional configuration determines this.

[0086] [(B) Preparation of the compound shown in formula (19) by reduction]

[0087]

[0088] The compound (optically active isoxazoline derivative) shown in formula (20) can be converted into the compound (alcohol) shown in formula (19) without compromising optical purity by treatment with a reducing agent. LiAlH4, LiBH4-EtOH, NaH2Al(OCH2CH2OMe)2, etc., can be used as reducing agents. The reaction is carried out in organic solvents such as tetrahydrofuran or ether. The preferred reaction temperature is approximately 0°C to room temperature. After the reaction, the target compound is recovered and purified by column chromatography or similar methods.

[0089] [(C) Preparation of the compound shown in formula (16) by oxidation and reaction of hornol with Evans asymmetric cofactor]

[0090]

[0091] First, the compound (alcohol) shown in formula (19) above is oxidized to produce the compound (aldehyde) shown in formula (18) above. In the oxidation reaction, weak oxidizing agents such as dimethyl sulfoxide, tetrapropylammonium perruthenate, or desmartin oxidant can be used. The reaction is carried out in an organic solvent such as dichloromethane. The preferred reaction temperature is approximately 0°C to room temperature. The resulting compound (18) above can be used directly in subsequent reactions without separation.

[0092] Next, in the presence of boron-trifluoromethanesulfonate and an amine, the compound shown in formula (18) and the compound shown in formula (17) are reacted with hydroxyl to produce the compound shown in formula (16). In formula (17), R 12 This has the same meaning as formula (22) above. Triethylamine, 2,6-dimethylpyridine, etc., can be used as the amine. The reaction is carried out in organic solvents such as dichloromethane, tetrahydrofuran, and 1,2-dimethoxyethane. The preferred reaction temperature is approximately -78℃ to 0℃. After the reaction, the target substance is recovered and purified by column chromatography or similar methods.

[0093] [(D) Prepare compound (Wynleramide) of formula (15) from compound (16)]

[0094]

[0095] The compound shown in formula (16) above can be readily converted into the compound shown in formula (15) above (Winleber amide) by reacting it with N,O-dimethylhydroxylamine. In formula (15) above, Me represents methyl. The reaction is carried out in an organic solvent such as tetrahydrofuran. The reaction temperature is preferably around 0°C. After the reaction, the target substance is recovered and purified by column chromatography or the like.

[0096] [(E) Preparation of the compound shown in formula (14) by hydroxyl protection]

[0097]

[0098] In formula (14) above, Z represents the protecting group of the hydroxyl group. Preferably, Z is a protecting group that can protect the hydroxyl group under mild conditions and is stable under alkaline conditions. Examples of preferred protecting groups include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and other trialkylsilyl groups.

[0099] The protection of the hydroxyl group is preferably carried out as follows: Trialkylsilyl trifluoromethane esters are reacted in an organic solvent such as dichloromethane using 2,6-dimethylpyridine, which acts as a weak base, as a catalyst. The reaction temperature is preferably around 0°C. After the reaction, the target compound is recovered and purified by column chromatography or similar methods.

[0100] [(F) Preparation of the compound shown in formula (11) by reduction and Wittig reaction]

[0101]

[0102] First, the compound (amide) shown in formula (14) above is reduced to produce the compound (aldehyde) shown in formula (13) above. Diisobutylaluminum hydride is preferably used as the reducing agent because the reduction can be stopped by the aldehyde. The reaction is carried out in organic solvents such as tetrahydrofuran, toluene, hexane, or dichloromethane. The preferred reaction temperature is approximately -78°C to 0°C. The target compound is recovered after the reaction.

[0103] Next, the compound shown in formula (11) can be prepared by subjecting the compound (aldehyde) shown in formula (13) and the compound (Wittig reagent) shown in formula (12) to a Wittig reaction. The reaction is carried out in an organic solvent such as dichloromethane. The reaction temperature is preferably around 35°C. After the reaction, the target substance is recovered and purified by column chromatography or the like.

[0104] [(G) The compound shown in formula (10) is prepared by reduction]

[0105]

[0106] By reducing the compound (amide) shown in formula (11) as described in step (F) above, the compound (aldehyde) shown in formula (10) above can be produced. The reaction conditions are the same as those in step (F) above.

[0107] [(H) Prepare the compound of formula (8) by the Wittig reaction]

[0108]

[0109] The compound shown in formula (8) can be prepared by subjecting the compound (aldehyde) shown in formula (10) and the compound (Wittich reagent) shown in formula (9) to the Wittich reaction in the same manner as in step (F) above. The reaction conditions are the same as in step (F) above.

[0110] [(I) The compound shown in formula (7) was prepared by reduction]

[0111]

[0112] The compound (amide) shown in formula (8) can be produced by reducing it in the same way as in step (F) above. The reaction conditions are the same as in step (F) above.

[0113] [(J) Preparation of the compound shown in formula (6) via an intramolecular Diels-Alder reaction]

[0114]

[0115] The intramolecular Diels-Alder reaction can be promoted by the driving force of the transformation of the 8π system in the chain structure molecule into the more stable 4π+4σ system in the cyclic structure molecule. A catalyst such as diethylaluminum chloride is preferably used in the reaction. The reaction is carried out in an organic solvent such as dichloromethane. The preferred reaction temperature is approximately -78°C to room temperature. In addition to the compound shown in formula (6) above, the crude product also contains compounds with different stereostructures; therefore, the crude product is purified by thin-layer chromatography or other methods to recover the target compound.

[0116] [(K) produced the compound of formula (3) by Horner-Wozworth-Emmons reaction and hydrolysis]

[0117]

[0118] In equation (5) above, R 10 R 11 Each can be used independently to represent an alkyl group. As R 10 R 11The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, and more preferably an alkyl group having 1 to 4 carbon atoms. The alkyl group can be any of straight-chain, branched, or cyclic. Specific examples of alkyl groups include methyl, ethyl, isopropyl, isobutyl, and cyclohexyl, with methyl and ethyl being preferred.

[0119] First, the compound shown in formula (6) and the compound shown in formula (5) are subjected to the Horner-Wozworth-Emmons reaction to produce the compound shown in formula (4). Specifically, a base is reacted with the compound shown in formula (5) (alkyl sulfonate) to generate a carboanion, which is then reacted with the compound shown in formula (6) (aldehyde) to produce the compound shown in formula (4) (olefin). Lithium bis(trimethylsilyl)amino, lithium diisopropylamino, etc., are preferably used as the base. The reaction is carried out in an organic solvent such as tetrahydrofuran or dichloromethane. The reaction temperature is preferably around -78°C to room temperature. The crude product contains compounds with different stereostructures in addition to the compound shown in formula (4), therefore the crude product is purified by thin-layer chromatography or the like to recover the target compound.

[0120] Next, the compound shown in formula (3) can be prepared by hydrolyzing the compound shown in formula (4). When hydrolysis is carried out in a protected state of hydroxyl groups, it can be carried out under an alkaline catalyst such as sodium hydroxide or lithium hydroxide.

[0121] [(L) Prepare the compound shown in formula (1) from the compound shown in formula (3)]

[0122]

[0123] The carboxyl group of the compound shown in formula (3) above is converted to R. 9 After manufacturing the compound shown in formula (2) above, the -OZ of the compound shown in formula (2) above is converted to R. 2 Thus, the compound shown in formula (1) above can be produced.

[0124] The conversion from the compound shown in formula (3) to the compound shown in formula (2) can be carried out using methods commonly used in organic synthesis, such as various combinations of esterification, amidation, halogenation, anhydrideation, etherification, amination, oxidation, reduction, coupling reaction, protection, and deprotection. Reaction examples are shown below.

[0125]

[0126] The carboxyl group of the compound shown in formula (3) above is reduced with a reducing agent such as lithium aluminum hydride, and then reacted with R. d The Williamson synthesis of the haloalkyl reaction shown in X yields R. 9 -CH2ORd The compound. Additionally, the carboxyl group of the compound shown in formula (3) above is reacted with NHR. e R f The amine shown undergoes a dehydration condensation reaction to yield R. 9 -C(O)NR e R f The compound. Additionally, reducing agents such as lithium aluminum hydride are used to reduce R... 9 -C(O)NR e R f The reduction of the compound yields R. 9 -CH2NR e R f The compound. Additionally, the carboxyl group of the compound shown in formula (3) above is reacted with R. d The alcohol represented by OH undergoes a dehydration condensation reaction to give R. 9 -C(O)OR d The compound. Additionally, after reducing the carboxyl group of the compound shown in formula (3) to a hydroxymethyl group, it is oxidized to a formyl group and reacts with R. d The Grignard reagent reaction shown by MgX yields R. 9 -CH(OH)R d The compound. Then R 9 -CH(OH)R d The oxidation of the compound yields R. 9 -COR d Compounds.

[0127] The conversion from the compound shown in formula (2) to the compound shown in formula (1) can be carried out by methods commonly used in organic synthesis, such as various combinations of esterification, etherification, halogenation, amination, oxidation, reduction, protection, and deprotection. As an intermediate in the conversion, in the process of converting to R... 9 When hydroxyl, carboxyl, or amino groups are introduced, these groups can be protected or deprotected if required in subsequent reactions. Reaction examples are shown below.

[0128]

[0129] First, by removing the protecting group Z from the -OZ group of the compound shown in formula (2) above to make it a hydroxyl group, it is transformed into various groups. For example, if the hydroxyl group is reacted with R... a The Williamson synthesis of the haloalkyl reaction shown in X yields R. 2 For -OR a Compounds. Additionally, if the hydroxyl group is reacted with R... a The carboxylic acid represented by COOH undergoes a dehydration condensation reaction to obtain R.2 -O(CO)R a Compounds. Additionally, if an alcohol with a hydroxyl group is oxidized to a ketone and then reduced using a reducing agent such as diisobutylaluminum hydride, then from R... 1 and R 3 Hydride attack is performed on the side opposite to the direction of the substituent, thus yielding a stereoinverted alcohol. The hydroxyl group of this alcohol is activated with diethyl azodicarboxylate and triphenylphosphine to react with R... b R c The NH reaction, i.e., the photoelectrophoresis reaction, introduces an amino group that undergoes another stereoinversion, yielding R. 2 For -NR c R d The compound. Alternatively, by reacting the hydroxyl group with 1,1'-thiocarbonyldiimidazole to form a thiocarbamate, followed by free radical reduction using tributyltin hydride and azobisisobutyronitrile, R can be obtained. 2 Compounds containing hydrogen atoms.

[0130] <Pharmaceutical Compositions>

[0131] The pharmaceutical composition of this embodiment contains the compound shown in formula (1) above and a pharmaceutically permissible carrier.

[0132] The compound represented by formula (1) above exhibits the same inhibitory effect on cell proliferation against various cancers as its analogue M-COPA. Therefore, the pharmaceutical composition of this embodiment can be used as a pharmaceutical composition for treating various cancers. It should be noted that "treatment" includes not only the disappearance or reduction of disease symptoms, but also the inhibition of symptom progression.

[0133] In particular, the compound shown in formula (1) above, like the analogue M-COPA, can inhibit the movement of receptor-type tyrosine kinases (KIT, FLT3, FGFR3, EGFR, MET, etc.) to the Golgi apparatus or cell membrane by inhibiting the transport of receptor-type tyrosine kinases (KIT, FLT3, FGFR3, EGFR, MET, etc.) between the endoplasmic reticulum and Golgi apparatus. Therefore, the pharmaceutical composition of this embodiment is also effective for the treatment of the following cancers: cancers with KIT activation mutations (e.g., gastrointestinal stromal tumors, mast cell leukemia, acute myeloid leukemia); cancers with high expression of tyrosine kinase receptors such as FLT3, FGFR3, EGFR, MET, etc. (e.g., acute myeloid leukemia, multiple myeloma, lung adenocarcinoma, gastric cancer, etc.); and cancers resistant to tyrosine kinase receptor inhibitors (e.g., imatinib-resistant acute myeloid leukemia, imatinib-resistant gastrointestinal stromal tumors, multiple myeloma, gefitinib-resistant and osimertinib-resistant non-small cell lung adenocarcinoma).

[0134] Pharmaceutically permissible carriers include various organic and inorganic carriers commonly used as formulation materials. In solid dosage forms, these carriers can function as excipients, lubricants, binders, disintegrants, etc., while in liquid dosage forms, they can function as solvents, solubilizers, suspending agents, isotonic agents, buffers, etc. Furthermore, pharmaceutical compositions may contain formulation additives such as preservatives, antioxidants, and colorants.

[0135] There are no particular restrictions on the dosage form of a pharmaceutical composition. Examples of dosage forms for pharmaceutical compositions include oral dosage forms such as tablets, capsules, emulsions, and suspensions; and non-oral dosage forms such as injections, drops, and topical preparations.

[0136] The dosage of the drug composition can be appropriately determined based on the recipient, route of administration, disease, symptoms, etc.

[0137] Example

[0138] The following describes embodiments of the present invention, but the scope of the present invention is not limited to these embodiments.

[0139] In the following examples, compounds RS1 to RS10, which are compounds represented by the above formula (1), were prepared. In addition, M-COPA was also prepared for comparison.

[0140]

[0141] <Synthetic Example 1: Synthesis of (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(oxazol-5'-ylmethyl)pent-2,4-dieneamide (compound RS1)>

[0142]

[0143] [Preparation of (2E,4E)-1-bromohex-2,4-diene (compounds 1-2)]

[0144] A solution (51 mL) of dichloromethane containing 10.0 g (102 mmol) of 2,4-hexadien-1-ol was added dropwise with phosphorus tribromide (9.7 mL, 102 mmol) at 0 °C, and the mixture was stirred for 1 hour. After dilution with water at 0 °C, the organic layer was separated from the reaction mixture. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Crude purification was performed using a pre-cooled silica gel via gel filtration (developing solvent: hexane / ethyl acetate = 10 / 1, using a developing solvent pre-cooled to 0 °C). Filtration and concentration under reduced pressure yielded the crude products of compounds 1-2. These crude products were used directly in subsequent reactions without further purification.

[0145]

[0146] [Asymmetric alkylation]

[0147] A tetrahydrofuran solution (39 mL) containing (S)-4-benzyl-3-propionyloxazolin-2-one (compound 1-3a) (9.0 g, 38.7 mmol) was mixed with a tetrahydrofuran solution (1.0 M, 43 mL, 43.0 mmol) of sodium bis(trimethylsilyl)aminoacetate at -78 °C. After stirring the reaction mixture for 15 min, (2E,4E)-1-bromohex-2,4-diene (compound 1-2) (12.5 g, 77.4 mmol) and tetrabutylammonium iodide (1.48 g, 4.0 mmol) were added, and the mixture was heated to room temperature and stirred for 1.5 h. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride to the reaction system at 0 °C. Ethyl acetate was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (developing solvent: hexane / ethyl acetate = 7 / 1) to give (S)-4-benzyl-3-((R,4'E,6'E)-2'-methyloctyl-4',6'-dienoyl)oxazolin-2-one (compounds 1-4) (8.8 g, 72%).

[0148]

[0149] [reduction]

[0150] A tetrahydrofuran solution (133 mL) containing lithium aluminum hydride (3.4 g, 89.6 mmol) was mixed with a tetrahydrofuran solution (66 mL) containing (S)-4-benzyl-3-((R,4'E,6'E)-2'-methyloctyl-4',6'-dienoyl)oxazoline-2-one (compounds 1-4) (18.7 g, 59.7 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction was stopped by adding methanol and 1.0 M hydrochloric acid to the reaction system at 0 °C. Ethyl acetate was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (developing solvent: hexane / ethyl acetate = 5 / 1) to give (R,4E,6E)-2-methyloct-4,6-dien-1-ol (compounds 1-5) (7.2 g, 86%).

[0151]

[0152] [Oxidation]

[0153] For a dichloromethane solution (131 mL) containing (R,4E,6E)-2-methyloctyl-4,6-dien-1-ol (compounds 1-5) (6.9 g, 49.3 mmol), dimethyl sulfoxide (32.8 mL, 462 mmol) and triethylamine (54.6 mL, 394 mmol) were added at room temperature. After the reaction mixture was brought to 0 °C, a sulfur trioxide-pyridine complex (31.4 g, 197 mmol) was added, and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture containing the crude products of compounds 1-6 was used directly in subsequent reactions without purification.

[0154] [Reaction of hornail hydrol using Evans' asymmetric cofactor]

[0155] A 164 mL solution of dichloromethane containing (R)-4-benzyl-3-propionyloxazoline-2-one (compounds 1-3b) (11.5 g, 49.3 mmol) was added to a dichloromethane solution of dibutylboron trifluoromethanesulfonate (49.3 mL, 49.3 mmol) and triethylamine (6.8 mL, 49.3 mmol) at 0 °C, and the mixture was stirred for 10 minutes. After the reaction mixture reached -78 °C, the reaction mixture containing the crude products of compounds 1-6 was added via a tube, and the mixture was stirred for 30 minutes. The temperature was then raised to 0 °C, and the mixture was stirred for another 1 hour. The reaction was stopped by adding phosphate buffer (pH 7) to the reaction system at 0 °C. Dichloromethane was added, and the organic layer was separated. The aqueous layer was then extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (developing solvent: hexane / ethyl acetate = 10 / 1 → 3 / 1) to give (R)-4-benzyl-3-((2'R,3'S,4'R,6'E,8'E)-3'-hydroxy-2',4'-dimethyldecyl-6',8'-dienoyl)oxazoline-2-one (compounds 1-7) (14.6 g, 80% yield in two steps).

[0156]

[0157] [Conversion to Weinleberamide]

[0158] A tetrahydrofuran solution (230 mL) of N,O-dimethylhydroxylamine hydrochloride (6.83 g, 70.0 mmol) was added to a hexane solution of trimethylaluminum (1.0 M, 70 mL, 70.0 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes, then heated to room temperature and stirred for another 15 minutes. A tetrahydrofuran solution (120 mL) of (R)-4-benzyl-3-((2'R,3'S,4'R,6'E,8'E)-3'-hydroxy-2',4'-dimethyldecyl-6',8'-dienoyl)oxazoline-2-one (compounds 1-7) (13.0 g, 35.0 mmol) was added to the reaction mixture at 0 °C, and the mixture was stirred for 15 minutes. The reaction was stopped by adding a saturated sodium potassium tartrate aqueous solution to the reaction system at 0 °C. Ethyl acetate was added, and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (developing solvent: hexane / ethyl acetate = 3 / 1 → 1 / 1) to obtain (2R,3S,4R,6E,8E)-3-hydroxy-N-methoxy-N,2,4-trimethyldecyl-6,8-dieneamide (compounds 1-8) (8.5 g, 95%).

[0159]

[0160] [Hydroxyprotection]

[0161] A 170 mL solution of dichloromethane containing (2R,3S,4R,6E,8E)-3-hydroxy-N-methoxy-N,2,4-trimethyldecyl-6,8-dieneamide (compounds 1-8) (8.63 g, 33.8 mmol) was added at 0 °C to 2,6-dimethylpyridine (15.8 mL, 135 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (15.5 mL, 67.6 mmol). The reaction mixture was stirred at 0 °C for 15 minutes. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride at 0 °C. Dichloromethane was added, and the organic layer was separated. The aqueous layer was then extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (developing solvent: hexane / ethyl acetate = 20 / 1 → 5 / 1) to give (2R,3S,4R,6E,8E)-3-((tert-butyldimethylsilyl)oxy)-N-methoxy-N,2,4-trimethyldecyl-6,8-dieneamide (compounds 1-9) (12.4 g, 99%).

[0162]

[0163] [reduction]

[0164] A tetrahydrofuran solution (5.7 mL) containing (2R,3S,4R,6E,8E)-3-((tert-butyldimethylsilyl)oxy)-N-methoxy-N,2,4-trimethyldecyl-6,8-dieneamide (compounds 1-9) (211 mg, 0.570 mmol) was added to a hexane solution of diisobutylaluminum hydride (1.03 M, 0.72 mL, 0.74 mmol) at -78 °C, and the mixture was heated to 0 °C and stirred for 1.5 hours. The reaction was stopped by adding methanol and a saturated sodium potassium tartrate aqueous solution to the reaction system at 0 °C. Ethyl acetate was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude products of compounds 1-10. These crude products were used directly in subsequent reactions without purification.

[0165] [Vitic's reaction]

[0166] For a dichloromethane solution (5.7 mL) containing the crude products of compounds 1-10, N-methoxy-N-methyl-2-(triphenyl-λ) was added at room temperature. 5(-phosphonyl)acetamide (414 mg, 1.140 mmol) was heated to 35 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (developing solvent: hexane / ethyl acetate = 4 / 1) to give (2E,4S,5S,6R,8E,10E)-5-((tert-butyldimethylsilyl)oxy)-N-methoxy-N,4,6-trimethyldodecyl-2,8,10-trienamide (compound 1-11) (132 mg, two-step yield 56%). At this point, 59.4 mg (28%) of compound 1-10 was recovered. The physical properties of compounds 1-10 and 1-11 are as follows.

[0167] (2R,3S,4R,6E,8E)-3-((tert-butyldimethylsilyl)oxy)-2,4-dimethyldecyl-6,8-dienal (compounds 1-10):

[0168] 1 H NMR (400MHz, CDCl3): δ9.81 (d, J=0.8Hz, 1H, CHO), 6.07-5.93 (m, 2H, H-7, H-8), 6.07- 5.93 (m, 1H, H-9), 5.50-5.40 (m, 1H, H-6), 4.00 (dd, J=4.8, 4.0Hz, 1H, H-3), 2.58-2.47 (m, 1H, H-2), 2.27-2.16 (m, 1H, H-5), 1.94-1.83 (m, 1H, H-5), 1.07 (d, J=7.2Hz, 1H, 2-M e), 0.89 (s, 9H, TBS), 0.84 (d, J=6.8Hz, 3H, 4-Me), 0.08 (s, 3H, TBS), 0.03 (s, 3H, TBS).

[0169] (2E,4S,5S,6R,8E,10E)-5-((tert-butyldimethylsilyl)oxy)-N-methoxy-N,4,6-trimethyldodecyl-2,8,10-trienamide (compounds 1-11):

[0170] 1H NMR (400MHz, CDCl3): δ6.94 (dd, J=15.6, 8.8Hz, 1H, H-3), 6.34 (d, J=15.6Hz, 1H, H-2), 6.04-5.90 (m, 2H, H-9, H- 10), 5.61-5.50 (m, 1H, H-11), 5.50-5.40 (m, 1H, H-8), 3.67 (s, 3H, NMe), 3.50 (dd, J=6.4, 3.2Hz, 1H, H-5), 3.22 ( s, 3H, OMe), 2.61-2.47 (m, 1H, H-4), 1.94-1.84 (m, 1H, H-7), 1.71 (d, J=6.8Hz, 3H, H-12), 1.66-1.56 (m, 1H, H-6) , 1.05 (d, J=5.6Hz, 3H, 4-Me), 0.90 (s, 9H, TBS), 0.81 (d, J=6.8Hz, 3H, 6-Me), 0.04 (s, 3H, TBS), 0.04 (s, 3H, TBS).

[0171]

[0172] [reduction]

[0173] A tetrahydrofuran solution (6.6 mL) containing (2E,4S,5S,6R,8E,10E)-5-((tert-butyldimethylsilyl)oxy)-N-methoxy-N,4,6-trimethyldodecyl-2,8,10-trienamide (compounds 1-11) (132 mg, 0.332 mmol) was added to a hexane solution of diisobutylaluminum hydride (1.03 M, 0.42 mL, 0.43 mmol) at -78 °C, and the mixture was heated to 0 °C and stirred for 10 minutes. The reaction was stopped by adding methanol and a saturated aqueous solution of sodium potassium tartrate at 0 °C. Ethyl acetate was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (developing solvent: hexane / ethyl acetate = 4 / 1) to give (2E,4S,5S,6R,8E,10E)-5-((tert-butyldimethylsilyl)oxy)-4,6-dimethyldodecyl-2,8,10-trienal (compounds 1-12) (82.8 mg, 74%). At this point, 7.5 mg (6%) of compounds 1-11 was recovered. The physical properties of compounds 1-12 are as follows.

[0174] (2E,4S,5S,6R,8E,10E)-5-((tert-butyldimethylsilyl)oxy)-4,6-dimethyldodecyl-2,8,10-trienal (compounds 1-12):

[0175] 1 H NMR (400MHz, CDCl3): δ9.51 (d, J=7.6Hz, 1H, CHO), 6.94 (dd, J=16.0, 6.8Hz, 1H, H-3), 6.08 (ddd, J=16.0, 7.6, 1.6Hz, 1H, H-3) 2), 6.03-5.93 (m, 2H, H-9, H-10), 5.64-5.52 (m, 1H, H-11), 5.49-5.40 (m, 1H, H-8), 3.63 (dd, J=6.0, 2.8Hz, 1H, H-5), 2.66 ( dqd, J=6.8, 6.8, 6.4Hz, 1H, H-4), 2.17-2.08 (m, 1H, H-7), 1.97-1.85 (m, 1H, H-7), 1.72 (d, J=6.4Hz, 3H, H-12), 1.64-1.55 ( m, 1H, H-6), 1.09 (d, J=6.8Hz, 3H, 4-Me), 0.92 (s, 9H, TBS), 0.79 (d, J=7.6Hz, 3H, 4-Me), 0.07 (s, 3H, TBS), 0.05 (s, 3H, TBS).

[0176]

[0177] [Vitic's reaction]

[0178] For a 2.5 mL solution of dichloromethane containing (2E,4S,5S,6R,8E,10E)-5-((tert-butyldimethylsilyl)oxy)-4,6-dimethyldodecyl-2,8,10-trienal (compounds 1-12), N-methoxy-N-methyl-2-(triphenyl-λ)-2 ...methyl-2-(triphenyl-λ)-2-methyl-2-methyl-2-methyl-2-(triphenyl-λ)-2-methyl 5 (-phosphononyl)acetamide (179 mg, 0.492 mmol) was heated to 35 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by thin-layer chromatography (developing solvent: hexane / ethyl acetate = 4 / 1) to give (2E,4E,6S,7S,8R,10E,12E)-7-(tert-butyldimethylsiloxy)-N-methoxy-N,6,8-trimethyltetradecanoic-2,4,10,12-tetraenoamide (compounds 1-13) (73.5 mg, 71%). At this point, 59.4 mg (10%) of compounds 1-12 was recovered. The physical properties of compounds 1-13 are as follows.

[0179] (2E,4E,6S,7S,8R,10E,12E)-7-(tert-butyldimethylsiloxy)-N-methoxy-N,6,8-trimethyltetradecano-2,4,10,12-tetraenoamide (compounds 1-13):

[0180] 1 H NMR (400MHz, CDCl3): δ7.31 (d, J=15.6, 10.0Hz, 1H, 3-H), 6.22-6.06 (m, 2H, H-4, H-5), 6.06-5.90 (m, 2H, H-11, H-12), 5.62-5.51 (m, 1H, H-11), 5.49-5.40 (m, 1H, H-10), 3.70 (s, 3H, NMe), 3.46 (dd, J=6.4, 3.2Hz, 1H, H-7), 3.24 (s, 3H, OMe) , 2.53-2.40 (m, 1H, H-6), 2.30-2.18 (m, 1H, H-9), 1.94-1.82 (m, 1H, H-9), 1.72 (d, J=6.4Hz, 3H, H-14), 1.63-1.58 (m, 1H , H-8), 1.02 (d, J=6.8Hz, 3H, 6-Me), 0.90 (s, 9H, TBS), 0.80 (d, J=6.4Hz, 3H, 8-Me), 0.04 (s, 3H, TBS), 0.03 (s, 3H, TBS).

[0181]

[0182] [reduction]

[0183] A tetrahydrofuran solution (1.7 mL) containing (2E,4E,6S,7S,8R,10E,12E)-7-(tert-butyldimethylsiloxy)-N-methoxy-N,6,8-trimethyldodecyl-2,4,10,12-tetraenoamide (compounds 1-13) (73.5 mg, 0.174 mmol) was prepared at -78 °C. A hexane solution of diisobutylaluminum hydride (1.03 M, 0.22 mL, 0.23 mmol) was added, and the mixture was heated to 0 °C and stirred for 20 minutes. The reaction was stopped at 0 °C by adding methanol and a saturated aqueous solution of sodium potassium tartrate. Ethyl acetate was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (developing solvent: hexane / ethyl acetate = 4 / 1) to give (2E,4E,6S,7S,8R,10E,12E)-7-((tert-butyldimethylsilyl)oxy)-6,8-dimethyltetradecanoate-2,4,10,12-tetraenal (compounds 1-14) (82.8 mg, 74%). The physical properties of compounds 1-14 are as follows.

[0184] (2E,4E,6S,7S,8R,10E,12E)-7-((tert-butyldimethylsilyl)oxy)-6,8-dimethyltetradecano-2,4,10,12-tetraenal (compounds 1-14):

[0185] 1 H NMR (400MHz, CDCl3): δ9.51 (d, J=8.4Hz, 1H, CHO), 7.08 (dd, J=15.2, 9.6Hz, 1H, H-3), 6.34-6.24 (m, 2H, H-4, H-6), 6.09 (dd, J=15.2, 8.4, 1H, H-2), 6.04-5.94 (m, 2H, H-11, H-12), 5.64-5.52 (m, 1H, H-13), 5.52-5.40 (m, 1H, H-10), 3.51 (dd, J=6.0, 3.2 Hz, 1H, H-7), 2.58-2.50 (m, 1H, H-6), 2.18-2.08 (m, 1H, H-9), 1.96-1.86 (m, 1H, H-9), 1.73 (d, J=6.8Hz, 3H, H-14), 1.69-1.56 (m, 1H, H-8), 1.06 (d, J=7.2Hz, 3H, 6-Me), 0.92 (s, 9H, TBS), 0.82 (d, J=7.6Hz, 3H, 8-Me), 0.06 (s, 3H, TBS), 0.04 (s, 3H, TBS).

[0186]

[0187] [Molecular Diels-Alder reaction]

[0188] A 2.0 mL solution of dichloromethane containing (2E,4E,6S,7S,8R,10E,12E)-7-((tert-butyldimethylsilyl)oxy)-6,8-dimethyltetradecanoate-2,4,10,12-tetraenal (compound 1-14) (21.2 mg, 0.0585 mmol) was added to a 1.0 M, 0.06 mL, 0.06 mmol solution of diethylaluminum chloride in n-hexane at -78 °C. The reaction mixture was heated to -45 °C and stirred for 20 minutes, then heated to room temperature and stirred for 1.5 hours. The reaction was stopped by adding methanol and a saturated aqueous solution of sodium potassium tartrate to the reaction mixture at 0 °C. Dichloromethane was added, and the organic layer was separated. The aqueous layer was then extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (developing solvent: hexane / ethyl acetate = 4 / 1) to give (E)-3-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)acrylonitrile (compound) Compounds 1-15 (10.5 mg, 50%) and (E)-3-((1'R,2'R,4'aS,6'R,7'S,8'S,8'aR)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)acrylonitrile (compounds 1-16) (3.7 mg, 17%). The physical properties of compounds 1-15 are as follows.

[0189] (E)-3-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphth-1'-yl)acrylonitrile (compounds 1-15):

[0190] 1H NMR (400MHz, CDCl3): δ9.52 (d, J=8.0Hz, 1H, CHO), 6.82 (dd, J=15.6, 10.8Hz, 1H, H-3), 6.04 (dd, J=15.6, 8.0Hz, 1H, H-2), 5.64-5.52 (m, 2H, H-3', H-4'), 2.86 (dd, J=9.6, 9.6Hz, 1H, H-7), 2.63 (ddd, J=10.4, 7.6, 6.0Hz, 1H, H-1'), 2.38-2.22 (m, 1H, H-2'), 1.92-1.83 (m, 1H, H-4'a), 1.80 (ddd, J=13.2, 7.2, 3.6Hz, 1H, H-5'), 1.64-1.48 (m, 3H, H-5', H-6', H-8'), 1.48-1.36 (m, 1H, 8'aH), 0.98 (d, J=7 .6Hz, 3H, 2'-Me), 0.97 (d, J=6.4Hz, 3H, 6'-Me), 0.97 (d, J=6.4Hz, 3H, 8'-Me), 0.90 (s, 9H, TBS), 0.06 (s, 3H, TBS), 0.06 (s, 3H, TBS).

[0191]

[0192] [Hornar-Wozworth-Emmons reaction]

[0193] A tetrahydrofuran solution (0.7 mL) containing ethyl diethylphosphonobromoethyl acetate (compound 2-0) (26.3 mg, 0.0869 mmol) was prepared by adding a tetrahydrofuran solution (1.0 M, 0.08 mL, 0.946 mmol) of lithium bis(trimethylsilyl)aminoacetate dropwise at -78 °C. After stirring the reaction mixture at -78 °C for 30 minutes, a tetrahydrofuran solution (0.3 mL) containing compound 1-15 (10.5 mg, 0.0290 mmol) was added, and the mixture was heated to room temperature and stirred for 10 minutes. The reaction was stopped by adding a saturated aqueous ammonium chloride solution to the reaction system at 0 °C. Ethyl acetate was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (developing solvent: hexane / ethyl acetate = 4 / 1) to give (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)pent-2,4-dienoic acid ethyl ester (compound 2-1) Compound 2-1 (8.8 mg, 59% yield in two processes) and (2E,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)pent-2,4-dienoic acid ethyl ester (compound 2-2) (4.0 mg, 27% yield in two processes). The physical properties of compound 2-1 are as follows.

[0194] (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphth-1'-yl)pent-2,4-dienoic acid ethyl ester (compound 2-1):

[0195] 1H NMR (500MHz, CDCl3): δ7.65 (d, J=9.0Hz, 1H, H-3), 6.47-6.30 (m, 2H, H-4, H-5), 5.58 (ddd, J=9.5, 3.0, 2.5Hz, 1H, H-4'), 5.49 (ddd, J=9.5, 2.0, 2.0Hz, 1H, H-3'), 4.29 (q, J=7.5Hz, 2H, OEt), 2.86 (dd, J=9.5, 9.5Hz, 1H, H-7'), 2.54 (ddd, J=9.0, 9.0, 5.0Hz, 1H, H-1'), 2.30-2.18 (m, 1H, H-2' ), 1.91-1.82 (m, 1H, H-4'a), 1.76 (ddd, J=13.0, 3.5, 3.5Hz, 1H, H-5'), 1 .60-1.49 (m, 3H, H-5', H-6', H-8'), 1.46-1.36 (m, 1H, H-8'a), 1.35 (t, J =7.5Hz, 3H, OEt), 1.00 (d, J = 6.5Hz, 3H, 2'-Me), 0.98 (d, J = 7.0Hz, 3H, 8'-Me), 0.96 (d, J = 6.5Hz, 3H, 6'-Me), 0.91 (s, 9H, TBS), 0.07 (s, 6H, TBS).

[0196]

[0197] [hydrolysis]

[0198] For a mixed solution of methanol (1.0 mL) and tetrahydrofuran (2.0 mL) containing ethyl 2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)pent-2,4-dienoic acid (compound 2-1) (84.7 mg, 0.166 mmol), 4.0 M lithium hydroxide aqueous solution (1.0 mL, 4.00 mmol) was added at 0 °C, and the mixture was heated to room temperature and stirred for 12 hours. The reaction was stopped by adding 1.0 M hydrochloric acid to the reaction system at 0 °C, followed by the addition of ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude products of compounds 2-3. These crude products were used directly in subsequent reactions without purification.

[0199] [Amide-coating]

[0200] For a 5.5 mL solution of the crude product containing compounds 2-3 in dichloromethane, 2-methyl-6-nitrobenzoic anhydride (85.5 mg, 0.248 mmol) and 4-dimethylaminopyridine (60.7 mg, 0.497 mmol) were added at room temperature. After stirring the reaction mixture for 10 minutes, 5-aminomethyl-1,3-oxazole (amine A-1) (162.4 mg, 1.66 mmol) was added, and the mixture was stirred for another 10 minutes at room temperature. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride to the reaction system at 0 °C. Dichloromethane was then added, and the organic layer was separated. The aqueous layer was then extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (developing solvent: chloroform / methanol = 20 / 1) to give (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(oxazol-5”-ylmethyl)pent-2,4-dieneamide (compound 2-4) (75.6 mg, 81% yield in two steps). The physical properties of compound 2-1 are as follows.

[0201] (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphth-1'-yl)-N-(oxazol-5”-ylmethyl)pent-2,4-dieneamide (compounds 2-4):

[0202] 11H NMR (500 MHz, CDCl3): δ 7.85 (s, 1H, H-2”), 7.77 (d, J = 10.5 Hz, 1H, H-3), 7.04 (s, 1H, H-4”), 6.94 (brt, J = 5.5 Hz, 1H, NH), 6.36 (dd, J = 15.0, 10.5 Hz, 1H, H-4), 6.28 (dd, J = 15.0, 10.0 Hz, 1H, H-5), 5.57 (ddd, J = 9.5, 4.0, 3.0 Hz, 1H, H-4’), 5.47 (ddd, J = 9.5, 2.0, 2.0 Hz, 1H, H-3’), 4.60 (d, J = 5.5 Hz, 2H, CH2Ar), 2.85 (dd, J = 9.5, 9.5 Hz, 1H, H-7’), 2.51 (ddd, J = 10.0, 8.5, 6.0 Hz, 1H, H-1’), 2.27 - 2.17 (m, 1H, H-2’), 1.91 - 1.78 (m, 1H, H-4’a), 1.88 - 1.71 (m, 2H, H-6’, H-8’), 1.58 - 1.47 (m, 1H, H-5’), 1.44 - 1.30 (m, 1H, H-8’a), 0.98 (d, J = 7.0 Hz, 3H, 2’-Me), 0.97 (d, J = 7.0 Hz, 3H, 8’-Me), 0.94 (d, J = 6.5 Hz, 3H, 6’-Me), 0.89 (s, 9H, TBS), 0.06 (s, 6H, TBS).

[0203]

[0204] [Deprotection]

[0205] For a mixed solution of methanol (2.0 mL) and tetrahydrofuran (2.0 mL) containing (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphth-1'-yl)-N-(oxazol-5”-ylmethyl)pentan-2,4-dieneamide (compound 2-4) (75.6 mg, 0.134 mmol), 12 M hydrochloric acid (0.40 mL, 4.80 mmol) was added at 0 °C, the mixture was heated to room temperature and stirred for 12 hours. Saturated... The reaction was stopped by adding sodium bicarbonate solution. Ethyl acetate was added, and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (developing solvent: chloroform / methanol = 20 / 1) to give (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(oxazol-5'-ylmethyl)pent-2,4-dieneamide (compound RS1) (57.3 mg, 95%). The physical properties of compound RS1 are as follows.

[0206] (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(oxazol-5'-ylmethyl)pent-2,4-dieneamide (compound RS1):

[0207] 1H NMR (500MHz, CDCl3): δ7.85 (s, 1H, H-2”), 7.78 (d, J=10.5Hz, 1H, H-3), 7.04 (s , 1H, H-4”), 6.95 (brt, J=5.5Hz, 1H, NH), 6.41 (dd, J=15.0, 10.5Hz, 1H, H-4), 6. 30 (dd, J=15.0, 10.0Hz, 1H, H-5), 5.58 (ddd, J=9.5, 4.0, 3.0Hz, 1H, H-4'), 5.4 5 (ddd, J=9.5, 2.0, 2.0Hz, 1H, H-3'), 4.61 (d, J=5.5Hz, 2H, CH2Ar), 2.73 (dd, J= 9.5, 9.5Hz, 1H, H-7'), 2.54 (ddd, J=10.0, 10.0, 5.0Hz, 1H, H-1'), 2.27-2.17( m, 1H, H-2'), 1.92-1.82 (m, 1H, H-4'a), 1.80-1.71 (m, 2H, H-5'), 1.76-1.64 (m, 2H, H-6', H-8'), 1.54-1.44 (m, 1H, H-5'), 1.36-1.22 (m, 1H, H-8'a), 1.07 (d, J= 6.5Hz, 3H, 2'-Me), 1.04 (d, J=7.0Hz, 3H, 8'-Me), 0.95 (d, J=6.5Hz, 3H, 6'-Me).

[0208] <Synthetic Example 2: Synthesis of (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(thiazolyl-5'-ylmethyl)pent-2,4-dieneamide (compound RS2)>

[0209]

[0210] [hydrolysis]

[0211] For a mixed solution of methanol (0.45 mL) and tetrahydrofuran (0.90 mL) containing ethyl 2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)pent-2,4-dienoic acid (compound 2-1) (45.7 mg, 0.089 mmol), 4.0 M lithium hydroxide aqueous solution (0.45 mL, 1.80 mmol) was added at 0 °C, and the mixture was heated to room temperature and stirred for 14 hours. The reaction was stopped by adding 1.0 M hydrochloric acid to the reaction system at 0 °C, followed by the addition of ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude products of compounds 2-3. These crude products were used directly in subsequent reactions without purification.

[0212] [Amide-coating]

[0213] For a 3.0 mL solution of the crude product containing compounds 2-3 in dichloromethane, 2-methyl-6-nitrobenzoic anhydride (46.1 mg, 0.134 mmol) and 4-dimethylaminopyridine (32.7 mg, 0.268 mmol) were added at room temperature. After stirring the reaction mixture for 10 minutes, 5-aminomethyl-1,3-thiazole (amine B-1) (102.0 mg, 0.893 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride to the reaction system at 0 °C. Dichloromethane was added, and the organic layer was separated. The aqueous layer was then extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (developing solvent: chloroform / methanol = 20 / 1) to give (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(thiazolyl-5'-ylmethyl)pent-2,4-dieneamide (compound 2-5) (50.6 mg, 98% yield in two steps). The physical properties of compound 2-5 are as follows.

[0214] (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(thiazolyl-5'-ylmethyl)pent-2,4-dieneamide (compounds 2-5):

[0215] 1 H NMR (500MHz, CDCl3): δ8.80 (s, 1H, H-2”), 7.84 (s, 1H, H-4”), 7.78 (d, J=10.5Hz, 1H, H-3), 7.05 (brt, J=5.5Hz, 1H, NH), 6.38 (dd, J=15.0, 10.5Hz, 1H, H-4), 6.28 (dd, J=15.0, 10.0Hz, 1H, H-5), 5.60-5.54 (m, 1H, H-4'), 5.50-5 .45 (m, 1H, H-3'), 4.75 (d, J=5.5Hz, 2H, CH2Ar), 2.86 (dd, J=9.0, 9.0Hz, 1H , H-7'), 2.52 (ddd, J=10.0, 10.0, 5.5Hz, 1H, H-1'), 2.27-2.18 (m, 1H, H-2' ), 1.92-1.60 (m, 4H, H-4'a, H-5', H-6', H-8'), 1.60-1.44 (m, 1H, H-5'), 1. 44-1.34 (m, 1H, H-8'a), 0.98 (d, J=6.0Hz, 3H, 2'-Me), 0.97 (d, J=6.0Hz, 3H , 8'-Me), 0.96 (d, J=7.0Hz, 3H, 6'-Me), 0.90 (s, 9H, TBS), 0.07 (s, 6H, TBS).

[0216]

[0217] [Deprotection]

[0218] For a mixed solution of methanol (1.6 mL) and tetrahydrofuran (1.6 mL) containing (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-((tert-butyldimethylsilyl)oxy)-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(thiazolyl-5”-ylmethyl)pentan-2,4-dieneamide (compound 2-5) (50.6 mg, 0.087 mmol), 12 M hydrochloric acid (0.32 mL, 3.84 mmol) was added at 0 °C, the mixture was heated to room temperature and stirred for 14 hours. Saturated... The reaction was stopped by adding sodium bicarbonate solution. Ethyl acetate was added, and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (developing solvent: chloroform / methanol = 20 / 1) to give (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(thiazolyl-5'-ylmethyl)pentane-2,4-dieneamide (compound RS2) (37.0 mg, 91%). The physical properties of compound RS2 are as follows.

[0219] (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(thiazolyl-5'-ylmethyl)pent-2,4-dieneamide (compound RS2):

[0220] 1H NMR (500MHz, CDCl3): δ8.92 (s, 1H, H-2”), 7.91 (s, 1H, H-4”), 7.80 (d, J=10.5Hz, 1H, H-3), 7.14-7.11 (brm, 1H, NH), 6.44 (dd, J=15.5, 10.5H z, 1H, H-4), 6.31 (dd, J=15.0, 10.0Hz, 1H, H-5), 5.61-5.55 (m, 1H, H-4'), 5.48-5.42 (m, 1H, H-3'), 4.76 (d, J=6.0Hz, 2H, CH2Ar), 2.74 (dd, J= 10.0, 10.0Hz, 1H, H-7'), 2.55 (ddd, J=10.0, 10.0, 5.5Hz, 1H, H-1'), 2.30-2.17 (m, 1H, H-2'), 1.97-1.70 (m, 4H, H-4'a, H-5', H-6', H-8'), 1 .56-1.43 (m, 1H, H-5'), 1.37-1.28 (m, 1H, H-8'a), 1.07 (d, J=6.0Hz, 3H, 2'-Me), 1.05 (d, J=6.0Hz, 3H, 8'-Me), 0.96 (d, J=7.0Hz, 3H, 6'-Me).

[0221] <Synthetic Example 3: Synthesis of (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(oxazol-4'-ylmethyl)pent-2,4-dieneamide (compound RS3)>

[0222] In the amidation of compounds 2-3, 4-aminomethyl-1,3-oxazole was used instead of 5-aminomethyl-1,3-oxazole, and the process was otherwise carried out in the same manner as in Synthesis Example 1, to synthesize compound RS3. The physical properties of compound RS3 are as follows.

[0223]

[0224] (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(oxazol-4'-ylmethyl)pent-2,4-dieneamide (compound RS3):

[0225] 1H NMR (500MHz, CDCl3): δ7.87 (s, 1H, H-2”), 7.75 (s, 1H, H-3), 7.65 (s, 1H, H-5”), 7.18-7.09 (brm, 1H, NH), 6.44-6.25 (m, 2H, H -4, H-5), 5.62-5.53 (m, 1H, H-3'), 4.47 (d, J=5.0Hz, 2H, CH2Ar), 2.78-2.68 (m, 1H, H-7'), 2.53 (ddd, J=9.5, 9.5, 5.0Hz, 1H, H -1'), 2.28-2.16 (m, 1H, H-2'), 1.94-1.82 (m, 1H, H-6'), 1.80-1.71 (m, 1H, H-5'), 1.71-1.56 (m, 1H, H-8'), 1.56-1.42 (m, 1H , H-5'), 1.38-1.22 (m, 1H, H-8'a), 1.06 (d, J=6.0Hz, 3H, 2'-Me), 1.04 (d, J=6.0Hz, 3H, 8'-Me), 0.95 (d, J=7.0Hz, 3H, 6'-Me).

[0226] <Synthetic Example 4: Synthesis of (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(thiazolyl-2'-ylmethyl)pent-2,4-dieneamide (compound RS4)>

[0227] In the amidation of compounds 2-3, 2-aminomethyl-1,3-thiazole was used instead of 5-aminomethyl-1,3-oxazole, and the process was otherwise carried out in the same manner as in Synthesis Example 1, to synthesize compound RS4. The physical properties of compound RS4 are as follows.

[0228]

[0229] (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(thiazolyl-2'-ylmethyl)pent-2,4-dieneamide (compound RS4):

[0230] 1H NMR (400MHz, CD3OD): δ7.72 (s, 1H, H-4”), 7.63 (s, 1H, H-3), 7.52 (d, J=3.2Hz, 1H, H-5”), 6.54-6.36 (m, 2H, H-4, H-5), 5.61 (ddd, J=9.2, 4.4, 2.8Hz, 1H, H-4'), 5.49 (ddd, J=9.2, 1.6, 1.6Hz, 1H, H-3'), 4.77 (s, 2H, CH2Ar), 2.63 (dd, J=9.6, 9.6Hz, 1H, H-7'), 2.57 (ddd, J=8.4 , 8.4, 2.8Hz, 1H, H-1'), 2.30-2.14 (m, 1H, H-2'), 1.95-1.82 (m, 1H, H-4'a), 1.77 (ddd, J=13.2, 3.6, 3.6Hz, 1H, H-5'), 1.54-1.40 (m, 1H, H-6'), 1.37-1.21 (m, 3H, H-5', H-8', H-8'a), 1.08 (d, J=6.4Hz, 3H, 2'-Me), 1.03 (d, J=6.0Hz, 3H, 8'-Me), 0.99 (d, J=7.2Hz, 3H, 6'-Me).

[0231] <Synthetic Example 5: Synthesis of (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(pyridin-3'-ylmethyl)pent-2,4-dieneamide (compound RS5)>

[0232] In the amidation of compounds 2-3, 3-aminomethylpyridine was used instead of 5-aminomethyl-1,3-oxazole, and the process was otherwise carried out in the same manner as in 1, to synthesize compound RS5. The physical properties of compound RS5 are as follows.

[0233]

[0234] (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphth-1'-yl)-N-(pyridin-3'-ylmethyl)pent-2,4-dieneamide (compound RS5):

[0235] 1H NMR (500MHz, C6D6): δ8.40 (s, 1H, H-2”), 8.37 (d, J=3.0Hz, 1H, H-6”), 8.08 (d, J=11.0Hz, 1H, H-3), 7.16-7.09 (m, 1H, H-4”), 6.59 (dd, J=7.5, 4.5Hz, 1H, H-5”), 6.46 (brt, J=6.5Hz, 1H, NH), 6.37 (dd, J=15.5, 10.5Hz, 1H, H-4), 6.05 (dd, J=15.5, 10.0Hz, 1H, H-5), 5.44 (dd d, J=9.5, 4.0, 3.0Hz, 1H, H-4'), 5.33 (ddd, J=9.5, 2.0, 2, 0Hz, 1H, H-3'), 3.96 (d, J=5.5Hz , 2H, CH2Ar), 2.35 (dd, J=10.0, 10.0Hz, 1H, H-7'), 2.22 (ddd, J=9.5, 9.5, 5.5Hz, 1H, H-1') ), 2.00-1.90 (m, 1H, H-2'), 1.59-1.51 (m, 1H, H-4'a), 1.43 (ddd, J=13.0, 3.5, 3.5Hz, 1H, H -5'), 1.39-1.19 (m, 2H, H-6', H-8'), 1.24-1.12 (m, 1H, H-5'), 1.04-0.88 (m, 1H, H-8'a), 0.92 (d, J=6.5Hz, 3H, 2'-Me), 0.91 (d, J=6.5Hz, 3H, 8'-Me), 0.73 (d, J=7.5Hz, 3H, 6'-Me).

[0236] <Synthetic Example 6: Synthesis of (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,7'S,8'S,8'aS)-7'-hydroxy-2',8'-dimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(thiazolyl-5'-ylmethyl)pent-2,4-dieneamide (compound RS6)>

[0237] In the oxidation and reaction of hornol using the Evans asymmetric cofactor, (4E,6E)-oct-4,6-dien-1-ol was used instead of compounds 1-5, otherwise the process was carried out in the same manner as in Synthesis Example 2, and compound RS6 was synthesized. The physical properties of compound RS6 are as follows.

[0238]

[0239] (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,7'S,8'S,8'aS)-7'-hydroxy-2',8'-dimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(thiazolyl-5'-ylmethyl)pent-2,4-dieneamide (compound RS6):

[0240] 1 H NMR (300MHz, CD3OD): δ8.89 (s, 1H, H-2”), 7.79 (d, J=3.0Hz, 1H, H-4”), 7.59 (d, J=9.6Hz, 1H, H-3), 6.53-6.30 (m, 2H, H-4, H-5), 5.60 ( ddd, J=9.3, 3.6, 3.0Hz, 1H, H-4'), 5.48 (ddd, J=9.3, 1.8, 1.8Hz, 1H, H-3'), 4.67 (s, 2H, CH2Ar), 3.08 (ddd, J=10.8, 10.8, 4.5Hz, 1H, H -7'), 2.56 (ddd, J=9.3, 9.3, 5.4Hz, 1H, H-1'), 2.30-2.12 (m, 1H, H-2'), 2.04-1.90 (m, 1H, H-4'a), 1.90-1.70 (m, 1H, H-5'), 1.48-1.2 7 (m, 1H, H-8'), 1.37-1.12 (m, 2H, H-6', H-8'a), 1.15-1.10 (m, 1H, H-6'), 1.06 (d, J=6.3Hz, 3H, 2'-Me), 0.97 (d, J=7.2Hz, 3H, 8'-Me).

[0241] <Synthetic Example 7: Synthesis of (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,7'S,8'S,8'aS)-7'-hydroxy-2',8'-dimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(pyridin-3'-ylmethyl)pent-2,4-dieneamide (compound RS7)>

[0242] In the oxidation and reaction of hornol using the Evans asymmetric cofactor, (4E,6E)-oct-4,6-dien-1-ol was used instead of compounds 1-5, otherwise the process was carried out in the same manner as in Synthesis Example 5, and compound RS7 was synthesized. The physical properties of compound RS7 are as follows.

[0243]

[0244] (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,7'S,8'S,8'aS)-7'-hydroxy-2',8'-dimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphth-1'-yl)-N-(pyridin-3'-ylmethyl)pent-2,4-dieneamide (compound RS7):

[0245] 1 H NMR (500MHz, CD3OD): δ8.50 (s, 1H, H-2”), 8.42 (d, J=4.5Hz, 1H, H-6”), 7.81-7.74 (m, 1H, H-4”), 7.59 (d, J=9.5Hz, 1H, H-3), 7.40 (dd, J=7. 5, 4.5Hz, 1H, H-5"), 6.49-6.35 (m, 2H, H-4, H-5), 5.60 (ddd, J=9.0, 4.0, 2.5Hz, 1H, H-4'), 5.49 (ddd, J=9.0, 3.0, 3.0Hz, 1H, H-3'), 4.50 (s , 2H, CH2Ar), 3.07 (ddd, J=11.0, 11.0, 5.0Hz, 1H, H-7'), 2.70-2.16 (m, 1H, H-2'), 2.05-1.93 (m, 1H, H-4'a), 1.86-1.75 (m, 1H, H-5'), 1.45 -1.31 (m, 1H, H-8'), 1.37-1.19 (m, 2H, H-6', H-8'a), 1.26-1.14 (m, 1H, H-6'), 1.06 (d, J=6.0Hz, 3H, 2'-Me), 0.97 (d, J=7.0Hz, 3H, 8'-Me).

[0246] <Synthetic Example 8: Synthesis of (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)-N-(pyridin-2'-ylmethyl)pent-2,4-dieneamide (compound RS8)>

[0247] In the amidation of compounds 2-3, 2-aminomethylpyridine was used instead of 5-aminomethyl-1,3-oxazole, and the process was otherwise carried out in the same manner as in Synthesis Example 1, to synthesize compound RS8. The physical properties of compound RS8 are as follows.

[0248]

[0249] (2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphth-1'-yl)-N-(pyridin-2'-ylmethyl)pent-2,4-dieneamide (compound RS8):

[0250] 1 ¹H NMR (400 MHz, acetone-d6): δ 8.56–8.50 (m, 1H, H⁻⁶”), 8.23 ​​(brt, J = 5.2 Hz, 1H, NH), 7.76 (ddd, J = 7.6, 7.6, 1.6 Hz, 1H, H⁻⁴”), 7.75 (d, J = 10.8 Hz, 1H, H⁻³”), 7.38–7.33 (m, 1H, H⁻³”), 7.29– 7.23 (m, 1H, H-5”), 6.56 (dd, J=15.2, 10.4Hz, 1H, H-4), 6.41 (dd, J=15.2, 10.4Hz, 1H, H-5 ), 5.61 (ddd, J=9.2, 4.4, 2.8Hz, 1H, H-4'), 5.48 (ddd, J=9.2, 2.0, 2.0Hz, 1H, H-5'), 4.60 (d, J=5.2Hz, 2H, CH2Ar), 3.50 (d, J=6.8Hz, 1H, H-7'), 2.67-2.57 (m, 1H, H-8'), 2.60 (ddd , J=10.4, 9.2, 5.2Hz, 1H, H-1'), 2.30-2.18 (m, 1H, H-2'), 1.96-1.84 (m, 1H, H-4'a), 1.74 (ddd, J=13.2, 3.6, 3.6Hz, 1H, H-5'), 1.54-1.39 (m, 1H, H-5'), 1.38-1.25 (m, 1H, H-8'a), 1.11 (d, J=6.0Hz, 3H, 8'-Me), 1.02 (d, J=6.0Hz, 3H, 2'-Me), 1.00 (d, J=7.6Hz, 3H, 6'-Me).

[0251] HRMS (ESI): For C 24 H 31 The calculated m / z of BrN₂O₂Na is 481.1461 [M+Na]. + The value was found to be 481.1444.

[0252] <Synthetic Example 9: Synthesis of pyridine-3”-ylmethyl(2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphth-1'-yl)pent-2,4-dienoic acid ester (compound RS9)>

[0253] In the dehydration condensation reaction of compounds 2-3, 3-pyridinemethanol was used instead of 5-aminomethyl-1,3-oxazole, and the process was otherwise carried out in the same manner as in Synthesis Example 1, to synthesize compound RS9. The physical properties of compound RS9 are as follows.

[0254]

[0255] Pyridin-3”-ylmethyl(2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphth-1'-yl)pent-2,4-dienoic acid ester (compound RS9):

[0256] 1 H NMR (500MHz, acetone-d6): δ8.69 (s, 1H, H-2”), 8.57 (d, J=3.5Hz, 1H, H-6”), 7.88- 7.85 (m, 1H, H-4”), 7.85 (d, J=10.5Hz, 1H, H-3), 7.43-7.38 (m, 1H, H-5”), 6.68 (dd, J=15.0, 10.5Hz, 1H, H-4), 6.46 (dd, J=15.0, 10.0Hz, 1H, H-5), 5.60 (ddd , J=9.0, 3.0, 3.0Hz, 1H, H-4'), 5.48 (ddd, J=9.0, 2.5, 1.5Hz, 1H, H-3'), 5.33( s, 2H, CH2Ar), 3.49 (d, J=7.0Hz, 1H, H-7'), 2.66-2.56 (m, 2H, H-8', H-1'), 2. 30-2.14 (m, 1H, H-2'), 1.94-1.84 (m, 1H, H-4'a), 1.75 (ddd, J=13.0, 3.0, 3.0H z, 1H, H-5'), 1.55-1.40 (m, 1H, H-5'), 1.39-1.25 (m, 1H, H-8'a), 1.08 (d, J=6 .0Hz, 3H, 8'-Me), 1.01 (d, J=6.0Hz, 3H, 2'-Me), 0.97 (d, J=7.5Hz, 3H, 6'-Me).

[0257] HRMS (ESI): For C 24 H 31 The calculated m / z of BrNO3 is 460.1482 [M+H]. + The value was found to be 460.1483.

[0258] <Synthetic Example 10: Synthesis of pyridin-2”-ylmethyl(2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphthyl-1'-yl)pent-2,4-dienoic acid ester (compound RS10)>

[0259] In the dehydration condensation reaction of compounds 2-3, 2-pyridinemethanol was used instead of 5-aminomethyl-1,3-oxazole, and the process was otherwise carried out in the same manner as in Synthesis Example 1, to synthesize compound RS10. The physical properties of compound RS10 are as follows.

[0260]

[0261] Pyridin-2”-ylmethyl(2Z,4E)-2-bromo-5-((1'S,2'S,4'aR,6'R,7'S,8'S,8'aS)-7'-hydroxy-2',6',8'-trimethyl-1',2',4'a,5',6',7',8',8'a-octahydronaphth-1'-yl)pent-2,4-dienoic acid ester (compound RS10):

[0262] 1¹H NMR (500 MHz, acetone-d6): δ 8.56 (d, J = 4.5 Hz, 1H, H⁻⁶”), 7.89 (d, J = 10.5 Hz, 1H, H⁻³”), 7.82 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H, H⁻⁴”), 7.49 (d, J = 8.0 Hz, 1H, H⁻³”), 7.32 (dd, J = 7.5) , 4.5Hz, 1H, H-5”), 6.70 (dd, J=15.0, 11.0Hz, 1H, H-4), 6.49 (dd, J=15.0, 10.0Hz, 1 H, H-5), 5.60 (ddd, J=9.0, 4.0, 3.0Hz, 1H, H-4'), 5.48 (ddd, J=10.0, 2.0, 1.5Hz, 1H, H-3'), 5.34 (d, J=1.5Hz, 2H, CH2Ar), 3.49 (d, J=6.5Hz, 1H, H-7'), 2.67-2.58 (m, 2H , H-8', H-1'), 2.31-2.19 (m, 1H, H-2'), 1.95-1.85 (m, 1H, H-4'a), 1.75 (ddd, J=13. 5, 3.5, 3.5Hz, 1H, H-5'), 1.57-1.40 (m, 1H, H-5'), 1.38-1.25 (m, 1H, H-8'a), 1.09 ( d, J=6.0Hz, 3H, 8'-Me), 1.02 (d, J=7.0Hz, 3H, 2'-Me), 0.99 (d, J=6.5Hz, 3H, 6'-Me).

[0263] HRMS (ESI): For C 24 H 30 The calculated m / z of BrNO3Na is 482.1301 [M+Na]. + The value was found to be 482.1318.

[0264] <Experimental Example 1>

[0265] Compounds RS1, RS2, and RS5 obtained in Synthetic Examples 1, 2, and 5, and M-COPA synthesized in the same manner as in Synthetic Example 1 of Patent Document 1, were investigated for their cell proliferation inhibitory activity against human cultured cancer cells with variants in KIT tyrosine kinase. GIST-T1 cells (KIT), a gastrointestinal stromal tumor cell line, were used as human cultured cancer cells. Δ560-578 Imatinib-sensitive) and GIST-R9 cells (KIT) Δ560-578 / D820V Imatinib resistance), and HMC-1.2 cells (KIT) as a mast cell leukemia cell line. V560G / D816V(Imatinib resistance). Cancer cells were seeded in 96-well plates and cultured overnight. Serially diluted compounds were added and cultured for 2 days. Cell proliferation was measured by quantifying ATP production (n=3). Cell proliferation curves of GIST-T1 cells, GIST-R9 cells, and HMC-1.2 cells are shown below. Figures 1-3 In addition, the IC50 values ​​of each compound were determined. 50 As shown in Table 1.

[0266] [Table 1]

[0267] <![CDATA[IC 50 (nM)]]> M-COPA RS1 RS2 RS5 GIST-T1 347±21 268 128 169 GIST-R9 528±59 363 169 292 HMC-1.2 86±9 50 37 42

[0268] like Figures 1-3 As shown in Table 1, compounds RS1, RS2, and RS5 inhibited the cell proliferation of GIST-T1, GIST-R9, and HMC-1.2 cells in a concentration-dependent manner, with IC50 values ​​of [missing information]. 50 Lower than M-COPA. In particular, comparing compounds RS5 and M-COPA reveals that replacing the methyl group in the structure of M-COPA with a bromine atom significantly enhances its anticancer activity.

[0269] <Experimental Example 2>

[0270] Compounds RS1-RS7 obtained in Synthetic Examples 1-7 and M-COPA synthesized in the same manner as in Synthetic Example 1 of Patent Document 1 were investigated for their inhibitory activity against cell proliferation in cultured human cancer cells. Eight human cancer cell lines were used as cancer cells (1 skin cancer, 1 ovarian cancer, 1 prostate cancer, 2 lung adenocarcinomas, 1 colorectal cancer, and 2 breast cancers). Each cancer cell was seeded in a 96-well plate and cultured for 2 days. After adding serially diluted compounds and culturing for another 2 days, cell proliferation was determined colorimetrically using water-soluble tetrazolium salt (WST-8). The 50% inhibitory concentration (GI) was then calculated from the cell proliferation curve. 50 ). The GI of each compound 50 As shown in Table 2.

[0271] [Table 2]

[0272]

[0273] As shown in Table 2, compounds RS1 to RS7 showed significantly superior cell proliferation inhibitory activity against multiple cancer cell lines compared to M-COPA.

[0274] <Experimental Example 3>

[0275] The inhibitory activity of compounds RS8-RS10 obtained in Synthetic Examples 8-10 against the cell proliferation of cultured human cancer cells was investigated. Two human lung adenocarcinoma cell lines and one human lung squamous cell carcinoma cell line were used as cancer cells. Each cancer cell line was seeded in a 96-well plate and cultured for 2 days. After adding serially diluted compounds and culturing for another 2 days, cell proliferation was determined colorimetrically using water-soluble tetrazolium salt (WST-8). The 50% inhibitory concentration (GI) was then calculated from the cell proliferation curve. 50 ). The GI of each compound 50 As shown in Table 3.

[0276] [Table 3]

[0277]

[0278] As shown in Table 3, compounds RS8 to RS10 exhibited excellent cell proliferation inhibitory activity against various cancer cell lines, especially the lung squamous cell carcinoma line H226.

Claims

1. A compound represented by the following formula (1), In equation (1), R 1 and R 6 It is methyl, R 2 For hydroxyl group, R 3 R is a hydrogen atom or a methyl group. 4 R 5 R 7 and R 8 For hydrogen atoms, R 9 -C(O)NR e R f The group shown, R e For hydrogen atoms, R f It is oxazol-4-ylmethyl, oxazol-5-ylmethyl, thiazol-2-ylmethyl, thiazol-5-ylmethyl, or pyridin-3-ylmethyl.

2. A method for manufacturing a compound represented by formula (1), comprising: The steps of subjecting the compound shown in formula (6) and the compound shown in formula (5) to the Horner-Wardsworth-Emmons reaction, followed by hydrolysis, to produce the compound shown in formula (3); and The steps for producing the compound shown in formula (1) from the compound shown in formula (3) below, In equation (1), R 1 and R 6 It is methyl, R 2 For hydroxyl group, R 3 R is a hydrogen atom or a methyl group. 4 R 5 R 7 and R 8 For hydrogen atoms, R 9 -C(O)NR e R f The group shown, R e For hydrogen atoms, R f It is oxazol-4-ylmethyl, oxazol-5-ylmethyl, thiazol-2-ylmethyl, thiazol-5-ylmethyl, or pyridin-3-ylmethyl; In equation (6), R 1 and R 3 ~R 8 Same as above, Z represents the protecting group of the hydroxyl group; In equation (5), R 10 and R 11 Each can be used independently to represent an alkyl group; In equation (3), R 1 R 3 ~R 8 Z has the same meaning as above.

3. The manufacturing method according to claim 2, comprising the steps of: cyclizing the compound represented by formula (7) via an intramolecular Diels-Alder reaction to produce the compound represented by formula (6). In equation (7), R 1 R 3 ~R 8 Z has the same meaning as above.

4. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically permissible carrier.

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