Novel amp-activated protein kinase activator

Abstract

The purpose of the present invention is to provide a novel AMP-activated protein kinase activator. The present invention relates to a compound represented by formula (I): [wherein each symbol is as defined in the description], or a salt of the compound, or a hydrate of the compound or the salt. The present invention also relates to: an AMP-activated protein kinase activator comprising the compound; and a medicine for preventing and / or treating cancer, the medicine containing the compound.

Description

Novel AMP-activated protein kinase activators

[0001] The present invention relates to novel polyether compounds that have AMP-activated protein kinase activating activity and are useful for the prevention and / or treatment of diseases caused by decreased activity of AMP-activated protein kinase. The present invention also relates to pharmaceutical compositions containing the novel polyether compounds.

[0002] In recent years, it has become clear that hyperglycemia and hyperinsulinemia increase the risk of cancer cell development, proliferation, and recurrence, and one of the causes is insulin resistance. AMP-activated protein kinase (AMPK) has recently attracted attention as a factor that improves insulin resistance (Non-Patent Document 1).

[0003] AMPK is a type of serine-threonine kinase (serine-threonine phosphorylating enzyme) present in eukaryotic cells from humans to yeast, and plays an important role as an intracellular energy sensor. It is a protein kinase activated by AMP (adenosine monophosphate), which is generated when ATP (adenosine triphosphate) is used as energy. That is, AMPK is activated in response to an increase in AMP under conditions in which the intracellular ATP supply is depleted, such as low glucose, hypoxia, ischemia, and heat shock.

[0004] When AMPK is activated, the synthesis of sugars, fats, and proteins is suppressed, and the breakdown (catabolism) of sugars, fats, and proteins is promoted, resulting in the production of ATP, which has the same effect as exercise and is known to be effective in treating obesity and diabetes (Non-patent Document 2).

[0005] In recent years, it has been reported that metabolic syndrome, in which AMPK activity is reduced, is a risk factor for cancer, that AMPK activity is also suppressed in cancer cells, and that activating AMPK can suppress the proliferation of cancer cells. AMPK is therefore considered a promising target for the prevention and / or treatment of cancer (Non-Patent Document 3).

[0006] As AMPK activators, metformin, cordycepin, resveratrol, oleanolic acid, cryptotanshinone, berberine, etc. have been reported so far (Non-Patent Document 4).

[0007] Under these circumstances, there is a need for the development of novel AMPK activators as effective preventive and / or therapeutic agents not only for obesity and type 2 diabetes but also for cancer.

[0008] J. Clin. Invest. , 2013, Jul; 123(7):2764-72. Diabetes Metab. J. , 2013, Feb; 37(1): 1-21. J. Physiol. , 2006, Jul 1; 574 (Pt 1): 63-71. Exp. Mol. Med. , 2016, April 1;48(4):e224.

[0009] An object of the present invention is to develop a novel AMPK activator that exhibits excellent AMPK activation activity, can be easily synthesized, and is stable and easy to handle. Another object of the present invention is to provide a cancer preventive and / or therapeutic agent containing the AMPK activator as an active ingredient.

[0010] As a result of extensive investigations to solve the above problems, the present inventors have discovered a compound represented by the formula (I):

[0011]

[0012] [In the formula, R １ represents a hydrogen atom or an optionally substituted C １−２０ represents an alkyl group; ２ represents an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group; １ is C optionally substituted with a hydroxy group １−２０ represents an alkylene group; ２ is the formula:

[0013]

[0014] Or the expression:

[0015]

[0016] (In the formula, R ３is a hydrogen atom or C １−６ represents an alkyl group; ＊ Is, L １ represents the bonding position with ＊＊ is R ２ and n represents an integer of 1 to 10.] (hereinafter, sometimes abbreviated as "compound (I)") or a pharmaceutically acceptable salt thereof has been found to exhibit excellent AMP-activated protein kinase activating activity, leading to the completion of the present invention.

[0017] That is, the present invention is as follows: [1] Formula (I):

[0018]

[0019] [In the formula, R １ represents a hydrogen atom or an optionally substituted C １−２０ represents an alkyl group; ２ represents an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group; １ is C optionally substituted with a hydroxy group １−２０ represents an alkylene group; ２ is the formula:

[0020]

[0021] Or the expression:

[0022]

[0023] (In the formula, R ３ is a hydrogen atom or C １−６ represents an alkyl group; ＊ Is, L １ represents the bonding position with ＊＊ is R ２ and n represents an integer of 1 to 10.] or a pharmaceutically acceptable salt thereof. [2] An AMP-activated protein kinase activator comprising, as an active ingredient, a compound represented by the formula: １ is a hydrogen atom, a hydroxy group or C ２−６ C optionally substituted with an alkynyl group １−１０is an alkyl group, R ２ is an optionally substituted 5-membered monocyclic aromatic heterocyclic group, L １ C optionally substituted with a hydroxy group １−２０ is an alkylene group, ２ But the formula:

[0024]

[0025] Or the expression:

[0026]

[0027] (In the formula ＊ and ＊＊ has the same meaning as defined above; and n is an integer of 1 to 8. [3] The AMP-activated protein kinase activator according to the above [1]. ２ is a halogen atom, optionally substituted C １−６ alkyl group, optionally substituted C ６−１０ Aryl group, cyano group, nitro group, carboxy group, C １−６ [4] The AMP-activated protein kinase activator according to the above-mentioned [3], wherein R is a 5-membered monocyclic aromatic heterocyclic group optionally substituted with a substituent selected from the group consisting of an alkoxy-carbonyl group and an acyl group. [5] The AMP-activated protein kinase activator according to the above-mentioned [4], wherein R is a thienyl group or a pyrazolyl group. [6] The AMP-activated protein kinase activator according to the above-mentioned [5], wherein R is a 5-membered monocyclic aromatic heterocyclic group optionally substituted with a substituent selected from the group consisting of an alkoxy-carbonyl group and an acyl group. １ is a hydrogen atom, a hydroxy group or C ２−６ C optionally substituted with an alkynyl group １−１０ is an alkyl group, R ２ are each a halogen atom, an optionally substituted C １−６ alkyl group, optionally substituted C ６−１０ Aryl group, cyano group, nitro group, carboxy group, C １−６ a thienyl group or a pyrazolyl group optionally substituted with a substituent selected from the group consisting of an alkoxy-carbonyl group and an acyl group; １ C optionally substituted with a hydroxy group １−２０ is an alkylene group,２ But the formula:

[0028]

[0029] Or the expression:

[0030]

[0031] (In the formula ＊ and ＊＊ [6] The AMP-activated protein kinase activator according to the above [1], wherein R is a divalent group represented by the formula: １ C optionally substituted with a hydroxy group or an ethynyl group ８−１０ is an alkyl group, R ２ are halogen atoms, C １−６ Alkyl group, cyano group, nitro group, carboxy group and C １−６ L is a 2-thienyl group, a 3-thienyl group or a 5-pyrazolyl group, each of which may be substituted by a substituent selected from the group consisting of alkoxy-carbonyl groups; １ But C ６−１２The AMP-activated protein kinase activator according to the above-mentioned [5], wherein n is an alkylene group, and n is an integer of 1 to 6. [7] A pharmaceutical composition for preventing or treating a disease caused by a decrease in AMP-activated protein kinase activity, comprising the AMP-activated protein kinase activator according to any of the above-mentioned [1] to [6] as an active ingredient. [8] The pharmaceutical composition according to the above-mentioned [7], wherein the disease caused by a decrease in AMP-activated protein kinase activity is diabetes, obesity, or cancer. [9] The pharmaceutical composition according to the above-mentioned [8], wherein the disease caused by a decrease in AMP-activated protein kinase activity is cancer.

[10] The pharmaceutical composition according to the above-mentioned [9], wherein the pharmaceutical composition is used in combination with another drug.

[11] The pharmaceutical composition according to the above-mentioned

[10] , wherein the other drug is an anticancer drug.

[12] The pharmaceutical composition according to the above-mentioned

[11] , wherein the anticancer drug is at least one drug selected from the group consisting of chemotherapeutic agents, immunotherapeutic agents, and hormonal therapeutic agents.

[13] The pharmaceutical composition according to any one of

[10] to

[12] above, wherein the pharmaceutical composition according to any one of [7] to [9] above and the other drug are administered separately.

[14] The pharmaceutical composition according to any one of

[10] to

[12] above, wherein the pharmaceutical composition according to any one of [7] to [9] above and the other drug are administered simultaneously or sequentially.

[15] A compound of formula (I):

[0032]

[0033] [In the formula, R １ is a hydrogen atom, a hydroxy group or C ２−６ C optionally substituted with an alkynyl group １−１０ represents an alkyl group; ２ are each a halogen atom, an optionally substituted C １−６ alkyl group, optionally substituted C ６−１０ Aryl group, cyano group, nitro group, carboxy group, C １−６ L represents a thienyl group or a pyrazolyl group, which may be substituted with a substituent selected from the group consisting of an alkoxy-carbonyl group and an acyl group; １ is C optionally substituted with a hydroxy group １−２０ represents an alkylene group; ２ is the formula:

[0034]

[0035] Or the expression:

[0036]

[0037] (In the formula, ＊ Is, L １ represents the bonding position with ＊＊ is R ２ and n represents an integer of 1 to 8.] or a salt thereof.

[16] R １ C optionally substituted with a hydroxy group or an ethynyl group ８−１０ is an alkyl group, R ２ are halogen atoms, C １−６ Alkyl group, cyano group, nitro group, carboxy group and C １−６ L is a 2-thienyl group, a 3-thienyl group or a 5-pyrazolyl group, each of which may be substituted by a substituent selected from the group consisting of alkoxy-carbonyl groups; １ But C ６−１２

[16] The compound or salt thereof according to the above

[15] , wherein n is an alkylene group, and n is an integer of 1 to 6.

[17] A method for preventing and / or treating cancer, comprising administering a prophylactically and / or therapeutically effective amount of the compound or salt thereof according to the above

[15] or

[16] to a subject.

[18] The compound or salt thereof according to the above

[15] or

[16] for use in the prevention and / or treatment of cancer.

[19] A pharmaceutical composition comprising the compound or salt thereof according to the above

[15] or

[16] for use in the prevention and / or treatment of cancer.

[20] Use of the compound or salt thereof according to the above

[15] or

[16] for the manufacture of a medicament for use in the prevention and / or treatment of cancer.

[0038]

[0023] Compound (I) of the present invention or a pharmaceutically acceptable salt thereof (hereinafter, these may be collectively referred to as "the compound of the present invention") exhibits excellent AMP-activated protein kinase activating activity, and therefore, a medicament (pharmaceutical composition) containing the compound of the present invention is useful for the prevention and / or treatment of diseases caused by decreased activity of AMP-activated protein kinase (e.g., diabetes, obesity, cancer, etc.), and in particular, can be an excellent agent for the prevention and / or treatment of solid cancers such as glioblastoma, gastric cancer, colon cancer, lung cancer, breast cancer, germ cell cancer, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, cervical cancer, and ovarian cancer. In addition, the compound of the present invention has the advantages of being easy to synthesize, stable, and easy to handle.

[0039] FIG. 1 shows the growth inhibitory effect of the compound of the present invention on mouse glioblastoma stem cells. FIG. 2 shows the synergistic effect of the combined use of temozolomide and a compound of the present invention (compound (I-5)) on the growth inhibitory effect on human glioblastoma cells. FIG. 3 shows the in vivo antitumor effect of the compound of the present invention (compound (I-5)) in a mouse glioblastoma transplant model. FIG. 4 shows the growth inhibitory effect of the compounds of the present invention (compounds (I-4), (I-5), and (I-10)) on human colon cancer SW48 cells. FIG. 5 shows the effect of the compound of the present invention (compound (I-5)) on increasing the AMP / ATP ratio in human colon cancer SW48 cells. FIG. 6 shows the effect of the compounds of the present invention (compounds (I-4), (I-5), and (I-10)) on increasing phosphorylated AMPK in human colon cancer SW48 cells. Figure 7 (A) shows the change in tumor volume over time in a mouse subcutaneous transplant model of human colon cancer SW48 cells treated with the compound of the present invention (compound (I-5)), (B) shows the tumor mass in a mouse subcutaneous transplant model of human colon cancer SW48 cells 3.5 weeks after administration of the compound of the present invention (compound (I-5)), and (C) shows the change in body weight following daily intraperitoneal administration of the compound of the present invention (compound (I-5)) for 3.5 weeks. Figure 8 shows the growth inhibitory effect of the compound of the present invention on human lung cancer A549 cells. Figure 9 shows the phosphorylated AMPK-increasing effect of the compound of the present invention (compound (I-16)) on human lung cancer A549 cells.

[0040] The definitions of the terms and symbols used in this specification are explained below.

[0041] In this specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0042] In the present specification, the term "alkyl (group)" refers to a linear or branched monovalent group having one or more carbon atoms formed by removing one hydrogen atom from any carbon atom of an alkane. When there is no particular limitation on the range of the carbon number, the term "alkyl (group)" refers to a C １−２０ It is an alkyl group.

[0043] In this specification, "C １−２０ The term "alkyl (group)" means an alkyl group having 1 to 20 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, and eicosyl.

[0044] In this specification, "C １−１０ The term "alkyl (group)" means an alkyl group having 1 to 10 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, sec-pentyl (pentan-2-yl), 3-pentyl (pentan-3-yl), tert-pentyl (1,1-dimethylpropyl), hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, and decyl.

[0045] In this specification, "C １−６The term "alkyl (group)" means an alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, sec-pentyl (pentan-2-yl), 3-pentyl (pentan-3-yl), tert-pentyl (1,1-dimethylpropyl), hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0046] In this specification, "C １−４ The term "alkyl (group)" means an alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0047] In the present specification, the term "alkylene (group)" refers to a divalent group obtained by removing one hydrogen atom from the alkyl group. １−２０ It is an alkylene group.

[0048] In this specification, "C １−２０ The term "alkylene (group)" means a linear or branched alkylene group having 1 to 20 carbon atoms, for example, -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ -, -(CH ２ ) ６ -, -(CH ２ ) ７ -, -(CH ２ ) ８ -, -(CH ２ ) ９ -, -(CH ２ ) １０ -, -(CH ２ ) １１ -, -(CH ２ ) １２ -, -(CH ２ ) １３ -, -(CH２ ) １４ -, -(CH ２ ) １５ -, -(CH ２ ) １６ -, -(CH ２ ) １７ -, -(CH ２ ) １８ -, -(CH ２ ) １９ -, -(CH ２ ) ２０ -, -CH(CH ３ ) -, -C(CH ３ ) ２ -, -CH(C ２ H ５ ) -, -CH(C ３ H ７ )-, -CH(CH(CH ３ ) ２ )-,-(CH(CH ３ )) ２ -, -CH ２ -CH(CH ３ ) -, -CH(CH ３ )-CH ２ -, -CH ２ -CH ２ -C(CH ３ ) ２ -, -C(CH ３ ) ２ -CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -C(CH ３ ) ２ -, -C(CH ３ ) ２ -CH ２ -CH ２ -CH ２ -etc.

[0049] In the present specification, the term "alkynyl (group)" refers to a group in which one hydrogen atom has been removed from any carbon atom of a straight-chain or branched-chain alkyne having two or more carbon atoms, and when there is no particular limitation on the range of the number of carbon atoms, it is ２−２０ Alkynyl groups, among which C ２−６ Alkynyl groups are preferred.

[0050] In this specification, "C ２−６ Examples of the "alkynyl (group)" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl.

[0051] In the present specification, the term "cycloalkyl (group)" refers to a cyclic alkyl group, and when there is no particular limitation on the range of the number of carbon atoms, it is preferably a C ３−８ It is a cycloalkyl group.

[0052] In this specification, "C ３−８ The term "cycloalkyl (group)" refers to a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. ３−６ Cycloalkyl groups are preferred.

[0053] In the present specification, the term "alkoxy (group)" refers to a group in which a linear or branched alkyl group is bonded to an oxygen atom, and the range of the carbon number is not particularly limited, but preferably is C １−１０ is an alkoxy group, more preferably C １−６ It is an alkoxy group.

[0054] In this specification, "C １−６ The term "alkoxy (group)" means an alkoxy group having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, and the like. １−４ Alkoxy groups are preferred.

[0055] In the present specification, the term "alkoxy-carbonyl (group)" refers to a group in which the above-mentioned alkoxy group is bonded to a carbonyl group, and the range of the number of carbon atoms is not particularly limited, but preferably, １−１０ is an alkoxy-carbonyl group, more preferably C １−６ It is an alkoxy-carbonyl group.

[0056] In the present specification, the term "aryl (group)" refers to a monocyclic or polycyclic (fused) hydrocarbon group exhibiting aromaticity, and specifically includes, for example, C aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, and fluorenyl. ６−１４ aryl groups, among which C ６−１０ Aryl groups are preferred.

[0057] In this specification, "C ６−１０ Examples of the "aryl (group)" include phenyl, 1-naphthyl, and 2-naphthyl, and among these, phenyl is preferred.

[0058] In this specification, "C ７−１８ The term "aralkyl (group)" refers to the C ６−１４ The aryl group is １−４ It means a group bonded to an alkyl group, and specific examples thereof include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl, etc. Among them, C ７−１４ Aralkyl group (C ６−１０ Aryl-C １−４ An alkyl group is preferred, and a benzyl group is particularly preferred.

[0059] In this specification, "C ７−１８ The term "aralkyloxy (group)" refers to the C ７−１８ It means an aralkyl group bonded to an oxygen atom, and specific examples include benzyloxy, phenethyloxy, naphthylmethyloxy, biphenylylmethyloxy, etc. Among these, the benzyloxy group is particularly preferred.

[0060] In the present specification, the term "acyl (group)" means alkanoyl or aroyl, and the carbon number range is not particularly limited, but preferably is １−７ Alkanoyl group or C ７−１１ It is Aroil.

[0061] In this specification, "C １−７ The term "alkanoyl (group)" refers to a straight or branched chain formyl or alkylcarbonyl having 1 to 7 carbon atoms (i.e., C １−６alkyl-carbonyl), such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl, and the like.

[0062] In this specification, "C ７−１１ The term "aroyl (group)" refers to an arylcarbonyl having 7 to 11 carbon atoms (i.e., C ６−１０ aryl-carbonyl), such as benzoyl.

[0063] In the present specification, the term "acyloxy (group)" refers to a group in which the above-mentioned alkanoyl group or aroyl group is bonded to an oxygen atom, and the range of the number of carbon atoms is not particularly limited, but preferably, １−７ Alkanoyloxy group or C ７−１１ It is an aroyloxy group.

[0064] In this specification, "C １−７ Examples of the "alkanoyloxy (group)" include formyloxy, acetoxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy (pivaloyloxy), pentylcarbonyloxy, isopentylcarbonyloxy, neopentylcarbonyloxy, hexylcarbonyloxy, and the like, and preferably acetoxy or pivaloyloxy.

[0065] In this specification, "C ７−１１ Examples of the "aroyloxy (group)" include benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, and the like.

[0066] In this specification, "C １−６ The term "alkylsulfonyl (group)" refers to a sulfonyl group having the above-mentioned "C １−６ The term "C" refers to a group having an "alkyl" group bonded thereto, i.e., a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms. １−６Examples of the alkylsulfonyl (group) include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, and the like.

[0067] In the present specification, the term "alkylsulfonyloxy (group)" refers to a group in which the above-mentioned "alkylsulfonyl group" is bonded to an oxygen atom, and the range of the number of carbon atoms is not particularly limited, but preferably, １−６ It is an alkylsulfonyloxy group.

[0068] In this specification, "C １−６ The term "alkylsulfonyloxy (group)" refers to C １−６ It means a group in which an alkylsulfonyl group is bonded to an oxygen atom, and examples thereof include methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, and butylsulfonyloxy.

[0069] In the present specification, the term "arylsulfonyl (group)" refers to a group in which the above-mentioned "aryl group" is bonded to a sulfonyl group, and the carbon number range is not particularly limited, but preferably is ６−１０ It is an arylsulfonyl group.

[0070] In this specification, "C ６−１０ The term "arylsulfonyl (group)" refers to "C ６−１０ "Aryl group" means a group bonded to a sulfonyl group, and examples thereof include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, and the like.

[0071] In the present specification, the term "arylsulfonyloxy (group)" refers to a group in which an arylsulfonyl group is bonded to an oxygen atom, and the range of the number of carbon atoms is not particularly limited, but preferably, ６−１０ It is an arylsulfonyloxy group.

[0072] In this specification, "C ６−１０ The term "arylsulfonyloxy (group)" refers to C ６−１０It means a group in which an arylsulfonyl group is bonded to an oxygen atom, and examples thereof include phenylsulfonyloxy, 1-naphthylsulfonyloxy, and 2-naphthylsulfonyloxy.

[0073] As used herein, the term "substituted amino group" refers to an amino group in which at least one of the two hydrogen atoms is substituted with a group other than a hydrogen atom, and when both of the two hydrogen atoms are substituted with substituents, the substituents may be the same or different.

[0074] As used herein, the term "trisubstituted silyl (group)" refers to a silyl group having three identical or different substituents (e.g., C １−６ Alkyl group, C ６−１０ The term "silyl group substituted with a silyl group" refers to a silyl group substituted with a trialkylsilyl group (preferably a triC １−６ alkylsilyl group, more preferably triC １−４ alkylsilyl group), tert-butyldiphenylsilyl group, triphenylsilyl group, and the like are preferred.

[0075] In the present specification, the term "trisubstituted silyloxy (group)" refers to a group in which a trisubstituted silyl group is bonded to an oxygen atom, and examples of the group include trialkylsilyloxy groups such as trimethylsilyloxy group, triethylsilyloxy group, triisopropylsilyloxy group, and tert-butyldimethylsilyloxy group (preferably, triC １−６ alkylsilyloxy group, more preferably triC １−４ alkylsilyloxy group), tert-butyldiphenylsilyloxy group, triphenylsilyloxy group, and the like are preferred.

[0076] In the present specification, examples of the substituent constituting the "substituted amino group" include the protecting groups for amino groups described in Protective Groups in Organic Synthesis, John Wiley and Sons (3rd edition, 1999), and examples thereof include C １−６ Alkyl group, C １−６ Alkylsulfonyl, C ７−２２Aralkyl group, C ６−１０ Aryl group, C １−７ Alkanoyl group, C ７−１１ Aroyl group, C ７−１４ Aralkyl-carbonyl group, C １−６ Alkoxy-carbonyl group, C ７−１４ Aralkyloxy-carbonyl group, C ６−１０ Arylsulfonyl, Tri C １−６ Alkylsilyl group (e.g., tri-C １−６ Examples of the protecting group include a halogen atom, a C １−６ Alkyl group, C １−６ It may be further substituted with an alkoxy group or a nitro group. Specific examples of the protecting group for the amino group include methyl (monomethyl or dimethyl), benzyl, trityl, acetyl, trifluoroacetyl, pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, etc.

[0077] In the present specification, examples of the "5- or 6-membered monocyclic aromatic heterocyclic group" include a 5- or 6-membered monocyclic aromatic heterocyclic group containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.

[0078] Suitable examples of the 5- or 6-membered monocyclic aromatic heterocyclic group include furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and the like, and among these, thienyl or pyrazolyl is preferred.

[0079] The term "optionally substituted" means that the group is unsubstituted or has 1 to 5 (preferably 1 to 3) substituents at substitutable positions, and each substituent may be the same or different.

[0080] Examples of the "optionally substituted" substituent include: (1) a halogen atom, (2) a hydroxy group, (3) a cyano group, (4) a nitro group, (5) an azide group, (6) a substituted amino group, and (7) a C １−６ (8) alkyl group, １−６ Alkoxy group, (9) C ３−８ cycloalkyl group, (10) C ２−６ Alkynyl group, (11) C ６−１０ aryl group, (12) C ７−１８ Aralkyl group, (13) C ７−１８ (14) an acyl group (e.g., C １−７ Alkanoyl group, C ７−１１ aroyl group), (15) C １−７ Alkanoyloxy group, (16) C ７−１１ aroyloxy group, (17) C １−６ Alkoxy-carbonyl group, (18) C １−６ a carbamoyl group optionally mono- or di-substituted by an alkyl group; (19) C １−６ Alkylsulfonyloxy group, (20) C ６−１０ (21) an arylsulfonyloxy group, (22) a trisubstituted silyl group, (23) a carboxy group, etc. Among these, halogen atoms, C １−６ Alkyl, C １−６ Preferred substituents for the "optionally substituted alkyl" or "optionally substituted alkylene" include "(7) C １−６ Alkyl group" and "(12) C ７−１８ Examples of substituents include those excluding "aralkyl groups."

[0081] The above substituents may further each contain one or more of a halogen atom, a hydroxy group, C １−６ Alkyl group, C１−６ It may be substituted with an alkoxy group, a cyano group, a nitro group, a phenyl group, a carboxy group, or the like.

[0082] In the present specification, the term "a pharmaceutically acceptable salt thereof" means a salt that can be used as a medicine. When the compound (I) of the present invention has an acidic or basic group, it can be converted into a basic salt or an acid salt by reacting it with a base or an acid, and therefore the term refers to such a salt.

[0083] Examples of the pharmaceutically acceptable "basic salt" of compound (I) of the present invention include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as magnesium salt and calcium salt; organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, and picoline salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, and aspartic acid salt, and the like, with alkali metal salts being preferred.

[0084] Examples of pharmaceutically acceptable "acid salts" of compound (I) of the present invention include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate, etc.; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.; arylsulfonates such as benzenesulfonate, p-toluenesulfonate, etc.; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.; amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate, etc.; and the like, preferably hydrohalides (particularly hydrochloride).

[0085] In the present specification, "salts thereof" refers to all salts including the above-mentioned "pharmaceutically acceptable salts thereof."

[0086] As used herein, "prevention" includes preventing the onset of a disease, delaying the onset of a disease, and preventing the occurrence of a pathological condition. A "prophylactically effective amount" refers to a dose of an active ingredient sufficient to achieve the purpose of prevention.

[0087] As used herein, "treatment" includes curing a disease, improving the pathology of a disease (e.g., one or more symptoms), and inhibiting the progression of a disease (or its severity). A "therapeutically effective amount" refers to a dose of an active ingredient sufficient to achieve the therapeutic purpose. Therefore, "improvement" is a concept encompassed by "treatment."

[0088] As used herein, the term "subject" refers to a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of an active ingredient is administered to prevent and / or treat (or improve) a disease or the pathology of a disease. The "subject" includes humans and non-human animals (particularly mammals (e.g., mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.)).

[0089] As used herein, the term "AMP-activated protein kinase activator" refers to a drug that activates (or induces) AMP-activated protein kinase and exhibits AMP-activated protein kinase agonist activity. The AMP-activated protein kinase activating effect (AMP-activated protein kinase agonist activity) can be measured by a method described in the literature (e.g., J. Cell Sci., 2004, Nov. 1; 117 (Pt 23): 5479-87) or a method described in the test examples below.

[0090] (Compound (I) of the Present Invention) Hereinafter, each group of compound (I) of the present invention will be explained.

[0091] R １ represents a hydrogen atom or an optionally substituted C １−２０ represents an alkyl group.

[0092] R １ is preferably a hydrogen atom, a hydroxy group or C ２−６ C optionally substituted with an alkynyl group １−１０ is an alkyl group, more preferably a hydrogen atom, a hydroxy group, or２−６ C optionally substituted with an alkynyl group １−１０ C alkyl group, and more preferably C ８−１０ It is an alkyl group.

[0093] R ２ represents an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group.

[0094] R ２ is preferably an optionally substituted 5-membered monocyclic aromatic heterocyclic group, more preferably a halogen atom, an optionally substituted C １−６ alkyl group, optionally substituted C ６−１０ Aryl group, cyano group, nitro group, carboxy group, C １−６ a 5-membered monocyclic aromatic heterocyclic group optionally substituted with a substituent selected from the group consisting of an alkoxy-carbonyl group and an acyl group, and more preferably a halogen atom, an optionally substituted C １−６ alkyl group, optionally substituted C ６−１０ Aryl group, cyano group, nitro group, carboxy group, C １−６ A thienyl group or a pyrazolyl group, each of which may be substituted with a substituent selected from the group consisting of an alkoxy-carbonyl group and an acyl group, is particularly preferably a halogen atom, C １−６ Alkyl group, cyano group, nitro group, carboxy group and C １−６ It is a 2-thienyl group, a 3-thienyl group or a 5-pyrazolyl group, each of which may be substituted with a substituent selected from the group consisting of alkoxy-carbonyl groups.

[0095] L １ is C optionally substituted with a hydroxy group １−２０ Represents an alkylene group.

[0096] L １ is preferably C optionally substituted with a hydroxy group. １−２０ is an alkylene group, more preferably C ６−１２ It is an alkylene group.

[0097] L ２is the formula:

[0098]

[0099] Or the expression:

[0100]

[0101] (In the formula, R ３ is a hydrogen atom or C １−６ represents an alkyl group; ＊ Is, L １ represents the bonding position with ＊＊ is R ２ represents the bonding position with

[0102] L ２ is preferably of the formula:

[0103]

[0104] Or the expression:

[0105]

[0106] (In the formula ＊ and ＊＊ has the same meaning as defined above.) is a divalent group represented by the formula:

[0107]

[0108] (In the formula ＊ and ＊＊ has the same meaning as defined above.

[0109] n represents an integer from 1 to 10

[0110] n is preferably an integer of 1 to 8, more preferably an integer of 1 to 6, and particularly preferably an integer of 3 to 5.

[0111] As compound (I), the following compounds are suitable.

[0112] [Compound (IA)] R １ is a hydrogen atom, a hydroxy group or C ２−６ C optionally substituted with an alkynyl group １−１０ is an alkyl group; R ２is an optionally substituted 5-membered monocyclic aromatic heterocyclic group; L １ C optionally substituted with a hydroxy group １−２０ is an alkylene group; ２ But the formula:

[0113]

[0114] Or the expression:

[0115]

[0116] (In the formula, ＊ Is, L １ and ＊＊ is R ２ and n is an integer of 1 to 8.

[0117] [Compound (IB)] R １ is a hydrogen atom, a hydroxy group or C ２−６ C optionally substituted with an alkynyl group １−１０ is an alkyl group; R ２ is a halogen atom, optionally substituted C １−６ alkyl group, optionally substituted C ６−１０ Aryl group, cyano group, nitro group, carboxy group, C １−６ a 5-membered monocyclic aromatic heterocyclic group optionally substituted with a substituent selected from the group consisting of an alkoxy-carbonyl group and an acyl group; L １ C optionally substituted with a hydroxy group １−２０ is an alkylene group; ２ But the formula:

[0118]

[0119] Or the expression:

[0120]

[0121] (In the formula, ＊ Is, L １ and ＊＊ is R ２and n is an integer of 1 to 8.

[0122] [Compound (IC)] R １ is a hydrogen atom, a hydroxy group or C ２−６ C optionally substituted with an alkynyl group １−１０ is an alkyl group; R ２ are each a halogen atom, an optionally substituted C １−６ alkyl group, optionally substituted C ６−１０ Aryl group, cyano group, nitro group, carboxy group, C １−６ a thienyl group or a pyrazolyl group optionally substituted with a substituent selected from the group consisting of an alkoxy-carbonyl group and an acyl group; L １ C optionally substituted with a hydroxy group １−２０ is an alkylene group; ２ But the formula:

[0123]

[0124] Or the expression:

[0125]

[0126] (In the formula, ＊ Is, L １ and ＊＊ is R ２ and n is an integer of 1 to 8.

[0127] [Compound (ID)] R １ C optionally substituted with a hydroxy group or an ethynyl group ８−１０ is an alkyl group; R ２ are halogen atoms, C １−６ Alkyl group, cyano group, nitro group, carboxy group and C １−６ L is a 2-thienyl group, a 3-thienyl group, or a 5-pyrazolyl group, each of which may be substituted by a substituent selected from the group consisting of an alkoxy-carbonyl group; １But C ６−１２ is an alkylene group; ２ But the formula:

[0128]

[0129] Or the expression:

[0130]

[0131] (In the formula, ＊ But, L １ is the bonding position with ＊＊ But, R ２ and n is an integer of 1 to 6.

[0132] [Compound (IE)] R １ C optionally substituted with a hydroxy group or an ethynyl group ８−１０ is an alkyl group; R ２ are halogen atoms, C １−６ Alkyl group, cyano group, nitro group, carboxy group and C １−６ L is a 2-thienyl group, a 3-thienyl group, or a 5-pyrazolyl group, each of which may be substituted by a substituent selected from the group consisting of an alkoxy-carbonyl group; １ But C ６−１２ is an alkylene group; ２ But the formula:

[0133]

[0134] Or the expression:

[0135]

[0136] (In the formula, ＊ But, L １ is the bonding position with ＊＊ But, R ２ and n is an integer of 3 to 5.

[0137] Preferred specific examples of compound (I) include the compounds of Examples 1 to 27 (compounds (I-1) to (I-27)) described in the following Examples, and among them, compound (I-2), compound (I-4), compound (I-5), compound (I-6), compound (I-7), compound (I-15), compound (I-16), compound (I-17), compound (I-18), compound (I-20), compound (I-25), compound (I-26), or compound (I-27), or a pharmaceutically acceptable salt thereof, are particularly preferred.

[0138] (Method for producing compound (I) of the present invention) Hereinafter, a method for producing compound (I) of the present invention will be described. As examples of methods for producing compound (I), representative methods will be described below, but the methods are not limited to these.

[0139] Compound (I) can be produced by the method shown in the following synthesis scheme, the Reference Examples and Examples described below, or methods similar thereto.

[0140] Each starting compound may form a salt as long as it does not inhibit the reaction, and examples of such salts include the same as the pharmaceutically acceptable salts of compound (I). Unless a specific production method is described, starting compounds can be easily obtained commercially and used, or can be produced according to a method known per se or a method similar thereto. In addition, intermediates produced in the following production methods may be isolated and purified by methods such as column chromatography, recrystallization, distillation, etc., or may be used in the next step without isolation.

[0141] The reaction schemes for each step in the production of compound (I) are shown below, and the symbols for the compounds in the schemes are as defined above.

[0142] The contents of all patent, non-patent, or literature references explicitly cited in this specification are hereby incorporated by reference in their entirety.

[0143] Compound (I) of the present invention can be produced according to the following Production Methods 1 to 6, but is not limited thereto.

[0144] [Production Method 1]

[0145]

[0146] (In the formula, X １ represents a leaving group, and X ２ represents a hydroxy group or a leaving group, and X ３ represents a leaving group, -L- represents a group of the formula:

[0147]

[0148] Or the expression:

[0149]

[0150] and the other symbols are as defined above.)

[0151] (Step 1) This step is a step of reacting compound (1) with a silylating agent in the presence of a base to obtain compound (2).

[0152] The compound (1) is not particularly limited, but a commercially available product or one synthesized by a method known per se can be suitably used. The silylating agent is not particularly limited, but a commercially available product can be suitably used, preferably tert-butyldimethylsilyl chloride (TBSCl). The amount of the silylating agent (TBSCl) used is usually 1 to 1.5 mol, preferably 1 to 1.2 mol, per mol of compound (1).

[0153] The base to be used is not particularly limited, but examples thereof include organic bases such as triethylamine and N,N-diisopropylethylamine (DIPEA); inorganic bases such as sodium hydride, and among these, sodium hydride is preferred. The amount of the base to be used is usually 1 to 1.5 mol, preferably 1 to 1.2 mol, per mol of compound (1).

[0154] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include ethers such as tetrahydrofuran, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and halogenated hydrocarbons such as dichloromethane and chloroform. Among these, tetrahydrofuran is preferred.

[0155] The reaction temperature is usually −10° C. to 60° C., preferably 0° C. to 40° C., more preferably 0° C. to room temperature, and the reaction time is usually about 30 minutes to 6 hours.

[0156] (Step 2) This step is a step of obtaining compound (4) by reacting compound (2) with compound (3) in the presence of a base.

[0157] Compound (3) is not particularly limited, but a commercially available product or a compound synthesized by a method known per se (e.g., Luu, B. et al., Bioorganic & Medicinal Chemistry Letters, 2006, 16(10), 2637-2640) can be suitably used. The amount of compound (3) used is usually 1 to 1.5 mol, preferably 1 to 1.2 mol, per mol of compound (2).

[0158] The base to be used is not particularly limited, but examples thereof include organic bases such as triethylamine and N,N-diisopropylethylamine (DIPEA); inorganic bases such as sodium hydride, etc., and among these, sodium hydride is preferred. The amount of the base to be used is usually 1 to 1.5 mol, preferably 1 to 1.2 mol, per 1 mol of compound (2).

[0159] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include ethers such as tetrahydrofuran, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and halogenated hydrocarbons such as dichloromethane and chloroform. Among these, N,N-dimethylformamide is preferred.

[0160] The reaction temperature is usually −10° C. to 60° C., preferably 0° C. to 40° C., more preferably 0° C. to room temperature, and the reaction time is usually about 0.5 to 6 hours.

[0161] (Step 3) This step is a step of reacting compound (4) with iodine in the presence of triphenylphosphine and imidazole to obtain compound (5).

[0162] The amount of iodine used is usually 1 to 3 mol, preferably 1 to 2 mol, and more preferably 1.5 mol, relative to 1 mol of compound (4). The amount of triphenylphosphine used is usually 1 to 2 mol, preferably 1 to 1.2 mol, and more preferably 1 mol, relative to 1 mol of compound (4). The amount of imidazole used is usually 1 to 5 mol, preferably 1.5 to 3 mol, and more preferably 2 to 3 mol, relative to 1 mol of compound (4).

[0163] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include ethers such as tetrahydrofuran, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and halogenated hydrocarbons such as dichloromethane and chloroform. Among these, dichloromethane is preferred.

[0164] The reaction temperature is usually −10° C. to 60° C., preferably 0° C. to 40° C., more preferably 0° C. to room temperature, and the reaction time is usually about 1 to 24 hours.

[0165] (Step 4) This step is a step of azidating compound (5) to obtain compound (6).

[0166] The azidating agent to be used is not particularly limited, but commercially available products such as sodium azide and azidotrimethylsilane can be suitably used, and among them, sodium azide is preferred. The amount of the azidating agent to be used is usually 1 to 5 mol, preferably 1.5 to 3 mol, more preferably 2 mol, per 1 mol of compound (5).

[0167] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include ethers such as tetrahydrofuran, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane and chloroform, and dimethyl sulfoxide. Among these, dimethyl sulfoxide is preferred.

[0168] The reaction temperature is usually 0° C. to 60° C., preferably room temperature, and the reaction time is usually about 1 to 12 hours.

[0169] (Step 5) This step is a step of reducing compound (6) to obtain compound (7).

[0170] The reducing agent used is not particularly limited, but examples thereof include heterogeneous catalysts for catalytic hydrogen reduction (e.g., palladium on carbon, etc.), hydride reducing agents (e.g., lithium aluminum hydride, sodium borohydride-nickel(II) chloride, etc.), triphenylphosphine, etc. Among these, the Staudinger reaction using triphenylphosphine in the presence of water is preferred. The amount of triphenylphosphine used is usually 1 to 5 moles, preferably 1 to 2 moles, per mole of compound (6).

[0171] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include a mixed solvent of water and an ether such as diethyl ether or tetrahydrofuran. Among these, diethyl ether-water is preferred.

[0172] The reaction temperature is usually −10° C. to 60° C., preferably 0° C. to room temperature, and the reaction time is usually about 5 minutes to 72 hours.

[0173] (Step 6) In this step, compound (7) is alkylated by reaction with a hydride reducing agent in the presence of an aldehyde to obtain compound (7′). ３ may be omitted when preparing compound (I) in which is a hydrogen atom.

[0174] Examples of the aldehyde to be used include formaldehyde, acetaldehyde, etc. The amount of the aldehyde to be used is usually 1 to 1.5 mol, preferably 1 to 1.2 mol, more preferably 1 mol, per 1 mol of compound (7).

[0175] Examples of the hydride reducing agent to be used include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.

[0176] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include methanol, acetonitrile, 1,2-dichloroethane, and dichloromethane. Among these, methanol and 1,2-dichloroethane are preferred.

[0177] The reaction temperature is usually −10° C. to 60° C., preferably 0° C. to room temperature, and the reaction time is usually about 1 to 24 hours.

[0178] (Step 7) This step is a step of obtaining compound (9) by reacting compound (7) (or compound (7')) with compound (8).

[0179] Compound (8) is not particularly limited, but a commercially available product or a compound synthesized by a method known per se (e.g., WO 2004 / 043366) can be suitably used. The amount of compound (8) used is usually 1 to 5 moles, preferably 1.5 to 3 moles, per mole of compound (7) (or compound (7')).

[0180] Compound (8) is a compound in which -L- is -C(O)- and X ２is a hydroxy group, compound (9) can be produced by reacting compound (7) (or compound (7')) with compound (8) in the presence of a condensing agent in a solvent that does not affect the reaction. Examples of the condensing agent include carbodiimide compounds such as N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-cyclohexyl-N'-morpholinoethylcarbodiimide, and N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; azolide compounds such as N,N'-carbonyldiimidazole and N,N'-thionyldiimidazole; and phosphorus compounds such as diethyl cyanophosphate and diphenylphosphoryl azide. Among these, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is preferred. When the carbodiimide compound is used as a condensing agent, the reaction yield can be improved by using an additive as needed. Examples of such additives include 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, and N-hydroxyphthalimide, with 1-hydroxybenzotriazole being preferred. When the phosphorus compound is used as a condensing agent, the reaction yield can be improved by adding an organic base such as triethylamine or N,N-diisopropylethylamine as needed. When the azolide compound is used as a condensing agent, it is preferable to carry out the reaction in the presence of a base such as an organic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, or 1,8-diazabicyclo[5.4.0]undec-7-ene; or an alkali metal carbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or cesium carbonate.

[0181] The amount of the condensing agent used is usually 1 to 5 moles, preferably 1 to 3 moles, per mole of compound (7) (or compound (7')). The amount of the additive, organic base, and alkali metal carbonate used is usually 1 to 5 moles, preferably 1 to 3 moles, per mole of compound (7) (or compound (7')). This reaction can be carried out in a solvent that does not influence the reaction. The reaction solvent is not particularly limited, but examples thereof include alcohols such as methanol, ethanol, propanol, 2-propanol, and butanol; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide; and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene, and trifluoromethylbenzene, or mixtures thereof, and among these, tetrahydrofuran is preferred.

[0182] Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagents and reaction solvent used, but the reaction temperature is usually −30° C. to 150° C., preferably 0° C. to room temperature, and the reaction time is 30 minutes to 20 hours.

[0183] As the compound (8), X ２When a compound in which is a leaving group is used, this reaction is usually carried out in the presence of a base in a solvent that does not influence the reaction. The base used in this reaction is not particularly limited, but examples thereof include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and 4-dimethylaminopyridine; and inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate. This reaction can be carried out in a solvent that does not influence the reaction. The reaction solvent is not particularly limited, but examples thereof include alcohols such as methanol, ethanol, propanol, 2-propanol, and butanol; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide; and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene, and trifluoromethylbenzene, or mixtures thereof. The amount of the base used is usually 1 to 5 moles, preferably 1 to 3 moles, per mole of compound (7) (or compound (7')).

[0184] Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagents and reaction solvent used, but the reaction temperature is usually −30° C. to 150° C., preferably 0° C. to room temperature, and the reaction time is 30 minutes to 20 hours.

[0185] (Step 8) This step is a step of desilylating compound (9) to obtain compound (9′). Compound (9′) can be obtained by desilylating compound (I) (R １ is a hydrogen atom.

[0186] The desilylation agent used is preferably tetrabutylammonium fluoride (TBAF). The amount of the desilylation agent used is usually 1 to 30 mol, preferably 5 to 20 mol, and more preferably 10 mol, per 1 mol of compound (9).

[0187] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include ethers such as tetrahydrofuran, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and halogenated hydrocarbons such as dichloromethane and chloroform. Among these, tetrahydrofuran is preferred.

[0188] The reaction temperature is usually −10° C. to 60° C., preferably 0° C. to 40° C., more preferably 0° C. to room temperature, and the reaction time is usually about 30 minutes to 24 hours.

[0189] (Step 9) This step is a step of reacting compound (9') with compound (10) in the presence of a base to obtain compound (I).

[0190] Compound (10) is not particularly limited, but a commercially available product or a product synthesized by a method known per se (e.g., Baird, M.S. et al., Tetrahedron, 2005, 61(50), 11939-11951, etc.) can be suitably used. The amount of compound (10) used is usually 1 to 3 moles, preferably 2 moles, per mole of compound (9').

[0191] The base to be used is not particularly limited, but examples thereof include organic bases such as triethylamine and N,N-diisopropylethylamine (DIPEA); inorganic bases such as sodium hydride, etc., and among these, sodium hydride is preferred. The amount of the base to be used is usually 1 to 3 moles, preferably 2 moles, per mole of compound (9).

[0192] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include ethers such as tetrahydrofuran, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane and chloroform, and dimethyl sulfoxide. Among these, dimethyl sulfoxide is preferred.

[0193] The reaction temperature is usually −10° C. to 60° C., preferably 0° C. to 40° C., more preferably 0° C. to room temperature, and the reaction time is usually about 1 to 24 hours.

[0194] [Production Method 2]

[0195]

[0196] (The symbols in the formula have the same meanings as defined above.)

[0197] (Step 10) This step is a step of obtaining compound (6) by reacting compound (2) with compound (11) in the presence of a base.

[0198] The compound (11) is not particularly limited, but a compound synthesized by a method known per se (e.g., Romuald, C. et al., Organic Letters, 2013, 15(1), 184-187) can be suitably used. The amount of compound (11) used is usually 1 to 5 mol, preferably 2 to 3 mol, per mol of compound (2).

[0199] The base to be used is not particularly limited, but examples thereof include organic bases such as triethylamine and N,N-diisopropylethylamine (DIPEA); inorganic bases such as sodium hydride; and the like, with sodium hydride being preferred. The amount of base used is usually 1 to 3 moles, preferably 2 moles, per mole of compound (2). Furthermore, the reaction yield can be improved by adding a crown ether (e.g., 15-crown-5-ether) as needed.

[0200] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include ethers such as tetrahydrofuran, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane and chloroform, and dimethyl sulfoxide. Among these, N,N-dimethylformamide is preferred.

[0201] The reaction temperature is usually −10° C. to 60° C., preferably 0° C. to 40° C., more preferably 0° C. to room temperature, and the reaction time is usually about 1 to 24 hours.

[0202] Compound (I) can be produced by subjecting compound (6) obtained in step 10 to steps 5 to 9 described above.

[0203] [Production Method 3]

[0204]

[0205] (The symbols in the formula have the same meanings as defined above.)

[0206] (Step 11) This step is a step of desilylating compound (6) to obtain compound (12). This step can be performed under the same conditions as in the reaction of step 8 in Production Method 1.

[0207] (Step 12) This step is a step of reacting compound (12) with compound (10) in the presence of a base to obtain compound (13). This step can be performed under the same conditions as in the reaction of step 9 in Production Method 1.

[0208] (Step 13) This step is a step of reducing compound (13) to obtain compound (14). This step can be performed under the same conditions as in the reaction of step 5 of Production Method 1.

[0209] (Step 14) In this step, compound (14) is alkylated by reaction with a hydride reducing agent in the presence of an aldehyde to obtain compound (14′). ３ This step can be omitted when preparing Compound (I) in which is a hydrogen atom. This step can be carried out under the same conditions as in the reaction of Step 6 of Production Method 1.

[0210] (Step 15) This step is a step of reacting compound (14) (or compound (14')) with compound (8) to obtain compound (I). This step can be carried out under the same conditions as in the reaction of step 7 in Production Method 1.

[0211] [Production Method 4]

[0212]

[0213] (The symbols in the formula have the same meanings as defined above.)

[0214] (Step 16) This step is a step of reacting compound (15) with compound (3) in the presence of a base to obtain compound (16). This step can be performed under the same conditions as in the reaction of step 2 in Production Method 1.

[0215] (Step 17) In this step, compound (16) is reacted with iodine in the presence of triphenylphosphine and imidazole to obtain compound (17). This step can be performed under the same conditions as in the reaction in step 3 of Production Method 1.

[0216] (Step 18) This step is a step of azidating compound (17) to obtain compound (13). This step can be performed under the same conditions as in the reaction of step 4 of Production Method 1.

[0217] (Step 19) This step is a step of reducing compound (13) to obtain compound (14). This step can be performed under the same conditions as in the reaction of step 5 of Production Method 1.

[0218] (Step 20) In this step, compound (14) is alkylated by reaction with a hydride reducing agent in the presence of an aldehyde to obtain compound (14′). ３ This step can be omitted when preparing Compound (I) in which is a hydrogen atom. This step can be carried out under the same conditions as in the reaction of Step 6 of Production Method 1.

[0219] (Step 21) This step is a step of reacting compound (14) (or compound (14')) with compound (8) to obtain compound (I). This step can be carried out under the same conditions as in the reaction of step 7 in Production Method 1.

[0220] [Production Method 5]

[0221]

[0222] (The symbols in the formula have the same meanings as defined above.)

[0223] (Step 22) This step is a step of reacting compound (1) with compound (10) in the presence of a base to obtain compound (15). This step can be carried out under the same conditions as those for the reaction in step 9 of production method 1. If necessary, the reaction yield can be improved by adding a crown ether (e.g., 15-crown-5-ether).

[0224] (Step 23) This step is a step of reacting compound (15) with compound (11) in the presence of a base to obtain compound (13). This step can be performed under the same conditions as in the reaction of step 10 of Production Method 2.

[0225] (Steps 13 to 15) These steps can be carried out under the same conditions as those for the reactions in steps 13 to 15 of Production Method 3.

[0226] [Production Method 6]

[0227]

[0228] (In the formula, X ４ represents a leaving group, and the other symbols are as defined above.

[0229]

[0230] (Step 24) This step is a step of reacting compound (15) with compound (19) in the presence of a base to obtain compound (18).

[0231] Compound (19) is not particularly limited, but compounds synthesized by known methods (e.g., Lambert, T. H., et al., Org. Lett., 2013, 15(1), 38-41) can be suitably used. The amount of compound (19) used is usually 1 to 5 mol, preferably 2 to 3 mol, per mol of compound (15).

[0232] The base to be used is not particularly limited, but examples thereof include organic bases such as triethylamine and N,N-diisopropylethylamine (DIPEA); inorganic bases such as sodium hydride; and the like, with sodium hydride being preferred. The amount of base used is usually 1 to 3 moles, preferably 2 moles, per mole of compound (15). Furthermore, the reaction yield can be improved by adding a crown ether (e.g., 15-crown-5-ether) as needed.

[0233] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include ethers such as tetrahydrofuran, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane and chloroform, and dimethyl sulfoxide. Among these, N,N-dimethylformamide is preferred.

[0234] The reaction temperature is usually −10° C. to 60° C., preferably 0° C. to 40° C., more preferably 0° C. to room temperature, and the reaction time is usually about 1 to 24 hours.

[0235] (Step 25) In this step, the benzyl group of compound (18) is removed using hydrogen in a solvent in the presence of a suitable metal catalyst to obtain compound (16). The metal catalyst used is not particularly limited, but examples thereof include heterogeneous catalysts for catalytic hydrogen reduction (e.g., 10% palladium-carbon, 10% palladium hydroxide-carbon, etc.).

[0236] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. Among these, ethyl acetate is preferred.

[0237] The reaction temperature is usually −10° C. to 60° C., preferably 0° C. to room temperature, and the reaction time is usually about 10 minutes to 48 hours.

[0238] (Steps 17 and 18) These steps can be carried out under the same conditions as those for the reactions in steps 17 and 18 of Production Method 4.

[0239] (Steps 13 to 15) These steps can be carried out under the same conditions as those for the reactions in steps 13 to 15 of Production Method 3.

[0240] The starting compounds in each of the above methods can be produced by known methods and / or methods similar to those described in the Examples below. Introduction of protecting groups to functional groups and removal of protecting groups can be carried out by referring to known methods (e.g., PROTECTIVE GROUPS in ORGANIC SYNTHESIS (Theodora W. Greene, Peter G.M. Wuts)).

[0241] The compound (I) of the present invention produced as described above is isolated and purified in its free form or as a salt thereof. The salt can be produced by a commonly used salt formation treatment. Isolation and purification can be carried out by applying common chemical procedures such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.

[0242] When compound (I) of the present invention or a pharmaceutically acceptable salt thereof exists as an optical isomer based on an asymmetric carbon, it can be separated into individual optical isomers by conventional optical resolution methods (e.g., fractional crystallization, resolution using a chiral column). Alternatively, optical isomers can be synthesized using optically pure starting materials. Furthermore, optical isomers can be synthesized by stereoselectively carrying out each reaction using an asymmetric auxiliary group or an asymmetric catalyst.

[0243] When compound (I) of the present invention or a pharmaceutically acceptable salt thereof contains optical isomers, stereoisomers, positional isomers, rotamers, or tautomers, all of these isomers and mixtures of these isomers in any ratio are encompassed as compound (I). Furthermore, these isomers can be obtained as single products by known synthetic and separation techniques (concentration, solvent extraction, column chromatography, recrystallization, etc.). When compound (I) has optical isomers, optical isomers resolved from the compound are also encompassed as compound (I). Furthermore, compound (I) of the present invention may be a labeled product, i.e., a product in which one or more atoms constituting compound (I) of the present invention are substituted with an isotope (e.g., ２ H. ３ H. １１ C. １３ C. １４ C. １５ N. １８ O. １８ F. ３５ Also included are compounds labeled with .S, etc.

[0244] The compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be in the form of a crystal, and both a single crystal form and a mixture of crystal forms are included in the compound (I). The crystal can be produced by crystallization using a crystallization method known per se.

[0245] Compound (I) or a pharmaceutically acceptable salt thereof of the present invention may also include solvates thereof. These solvates are compounds in which solvent molecules are coordinated with compound (I) or a salt thereof, and also include hydrates. Examples of solvates include hydrates, ethanol solvates, and dimethyl sulfoxide solvates of compound (I) or a salt thereof.

[0246] Compound (I) of the present invention may be a prodrug.

[0247] The prodrug of compound (I) of the present invention refers to a compound that is converted to compound (I) in vivo by a reaction with an enzyme, gastric acid, or the like. The prodrug of compound (I) is a monoester or diester of a phosphate group, and the ester functional group preferably has a structure that is easily hydrolyzed or metabolized after administration to a patient. Specific examples of the ester functional group of such a prodrug include C-(C-amino)-1, which may be substituted with an acyloxy group. １−６Examples of the prodrugs other than the monoesters or diesters of the phosphate group include alkyl esters, phenyl esters, and benzyl esters (see Bioorganic Chemistry, 1984; 12: pp. 118-129). Examples of the prodrugs other than the monoesters or diesters of the phosphate group include compounds having a group derived from a phosphate group, such as those described in Current Opinion in Investigational Drugs, 2006; 7: pp. 109-117, J. Med. Chem. 1994; 37: pp. 1857-1864, and J. Med. Chem. 2000; 43: pp. 4570-4574. Other embodiments of the prodrug of compound (I) include, for example, when compound (I) has an amino group, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, a compound in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated or tert-butylated); when compound (I) has a hydroxy group, a compound in which the hydroxy group is acylated, alkylated, phosphorylated or borated (for example, a compound in which the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated or pivaloylated). When compound (I) has a carboxy group, examples thereof include compounds in which the carboxy group is esterified or amidated (for example, compounds in which the carboxy group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, 1-{(ethoxycarbonyl)oxy}ethyl-esterified, phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl-esterified, methylamidized, etc.). These compounds can be produced by known methods. Furthermore, the prodrug of compound (I) may be either a hydrate or a non-hydrate.Furthermore, the prodrug of compound (I) may be one that is converted into a compound represented by compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, "Molecular Design," pp. 163-198, Hirokawa Publishing, 1990.

[0248] (Medicine of the Present Invention) The medicine of the present invention is a medicine for preventing and / or treating a disease caused by a decrease in the activity of AMP-activated protein kinase, which contains, as an active ingredient, compound (I) or a pharmaceutically acceptable salt thereof, or an AMP-activated protein kinase activator consisting of compound (I) or a pharmaceutically acceptable salt thereof.

[0249] The pharmaceutical of the present invention may be either a pharmaceutical consisting solely of compound (I) or a pharmaceutically acceptable salt thereof (or an AMP-activated protein kinase activator consisting of compound (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, etc. The pharmaceutical of the present invention can be administered to a subject (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.) in a prophylactically effective amount or a therapeutically effective amount.

[0250] Examples of pharmaceutically acceptable carriers include excipients (e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), disintegrants (e.g., carboxymethylcellulose, talc, etc.), solvents (e.g., water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.), and the like. etc.), solubilizing agents (e.g., polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate etc.), suspending agents (e.g., surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate etc.); polyvinyl alcohol, poly Hydrophilic polymers such as vinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, etc.), isotonic agents (e.g., sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.), buffers (e.g., buffer solutions such as phosphates, acetates, carbonates, citrates, etc.), soothing agents (e.g., benzyl alcohol, etc.), preservatives (e.g., parahydroxybenzoates, chlorobutanol, etc.), alcohol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbates, etc.), coloring agents (e.g., water-soluble food tar dyes (e.g., food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble food tar dyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide), etc.), sweeteners (e.g., saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, etc.), etc.

[0251] The medicament (pharmaceutical composition) of the present invention can be prepared by mixing the above-mentioned components and then processing the mixture according to known means into preparations for oral administration such as tablets, fine granules, granules, capsules, dry syrup, etc., or for parenteral administration such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions, etc.), topical preparations (e.g., transdermal preparations, ointments, lotions, patches), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, implants, microcapsules, liposome preparations, etc. Among these, oral preparations such as tablets are preferred as the medicament of the present invention.

[0252] The content of compound (I) of the present invention or a pharmaceutically acceptable salt thereof in the medicament (pharmaceutical composition) of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight, based on the total weight of the preparation.

[0253] The dosage of compound (I) or a pharmaceutically acceptable salt thereof of the present invention can be appropriately selected depending on the subject (e.g., the subject's age, body weight, general health condition, sex, severity of symptoms, etc.), the administration route, the type of disease, etc. For example, in the case of humans, when orally administered to an adult patient (body weight approximately 60 kg), the daily dosage of compound (I) or a pharmaceutically acceptable salt thereof is usually 0.001 mg to 500 mg, preferably 0.01 mg to 100 mg, calculated as the active ingredient of compound (I), and can be administered once or several times a day, regardless of whether it is before, after, or between meals. The administration period is not particularly limited.

[0254] The above-mentioned "disease caused by a decrease in the activity of AMP-activated protein kinase" means a disease that develops or worsens due to a decrease in the activity of AMP-activated protein kinase, and specific examples thereof include diabetes, obesity, cancer, etc., and among these, the compound is particularly effective for the prevention or treatment of cancer (e.g., solid cancers such as glioblastoma, gastric cancer, colon cancer, lung cancer, breast cancer, germ cell cancer, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, cervical cancer, and ovarian cancer).

[0255] Compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be used in combination with other drugs (concomitant drugs), such as existing anticancer drugs, as long as the efficacy of the compound (I) is not impaired. In this case, the administration time is not limited, and these drugs may be administered to the subject simultaneously or at staggered times. Furthermore, compound (I) of the present invention and the concomitant drug may be administered in combination as a single preparation.

[0256] The dosage of the concomitant drug can be appropriately selected based on the clinically used dose. The mixing ratio of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof to the concomitant drug can be appropriately selected depending on the subject of administration, the administration route, the type of disease, symptoms, the type of the concomitant drug, etc.

[0257] Examples of concomitant drugs when compound (I) of the present invention or a pharmaceutically acceptable salt thereof is used for the treatment and / or prevention of cancer include chemotherapeutic agents, hormone therapy agents, molecular targeted drugs (epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors), antibody-drug conjugates (ADCs) that target cancer cells, oncolytic virus preparations, etc.

[0258] Examples of "chemotherapeutic agents" that can be used include alkylating agents, antimetabolites, anticancer antibiotics, and plant-derived anticancer agents.

[0259] Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptomycin, and benzophenone. Examples of drugs that can be used include putozocin, pipobroman, etoglucide, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trofosfamide, zinostatin stimalamer, adozelesin, systostin, bizelesin, and DDS preparations thereof.

[0260] Examples of the "antimetabolite" that can be used include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, emitefur, capecitabine), aminopterin, nelzarabine, leucovorin calcium, tabloid, butosin, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, tiazofurin, ambamustine, bendamustine, and DDS preparations thereof.

[0261] Examples of the "anticancer antibiotic" that can be used include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarkomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and DDS preparations thereof.

[0262] Examples of "plant-derived anticancer agents" that can be used include camptothecin, irinotecan, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, and DDS preparations thereof.

[0263] Examples of "hormonal therapeutic agents" include fosfestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, antiestrogens (e.g., tamoxifen citrate, toremifene citrate), birth control pills, mepitiostane, testololactone, aminoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin), droloxifene, epinephrine, and the like. Thiostanol, ethinylestradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride, anastrozole, letrozole, exemestane, vorozole, formestane), antiandrogens (e.g., flutamide, bicalutamide, nilutamide), 5α-reductase inhibitors (e.g., finasteride, epristeride), corticosteroid drugs (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors (e.g., abiraterone), retinoids and agents that slow the metabolism of retinoids (e.g., liarozole), and DDS preparations thereof, etc. may be used.

[0264] Examples of "molecularly targeted drugs" include tositumomab, ibritumomab, alemtuzumab, axitinib, bevacizumab, afatinib, bortezomib, bosutinib, carfilzomib, cetuximab, dasatinib, denosumab, edrecolomab, erlotinib, everolimus, vismodegib, gefitinib, gemtuzumab ozogamicin, imatinib, ipilimumab, lapatinib, lenalidomide, nilotinib, nimotuzumab, and ozogamicin. Examples of drugs that can be used include raparib, panitumumab, pazopanib, pertuzumab, rituximab, siltuximab, sorafenib, sunitinib, tamibarotene, temsirolimus, thalidomide, trastuzumab, tretinoin, vandetanib, vorinostat, cabozantinib, trametinib, dabrafenib, alectinib, ceritinib, ibrutinib, palbociclib, regorafenib, pilalalisib, and DDS formulations thereof.

[0265] Examples of antibody-drug conjugates (ADCs) that target cancer cells include trastuzumab deruxtecan (DS-8201) and its DDS formulations.

[0266] As the oncolytic virus preparation, for example, telomelysin and its DDS preparation, etc. are used.

[0267] Furthermore, when compound (I) of the present invention or a pharmaceutically acceptable salt thereof is used for the treatment and / or prevention of diabetes or obesity, examples of concomitant drugs include insulin sensitizers, HMG-CoA reductase inhibitors, angiotensin II receptor antagonists, non-statin antihypercholesterolemic drugs, antioxidants, etc.

[0268] Examples of "insulin sensitizers" that can be used include thiazolidine derivatives (e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate salt, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, FK-614, NN-622, AZ-242, BMS-298585, ONO-5816, LM-4156, BM-13-1258, MBX-102, GW-1536, etc.), biguanides (e.g., phenformin, metformin, buformin, etc.), etc.

[0269] Examples of "HMG-CoA reductase inhibitors" that can be used include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, rosuvastatin, or salts thereof (e.g., sodium salts, etc.).

[0270] Examples of "angiotensin II receptor antagonists" that can be used include candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, etc.

[0271] As the "non-statin antihypercholesterolemic drug", for example, ezetimibe is used.

[0272] Examples of "antioxidants" that can be used include vitamin E, betaine, pentoxifylline, and N-acetyl-L-cysteine.

[0273] When a concomitant drug is used, the administration timing is not limited, and they may be administered to the subject simultaneously or at staggered times. Staggered administration may involve administering the medicament of the present invention first and the concomitant drug later, or the concomitant drug first and the medicament of the present invention later. The administration methods may be the same or different. Furthermore, compound (I) of the present invention or a pharmaceutically acceptable salt thereof and the concomitant drug may be administered in combination as a single formulation.

[0274] The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. The compounding ratio of the compound of the present invention or a pharmaceutically acceptable salt thereof to the concomitant drug can be appropriately selected depending on the subject (the subject's age, body weight, general health condition, sex, severity of disease, etc.), administration route, type of disease, type of concomitant drug, etc.

[0275] The mass ratio of compound (I) or a pharmaceutically acceptable salt thereof to the concomitant drug is not particularly limited.

[0276] Furthermore, concomitant drugs that complement and / or enhance the therapeutic effect of compound (I) or a pharmaceutically acceptable salt thereof also include those that have not been discovered so far but will be discovered in the future, based on the above-mentioned mechanism.

[0277] The medicament or pharmaceutical composition of the present invention may be provided in the form of a kit together with instructions for administration, etc. The drugs contained in the kit are supplied in a container made of a material that maintains the activity of the components of the medicament or pharmaceutical composition for a long period of time, does not adsorb to the inside of the container, and does not alter the components. For example, a sealed glass ampoule may contain a buffer or the like sealed in the presence of a neutral, non-reactive gas such as nitrogen gas. The kit may also include instructions for use. The instructions for use of the kit may be printed on paper or stored on an electromagnetically readable medium such as a CD-ROM or DVD-ROM and provided to the user.

[0278] The present invention will be described in detail below based on Reference Examples, Examples, Test Examples, and Formulation Examples, but the present invention is not limited to the Examples and Test Examples and may be modified within the scope of the present invention. Furthermore, reagents, devices, and materials used in the present invention are commercially available unless otherwise specified.

[0279] % indicates mol / mol% for yield, and % by weight for other values ​​unless otherwise specified. Room temperature indicates a temperature between 15°C and 30°C unless otherwise specified. Other abbreviations used in the text have the following meanings: s: singlet d: doublet t: triplet q: quartet qn: quintet m: multiplet br: broad dd: double doublet td: triple doublet dt: double triplet tt: triple triplet J: coupling constant CDCl ３ : deuterated chloroform HRMS: high-resolution mass spectrometry FAB: fast atom bombardment EI: electron ionization ESI: electrospray ionization CI: chemical ionization IR (ATR): infrared spectroscopy (attenuated total reflectance) TBS: tert-butyldimethylsilyl DMF: N,N-dimethylformamide EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride DMAP: N,N-dimethyl-4-aminopyridine TIF: tetrahydrofuran DIAD: diisopropyl azodicarboxylate DPPA: diphenylphosphoryl azide DIPEA: N,N-diisopropylethylamine PPh ３ : Triphenylphosphine １ H NMR and １３ C NMR spectra were obtained in CDCl ３ All δ values ​​are expressed in ppm.

[0280] The raw material compounds used in the following examples are known compounds, and either commercially available products were used as they were or products synthesized and identified according to known methods were used.

[0281] Reference Example 1 Synthesis of 12-iodo-1-dodecine (compound (10a))

[0282]

[0283] Under a nitrogen atmosphere, sodium hydride (60% in oil, 1.76 g, 43.9 mmol) was added to a solution of 10-dodecyn-1-ol (Sigma-Aldrich) (1.00 g, 5.49 mmol) in 1,3-propanediamine (43 mL) under ice-cooling, and the mixture was stirred at 70°C for 5 hours. Water was added under ice-cooling, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 5:1) to obtain 11-dodecyn-1-ol (615 mg, 62%). To a solution of triphenylphosphine (1.18 g, 4.55 mmol) in anhydrous dichloromethane (10 mL), imidazole (306 mg, 4.55 mmol) and iodine (1.16 g, 4.55 mmol) were added under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. A solution of 11-dodecin-1-ol (615 mg, 3.37 mmol) in anhydrous dichloromethane (7 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous solution of sodium thiosulfate was added at room temperature, and the mixture was extracted with n-hexane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 100:1) to obtain 12-iodo-1-dodecine (compound (10a)) (918 mg, 93%). １ H NMR (400MHz, CDCl ３ ) δ: 1.23-1.47 (m, 12H), 1.47-1.61 (m, 2H), 1.82 (qn, 2H, J=7.1Hz), 1.9 5 (t, 1H, J=2.5Hz), 2.18 (td, 2H, J=7.1, 2.6Hz), 3.19 (t, 2H, J=7.1Hz).

[0284] Reference Example 2 Synthesis of 11-iodo-1-undecine (compound (10b))

[0285]

[0286] Under a nitrogen atmosphere, n-butyllithium (2.6 M n-hexane solution, 13.7 mL, 35.7 mmol) was added to a solution of propargyl alcohol (Tokyo Chemical Industry Co., Ltd.) (1.00 g, 17.8 mmol) in dehydrated tetrahydrofuran (59.5 mL) at −78°C, and the mixture was stirred at the same temperature for 1 hour. 1-Iodooctane (6.44 mL, 35.7 mmol) was added at −78°C, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous ammonium chloride solution was added at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 30:1 → 1:1) to obtain 2-undecin-1-ol (235 mg, 8%). Under a nitrogen atmosphere, sodium hydride (60% in oil, 446 mg, 11.2 mmol) was added to a solution of 2-undecin-1-ol (235 mg, 1.40 mmol) in 1,3-propanediamine (4.7 mL) under ice-cooling, and the mixture was stirred at 70°C for 8 hours. The mixture was cooled to room temperature, and water was added at the same temperature, followed by extraction with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:1) to give 10-undecin-1-ol (98.0 mg, 42%). To a solution of triphenylphosphine (199 mg, 0.757 mmol) in dehydrated dichloromethane (3.82 mL), imidazole (51.5 mg, 0.757 mmol) and iodine (192 mg, 0.757 mmol) were added under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. A solution of 10-undecin-1-ol (98.0 mg, 0.582 mmol) in dehydrated dichloromethane (2.00 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous sodium thiosulfate solution was added at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane) to obtain 11-iodo-1-undecine (compound (10b)) (71.8 mg, 44%). １ H NMR (400MHz, CDCl ３) δ: 1.16-1.46 (m, 10H), 1.46-1.62 (m, 4H), 1.82 (qn, 2H, J=7.1Hz), 1.9 5 (t, 1H, J=2.6Hz), 2.19 (td, 2H, J=7.0, 2.6Hz), 3.19 (t, 2H, J=7.0Hz).

[0287] Reference Example 3 Synthesis of 4-pentyn-1-yl p-toluenesulfonate (compound (10c))

[0288]

[0289] Under an argon atmosphere, triethylamine (3.98 mL, 28.5 mmol) and p-toluenesulfonyl chloride (5.00 g, 26.2 mmol) were added to a solution of 4-pentyn-1-ol (Tokyo Chemical Industry Co., Ltd.) (2.00 g, 24.0 mmol) in dehydrated dichloromethane (47.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 20:1 → 10:1) to obtain 4-pentyn-1-yl p-toluenesulfonate (compound (10c)) (5.18 g, 92%) as a colorless oil. １ H NMR (400MHz, CDCl ３ ) δ: 1.77-2.00 (m, 3H), 2.26 (td, 2H, J=6.9, 2.5Hz), 2.45 (s, 3H), 4 .15 (t, 2H, J = 6.1Hz), 7.35 (d, 2H, J = 8.1Hz), 7.80 (d, 2H, J = 8.1Hz). The synthesized compound (10c) １ The H NMR was consistent with the data for the same compound described in a non-patent document (Cheuug, F. K. et al., Org. Biomol. Chem., 2007, 5(7), 1093-1103).

[0290] Reference Example 4 Synthesis of 1-azido-12-bromododecane (compound (11a))

[0291]

[0292] Under a nitrogen atmosphere, triphenylphosphine (3.96 g, 15.1 mmol) was added to a solution of 12-bromo-1-dodecanol (compound (3a)) (Tokyo Chemical Industry Co., Ltd.) (2.00 g, 7.54 mmol) in dehydrated tetrahydrofuran (75.4 mL) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. Diisopropyl azodicarboxylate (4.87 mL, 22.6 mmol) and diphenylphosphoryl azide (3.25 mL, 15.1 mmol) were added under ice-cooling, and the mixture was stirred at 50°C for 15 hours. The solvent was evaporated under reduced pressure, and silica gel and chloroform were added, followed by evaporation again under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 20:1) to obtain 1-azido-12-bromododecane (compound (11a)) (1.74 g, 80%) as a colorless, transparent oil. １ H NMR (400MHz, CDCl ３ ) δ: 1.19-1.46 (m, 16H), 1.57-1.63 (m, 2H), 1.85 (qn, 2H, J = 7.1Hz), 3.26 (t, 2H, J = 7.0Hz), 3.41 (t, 2H, J = 6.9Hz). The synthesized compound (11a) １ The H NMR was consistent with the data for the same compound described in a non-patent document (Romuald, C. et al., Organic Letters, 2013, 15(1), 184-187).

[0293] Reference Example 5 Synthesis of 1-azido-9-bromononane (compound (11b))

[0294]

[0295] Under a nitrogen atmosphere, triphenylphosphine (4.69 g, 17.9 mmol) was added to a solution of 9-bromo-1-nonanol (compound (3b)) (Tokyo Chemical Industry Co., Ltd.) (2.00 g, 8.96 mmol) in dehydrated tetrahydrofuran (89.6 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. Diisopropyl azodicarboxylate (5.79 mL, 4.40 mmol) and diphenylphosphoryl azide (3.86 mL, 17.9 mmol) were added under ice-cooling, and the mixture was stirred at 50°C for 19 hours. The solvent was evaporated under reduced pressure, followed by the addition of silica gel and chloroform, and the solvent was evaporated again under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 20:1) to obtain 1-azido-9-bromononane (compound (11b)) (1.71 g, 77%) as a colorless, transparent oil. １ H NMR (400MHz, CDCl ３ ) δ: 1.23-1.56 (m, 10H), 1.39-1.48 (m, 2H), 1.83-1.90 (m, 2H), 3.26 (t, 2H, J = 7.0Hz), 3.41 (t, 2H, J = 6.8Hz). The synthesized compound (11b) １ The H NMR was consistent with the data for the same compound described in a non-patent document (Decroocw, C. et al., Chem. Eur. J., 2011, 17(49), 13825-13831).

[0296] Reference Example 6 Synthesis of 1-methyl-1H-pyrazole-5-sulfonic acid chloride (compound (8h))

[0297]

[0298] To a solution of 1-methyl-1H-pyrazole (246 mg, 3.00 mmol) in dehydrated tetrahydrofuran (10.0 mL), t-BuLi (Kanto Chemical) (1.6 M in n-pentane, 3.94 mL, 6.31 mmol) was added over 10 minutes at -78°C, followed by stirring at the same temperature for 1 hour. Sulfuryl chloride (Nacalai Tesque, Inc.) (0.362 mL, 4.50 mmol) was added to the reaction solution at the same temperature, followed by stirring for 1.5 hours. Water was added to the reaction solution under ice-cooling, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1→10:1) to obtain 1-methyl-1H-pyrazole-5-sulfonic acid chloride (compound (8h)) (127 mg, 24%) as a colorless, transparent oil. １ H NMR (500MHz, CDCl ３ ) δ: 4.23 (s, 3H), 7.02 (d, 1H, J = 1.8Hz), 7.57 (d, 1H, J = 1.8Hz); １３ C NMR (125 MHz, CDCl ３ ) δ: 39.0, 112.1, 137.9, 141.1; IR (NaCl) cm −１ : 1386, 1200; MS (EI) m / z: 182 (15.7) [M+2] ＋ , 180 (44.8) [M] ＋ , 145 (100.0); HRMS (EI) m / z: Calcd for C ４ H ５ ClN ２ O ２ S:179.9760;Found:179.9787[M] ＋ .

[0299] Reference Example 7 Synthesis of 1-benzyloxy-6-bromohexane (compound (19a))

[0300]

[0301] Under a nitrogen atmosphere, sodium hydride (Tokyo Chemical Industry Co., Ltd.) (60% in oil, 203 mg, 5.08 mmol) was added to a solution of benzyl alcohol (0.481 mL, 4.62 mmol) in dehydrated dimethylformamide (9.2 mL) under ice cooling and stirred at the same temperature for 20 minutes. 1,6-Dibromohexane (Tokyo Chemical Industry Co., Ltd.) (3.53 mL, 23.1 mmol) was added at the same temperature and stirred at room temperature for 21 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane → n-hexane:ethyl acetate = 200:1 → 50:1 → 10:1) to obtain 1-benzyloxy-6-bromohexane (compound (19a)) (734 mg, 59%) as a colorless, transparent oil. １ H NMR (500MHz, CDCl ３ ) δ: 1.37-1.48 (m, 4H), 1.63 (qn, 2H, J = 6.9Hz), 1.86 (qn, 2H, J = 6.8Hz), 3.4 0 (t, 2H, J=6.9Hz), 3.47 (t, 2H, J=6.8Hz), 4.50 (s, 2H), 7.26-7.36 (m, 5H). The synthesized compound (19a) １ The H NMR was consistent with the data for the same compound described in a non-patent document (Lambert, T. H., et al., Org. Lett., 2013, 15(1), 38-41).

[0302] Example 1 Synthesis of N-(21-hydroxy-13,16,19-trioxaheneicosan-1-yl)-thiophene-3-carboxamide (compound (I-1))

[0303]

[0304] (1-1) Synthesis of 8-(t-butyldimethylsilyloxy)-3,6-dioxa-1-octanol (compound (2a))

[0305]

[0306] Under a nitrogen atmosphere, triethylene glycol (compound (1a)) (Tokyo Chemical Industry Co., Ltd.) (5.33 mL, 40.0 mmol) was added to a solution of sodium hydride (60% in oil, 1.06 g, 44.0 mmol) in dehydrated tetrahydrofuran (80.0 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. t-Butyldimethylsilyl chloride (7.23 g, 48.0 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 2:1 → 1:1) to obtain 8-(t-butyldimethylsilyloxy)-3,6-dioxa-1-octanol (compound (2a)) (7.06 g, 67%) as a colorless, transparent oil. １ H NMR (400MHz, CDCl ３ ) δ: 0.07 (s, 6H), 0.90 (s, 9H), 3.56-3.68 (m, 4H), 3.72 (s, 4H), 3.53-3.58 (m, 4H), 3.62-3.65 (m, 6H). １ The H NMR was consistent with the data for the same compound described in a non-patent document (Lee, E. et al., ACS Catalyst, 2014, 4(10), 3590-3592).

[0307] (1-2) Synthesis of 1-azido-21-(t-butyldimethylsilyloxy)-13,16,19-trioxaheneicosane (compound (6a))

[0308]

[0309] Under a nitrogen atmosphere, sodium hydride (60% in oil, 95.9 mg, 4.00 mmol) was added to a solution of compound (2a) (500 mg, 2.00 mmol) in dehydrated dimethylformamide (0.500 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. Under ice-cooling, the mixture was added to a solution of 15-crown-5-ether (0.800 mL, 4.00 mmol) and 1-azido-12-bromododecane (compound (11a)) (1.16 g, 4.00 mmol) in dehydrated dimethylformamide (1.50 mL) and stirred at room temperature for 23 hours. Water was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane → n-hexane:ethyl acetate = 20:1 → 10:1) to obtain 1-azido-21-(t-butyldimethylsilyloxy)-13,16,19-trioxaheneicosane (compound (6a)) (586 mg, 62%) as a colorless oil. １ H NMR (400MHz, CDCl ３ ) δ: 0.05 (s, 6H), 0.88 (s, 9H), 1.25-1.60 (m, 20H), 3.24 (t, 2H, J=7.0Hz), 3.43 (t, 2H, J = 6.9Hz), 3.53-3.58 (m, 4H), 3.62-3.65 (m, 6H), 3.75 (t, 2H, J = 5.5Hz); １３ C NMR (125 MHz, CDCl ３ ) δ: -5.24, -5.21, 18.4, 26.0 (3C), 26.2, 26.8, 28.9, 29.2, 29.56, 29.57, 2 9.60, 29.64, 29.70, 29.73, 51.6, 62.8, 70.2, 70.8 (2C), 70.9, 71.7, 72.8; IR(NaCl)cm −１ :2095; MS(FAB) m / z:474[M+H] ＋ ; HRMS (FAB) m / z: Calcd for C ２４ H ５２ N ３ O ４ Si:474.3649; Found:474.3723[M+H] ＋ .

[0310] (1-3) Synthesis of N-{21-(t-butyldimethylsilyloxy)-13,16,19-trioxaheneicosan-1-yl}thiophene-3-carboxamide (compound (9a))

[0311]

[0312] To a solution of compound (6a) (1.17 g, 2.47 mmol) in diethyl ether (12.4 mL), triphenylphosphine (0.972 g, 3.71 mmol) was added under ice-cooling and stirred at the same temperature for 5 minutes. Water (12.4 mL) was added under ice-cooling, and the mixture was warmed to room temperature and stirred for 69 hours. A 6M aqueous solution of sodium hydroxide was added to the reaction mixture at room temperature to adjust the solution to pH 11, and the mixture was extracted with diethyl ether. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Under an argon atmosphere, 3-thiophenecarboxylic acid (compound (8a)) (0.633 g, 4.94 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.14 g, 5.93 mmol), and N,N-dimethyl-4-aminopyridine (0.664 g, 5.43 mmol) were added to a solution of the residue in dehydrated tetrahydrofuran (24.8 mL) under ice cooling, and the mixture was warmed to room temperature and stirred for 28 hours. Water was added at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 5:1 → 3:1) to obtain N-{21-(t-butyldimethylsilyloxy)-13,16,19-trioxaheneicosan-1-yl}thiophene-3-carboxamide (compound (9a)) (1.22 g, 86%) as a pale yellow solid. M.p. 37.6°C-39.2°C; １ H NMR (400MHz, CDCl ３)δ: 0.06 (s, 6H), 0.89 (s, 9H), 1.26-1.40 (m, 16H), 1.54-1.63 (m, 4H), 3 .41 (td, 2H, J=7.2, 6.1Hz), 3.45 (t, 2H, J=6.9Hz), 3.54-3.60 (m, 5H), 3 . 62-3.68 (m, 5H), 3.77 (t, 2H, J=5.5Hz), 6.00 (br, 1H), 7.33 (dd, 1H, J= 5.1, 3.0Hz), 7.37 (dd, 1H, J = 5.1, 1.4Hz), 7.84 (dd, 1H, J = 3.0, 1.4Hz); １３ C NMR (100MHz, CDCl ３ )δ: −5.4 (2C), 18.2, 25.8 (3C), 26.0, 26.9, 29.2, 29.35, 29.43 (4C), 29.5, 29.6, 39.7, 62.6, 70.0, 70.5 (2C), 70.6, 71.4, 72.5, 126.1 (2C), 127.8, 137.7, 163.0; IR(NaCl)cm −１ : 3326, 1625; MS (EI) m / z (%): 557 (5.9) [M] ＋ , 294 (49.9), 111 (90.0); HRMS (EI) m / z: Calcd for C ２９ H ５５ NO ５ SSi: 557.3570; Found: 557.3584[M] ＋ .

[0313] (1-4) Synthesis of compound (I-1))

[0314]

[0315] Under a nitrogen atmosphere, n-tetrabutylammonium fluoride (4.38 mL, 4.38 mmol, approximately 1.00 M tetrahydrofuran solution) was added to a solution of compound (9a) (0.253 g, 0.442 mmol) in dehydrated tetrahydrofuran (4.40 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride (4.40 mL) was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:3 → ethyl acetate) to obtain the title compound (compound (I-1)) (0.193 g, 98%) as a white solid. M.p. 58.4°C-60.4°C; １ H NMR (400MHz, CDCl ３ ) δ: 1.21-1.42 (m, 16H), 1.53-1.67 (m, 4H), 2.61 (t, 1H, J = 6.2Hz), 3.42 (q, 2H, J = 6.7Hz), 3.45 (t, 2H, J = 6.8Hz), 3.57 -3.75 (m, 12H), 5.96 (br, 1H), 7.34 (dd, 1H, J = 5.0, 2.9Hz), 7.36 (dd, 1H, J = 5.0, 1.1Hz), 7.84 (dd, 1H, J = 2.9, 1.1Hz); １３ C NMR (100MHz, CDCl ３ ) δ: 25.9 (2C), 26.9 (2C), 29.2, 29.3, 29.4 (3C), 29.6, 39.6, 61.6, 69.9, 70.2, 70.5, 71.5, 72.4 (2C), 126.0, 126.2, 127.8, 137.7, 163.1; IR(ATR)cm −１ : 3326, 1623; MS (EI) m / z (%): 443 (17.6) [M] ＋ , 310 (65.2), 294 (47.7), 111 (100.0); HRMS (EI) m / z: Calcd for C ２３ H ４１ NO ５ S:443.2705;Found:443.2703[M] ＋ .

[0316] Example 2 Synthesis of N-(13,16,19,22-tetraoxapentacosan-1-yl)thiophene-3-carboxamide (compound (I-2))

[0317]

[0318] Under a nitrogen atmosphere, sodium hydride (60% in oil, 22.6 mg, 0.939 mmol) was added to a solution of compound (I-1) (50.0 mg, 0.113 mmol) in dehydrated dimethylformamide (3.00 mL) under ice cooling, and the mixture was warmed to room temperature. After stirring for 10 minutes, 1-iodopropane (compound (10d)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (32.8 μL, 0.338 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 19 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 5:1 → ethyl acetate) to obtain the title compound (compound (I-2)) (42.0 mg, 77%) as a pale yellow solid. M.p. 40.7°C-42.5°C; １ H NMR (400MHz, CDCl ３ ) δ: 0.91 (t, J = 7.5Hz, 3H), 1.26-1.33 (m, 16H), 1.52-1.65 (m, 6H), 3.39-3.46 (m, 2H), 3.42 (t, 4H, J = 6.9Hz), 3.56-3.61 (m, 4 H), 3.63-3.67 (m, 8H), 5.93 (br, 1H), 7.34 (dd, 1H, J = 5.0, 2.8Hz), 7.37 (dd, 1H, J = 5.0, 1.5Hz), 7.84 (dd, 1H, J = 2.8, 1.5Hz); １３ C NMR (100MHz, CDCl ３ ) δ: 10.4, 25.9 (2C), 26.9, 29.2, 29.3 (2C), 29.4 (2C), 29.5 (2C), 29.6, 39.7, 69. 88, 69.89 (2C), 70.46, 70.47, 71.4, 72.9 (2C), 126.1 (2C), 127.8, 137.7, 163.0; IR(ATR)cm −１ : 3326, 1624; MS (EI) m / z (%): 485 (16.6) [M] ＋, 310 (61.4), 294 (50.6), 111 (100.0); HRMS (EI) m / z: Calcd for C ２６ H ４７ NO ５ S:485.3175;Found:485.3171[M] ＋ .

[0319] Example 3 Synthesis of N-(13,16,19,22-tetraoxaoctacosane-1-yl)thiophene-3-carboxamide (compound (I-3))

[0320]

[0321] Under a nitrogen atmosphere, sodium hydride (60% in oil, 90.2 mg, 3.76 mmol) was added to a solution of compound (I-1) (200 mg, 0.451 mmol) in dehydrated dimethylformamide (12.0 mL) under ice cooling, and the mixture was warmed to room temperature and stirred for 10 minutes. 1-Iodohexane (compound (10e)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (0.200 mL, 1.35 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 19 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 5:1 → ethyl acetate) to obtain the title compound (compound (I-3)) (0.200 g, 84%) as a pale yellow solid. M.p. 47.4°C-48.3°C; １ H NMR (300MHz, CDCl ３ ) δ: 0.87 (t, 3H, J = 6.9Hz), 1.18-1.41 (m, 22H), 1.53-1.62 (m, 6H), 3.38-3.45 (m, 2H), 3.45 (t, 4H, J = 6.8Hz), 3.56- 3.66 (m, 12H), 5.93 (br, 1H), 7.33 (dd, 1H, J = 5.1, 2.9Hz), 7.37 (dd, 1H, J = 5.1, 1.4Hz), 7.84 (dd, 1H, J = 2.9, 1.4Hz); １３ C NMR (100MHz, CDCl ３) δ: 13.9, 22.5 (2C), 25.6, 25.9, 26.9, 29.2 (2C), 29.3 (2C), 29.4 (2C), 29.5, 29.6, 31. 5, 39.7, 69.9 (2C), 70.4 (2C), 70.5 (2C), 71.4 (2C), 126.0, 126.1, 127.8, 137.7, 163.0; IR(ATR)cm −１ :3333,1623; MS (EI) m / z (%): 527 (18.4) [M] ＋ , 310 (66.6), 294 (51.2), 111 (100.0); HRMS (EI) m / z: Calcd for C ２９ H ５３ NO ５ S:527.3644;Found:527.3642[M] ＋ .

[0322] Example 4 Synthesis of N-(13,16,19,22-tetraoxahentriacontan-1-yl)thiophene-3-carboxamide (compound (I-4))

[0323]

[0324] Under a nitrogen atmosphere, sodium hydride (60% in oil, 22.6 mg, 0.939 mmol) was added to a solution of compound (I-1) (50.0 mg, 0.113 mmol) in dehydrated dimethylformamide (12.0 mL) under ice cooling, and the mixture was warmed to room temperature and stirred for 10 minutes. 1-Iodononane (compound (10f)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (66.6 μL, 0.338 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 19 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 5:1 → ethyl acetate) to obtain the title compound (compound (I-4)) (44.4 mg, 69%) as a pale yellow solid. M.p. 55.8°C-56.9°C; １ H NMR (400MHz, CDCl ３) δ: 0.88 (t, 3H, J = 6.8Hz), 1.26-1.33 (m, 28H), 1.54-1.61 (m, 6 H), 3.40 (q, 2H, J=6.9Hz), 3.44 (t, 4H, J=6.8Hz), 3.56-3.60 (m , 4H), 3.63-3.66 (m, 8H), 5.93 (br, 1H), 7.34 (dd, 1H, J=5.0, 2. 9Hz), 7.36 (dd, 1H, J=5.0, 1.1Hz), 7.84 (dd, 1H, J=2.9, 1.1Hz); １３ C NMR (100MHz, CDCl ３ ) δ: 14.0, 22.5, 25.9 (2C), 26.9, 29.1 (2C), 2 9.2 (2C), 29.3 (2C), 29.4, 29.5 (2C), 29.6 (2 C), 31.7 (2C), 39.7, 69.9 (2C), 70.4 (4C), 71 .4 (2C), 126.0, 126.1, 127.8, 137.7, 163.0; IR(ATR)cm −１ : 3332, 1623; MS (EI) m / z (%): 569 (28.0) [M] ＋ , 310 (89.0), 294 (74.1), 111 (100.0); HRMS (EI) m / z: Calcd for C ３２ H ５９ NO ５ S: 569.4114; Found: 569.4109 [M] ＋ .

[0325] Example 5 N-(13,16,19,22-テトラオキサドトリアコンタン-1 Synthesis of −イル)チオフェン−3−カルボキサミド (Compound (I−5))

[0326]

[0327] Under a nitrogen atmosphere, sodium hydride (60% in oil, 22.6 mg, 0.939 mmol) was added to a solution of compound (I-1) (50.0 mg, 0.113 mmol) in dehydrated dimethylformamide (3.00 mL) under ice cooling, and the mixture was warmed to room temperature and stirred for 10 minutes. 1-Iododecane (compound (10 g)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (75.5 μL, 0.338 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 19 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 5:1 → 1:3) to obtain the title compound (compound (I-5)) (38.9 mg, 59%) as a pale yellow solid. M.p. 60.0°C-62.0°C; １ H NMR (300MHz, CDCl ３ ) δ: 0.87 (t, 3H, J = 6.8Hz), 1.26-1.33 (m, 30H), 1.53-1.62 (m, 6H), 3.38-3.44 (m, 2H), 3.44 (t, 4H, J = 6.8Hz), 3.56- 3.66 (m, 12H), 5.92 (br, 1H), 7.33 (dd, 1H, J = 5.1, 2.9Hz), 7.36 (dd, 1H, J = 5.1, 1.4Hz), 7.84 (dd, 1H, J = 2.9, 1.4Hz); １３ C NMR (100MHz, CDCl ３ ) δ: 14.0, 22.6 (2C), 26.0 (2C), 26.9 (2C), 29.2 (3C), 29.37 (2C), 29.44 (2C), 29.5, 29.6 (2C), 3 1.8 (2C), 39.7, 69.9 (2C), 70.47 (2C), 70.48 (2C), 71.4 (2C), 126.1 (2C), 127.8, 137.7, 163.0; IR(ATR)cm −１ :3334,1622; MS (EI) m / z (%): 583 (24.4) [M] ＋ , 310 (81.9), 294 (66.6), 111 (100.0); HRMS (EI) m / z: Calcd for C ３３ H ６１ NO ５ S:583.4270;Found:583.4264[M]＋ .

[0328] Example 6 Synthesis of N-(13,16,19,22-tetraoxa-33-tetracoriacontin-1-yl)thiophene-3-carboxamide (compound (I-6))

[0329]

[0330] Under a nitrogen atmosphere, sodium hydride (60% in oil, 22.5 mg, 0.564 mmol) was added to a solution of compound (I-1) (50.0 mg, 0.113 mmol) in dehydrated N,N-dimethylformamide (1.13 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. 12-Iodo-1-dodecine (compound (10a)) (98.1 mg, 0.334 mmol) obtained in Reference Example 1 was added under ice-cooling, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 5:1 → 2:1) to obtain the title compound (compound (I-6)) (42.9 mg, 63%) as a white waxy solid. M. p. 52.3-53.7℃ (dec.); １ H NMR (400MHz, CDCl ３ ) δ: 1.26-1.41 (m, 30H), 1.48-1.66 (m, 6H), 1.94 (t, 1H, J = 2.6Hz), 2.18 (td, 2H, J = 7.1, 2.6Hz), 3.39-3.46 (m, 6H), 3.57-3.59 (m , 4H), 3.63-3.66 (m, 8H), 5.97 (brs, 1H), 7.34 (dd, 1H, J = 5.1, 2.9Hz), 7.37 (dd, 1H, J = 5.1, 1.3Hz), 7.84 (dd, 1H, J = 2.9, 1.3Hz); １３ C NMR (100Hz, CDCl ３) δ: 18.4, 26.0 (2C), 27.0, 28.5, 28.7 (2C), 29.1, 29.3, 29.4 (3C), 29.5 (3C), 29.6 (2C), 29.7 (2C), 39.8, 68.0, 70.0 (3C), 70.6 (3C), 71.5 (2C), 84.8, 125.9, 126.4, 127.8, 137.7, 163.0; IR(ATR)cm −１ : 3334, 1626; MS (FAB) m / z: 607 [M] ＋ ; HRMS (FAB) m / z: Calcd for C ３５ H ６１ NO ５ S:607.4270;Found:607.4272[M] ＋ .

[0331] Example 7 Synthesis of N-(13,16,19,22-tetraoxa-32-tritricoriacontin-1-yl)thiophene-3-carboxamide (compound (I-7))

[0332]

[0333] Under a nitrogen atmosphere, sodium hydride (60% in oil, 17.2 mg, 0.430 mmol) was added to a solution of compound (I-1) (38.2 mg, 86.0 μmol) in dehydrated N,N-dimethylformamide (0.860 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. 11-Iodo-1-undecine (compound (10b)) (71.8 mg, 0.258 mmol) obtained in Reference Example 2 was added under ice-cooling, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (compound (I-7)) (25.2 mg, 49%) as a white waxy solid. M. p. 60.6-62.1℃ (dec.); １ H NMR (400MHz, CDCl ３) δ: 1.26-1.84 (m, 34H), 1.94 (t, 1H, J = 2.6Hz), 2.18 (td, 2H, J = 7.1, 2.6Hz), 3.38-3.47 (m, 6H), 3.56-3.66 (m , 12H), 6.05 (brs, 1H), 7.33 (dd, 1H, J = 5.1, 2.9Hz), 7.38 (dd, 1H, J = 5.1, 1.4Hz), 7.85 (dd, 1H, J = 2.9, 1.4Hz); １３ C NMR (100Hz, CDCl ３ ) δ: 18.4, 26.03, 26.04, 27.0, 28.4, 28.7, 29.0, 29.28, 29.39 (2C), 29.43, 29.48, 29.51 (3C), 29.58 (2C), 2 9.7, 39.8, 68.0, 70.0, 70.57 (2C), 70.58 (2C), 71.49 (2C), 71.51, 84.8, 125.9, 126.4, 127.8, 137.8, 163.0; IR(ATR)cm −１ : 3339, 1622; MS (FAB) m / z: 593 [M] ＋ ; HRMS (FAB) m / z: Calcd for C ３４ H ５９ NO ５ S:593.4114;Found:593.4113[M] ＋ .

[0334] Example 8 Synthesis of N-(13,16,19,22-tetraoxa-25-heptacosin-1-yl)-5-methylthiophene-3-carboxamide (compound (I-8))

[0335]

[0336] (8-1) Synthesis of 21-azido-3,6,9-trioxa-1-henicosanol (compound (12a))

[0337]

[0338] Under a nitrogen atmosphere, tetrabutylammonium fluoride (approximately 1.00 M tetrahydrofuran solution, 2.56 mL, 2.56 mmol) was added to a solution of compound (6a) (243 mg, 0.513 mmol) obtained in Example 1 (1-2) in dehydrated tetrahydrofuran (5.13 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 21-azido-3,6,9-trioxa-1-henicosanol (compound (12a)) (181 mg, 98%) as a colorless, transparent oil. １ H NMR (400MHz, CDCl ３ ) δ: 1.23-1.40 (m, 16H), 1.55-1.67 (m, 4H), 2.54 (t, 1H, J = 6.4Hz), 3.26 (t, 2H, J = 7.1Hz), 3.45 (t, 2H, J = 6.8Hz), 3.58-3.75 (m, 12H); １３ C NMR (100MHz, CDCl ３ ) δ: 25.9 (2C), 26.5 (2C), 28.7 (2C), 29.0 (2C), 29.3, 29.4, 51.3, 61.5, 69.8, 70.2, 70.4 (2C), 71.4, 72.4; IR (ATR) cm −１ : 3445, 2091; MS (ESI) m / z: 382 [M+Na] ＋ ; HRMS (ESI) m / z: Calcd for C １８ H ３７ N ３ O ４ :382.2676;Found:382.2680[M+Na] ＋ .

[0339] (8-2) Synthesis of 27-azido-6,9,12,15-tetraoxa-1-peptacosin (compound (13a))

[0340]

[0341] Under a nitrogen atmosphere, sodium hydride (60% in oil, 86.4 mg, 2.16 mmol) was added to a solution of compound (12a) (388 mg, 1.08 mmol) in dehydrated dimethylformamide (0.270 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. Under ice-cooling, 15-crown-5-ether (0.43 mL, 2.16 mmol) and a solution of compound (10c) (515 mg, 2.16 mmol) obtained in Reference Example 3 in dehydrated dimethylformamide (0.810 mL) were added, and the mixture was stirred at room temperature for 26 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1→5:1) to obtain 27-azido-6,9,12,15-tetraoxa-1-peptacosin (compound (13a)) (406 mg, 88%) as a colorless, transparent oil. １ H NMR (500MHz, CDCl ３ ) δ: 1.27-1.37 (m, 16H), 1.55-1.62 (m, 4H), 1.80 (qn, 2H, J = 6.7Hz), 1.94 (t, 1H, J = 2.6Hz), 2. 29 (td, 2H, J = 7.1, 2.6Hz), 3.25 (t, 2H, J = 7.1Hz), 3.45 (t, 2H, J = 6.8Hz), 3.55-3.66 (m, 14H); １３ C NMR (100MHz, CDCl ３ ) δ: 15.1, 26.0, 26.7, 28.4, 28.8, 29.1, 29.4 (2C), 29.47, 29.50, 29.52, 29.6, 51.4, 68.4, 68.5, 70.0, 70.2, 70.5 (2C), 70.6 (2C), 71.5, 84.0; IR (ATR) cm −１ :2092; MS(ESI) m / z:448[M+Na] ＋ ; HRMS (ESI) m / z: Calcd for C ２３ H ４３ N ３ NaO ４ :448.3146;Found:448.3144[M+Na] ＋ .

[0342] (8-3) Synthesis of Compound (I-8)

[0343]

[0344] To a solution of compound (13a) (116 mg, 0.272 mmol) in a diethyl ether / water (1:1, 3.50 mL) mixture, triphenylphosphine (107 mg, 0.408 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 24 hours. A 6N aqueous solution of sodium hydroxide was added at room temperature, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To a solution of the residue in dehydrated tetrahydrofuran (0.543 mL), 5-methyl-3-thiophenecarboxylic acid (compound (8b)) (FUJIFILM Wako Pure Chemical Industries, Ltd.) (77.2 mg, 4.94 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104 mg, 0.543 mmol), and N,N-dimethyl-4-aminopyridine (66.3 mg, 0.543 mmol) were added under ice-cooling under an argon atmosphere, and the mixture was stirred at room temperature for 2 hours. Water was added at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) ​​to obtain the title compound (compound (I-8)) (96.5 mg, 62%) as a white waxy solid. M.p. 33.2-36.0°C; １ H NMR (400MHz, CDCl ３ ) δ: 1.23-1.35 (m, 16H), 1.53-1.60 (m, 4H), 1.79 (qn, 2H, J = 7.0Hz), 1.95 (t, 1H, J = 2.6Hz), 2.28 (td, 2H, J = 7.1, 2.6 Hz), 2.47 (s, 3H), 3.34-3.46 (m, 4H), 3.54-3.66 (m, 14H), 6.27 (br, 1H), 7.04-7.06 (m, 1H), 7.62 (d, 1H, J = 0.9Hz); １３ C NMR (100MHz, CDCl ３) δ: 15.1, 15.2, 26.0, 26.1, 26.9, 28.4, 29.2, 29.4, 29.45 (2C), 29.49, 29.6, 29.7, 39.7, 68 4, 69.5, 70.0, 70.1, 70.4, 70.5 (2C), 70.9, 71.4, 83.9, 124.0, 125.7, 137.3, 140.6, 163.1; IR(ATR)cm −１ : 3333, 1626; MS (EI) m / z (%): 523 (7) [M] ＋ , 426 (2), 125 (75), 97 (84); HRMS (EI) m / z: Calcd for C ２９ H ４９ NO ５ S:523.3342;Found:523.3331[M] ＋ .

[0345] Example 9 Synthesis of N-(13,16,19,22-tetraoxatricosan-1-yl)thiophene-3-carboxamide (compound (I-9))

[0346]

[0347] (9-1) Synthesis of 13,16,19,22-tetraoxa-1-tricosanol (compound (16a))

[0348]

[0349] Under a nitrogen atmosphere, sodium hydride (60% in oil, 0.182 g, 7.57 mmol) was added to a solution of triethylene glycol monomethyl ether (compound (15a)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (1.24 g, 7.57 mmol) in dehydrated dimethylformamide (5.00 mL) under ice cooling, and the mixture was warmed to room temperature and stirred for 50 minutes. A solution of 12-bromo-1-dodecanol (compound (3a)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (0.669 g, 2.52 mmol) in dehydrated dimethylformamide (5.00 mL) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 24 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1) to obtain 13,16,19,22-tetraoxa-1-tricosanol (compound (16a)) (0.542 g, 62%) as a colorless oil. １ H NMR (400MHz, CDCl ３ ) δ: 1.26-1.31 (s, 17H), 1.55-1.59 (m, 3H), 1.55-1.59 (m, 1H), 3.39 (s, 3H), 3.45 (t, 2H, J = 6.8Hz), 3.54-3.60 (m, 4H), 3.63-3.68 (m, 10H); １３ C NMR (100MHz, CDCl ３ ) δ: 25.8, 26.1, 29.5 (2C), 29.6 (3C), 29.7 (2C), 32.8, 59.1, 62.9, 70.1, 70.5, 70.6, 70.6 (2C), 71.6, 72.0; IR (CHCl ３ ) cm −１ :3466; MS (EI) m / z (%): 348 (0.2) [M] ＋ , 103 (34.6), 85 (62.1), 83 (91.8), 59 (100.0), 58 (59.2), 55 (53.4); HRMS (EI) m / z: Calcd for C １９ H ４０ O ５ :348.2876;Found:348.2874[M] ＋ .

[0350] (9-2) Synthesis of 13,16,19,22-tetraoxa-1-iodotricosane (compound (17a))

[0351]

[0352] To a solution of triphenylphosphine (579 mg, 2.21 mmol) and imidazole (410 mg, 6.03 mmol) in dehydrated dichloromethane (10.0 mL), iodine (561 mg, 3.08 mmol) was added under ice cooling, the mixture was warmed to room temperature, and stirred for 30 minutes in the dark. A solution of compound (16a) (579 mg, 2.21 mmol) in dehydrated dichloromethane (7.50 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 22 hours in the dark. A saturated aqueous solution of sodium thiosulfate (15 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain 13,16,19,22-tetraoxa-1-iodotricosane (compound (17a)) (0.787 g, 86%) as a yellow oil. １ H NMR (400MHz, CDCl ３ ) δ: 1.26-1.38 (m, 16H), 1.56-1.59 (m, 2H), 1.78-1.84 (m, 2H), 3.19 (t, 2H, J = 7.2Hz), 3.39 (s, 3H), 3.54-3.60 (m, 5H), 3.63-3.68 (m, 9H); １３ C NMR (100MHz, CDCl ３ ) δ: 7.39, 26.1, 28.6, 29.5, 29.5 (2C), 29.6 (2C), 29.7, 30.6, 33.6, 59.1, 70.1, 70.6, 70.6, 70.7, 70.8, 71.6, 71.9; MS (CI) m / z (%): 459 (49.0) [M+H] ＋ , 323 (64.3), 292 (100.0), 211 (33.3), 165 (50.9), 103 (54.2); HRMS (CI) m / z: Calcd for C １９ H ４０ IO ４ :459.1972;Found:459.1966[M+H] ＋ .

[0353] (9-3) Synthesis of 13,16,19,22-tetraoxa-1-azidotricosane (compound (13a))

[0354]

[0355] Sodium azide (61.2 mg, 0.941 mmol) was added to a solution of compound (17a) (0.228 g, 0.470 mmol) in dehydrated dimethyl sulfoxide (4.70 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed twice each with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2) to obtain 13,16,19,22-tetraoxa-1-azidotricosane (compound (13a)) (176 mg, quant.) as a colorless oil. １ H NMR (400MHz, CDCl ３ ) δ: 1.26 (s, 16H), 1.58-1.62 (m, 4H), 3.26 (t, 2H, J = 6.8Hz), 3.38 (s, 3H), 3.54-3.60 (m, 5H), 3.63-3.68 (m, 9H); １３ C NMR (100MHz, CDCl ３ ) δ: 26.1, 26.8, 28.9, 29.2, 29.5 (2C), 29.6 (3C), 29.7, 33.6, 51.5, 59.1, 70.1, 70.6 (2C), 70.7 (2C), 71.6, 72.0; IR (CHCl ３ ) cm −１ :2098; MS (CI) m / z (%): 374 (17.3) [M+H] ＋ , 346 (53.8), 270 (27.8), 226 (35.5), 198 (94.5), 182 (100.0), 103 (36.9); HRMS (CI) m / z: Calcd for C １９ H ４０ N ３ O ４ :374.3019;Found:374.3024[M+H] ＋ .

[0356] (9-4) Synthesis of 13,16,19,22-tetraoxa-1-tricosylamine (compound (14a))

[0357]

[0358] To a solution of compound (13a) (464 mg, 1.24 mmol) in diethyl ether (6.2 mL), triphenylphosphine (326 mg, 1.24 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 5 minutes. Water (6.2 mL) was added, and the mixture was stirred at room temperature for 20 hours. 6N hydrochloric acid was added to adjust the pH to 1, and the mixture was washed with diethyl ether. 6N aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to 11, and the mixture was extracted with diethyl ether. The solvent was evaporated under reduced pressure, and 13,16,19,22-tetraoxa-1-tricosylamine (compound (14a)) (427 mg, 99%) was obtained as a white waxy solid. １ H NMR (400MHz, CDCl ３ ) δ: 1.26-1.32 (s, 16H), 1.41-1.43 (m, 2H), 1.56-1.59 (m, 2H), 2.68 (t, 2H, J = 6.8Hz), 3.39 (s, 3H), 3.54-3.59 (m, 5H), 3.63-3.67 (m, 9H); １３ C NMR (100MHz, CDCl ３ ) δ: 26.1, 26.9, 29.5 (2C), 29.6 (5C), 33.9, 42.3, 59.0, 70.0, 70.5, 70.6 (3C), 71.5, 71.9; IR (CHCl ３ ) cm −１ :3378; MS (CI) m / z (%): 374 (17.3) [M+H] ＋ , 346 (53.8), 270 (27.8), 226 (35.5), 198 (94.5), 182 (100.0), 103 (36.9); HRMS (CI) m / z: Calcd for C １９ H ４２ NO ４ :348.3114;Found:348.3107[M+H] ＋ .

[0359] (9-5) Synthesis of Compound (I-9)

[0360]

[0361] To a solution of compound (14a) (61.5 mg, 0.177 mmol) in dehydrated tetrahydrofuran (0.850 mL), 3-thiophenecarboxylic acid (compound (8a)) (45.4 mg, 0.354 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81.4 mg, 0.425 mmol), and N,N-dimethyl-4-aminopyridine (43.2 mg, 0.354 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:2) to obtain the title compound (compound (I-9)) (65.6 mg, 81%) as a white solid. M.p. 39.3-42.0°C (dec.); １ H NMR (400MHz, CDCl ３ ) δ: 1.26-1.33 (m, 16H), 1.54-1.66 (m, 4H), 3.38 (s, 3H), 3.39-3.46 (m, 2H), 3.54-3.59 (m, 5H ), 3.63-3.67 (m, 9H), 5.97 (s, 1H), 7.32-7.34 (m, 1H), 7.36-7.38 (m, 1H), 7.84-7.85 (m, 1H); １３ C NMR (100MHz, CDCl ３ ) δ: 26.1, 27.1, 29.4, 29.6 (6C), 29.8, 39.9, 59.1, 70.1, 70.7 (4C), 71.6, 72.0, 126.3 (2C), 128.0, 137.9, 163.2; IR (CHCl ３ ) cm −１ : 1651; MS (EI) m / z (%): 457 (12.6) [M] ＋ , 310 (61.3), 294 (45.8), 111 (100.0), 59 (28.6); HRMS (EI) m / z: Calcd for C ２４ H ４３ NO ５ S:457.2862;Found:457.2856[M] ＋ .

[0362] Example 10 Synthesis of N-(13,16,19,22-tetraoxatricosan-1-yl)-5-methylthiophene-3-carboxamide (compound (I-10))

[0363]

[0364] To a solution of compound (14a) (100 mg, 0.288 mmol) obtained in Example 9 (9-4) in dehydrated tetrahydrofuran (1.44 mL), 5-methylthiophene-3-carboxylic acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (compound (8b)) (82.0 mg, 0.576 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (132 mg, 0.691 mmol), and N,N-dimethyl-4-aminopyridine (70.0 mg, 0.576 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:2) to obtain the title compound (compound (I-10)) (126 mg, 75%) as a white solid. M. p. 43.6-45.0℃ (dec.); １ H NMR (400MHz, CDCl ３ ) δ: 1.26-1.33 (m, 16H), 1.53-1.60 (m, 4H), 2.48 (d, 3H, J = 4.4Hz), 3.38 (s, 3H), 3.40-3.4 7 (m, 4H), 3.55-3.67 (m, 12H), 5.91 (br, 1H), 7.02 (m, 1H, J = 1.6Hz), 7.58 (d, 1H, J = 2.0Hz); １３ C NMR (100MHz, CDCl ３ ) δ: 15.1, 26.0, 26.9, 29.2, 29.4 (5C), 29.5, 29.6, 39.7, 58.9, 69.9, 70.4, 70.5 (3C), 71.4, 71.8, 124.0, 125.7, 137.3, 140.6, 163.1; IR(neat)cm −１ : 3330, 1625; MS (EI) m / z: 471 (29.2) [M] ＋, 324 (45.3), 308 (29.5), 125 (100); HRMS (EI) m / z: Calcd for C ２５ H ４５ NO ５ S:471.3018;Found:471.3023[M] ＋ .

[0365] Example 11 Synthesis of N-(13,16,19,22-tetraoxatricosan-1-yl)-2-methylthiophene-3-carboxamide (compound (I-11))

[0366]

[0367] To a solution of compound (14a) (200 mg, 0.576 mmol) obtained in Example 9 (9-4) in dehydrated tetrahydrofuran (2.88 mL), 2-methylthiophene-3-carboxylic acid (Sigma-Aldrich) (compound (8c)) (164 mg, 1.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg, 1.38 mmol), and N,N-dimethyl-4-aminopyridine (140 mg, 1.15 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:2) to obtain the title compound (compound (I-11)) (262 mg, 78%) as a pale yellow oil. １ H NMR (400MHz, CDCl ３ ) δ: 1.26-1.33 (m, 16H), 1.58-1.59 (m, 4H), 2.70 (s, 3H), 3.38 (s, 3H), 3.41-3.47 (m, 4H), 3.55-3.67 (m, 12H), 5.76 (br, 1H), 7.03 (d, 1H, J = 7.2Hz), 7.08 (d, 1H, J = 7.2Hz); １３ C NMR (100MHz, CDCl ３) δ: 14.5, 25.8, 26.8, 29.1, 29.2, 29.3 (5C), 29.4, 39.4, 58.7, 69.7, 70.2 (2C), 70.3 (2C), 71.2, 71.6, 121.3, 126.3, 132.0, 143.7, 164.4; IR(neat)cm −１ :3334,1632; MS (EI) m / z (%): 471 (18.3) [M] ＋ , 324 (32.2), 125 (100.0); HRMS (EI) m / z: Calcd for C ２５ H ４５ NO ５ S:471.3018;Found:471.3021[M] ＋ .

[0368] Example 12 Synthesis of N-(13,16,19,22-tetraoxatricosan-1-yl)-4-methylthiophene-3-carboxamide (compound (I-12))

[0369]

[0370] To a solution of compound (14a) (86.5 mg, 0.249 mmol) obtained in Example 9 (9-4) in dehydrated tetrahydrofuran (1.24 mL), 4-methylthiophene-3-carboxylic acid (Sigma-Aldrich) (compound (8d)) (70.8 mg, 0.498 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.597 mmol), and N,N-dimethyl-4-aminopyridine (60.8 mg, 0.498 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2) to obtain the title compound (compound (I-12)) (94.3 mg, 79%) as a pale yellow oil. １ H NMR (400MHz, CDCl ３) δ: 1.26-1.33 (m, 16H), 1.58 (m, 4H), 2.42 (s, 3H), 3.38 (s, 3H), 3.41-3.47 (m , 4H), 3.55-3.67 (m, 12H), 5.84 (br, 1H), 6.94 (m, 1H), 7.58 (d, 1H, J = 4.4Hz); １３ C NMR (100MHz, CDCl ３ ) δ: 15.4, 25.9, 26.8, 29.2, 29.3, 29.4 (5C), 29. , 39.6, 58.8, 69.8, 70.3, 70.4 (3C), 71.3, 71.7, 122.5, 127.0, 137.1, 137.3, 164.8; IR (neat) cm −１ : 3335, 1635; MS (EI) m / z: 471 (22.1) [M] ＋ , 324 (43.1), 308 (30.2), 125 (100); HRMS (EI) m / z: Calcd for C ２５ H ４５ NO ５ S:471.3018;Found:471.3014[M] ＋ .

[0371] Example 13 Synthesis of N-(13,16,19,22-tetraoxatricosan-1-yl)-5-bromothiophene-3-carboxamide (compound (I-13))

[0372]

[0373] To a solution of compound (14a) (155 mg, 0.446 mmol) obtained in Example 9 (9-4) in dehydrated tetrahydrofuran (2.23 mL), 5-bromothiophene-3-carboxylic acid (Sigma-Aldrich) (compound (8e)) (185 mg, 0.892 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (205 mg, 1.07 mmol), and N,N-dimethyl-4-aminopyridine (109 mg, 0.892 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 23 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:2) to obtain the title compound (compound (I-13)) (209 mg, 87%) as a white solid. M. p. 35.6-37.0℃ (dec.); １ H NMR (400MHz, CDCl ３ ) δ: 1.26-1.32 (m, 16H), 1.53-1.60 (m, 4H), 3.38 (s, 3H), 3.40-3.47 (m, 4H), 3. 54-3.67 (m, 12H), 5.93 (br, 1H), 7.32 (d, 1H, J = 2.4Hz), 7.74 (d, 1H, J = 2.4Hz); １３ C NMR (100MHz, CDCl ３ ) δ: 25.9, 26.9, 29.2, 29.3, 29.4 (6C), 39.8, 58.8, 69.9, 70.3 (2C), 70.4 (2C), 71.3, 71.7, 112.8, 128.8, 129.2, 137.8, 161.8; IR (neat) cm −１ : 3301, 1611; MS (EI) m / z: 537 (13.8) [M+2] ＋ , 535 (12.6) [M] ＋ , 456 (35.6), 388 (64.1), 59 (100); HRMS (EI) m / z: Calcd for C ２４ H ４２ BrNO ５ S:535.1967;Found:535.1962[M] ＋ .

[0374] Example 14 Synthesis of N-(13,16,19,22-tetraoxatricosan-1-yl)-4-bromothiophene-3-carboxamide (compound (I-14))

[0375]

[0376] To a solution of compound (14a) (155 mg, 0.446 mmol) obtained in Example 9 (9-4) in dehydrated tetrahydrofuran (2.23 mL), 4-bromothiophene-3-carboxylic acid (Sigma-Aldrich) (compound (8f)) (185 mg, 0.892 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (205 mg, 1.07 mmol), and N,N-dimethyl-4-aminopyridine (109 mg, 0.892 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:2) to obtain the title compound (compound (I-14)) (224 mg, 94%) as a colorless oil. １ H NMR (400MHz, CDCl ３ ) δ: 1.27-1.39 (m, 16H), 1.53-1.67 (m, 4H), 3.38 (s, 3H), 3.42-3.47 (m, 4H), 3. 56-3.66 (m, 12H), 6.67 (br, 1H), 7.33 (d, 1H, J = 4.8Hz), 8.05 (d, 1H, J = 4.8Hz); １３ C NMR (100MHz, CDCl ３ ) δ: 25.8, 26.7, 29.0, 29.1, 29.2 (2C), 29.3 (3C), 29.4, 39.6, 58.7, 69.8, 70.2, 70.3 (3C), 71.2, 71.6, 107.2, 125.0, 131.0, 135.7, 161.6; IR(neat)cm −１ : 3307, 1644; MS (EI) m / z: 537 (4.7) [M+2] ＋ , 535 (5.5) [M] ＋ , 388 (19.2), 83 (100); HRMS (EI) m / z: Calcd for C２４ H ４２ BrNO ５ S:535.1967;Found:535.1965[M] ＋ .

[0377] Example 15 Synthesis of N-(13,16,19,22,25-pentaoxadotriacontan-1-yl)thiophene-3-carboxamide (compound (I-15))

[0378]

[0379] (15-1) Synthesis of 11-(t-butyldimethylsilyloxy)-3,6,9-trioxa-1-undecanol (compound (2b))

[0380]

[0381] Under a nitrogen atmosphere, sodium hydride (60% in oil, 1.13 g, 28.3 mmol) was added to dehydrated tetrahydrofuran (51.4 mL), and tetraethylene glycol (Tokyo Chemical Industry Co., Ltd.) (compound (1b)) (4.44 mL, 25.7 mmol) was added under ice cooling and stirred at the same temperature for 10 minutes. t-Butyldimethylsilyl chloride (4.66 g, 30.9 mmol) was added at the same temperature and stirred at room temperature for 3 hours. Water was added at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 2:1 → 1:1) to obtain 11-(t-butyldimethylsilyloxy)-3,6,9-trioxa-1-undecanol (compound (2b)) (3.16 g, 40%) as a pale yellow oil. １ H NMR (400MHz, CDCl ３ ) δ: 0.07 (s, 6H), 0.89 (s, 9H), 3.56 (t, 2H, J = 5.3Hz), 3.61-3.63 (m, 2H), 3.67-3.68 (m, 8H), 3.71-3.74 (m, 2H), 3.77 (t, 2H, J = 5.4Hz). The synthesized compound (2b) １The 1 H NMR was consistent with the data for the same compound described in a non-patent document (Bar-Shir, A. et al., J. Org. Chem., 2005, 70(7), 2660-2666).

[0382] (15-2) Synthesis of 1-azido-24-(t-butyldimethylsilyloxy)-13,16,19,22-tetraoxatetracosane (compound (6b))

[0383]

[0384] Under a nitrogen atmosphere, sodium hydride (60% in oil, 51.8 mg, 1.30 mmol) was added to a solution of compound (2b) (200 mg, 0.648 mmol) in dehydrated dimethylformamide (0.648 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. At the same temperature, 15-crown-5-ether (0.256 mL, 1.30 mmol) and 1-azido-12-bromododecane (compound (11a)) (376 mg, 1.30 mmol) obtained in Reference Example 4 were added, and the mixture was stirred at room temperature for 29 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1→5:1) to obtain 1-azido-24-(t-butyldimethylsilyloxy)-13,16,19,22-tetraoxatetracosane (compound (6b)) (0.255 g, 76%) as a colorless, transparent oil. １ H NMR (400MHz, CDCl ３ ) δ: 0.07 (s, 6H), 0.89 (s, 9H), 1.24-1.40 (m, 16H), 1.54-1.66 (m, 4H), 3.26 (t, 2H, J = 7.0H z), 3.45 (t, 2H, J = 6.8Hz), 3.54-3.59 (m, 4H), 3.63-3.68 (m, 10H), 3.77 (t, 2H, J = 5.4Hz); １３ C NMR (75 MHz, CDCl ３) δ: -5.3 (2C), 18.3, 25.9 (3C), 26.0, 26.7, 28.8, 29.1, 29.42, 29.43, 29.47, 29.5 1, 29.52, 29.6, 51.4, 62.7, 70.0, 70.55, 70.58, 70.65, 70.66, 71.49, 71.50, 72.6; IR(ATR)cm −１ : 2093, 1102; MS (ESI) m / z: 540 [M+Na] ＋ ; HRMS (ESI) m / z: Calcd for C ２６ H ５５ N ３ NaO ５ Si: 540.3803; Found: 540.3794 [M+Na] ＋ .

[0385] (15-3) Synthesis of 24-azido-3,6,9,12-tetraoxa-1-tetracosanol (compound (12b))

[0386]

[0387] Under an argon atmosphere, tetra-n-butylammonium fluoride (approximately 1.00 M tetrahydrofuran solution, 6.29 mL, 6.29 mmol) was added dropwise to a solution of compound (6b) (326 mg, 0.629 mmol) in dehydrated tetrahydrofuran (6.29 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1 → 1:2) to obtain 24-azido-3,6,9,12-tetraoxa-1-tetracosanol (compound (12b)) (204 mg, 80%) as a pale yellow oil. １ H NMR (500MHz, CDCl ３ ) δ: 1.26-1.39 (m, 16H), 1.55-1.74 (m, 4H), 2.69 (br, 1H), 3.26 (t, 2H, J = 7.0Hz), 3.45 (t, 2H, J = 6.8Hz), 3.58-3.74 (m, 16H); １３ C NMR (75 MHz, CDCl ３) δ: 28.7, 29.1 (2C), 29.37 (2C), 29.42, 29.45, 29.47, 26.0, 26.6, 51.4, 61.6, 69.9, 70.2, 70.44, 70.47, 70.50, 70.51, 71.5, 72.5; IR(ATR)cm −１ : 3458, 2093, 1105; MS (ESI) m / z: 426 [M+Na] ＋ ; HRMS (ESI) m / z: Calcd for C ２０ H ４１ N ３ NaO ５ :426.2938;Found:426.2939[M+Na] ＋ .

[0388] (15-4) Synthesis of 1-azido-13,16,19,22,25-pentaoxadotriacontane (compound (13b))

[0389]

[0390] Under a nitrogen atmosphere, sodium hydride (60% in oil, 23.2 mg, 0.580 mmol) was added to a solution of compound (12b) (117 mg, 0.290 mmol) in dehydrated dimethylformamide (0.970 mL) under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. 1-Iodoheptane (manufactured by Tokyo Chemical Industry Co., Ltd.) (compound (10h)) (95.0 μL, 0.580 mmol) was added at room temperature, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:2) to obtain 1-azido-13,16,19,22,25-pentaoxadotriacontane (compound (13b)) (108 mg, 74%) as a colorless, transparent oil. １ H NMR (400MHz, CDCl ３ ) δ: 0.88 (t, 3H, J = 6.9Hz), 1.23-1.40 (m, 24H), 1.54-1.68 (m, 6H), 3.26 (t, 2 H, J = 7.0Hz), 3.45 (t, 4H, J = 6.8Hz), 3.57-3.59 (m, 4H), 3.63-3.66 (m, 12H);１３ C NMR (100MHz, CDCl ３ ) δ: 14.1, 22.6, 25.98, 26.01 (2C), 26.7, 28 .8,29.1,29.42,29.43,29.47,29.49,29.50 ,29.52,29.55,31.8,51.4,70.0,70.49 (2C ), 70.50 (2C), 70.53 (2C), 70.54, 71.5 (2C); IR(ATR)cm −１ : 2093, 1107; MS (ESI) m / z: 524 [M+Na] ＋ ; HRMS (ESI) m / z: Calcd for C ２７ H ５５ N ３ NaO ５ :524.4034; Found:524.4039[M+Na] ＋ .

[0391] (15-5) Synthesis of compound (I-15)

[0392]

[0393] To a solution of compound (13b) (174 mg, 0.347 mmol) in diethyl ether / water (1:1, 3.47 mL), triphenylphosphine (137 mg, 0.520 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 18 hours. A 3M aqueous solution of sodium hydroxide was added at room temperature, and the mixture was extracted with diethyl ether. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Under an argon atmosphere, 3-thiophenecarboxylic acid (compound (8a)) (89.0 mg, 0.694 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (133 mg, 0.694 mmol), and N,N-dimethyl-4-aminopyridine (85.0 mg, 0.694 mmol) were added to a solution of the residue in dehydrated tetrahydrofuran (6.94 mL) under ice cooling, and the mixture was stirred at room temperature for 28 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1) to obtain the title compound (compound (I-15)) (0.112 g, 55%) as a white waxy solid. M.p. 51.6-52.4°C; １ H NMR (500MHz, CDCl ３ ) δ: 0.88 (t, 3H, J=7.0Hz), 1.22-1.39 (m, 24H), 1.55-1.63 (m, 6H), 3.40-3.46 (m, 6H), 3.57-3.60 (m, 4H), 3.62-3. 66 (m, 12H), 5.96 (br, 1H), 7.34 (dd, 1H, J = 5.0, 3.0Hz), 7.37 (dd, 1H, J = 5.0, 1.3Hz), 7.84 (dd, 1H, J = 3.0, 1.3Hz); １３ C NMR (75 MHz, CDCl ３ ) δ: 14.0, 22.5, 25.95, 25.98, 27.0, 29.0, 29.2, 29.37 (2C), 29.43, 29.45 (2C), 29.52, 29.53, 29 .6, 31.7, 39.8, 69.9 (3C), 70.48 (2C), 70.52 (3C), 71.4 (2C), 126.1, 126.2, 127.8, 137.7, 163.0; IR(ATR)cm −１:3333,1622; MS (EI) m / z (%): 585 (11.3) [M] ＋ , 310 (44.3), 294 (42.4), 111 (100.0); HRMS (EI) m / z: Calcd for C ３２ H ５９ NO ６ S:585.4063;Found:585.4066[M] ＋ .

[0394] Example 16 Synthesis of N-(10,13,16,19,22-pentaoxadotriacontan-1-yl)thiophene-3-carboxamide (compound (I-16))

[0395]

[0396] (16-1) Synthesis of 1-azido-21-(t-butyldimethylsilyloxy)-10,13,16,19-tetraoxaheneicosane (compound (6c))

[0397]

[0398] Under a nitrogen atmosphere, sodium hydride (60% in oil, 51.8 mg, 1.30 mmol) was added to a solution of compound (2b) (200 mg, 0.648 mmol) obtained in Example 15 (15-1) in dehydrated dimethylformamide (0.648 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. 1-Azido-9-bromononane (compound (11b)) (481 mg, 1.94 mmol) obtained in Reference Example 5 was added at the same temperature, and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1→5:1) to obtain 1-azido-21-(t-butyldimethylsilyloxy)-10,13,16,19-tetraoxaheneicosane (compound (6c)) (0.171 g, 56%) as a colorless, transparent oil. １ H NMR (500MHz, CDCl ３) δ: 0.06 (s, 6H), 0.89 (s, 9H), 1.25-1.37 (m, 10H), 1.55-1.65 (m, 4H), 3.26 (t, 2H, J=7.0H z), 3.45 (t, 2H, J = 6.8Hz), 3.55-3.59 (m, 4H), 3.63-3.66 (m, 10H), 3.77 (t, 2H, J = 5.5Hz); １３ C NMR (75 MHz, CDCl ３ ) δ: -5.3 (2C), 18.3, 25.9 (3C), 26.0, 26.7, 28.8, 29.0, 29.3, 29.4, 29.6, 51.4, 62.7, 70.0, 70.57 (2C), 70.60, 70.7, 71.5 (2C), 72.6; IR(ATR)cm −１ : 2093, 1101; MS (ESI) m / z: 498 [M+Na] ＋ ; HRMS (ESI) m / z: Calcd for C ２３ H ４９ N ３ NaO ５ Si:498.3334; Found:498.3339 [M+Na] ＋ .

[0399] (16-2) Synthesis of 21-azido-3,6,9,12-tetraoxaheneicosan-1-ol (compound (12c))

[0400]

[0401] Under an argon atmosphere, tetra-n-butylammonium fluoride (approximately 1.00 M tetrahydrofuran solution, 8.37 mL, 8.37 mmol) was added dropwise to a solution of compound (6c) (398 mg, 0.837 mmol) in dehydrated tetrahydrofuran (8.37 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1 → 1:2) to obtain 21-azido-3,6,9,12-tetraoxaheneicosan-1-ol (compound (12c)) (281 mg, 93%) as a pale yellow oil. １ H NMR (500MHz, CDCl３ ) δ: 1.25-1.39 (m, 10H), 1.55-1.62 (m, 4H), 2.84 (br, 1H), 3.26 (t, 2H, J = 7.0Hz), 3.45 (t, 2H, J = 6.8Hz), 3.58-3.74 (m, 16H); １３ C NMR (75 MHz, CDCl ３ ) δ: 25.9, 26.6, 28.7, 29.0, 29.2, 29.3, 29.5, 51.3, 61.6, 69.9, 70.2, 70.42, 70.44, 70.47, 70.48, 71.4, 72.5; IR (ATR) cm −１ : 3456, 2092; MS (ESI) m / z: 384 [M+Na] ＋ ; HRMS (ESI) m / z: Calcd for C １７ H ３５ N ３ NaO ５ :384.2469;Found:384.2471[M+Na] ＋ .

[0402] (16-3) Synthesis of 1-azido-10,13,16,19,22-pentaoxadotriacontane (compound (13c))

[0403]

[0404] Under a nitrogen atmosphere, sodium hydride (60% in oil, 37.8 mg, 0.946 mmol) was added to a solution of compound (12c) (171 mg, 0.473 mmol) in dehydrated dimethylformamide (1.58 mL) under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. 1-Iododecane (compound (10 g)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (0.211 mL, 0.946 mmol) was added at room temperature, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 5:1) to obtain 1-azido-10,13,16,19,22-pentaoxadotriacontane (compound (13c)) (191 mg, 81%) as a colorless, transparent oil. １ H NMR (500MHz, CDCl ３) δ: 0.88 (t, 3H, J=7.0Hz), 1.26-1.38 (m, 24H), 1.55-1.69 (m, 6H), 3.26 (t, 2 H, J=7.0Hz), 3.45 (t, 4H, J=6.8Hz), 3 .57-3.60 (m, 4H), 3.62-3.66 (m, 12H); １３ C NMR (75MHz, CDCl ３ ) δ: 14.1, 22.6, 25.97, 26.02, 26.6 (2C), 28.8, 29.0, 29.25, 29.28, 29.33, 29.4, 29. 50, 29.54, 29.6, 31.8, 51.4, 70.0 (2C), 70 .52(2C),70.54(2C),71.4(2C),71.5(2C); IR(ATR)cm −１ : 2093, 1106; MS (ESI) m / z: 524 [M+Na] ＋ ; HRMS (ESI) m / z: Calcd for C ２７ H ５５ N ３ NaO ５ :524.4034; Found:524.4035[M+Na] ＋ .

[0405] (16-4) Synthesis of compound (I-16)

[0406]

[0407] To a solution of compound (13c) (169 mg, 0.337 mmol) in diethyl ether / water (1:1, 3.37 mL), triphenylphosphine (177 mg, 0.674 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 68 hours. A 3M aqueous solution of sodium hydroxide was added at room temperature, and the mixture was extracted with diethyl ether. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Under an argon atmosphere, 3-thiophenecarboxylic acid (compound (8a)) (144 mg, 1.01 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (194 mg, 1.01 mmol), and N,N-dimethyl-4-aminopyridine (123 mg, 1.01 mmol) were added to a solution of the residue in dehydrated tetrahydrofuran (6.74 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1) to obtain the title compound (compound (I-16)) (165 mg, 84%) as a white waxy solid. M.p. 50.5-52.3°C; １ H NMR (500MHz, CDCl ３ ) δ: 0.88 (t, 3H, J = 7.0Hz), 1.23-1.40 (m, 24H), 1.55-1.63 (m, 6H), 3.43 (td, 2H, J = 7.2, 6.0Hz), 3.45 (t, 4H, J = 6.8Hz), 3.57-3.60 (m, 4H), 3.62-3.66 (m, 12H), 5.96 (br, 1H), 7.34 (dd, 1H, J = 5.1, 3.1Hz), 7.38 (dd, 1H, J = 5.1, 1.3Hz), 7.85 (dd, 1H, J = 3.1, 1.3Hz); １３ C NMR (75 MHz, CDCl ３ ) δ: 14.0, 22.6, 25.9, 26.0, 26.8, 29.1, 29.21, 29.24, 29.3, 29.4 (2C), 29.45 (2C), 29.49, 29.6, 31.8 , 39.7, 69.90, 69.91, 70.4 (3C), 70.5 (2C), 71.36, 71.43 (2C), 126.09, 126.10, 127.8, 137.7, 163.0; IR(ATR)cm −１: 3332, 1622; MS (EI) m / z (%): 585 (78.3) [M] ＋ , 268 (69.6), 252 (71.2), 111 (100.0); HRMS (EI) m / z: Calcd for C ３２ H ５９ NO ６ S:585.4063;Found:585.4064[M] ＋ .

[0408] Example 17 Synthesis of N-(13,16,19,22-tetraoxaoctacosane-1-yl)-1-methylpyrazole-5-carboxamide (compound (I-17))

[0409]

[0410] (17-1) Synthesis of 1-azido-13,16,19,22-tetraoxaoctacosane (compound (13d))

[0411]

[0412] Under an argon atmosphere, sodium hydride (60% in oil, 11.3 mg, 0.464 mmol) was added to a solution of 21-azido-3,6,9-trioxa-1-heneicosanol (compound (12a)) (167 mg, 0.464 mmol) obtained in Example 8 (8-1) in dehydrated dimethylformamide (2.00 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. 1-Iodohexane (compound (10e)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (0.102 mL, 0.696 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to obtain 1-azido-13,16,19,22-tetraoxaoctacosane (compound (13d)) (87.7 mg, 43%) as a colorless, transparent oil. １ H NMR (300MHz, CDCl ３) δ: 0.88 (t, 3H, J = 6.8Hz), 1.27-1.35 (m, 22H), 1.53-1.64 (m, 6H), 3.25 (t, 2H, J=7.0Hz), 3.45 (t, 4H, J=6.8Hz), 3.56-3.66 (m, 12H); １３ C NMR (100MHz, CDCl ３ ) δ: 14.0, 22.5, 25.7, 26.0, 26.6, 28.7, 29.1, 29.4 (3C) , 29.5 (4C), 29.6, 51.4, 70.0 (2C), 70.5 (4C), 71.4 (2C); IR(ATR)cm −１ : 2093; MS (ESI) m / z: 466 [M] ＋ ; HRMS (ESI) m / z: Calcd for C ２４ H ４９ N ３ O ４ : 466.3615; Found: 466.3614 [M+Na] ＋ .

[0413] (17-2) Synthesis of compound (I-17)

[0414]

[0415] To a solution of compound (13d) (77.7 mg, 0.175 mmol) in diethyl ether / water (1:1, 3.50 mL), triphenylphosphine (69.0 mg, 0.263 mmol) was added at room temperature and stirred at the same temperature for 69 hours. 1M aqueous sodium hydroxide was added to the reaction mixture at room temperature to adjust the solution to basicity (pH = 11), followed by extraction with diethyl ether. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Under an argon atmosphere, 1-methylpyrazole-5-carboxylic acid (compound (8g)) (44.1 mg, 0.175 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 0.350 mmol), and N,N-dimethyl-4-aminopyridine (42.8 mg, 0.350 mmol) were added to a solution of the residue in dehydrated tetrahydrofuran (3.50 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane → n-hexane:ethyl acetate = 5:1) to obtain the title compound (compound (I-17)) (63.3 mg, 69%) as a colorless, transparent oil. １ H NMR (300MHz, CDCl ３ ) δ: 0.88 (t, 3H, J = 6.7Hz), 1.22-1.37 (m, 22H), 1.53-1.59 (m, 6H), 3.37 (t, 2H, J = 6.8Hz), 3.44 (t, 4H, J = 6.8Hz), 3.56-3.66 (m, 12H), 4.17 (s, 3H) 6.28 (br, 1H), 6.51 (d, 1H, J = 2.0Hz), 7.42 (d, 1H, J = 2.0Hz); １３ C NMR (100MHz, CDCl ３ ) δ: 13.9, 22.5, 25.7, 26.0, 26.9, 29.2, 29.4 (4C), 29.5 (3C), 31.6 (2C), 39.1, 39.5, 70.0 (2C), 70.5 (4C), 71.4 (2C), 105.9, 135.4, 137.4, 160.0; IR(ATR)cm −１ :3324,1666; MS (EI) m / z (%): 525 (15.3) [M] ＋, 416 (25.1), 308 (100.0), 292 (82.2), 138 (38.8), 109 (100.0), 85 (51.2), 43 (75.9); HRMS (EI) m / z: Calcd for C ２９ H ５５ N ３ O ５ :525.4142;Found:525.4141[M] ＋ .

[0416] Example 18 Synthesis of N-(13,16,19,22-tetraoxadotriacontan-1-yl)-1-methylpyrazole-5-carboxamide (compound (I-18))

[0417]

[0418] (18-1) Synthesis of 1-azido-13,16,19,22-tetraoxadotriacontane (compound (13e))

[0419]

[0420] Under a nitrogen atmosphere, sodium hydride (60% in oil, 6.9 mg, 0.288 mmol) was added to a solution of 21-azido-3,6,9-trioxa-1-heneicosanol (compound (12a)) (104 mg, 0.288 mmol) obtained in Example 8 (8-1) in dehydrated dimethylformamide (0.961 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. Then, 1-iododecane (compound (10 g)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (92.2 μL, 0.432 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=30:1→10:1) to obtain 1-azido-13,16,19,22-tetraoxadotriacontane (compound (13e)) as a colorless, transparent oil (86.5 mg, 60%). １ H NMR (300MHz, CDCl ３) δ: 0.88 (t, 3H, J = 6.7Hz), 1.22-1.38 (m, 30H), 1.53-1.62 (m, 6H), 3.26 (t, 2H, J=7.0Hz), 3.45 (t, 4H, J=6.8Hz), 3.56-3.66 (m, 12H); １３ C NMR (100MHz, CDCl ３ ) δ: 14.0, 22.6, 25.7, 26.0, 26.6, 28.8 (2C), 29.0 (3C), 29.3 (4C), 29.5 (2C), 29.6, 29.7, 31.8, 51.4, 70.0 (2C), 70.5 (4C), 71.4 (2C); IR(ATR)cm −１ : 2093; MS (ESI) m / z: 522 [M+Na] ＋ ; HRMS (ESI) m / z: Calcd for C ２８ H ５７ N ３ O ４ :522.4241; Found:522.4250[M+Na] ＋ .

[0421] (18-2) Synthesis of compound (I-18)

[0422]

[0423] To a solution of compound (13e) (127 mg, 0.283 mmol) in a diethyl ether / water (1:1, 2.83 mL) mixture, triphenylphosphine (112 mg, 0.424 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 24 hours. A 1 M aqueous solution of sodium hydroxide was added to the reaction mixture at room temperature, followed by extraction with diethyl ether, and the solvent was evaporated under reduced pressure. Under a nitrogen atmosphere, 1-methylpyrazole-5-carboxylic acid (compound (8g)) (357 mg, 2.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (543 mg, 2.83 mmol), and N,N-dimethyl-4-aminopyridine (346 mg, 2.83 mmol) were added to a solution of the residue in dehydrated tetrahydrofuran (2.84 mL) under ice cooling. The mixture was stirred at room temperature for 23 hours, followed by addition of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane → n-hexane:ethyl acetate = 2:1) to give the title compound (compound (I-18)) as a white solid (86.8 mg, 53%). M.p. 35.8°C-38.6°C; １ H NMR (400MHz, CDCl ３ ) δ: 0.86 (t, 3H, J = 6.7Hz), 1.18-1.32 (m, 30H), 1.52-1.61 (m, 6H ２ ), 3.52-3.45 (m, 6H), 3.55-3.65 (m, 12H), 4.16 (s, 3H) 5.95 (br, 1H), 6.45 (d, 1H, J = 2.0Hz), 7.42 (d, 1H, J = 2.0Hz); １３ C NMR (100MHz, CDCl ３ ) δ: 14.1, 22.6, 26.0, 26.1, 26.9, 29.2, 29.3 (2C), 29.4 (4C), 29.5 (4C), 29.7 (2C) , 31.8, 39.2, 39.5, 70.0, 70.5 (4C), 70.9 (2C), 71.5, 105.9, 135.4, 137.4, 160.0; IR(ATR)cm −１ :3271,1641; MS (EI) m / z (%): 581 (8.2) [M] ＋, 308 (78.4), 270 (69.0), 109 (100.0); HRMS (EI) m / z: Calcd for C ３３ H ６３ N ３ O ５ :581.4768;Found:581.4768[M] ＋ .

[0424] Example 19 Synthesis of N-(13,16,19,22-tetraoxadotriacontan-1-yl)2-methylpyrazole-3-sulfonamide (I-19)

[0425]

[0426] To a solution of compound (13e) (50.0 mg, 0.100 mmol) in a diethyl ether / water (1:1, 1.00 mL) mixture, triphenylphosphine (39.3 mg, 0.150 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 23 hours. A 3M aqueous sodium hydroxide solution was added to the reaction mixture at room temperature, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Under a nitrogen atmosphere, 3-methylpyrazole-2-sulfonic acid chloride (compound (8h)) (27.1 mg, 0.150 mmol) obtained in Reference Example 6 and distilled triethylamine (0.419 mL, 0.300 mmol) were added to a solution of the residue in dehydrated dichloromethane (1.00 mL) at room temperature, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane → n-hexane:ethyl acetate = 5:1 → 3:1) to obtain N-(13,16,19,22-tetraoxadotriacontan-1-yl)2-methylpyrazole-3-sulfonamide (compound (I-19)) (57.9 mg, 94%) as a white waxy solid. M.p. 40°C or less; １ H NMR (300MHz, CDCl ３)δ: 0.86 (t, 3H, J=6.7Hz), 1.22-1.32 (m, 30H), 1. 48 (qn, 2H, J = 6.7Hz), 1.56 (qn, 4H, J = 6.7Hz), 3.04 (q, 2H, J=6.7Hz), 3.45 (t, 4H, J=6.7Hz), 3.55-3.5 8 (m, 4H), 3.61-6.65 (m, 8H), 4.08 (s, 3H), 4.89 (br s, 1H), 6.74 (d, 1H, J=2.0Hz), 7.45 (d, 1H, J=2.0Hz); １３ C NMR (75MHz, CDCl ３ ) δ: 14.1, 22.6, 26.0, 26.1, 26.4, 29.0, 29.3, 29.35 ,29.40(2C),29.44,29.45(2C),29.48,29.54,29.5 7 (2C), 29.63, 31.9, 38.5, 43.3, 70.0, 70.56, 70.57 (2C), 71.50 (2C), 71.52 (2C), 111.0, 137.6, 139.0; IR(ATR)cm −１ : 3291, 1325, 1143; MS (FAB): m / z (%) = 618 [M+H] ＋ ; HRMS (FAB): m / z[M+H] ＋ calcd for C ３２ H ６４ N ３ O ６ S: 618.4516; found: 618.4511.

[0427] Example 20 N−(13,16,19,22−テトラオキサドトリアコンタンSynthesis of −1−イル)チオフェン−2−カルボキサミド(I−20)

[0428]

[0429] To a solution of compound (13e) (50.0 mg, 0.100 mmol) in a diethyl ether / water (1:1, 1.00 mL) mixture, triphenylphosphine (39.3 mg, 0.150 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 26 hours. A 1 M aqueous solution of sodium hydroxide was added to the reaction solution at room temperature, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Under a nitrogen atmosphere, 2-thiophenecarboxylic acid (compound (8i)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (25.6 mg, 0.200 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38.3 mg, 0.200 mmol), and N,N-dimethyl-4-aminopyridine (24.4 mg, 0.200 mmol) were added to a solution of the residue in dehydrated tetrahydrofuran (2.00 mL) under ice cooling, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain N-(13,16,19,22-tetraoxadotriacontan-1-yl)thiophene-2-carboxamide (compound (I-20)) (50.3 mg, 86%) as a white waxy solid. M.p. 42.1-43.3°C; １ H NMR (300MHz, CDCl ３ ) δ: 0.87 (t, 3H, J=6.9Hz), 1.25-1.38 (m, 30H), 1.57 (qn, 4H), 1.60 (qn, 2H), 3.41 (t, 2H, J = 6.9Hz), 3.44 (t, 4H, J = 6.9Hz), 3.56-3.58 (m, 4H), 3.63-3.66 (m, 8H), 5.98 (br s, 1H), 7.07 (dd, 1H, J = 5.0, 3.8Hz), 7.46 (d, 1H, J = 5.0Hz), 7.48 (d, 1H, J = 3.8Hz); １３ C NMR (75 MHz, CDCl ３) δ: 14.1, 22.7, 26.0, 26.1, 26.9, 29.26, 29.29, 29.4, 29.46, 29.47, 29.50, 29.51, 29.52, 29.53, 29.58, 29.5 9, 29.65, 29.66, 31.9, 40.0, 70.0 (2C), 70.57 (2C), 70.59 (2C), 71.5 (2C), 127.5, 127.7, 129.5, 139.2, 161.8; IR(ATR)cm −１ :3321,1622; MS (EI): m / z (%) = 584 (13.6) [M+H] ＋ , 472 (7.5), 310 (83.9), 294 (66.1), 111 (100), 83 (13.7); HRMS (EI) m / z: Calcd for C ３３ H ６１ NO ５ S:583.4270;found:583.4268[M] ＋ .

[0430] Example 21 Synthesis of N-(13,16,19,22-tetraoxadotriacontan-1-yl)pyrimidine-4-carboxamide (I-21)

[0431]

[0432] To a solution of compound (13e) (50.0 mg, 0.100 mmol) in a diethyl ether / water (1:1, 1.00 mL) mixture, triphenylphosphine (39.3 mg, 0.150 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 18 hours. A 1 M aqueous solution of sodium hydroxide was added to the reaction solution at room temperature, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Under a nitrogen atmosphere, 4-pyrimidinecarboxylic acid (compound (8j)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (24.8 mg, 0.200 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38.8 mg, 0.200 mmol), and N,N-dimethyl-4-aminopyridine (24.4 mg, 0.200 mmol) were added to a solution of the residue in dehydrated tetrahydrofuran (2.00 mL) under ice cooling, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain N-(13,16,19,22-tetraoxadotriacontan-1-yl)pyrimidine-4-carboxamide (compound (I-21)) (56.8 mg, 98%) as a white waxy solid. M.p. 46.9-47.5°C; １ H NMR (300MHz, CDCl ３ ) δ: 0.88 (t, 3H, J = 6.7Hz), 1.26-1.41 (m, 30H), 1.53-1.69 (m, 6H), 3.42-3.51 (m, 6H), 3.56-3.60 (m, 4H), 3.63-3.66 (m, 8H), 8.00 (br s, 1H), 8.13 (dd, 1H, J = 5.2, 1.2Hz), 8.97 (d, 1H, J = 5.2Hz), 9.23 (d, 1H, J = 1.2Hz); １３ C NMR (75 MHz, CDCl ３) δ: 14.1, 22.7, 26.1, 26.9, 29.27, 29.31, 29.45, 29.48, 29.49, 29.55, 29.56, 29.60, 29.62 (4C), 29. 7 (2C), 31.9, 39.6, 70.0 (2C), 70.60 (2C), 70.62 (2C), 71.5 (2C), 118.5, 156.4, 157.7, 159.2, 162.5; IR(ATR)cm −１ : 3364, 1656; MS (ESI) m / z: 602 [M+Na] ＋ ; HRMS (FAB) m / z: Calcd for C ３３ H ６１ N ３ NaO ５ :602.4509;found:602.4504[M+Na] ＋ .

[0433] Example 22 Synthesis of N-(13,16,19,22-tetraoxadotriacontan-1-yl)thiophene-3-sulfonamide (I-22)

[0434]

[0435] To a solution of compound (13e) (50.0 mg, 0.100 mmol) in diethyl ether / water (1:1, 1.00 mL) was added triphenylphosphine (39.3 mg, 0.150 mmol) at room temperature, followed by stirring at the same temperature for 18 hours. A 1M aqueous solution of sodium hydroxide was added to the reaction solution at room temperature, followed by extraction with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Under a nitrogen atmosphere, 3-thiophenesulfonic acid chloride (compound (8k)) (manufactured by Combi-Blocks) (27.4 mg, 0.150 mmol) and distilled triethylamine (0.419 mL, 0.300 mmol) were added to a solution of the residue in dehydrated dichloromethane (1.00 mL) at room temperature, followed by stirring at the same temperature for 19 hours. Water was added to the reaction solution at room temperature, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain N-(13,16,19,22-tetraoxadotriacontan-1-yl)thiophene-3-sulfonamide (compound (I-22)) (21.4 mg, 35%) as a white waxy solid. M.p. 40.6-41.7°C; １ H NMR (300MHz, CDCl ３ ) δ: 0.88 (t, 3H, J = 6.7Hz), 1.22-1.33 (m, 30H), 1.42-1.58 (m, 6H), 3.00 (q, 2H, J = 6.8Hz), 3.45 (t, 4H, J = 6.9Hz), 3.56-3.60 (m, 4H), 3.63-3.66 (m, 8H), 4.33 (br t, 1H, J = 6.0Hz), 7.36 (dd, 1H, J = 5.1, 1.3Hz), 7.43 (dd, 1H, J = 5.1, 3.0Hz), 7.96 (dd, 1H, J = 3.0, 1.3Hz); １３ C NMR (75 MHz, CDCl ３) δ: 14.1, 22.7, 26.07, 26.08, 26.5, 29.0, 29.3, 29.4, 29.46, 29.49 (2C), 29.53, 29.57 (2C), 29.60, 29 .62 (2C), 29.7, 31.9, 43.3, 70.0 (2C), 70.61 (2C), 70.62 (2C), 71.5, 71.6, 125.4, 127.9, 130.3, 140.1; IR(ATR)cm −１ : 3277, 1320, 1146; MS (ESI) m / z: 642 [M+Na] ＋ ; HRMS (ESI) m / z: Calcd for C ３２ H ６１ NNaO ６ S ２ :642.3838;found:642.3837[M+Na] ＋ .

[0436] Example 23 Synthesis of N-(13,16,19,22-tetraoxadotriacontan-1-yl)thiophene-2-sulfonamide (I-23)

[0437]

[0438] To a solution of compound (13e) (354 mg, 0.708 mmol) in a diethyl ether / water (1:1, 7.10 mL) mixture, triphenylphosphine (300 mg, 1.06 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 24 hours. A 1 M aqueous sodium hydroxide solution was added to the reaction solution at room temperature, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Under a nitrogen atmosphere, 2-thiophenesulfonic acid chloride (compound (8l)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (369 mg, 2.02 mmol) and distilled triethylamine (0.564 mL, 4.04 mmol) were added to a solution of the residue in dehydrated dichloromethane (13.4 mL) at room temperature, and the mixture was stirred at the same temperature for 17 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain N-(13,16,19,22-tetraoxadotriacontan-1-yl)thiophene-2-sulfonamide (compound (I-23)) (209 mg, 48%) as a white waxy solid. M.p. 40°C or less; １ H NMR (300MHz, CDCl ３ ) δ: 0.88 (t, 3H, J = 6.7Hz), 1.23-1.33 (m, 30H), 1.44-1.60 (m, 6H), 3.04 (q, 2H, J = 6.9Hz), 3.45 (t, 4H, J = 6.9Hz), 3.56-3.60 (m, 4H), 3.63-3.66 (m, 8H), 4,43 (br t, 1H, J = 6.0Hz), 7.10 (dd, 1H, J = 3.7, 1.4Hz), 7.59 (dd, 1H, J = 5.0, 1.4Hz), 7.61 (dd, 1H, J = 5.0, 3.7Hz); １３ C NMR (75 MHz, CDCl ３ ) δ: 14.1, 22.7, 26.06, 26.08, 26.5, 29.0, 29.3, 29.4, 29.45 (3C), 29.49 (2C), 29.53, 29.57, 29.61 , 29.62, 29.7, 31.9, 43.5, 70.0 (2C), 70.6 (2C), 71.5 (2C), 71.6 (2C), 127.3, 131.7, 132.0, 141.0; IR(ATR)cm−１ : 3269, 1336, 1155; MS (ESI) m / z: 642 [M+Na] ＋ ; HRMS (ESI) m / z: Calcd for C ３２ H ６１ NNaO ６ S ２ :642.3838;found:642.3827[M+Na] ＋ .

[0439] Example 24 Synthesis of N-(13,16,19-trioxanonacosan-1-yl)thiophene-3-carboxamide (compound (I-24))

[0440]

[0441] (24-1) Synthesis of 3,6-dioxa-1-heptadecanol (compound (15b))

[0442]

[0443] Under a nitrogen atmosphere, sodium hydride (manufactured by Tokyo Chemical Industry Co., Ltd.) (60% in oil, 565 mg, 14.1 mmol) and 15-crown-5 ether (manufactured by Tokyo Chemical Industry Co., Ltd.) (1.87 mL, 9.42 mmol) were added to a solution of diethylene glycol (Nacalai Tesque) (compound 1c) (0.893 mL, 9.42 mmol) in dehydrated dimethylformamide (9.42 mL) under ice cooling, and the mixture was stirred for 10 minutes. 1-Iododecane (compound (10 g)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (3.00 mL, 14.1 mmol) was added to the reaction solution at the same temperature over 30 minutes, and the mixture was stirred at room temperature for 23 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane → n-hexane:ethyl acetate = 2:1) to obtain 3,6-dioxa-1-heptadecanol (compound (15b)) (873 mg, 38%) as a pale yellow transparent oil. １ H NMR (500MHz, CDCl ３) δ: 0.88 (t, 3H, J = 6.7Hz), 1.24-1.35 (m, 14H), 1.59 (qn, 2H, J = 6.8H z), 2.51 (t, 1H, J = 6.2Hz), 3.47 (t, 2H, J = 6.9Hz), 3.57-3.76 (m, 8H); １３ C NMR (75 MHz, CDCl ３ ) δ: 14.1, 22.7, 26.1, 29.3, 29.5, 29.56, 29.57, 29.58, 31.9, 61.9, 70.2, 70.5, 71.6, 72.5; IR (ATR) cm −１ :3424; MS(FAR) m / z:247[M+H] ＋ ; HRMS (FAB) m / z: Calcd for C １４ H ３１ O ３ :247.2273;found:247.2272[M+H] ＋ .

[0444] (24-2) Synthesis of 1-azido-13,16,19-trioxanonacosane (compound (13f)

[0445]

[0446] Under a nitrogen atmosphere, 15-crown-5 ether (manufactured by Tokyo Chemical Industry Co., Ltd.) (1.41 mL, 7.08 mmol) and sodium hydride (manufactured by Tokyo Chemical Industry Co., Ltd.) (60% in oil, 283 mg, 7.08 mmol) were added to a solution of compound (15b) (873 mg, 3.54 mmol) in dehydrated dimethylformamide (10.0 mL) under ice-cooling, and the mixture was stirred for 10 minutes. A solution of 1-azido-12-bromododecane (compound (11a)) (1.54 g, 5.31 mmol) in dehydrated dimethylformamide (1.80 mL) was added to the reaction solution at the same temperature, and the mixture was stirred at room temperature for 23 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=30:1→10:1) to obtain 1-azido-13,16,19-trioxanonacosane (compound (13f)) (1.38 g, 71%) as a pale yellow, transparent oil. １H NMR (500MHz, CDCl ３ ) δ: 0.88 (t, 3H, J=7.0Hz), 1.26-1.37 (m, 30H), 1.55-1.62 (m, 6H), 3.26 (t, 2H, J=7.0Hz), 3.45 (t, 4H, J=6.8Hz), 3.58-3.60 (m, 4H), 3.64-3.66 (m, 4H); １３ C NMR(75H,CDCl ３ ) δ: 14.1, 22.7, 26.1 (2C), 26.7, 28.8, 29.1, 29.3, 29.45, 29.48, 29.51, 29.53, 2 9.54, 29.56 (2C), 29.60, 29.64 (2C), 31. 9, 51.5, 70.1 (2C), 70.6 (2C), 71.5 (2C); IR(ATR)cm −１ : 2094; MS (FAB): m / z (%) = 456 [M + H] ＋ ; HRMS (FAB) m / z: Calcd for C ２６ H ５４ N ３ O ３ : 456.4165; found: 456.4161 [M+H] ＋ .

[0447] (24-3) Synthesis of compound (I-24)

[0448]

[0449] To a solution of compound (13f) (200 mg, 0.434 mmol) in a diethyl ether / water (1:1, 4.34 mL) mixture, triphenylphosphine (231 mg, 0.878 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 44 hours. A 3M aqueous solution of sodium hydroxide was added to the reaction solution at room temperature, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Under a nitrogen atmosphere, 3-thiophenecarboxylic acid (compound (8a)) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (185 mg, 1.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (250 mg, 1.30 mmol), and N,N-dimethyl-4-aminopyridine (159 mg, 1.30 mmol) were added to a solution of the residue in dehydrated tetrahydrofuran (8.68 mL) under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture at room temperature, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) ​​to obtain N-(13,16,19-trioxanonacosan-1-yl)thiophene-3-carboxamide (compound (I-24)) (201 mg, 86%) as a white waxy solid. M.p. 74.8-75.2°C; １ H NMR (500MHz, CDCl ３ ) δ: 0.86 (t, 3H, J = 6.7Hz), 1.24-1.36 (m, 30H), 1.51-1.62 (m, 6H), 3.35-3.45 (m, 6H), 3.55-3.65 (m, 8H), 6.18 (br s, 1H), 7.30 (dd, 1H, J = 5.0, 3.0Hz), 7.37 (dd, 1H, J = 5.0, 1.3Hz), 7.84 (dd, 1H, J = 3.0, 1.3Hz); １３ C NMR (75 MHz, CDCl ３) δ: 14.1, 22.6, 26.0 (2C), 26.9, 29.3 (2C), 29.41, 29.43, 29.47, 29.50 (3C), 29.51, 29.55, 29. 57 (2C), 29.7, 31.8, 39.8, 70.0 (2C), 70.6 (2C), 71.5 (2C), 126.0, 126.3, 127.8, 137.8, 163.0; IR(ATR)cm −１ : 3330, 1623; MS (FAB) m / z: 541 [M+H] ＋ ; HRMS (FAB) m / z: Calcd for C ３１ H ５８ NO ４ S:540.4087;found:540.4083[M+H] ＋ .

[0450] Example 25 Synthesis of N-(13,16,19,22,25-pentaoxapentatriacontan-1-yl)thiophene-3-carboxamide (compound (I-25))

[0451]

[0452] (25-1) Synthesis of 1-azido-13,16,19,22,25-pentaoxapentatriacontane (compound (13g))

[0453]

[0454] Under a nitrogen atmosphere, sodium hydride (manufactured by Tokyo Chemical Industry Co., Ltd.) (60% in oil, 309 mg, 7.72 mmol) and 15-crown-5 ether (manufactured by Tokyo Chemical Industry Co., Ltd.) (1.53 mL, 7.72 mmol) were added to a solution of tetraethylene glycol (Fujifilm Wako Pure Chemical Industries, Ltd.) (compound 1b) (0.885 mL, 5.15 mmol) in dehydrated dimethylformamide (4.2 mL) under ice cooling, and the mixture was stirred for 10 minutes. 1-Iododecane (compound (10 g)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (1.64 mL, 7.72 mmol) was added to the reaction solution at the same temperature, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 10:1 → 1:1 → ethyl acetate) to give 3,6,9,12-tetraoxa-1-tricosanol (681 mg, 40%) as a pale yellow, transparent oil. Under a nitrogen atmosphere, a solution of 3,6,9,12-tetraoxa-1-tricosanol (681 mg, 2.04 mmol) in dehydrated dimethylformamide (3.0 mL) was added with sodium hydride (Tokyo Chemical Industry Co., Ltd.) (60% in oil, 163 mg, 4.07 mmol) and 15-crown-5 ether (Tokyo Chemical Industry Co., Ltd.) (0.809 mL, 4.07 mmol) under ice-cooling, and the mixture was stirred for 10 minutes. A solution of 1-azido-12-bromododecane (compound (11a)) (886 mg, 3.05 mmol) in dehydrated dimethylformamide (3.78 mL) was added to the reaction solution at the same temperature, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 10:1 → 1:1) to obtain 1-azido-13,16,19,22,25-pentaoxapentatriacontane (compound (13g)) (813 mg, 73%) as a colorless, transparent oil. １ H NMR (500MHz, CDCl ３) δ: 0.86 (t, 3H, J=6.7Hz), 1.24-1.37 (m, 30H), 1.51-1.63 (m, 6H), 3.24 (t, 2 H, J=7.0Hz), 3.43 (t, 4H, J=6.8Hz), 3 .54-3.58 (m, 4H), 3.61-3.64 (m, 12H); １３ C NMR (75MHz, CDCl ３ ) δ: 14.1, 22.6, 26.0, 26.7, 28.8, 29.1, 29.3 ,29.41,29.43,29.45,29.46,29.49,29.50,2 9.52, 29.57, 29.59 (2C), 29.62, 31.9, 51.4, 70.0 (2C), 70.55 (4C), 70.58 (2C), 71.5 (2C); IR(ATR)cm −１ : 2092; MS (FAB) m / z: 544 [M+H] ＋ ; HRMS (FAB) m / z: Calcd for C ３０ H ６２ N ３ O ５ : 544.4689; found: 544.4700 [M+H] ＋ .

[0455] (25-2) Synthesis of compound (I-25)

[0456]

[0457] To a solution of compound (13g) (477 mg, 0.877 mmol) in a diethyl ether / water (1:1, 3.68 mL) mixture, triphenylphosphine (193 mg, 0.736 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 19 hours. A 1 M aqueous solution of sodium hydroxide was added to the reaction solution at room temperature, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Under a nitrogen atmosphere, 3-thiophenecarboxylic acid (compound (8a)) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (141 mg, 1.10 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (212 mg, 1.10 mmol), and N,N-dimethyl-4-aminopyridine (135 mg, 1.10 mmol) were added to a solution of the residue in dehydrated tetrahydrofuran (7.36 mL) under ice cooling, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform → chloroform:methanol = 50:1 → 20:1) to obtain N-(13,16,19,22,25-pentaoxapentatriacontan-1-yl)thiophene-3-carboxamide (compound (I-25)) (210 mg, 38%) as a white waxy solid. M.p. 60.2-61.1°C; １ H NMR (500MHz, CDCl ３ ) δ: 0.88 (t, 3H, J = 6.7Hz), 1.26-1.39 (m, 30H), 1.57 (qn, 6H, J = 6.7Hz ), 3.38-3.47 (m, 6H), 3.56-3.59 (m, 4H), 3.62-3.66 (m, 12H), 5.93 (br s, 1H) 7.34 (dd, 1H, J = 5.1, 3.0Hz), 7.37 (dd, 1H, J = 5.1, 1.5Hz), 7.84 (dd, 1H, J = 3.0, 1.5Hz); １３ C NMR (75 MHz, CDCl ３) δ: 14.1, 22.6, 26.0 (2C), 26.9, 29.3 (2C), 29.40, 29.43, 29.45, 29.48 (2C), 29.50, 29.55, 29.56, 29.5 7 (2C), 29.7, 31.8, 39.8, 70.0 (2C), 70.5 (4C), 70.6 (2C), 71.5 (2C), 126.0, 126.3, 127.8, 137.8, 163.0; IR(ATR)cm −１ : 1623; MS (FAB) m / z: 628 [M+H] ＋ ; HRMS (FAB) m / z: Calcd for C ３５ H ６６ NO ６ S:628.4611;found:628.4619[M+H] ＋ .

[0458] Example 26 Synthesis of N-(13,16,19,22,25,28-hexaoxaoctatriacontan-1-yl)thiophene-3-carboxamide (compound (I-26))

[0459]

[0460] (26-1) Synthesis of 1-azido-13,16,19,22,25,28-hexaoxaoctatriacontane (compound (13h))

[0461]

[0462] Under a nitrogen atmosphere, sodium hydride (manufactured by Tokyo Chemical Industry Co., Ltd.) (60% in oil, 252 mg, 6.30 mmol) and 15-crown-5 ether (manufactured by Tokyo Chemical Industry Co., Ltd.) (1.25 mL, 6.30 mmol) were added to a solution of pentaethylene glycol (Fujifilm Wako Pure Chemical Industries, Ltd.) (compound 1d) (0.885 mL, 4.20 mmol) in dehydrated dimethylformamide (4.2 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. 1-Iododecane (compound (10 g)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (1.34 mL, 6.30 mmol) was added to the reaction solution at the same temperature, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 10:1 → 1:1) to give 3,6,9,12,15-pentaoxa-1-pentacosanol (723 mg, 45%) as a pale yellow, transparent oil. Under a nitrogen atmosphere, a solution of 3,6,9,12,15-pentaoxa-1-pentacosanol (723 mg, 1.91 mmol) in dehydrated dimethylformamide (1.59 mL) was added with sodium hydride (Tokyo Chemical Industry Co., Ltd.) (60% in oil, 153 mg, 3.82 mmol) and 15-crown-5 ether (Tokyo Chemical Industry Co., Ltd.) (0.759 mL, 3.82 mmol) under ice cooling, and the mixture was stirred for 10 minutes. A solution of 1-azido-12-bromododecane (compound (11a)) (833 mg, 2.87 mmol) in dehydrated dimethylformamide (4.78 mL) was added to the reaction solution at the same temperature, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 10:1 → 1:1) to obtain 1-azido-13,16,19,22,25,28-hexaoxaoctatriacontane (compound (13h)) (705 mg, 63%) as a white waxy solid. M.p. 40°C or less; １ H NMR (500MHz, CDCl ３)δ: 0.85 (t, 3H, J=6.8Hz), 1.24-1.36 (m, 30H), 1.50-1.62 (m, 6H), 3.23 (t, 2 H, J=7.0Hz), 3.42 (t, 4H, J=6.8Hz), 3 .53-3.57 (m, 4H), 3.60-3.63 (m, 16H); １３ C NMR (75MHz, CDCl ３ ) δ: 14.0, 22.6, 26.0 (2C), 26.3, 28.8, 29.1, 29.2, 29.39, 29.40 (2C), 29.43, 29.47, 2 9.49 (2C), 29.52, 29.6 (2C), 31.8, 51.4, 70 .0 (2C), 70.51 (5C), 70.54 (3C), 71.5 (2C); IR(ATR)cm −１ : 2094; MS (FAB) m / z: 610 [M+Na] ＋ ; HRMS (FAB) m / z: Calcd for C ３２ H ６５ N ３ NaO ６ :610.4771; found:610.4762[M+Na] ＋ .

[0463] (26-2) Synthesis of compound (I-26)

[0464]

[0465] To a solution of compound (13h) (389 mg, 0.661 mmol) in a diethyl ether / water (1:1, 6.8 mL) mixture, triphenylphosphine (357 mg, 1.36 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 22.5 hours. A 1 M aqueous solution of sodium hydroxide was added to the reaction mixture at room temperature, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Under a nitrogen atmosphere, 3-thiophenecarboxylic acid (compound (8a)) (FUJIFILM Wako Pure Chemical Industries, Ltd.) (261 mg, 2.04 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (391 mg, 2.04 mmol), and N,N-dimethyl-4-aminopyridine (249 mg, 2.04 mmol) were added to a solution of the residue in dehydrated tetrahydrofuran (13.6 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture at room temperature, followed by extraction with chloroform, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→1:1) to obtain the title compound (compound (I-26)) (306 mg, 69%) as a white waxy solid. M.p. 57.4-57.8°C; １ H NMR (500MHz, CDCl ３ ) δ: 0.88 (t, 3H, J = 6.7Hz), 1.26-1.33 (m, 30H), 1.57 (qn, 6H, J = 7.0Hz ), 3.38-3.46 (m, 6H), 3.56-3.59 (m, 4H), 3.62-3.65 (m, 16H), 5.97 (br s, 1H), 7.35 (dd, 1H, J = 5.1, 2.9Hz), 7.37 (dd, 1H, J = 5.1, 1.4Hz), 7.84 (dd, 1H, J = 2.9, 1.4Hz); １３ C NMR (75 MHz, CDCl ３ ) δ: 14.1, 22.6, 26.01, 26.03, 26.9, 29.3 (2C), 29.40, 29.43, 29.45, 29.48 (2C), 29.51, 29.55, 29.56 (2C), 29.57, 29.7, 31.8, 39.8, 70.0 (2C), 70.5 (5C), 70.6 (3C), 71.48, 71.49, 126.0, 126.3, 127.8, 137.8, 163.0; IR(ATR)cm −１: 3334, 1623; MS (FAB) m / z: 672 [M+H] ＋ ; HRMS (FAB) m / z: Calcd for C ３７ H ７０ NO ７ S:672.4873;found:672.4879[M+H] ＋ .

[0466] Example 27 Synthesis of N-(7,10,13,16,19,22-hexaoxadotriacontan-1-yl)thiophene-3-carboxamide (compound (I-27)

[0467]

[0468] (27-1) Synthesis of 1-benzyloxy-7,10,13,16,19,22-hexaoxadotriacontane (compound (18a))

[0469]

[0470] Under a nitrogen atmosphere, sodium hydride (manufactured by Tokyo Chemical Industry Co., Ltd.) (60% in oil, 252 mg, 6.30 mmol) and 15-crown-5 ether (manufactured by Tokyo Chemical Industry Co., Ltd.) (1.25 mL, 6.30 mmol) were added to a solution of pentaethylene glycol (Fujifilm Wako Pure Chemical Industries, Ltd.) (compound 1d) (0.885 mL, 4.20 mmol) in dehydrated dimethylformamide (4.2 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. 1-Iododecane (compound (10 g)) (manufactured by Tokyo Chemical Industry Co., Ltd.) (1.34 mL, 6.30 mmol) was added to the reaction solution at the same temperature, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1 → ethyl acetate:methanol = 10:1) to obtain 3,6,9,12,15-pentaoxa-1-pentacosanol (785 mg, 49%) as a pale yellow, transparent oil. Under a nitrogen atmosphere, sodium hydride (manufactured by Tokyo Chemical Industry Co., Ltd.) (60% in oil, 166 mg, 4.15 mmol) and 15-crown-5 ether (manufactured by Tokyo Chemical Industry Co., Ltd.) (0.824 mL, 4.15 mmol) were added to a solution of 3,6,9,12,15-pentaoxa-1-pentacosanol (785 mg, 2.07 mmol) in dehydrated dimethylformamide (1.7 mL) under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, a solution of 6-bromohexabenzyl ether (compound (19a)) (846 mg, 3.12 mmol) obtained in Reference Example 6 in dehydrated dimethylformamide (5.2 mL) was added at the same temperature, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane → n-hexane:ethyl acetate = 2:1) to obtain 1-benzyloxy-7,10,13,16,19,22-hexaoxadotriacontane (compound (18a)) (705 mg, 61%)) as a pale, colorless, transparent oil. １ H NMR (500MHz, CDCl ３) δ: 0.88 (3H, t, J = 6.7Hz), 1.25-1.43 (m, 18H), 1.52-1.66 (m, 6H), 3.44 (t, 4H, J = 6.7Hz), 3. 45 (t, 2H, J = 6.7Hz), 3.55-3.58 (m, 4H), 3.61-3.65 (m, 16H), 4.49 (s, 2H), 7.23-7.37 (5H, m); １３ C NMR (75 MHz, CDCl ３ ) δ: 14.0, 22.6, 25.9, 25.98, 26.00, 29.2, 29.4, 29.49 (2C), 29.52, 29.54, 29.6, 31.8, 70.0 (2C), 70.3, 70.50 (6C), 70.53 (2C), 71.3, 71.5, 72.8, 127.4, 127.5 (2C), 128.2 (2C), 138.6; IR(ATR)cm −１ : No characteristic peak MS (EI): m / z (%) = 568 (3.8) [M] ＋ , 477 (2.0), 91 (100); HRMS (EI): m / z Calcd for C ３３ H ６０ O ７ :568.4339;found:568.4338[M] ＋ .

[0471] (27-2) Synthesis of 7,10,13,16,19,22-hexaoxa-1-dotriacontanol (compound (16b))

[0472]

[0473] Palladium hydroxide-activated carbon (Fujifilm Wako Pure Chemical Industries, Ltd.) (palladium 20%, approximately 50% water content, 61.4 mg) was added to a solution of compound (18a) (614 mg, 1.08 mmol) in dehydrated ethyl acetate (10.8 mL) at room temperature, and the mixture was stirred at the same temperature for 3 hours under a hydrogen atmosphere at 3 atmospheres. The mixture was filtered through Celite, washed with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 7,10,13,16,19,22-hexaoxa-1-dotriacontanol (compound (16b)) (475 mg, 89%) as a colorless, transparent oil. １ H NMR (500MHz, CDCl３ ) δ: 0.84 (t, 3H, J = 6.8Hz), 1.22-1.36 (m, 18H), 1.49-1.58 (m, 6H), 1.80 (br) s, 1H), 3.41 (t, 2H, J=6.6Hz), 3.42 (t, 2H, J=6 .6Hz), 3.52-3.56 (m, 4H), 3.59-3.62 (m, 18H); １３ C NMR (75MHz, CDCl ３ ) δ: 14.0, 22.6, 25.5, 25.8, 26.0, 29.2, 29.38, 29.44, 29.46, 29.50, 29 .51, 31.8, 32.6, 62.6, 69.9, 70.0, 70.48 (6C), 70.50 (2C), 71.2, 71.4; IR(ATR)cm −１ : 3472; MS (FAB) m / z: 479 [M+H] ＋ ; HRMS (FAB) m / z: Calcd for C ２６ H ５５ O ７ : 479.3948; found: 479.3949 [M+H] ＋ .

[0474] (27-3) Synthesis of 7, 10, 13, 16, 19, 22-ヘキサオキサ-1-ヨードドトリアコンタン (compound (17b))

[0475]

[0476] Under a nitrogen atmosphere, imidazole (72.1 mg, 1.06 mmol) and iodine (269 mg, 1.06 mmol) were added to a solution of triphenylphosphine (278 mg, 1.06 mmol) in dehydrated dichloromethane (1.1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction solution, a solution of compound (16b) (392 mg, 0.818 mmol) in dehydrated dichloromethane (3.0 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 45 minutes. A saturated aqueous solution of sodium thiosulfate was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to obtain 7,10,13,16,19,22-hexaoxa-1-iododotriacontane (compound (17b)) (441 mg, 91%) as a pale yellow, transparent oil. １ H NMR (500MHz, CDCl ３ ) δ: 0.85 (t, 3H, J = 6.7Hz), 1.23-1.44 (m, 18H), 1.50-1.61 (m, 4H), 1.80 (qn, 2H, J = 7.0Hz), 3.16 (t, 2H, J = 7.0Hz), 3.42 (t, 2H, J = 7.0Hz), 3.43 (t, 2H, J = 6.6Hz), 3.53-3.57 (m, 4H), 3.60-3.63 (m, 16H); １３ C NMR (75Hz, CDCl ３ ) δ: 7.0, 14.1, 22.6, 25.0, 26.0, 29.3, 29.4, 29.49, 29.53 (2C), 29.6, 30.2, 31.8, 33.4, 69.97, 70.03, 70.5 (6C), 70.6 (2C), 71.1, 71.5; IR(ATR)cm −１ : No characteristic peak MS (FAB) m / z: 589 [M + H] ＋ ; HRMS (FAB) m / z: Calcd for C ２６ H ５４ IO ６ :589.2965;found:589.2980[M+H] ＋ .

[0477] (27-4) Synthesis of 1-azido-7,10,13,16,19,22-hexaoxadotriacontane (compound (13i))

[0478]

[0479] Sodium azide (85.7 mg, 1.30 mmol) was added to a solution of compound (17b) (382 mg, 0.649 mmol) in dehydrated dimethyl sulfoxide (2.2 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 20:1 → 10:1 → 5:1 → 1:1) to obtain 1-azido-7,10,13,16,19,22-hexaoxadotriacontane (compound (13i)) (308 mg, 94%)) as a colorless, transparent oil. １ H NMR (500MHz, CDCl ３ ) δ: 0.85 (t, 3H, J = 6.7Hz), 1.23-1.38 (m, 18H), 1.50-1.62 (m, 6H), 3.23 (t, 2H, J = 6.8Hz ), 3.42 (t, 2H, J = 6.8Hz), 3.43 (t, 2H, J = 6.8Hz), 3.53-3.56 (m, 4H), 3.60-3.63 (m, 16H); １３ C NMR (75 MHz, CDCl ３ ) δ: 14.0, 22.59, 25.61, 26.0, 26.5, 28.7, 29.24, 29.39, 29.41, 29.48, 29.52, 29.6, 31.8, 51.3, 69.96, 70.02, 70.5 (8C), 71.1, 71.5; IR(ATR)cm −１ :2092; MS(FAB) m / z:504[M+H] ＋ ; HRMS (FAB) m / z: Calcd for C ２６ H ５４ N ３ O ６ :504.4013;found:504.4034[M+H] ＋ .

[0480] (27-5) Synthesis of Compound (I-27)

[0481]

[0482] To a solution of compound (13i) (239 mg, 0.474 mmol) in a diethyl ether / water (1:1, 4.7 mL) mixture, triphenylphosphine (249 mg, 0.950 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 24 hours. A 1 M aqueous solution of sodium hydroxide was added to the reaction solution at room temperature, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Under a nitrogen atmosphere, 3-thiophenecarboxylic acid (compound (8a)) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (181 mg, 1.41 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg, 1.41 mmol), and N,N-dimethyl-4-aminopyridine (172 mg, 1.41 mmol) were added to a solution of the residue in dehydrated tetrahydrofuran (9.4 mL) under ice cooling, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution at room temperature, and the solvent was distilled off under reduced pressure. Extraction was performed using chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:chloroform = 5:1 → 3:1 → 1:1 → chloroform) to obtain N-(7,10,13,16,19,22-hexaoxadotriacontan-1-yl)thiophene-3-carboxamide (compound (I-27)) (205 mg, 74%) as a light brown waxy solid. M.p. 40°C or less; １ H NMR (500MHz, CDCl ３ ) δ: 0.88 (t, 3H, J = 6.7Hz), 1.26-1.42 (m, 18H), 1.52-1.65 (m, 6H), 3.38-3.48 (m, 6H), 3.55-3.59 (m, 4H), 3.62-3.65 (m, 16H), 6.07 (br s, 1H), 7.33 (dd, 1H, J = 5.1, 3.1Hz), 7.39 (dd, 1H, J = 5.1, 1.4Hz), 7.86 (dd, 1H, J = 3.1, 1.4Hz); １３ C NMR (75 MHz, CDCl ３) δ: 14.1, 22.6, 25.7, 26.0, 26.6, 29.3, 29.37, 29.42, 29.50, 29.54 (2C), 29.6, 31.8, 39 .6, 69.97, 69.99, 70.5 (6C), 70.6 (2C), 71.1, 71.5, 126.1, 126.2, 127.9, 137.7, 163.1; IR(ATR)cm −１ : 3329, 1622; MS (FAB) m / z: 588 [M+H] ＋ ; HRMS (FAB) m / z: Calcd for C ３１ H ５８ NO ７ S:588.3934;found:588.3925[M+H] ＋ .

[0483] Test Example 1: Growth inhibitory effect on mouse glioblastoma stem cells <Experimental method> Mouse glioblastoma stem cells were established according to the method described in the literature (Tanigawa S, et al. Cancer Gene Therapy (2021). https: / / doi.org / 10.1038 / s41417-020-00282-5), and the cells were cultured as neurosphere cells at 37°C, 5% CO using a neural stem cell culture medium containing Neurobasal Medium supplemented with B27 and N2 supplement (Gibco / Thermo Fisher Scientific, Waltham, MA, USA) and 10 ng / mL EGF and bFGF (R&D Systems, Minneapolis, MN, USA). ２ The neurospheres were cultured in an incubator. The neurospheres were treated with Accutase (Innovative Cell Technologies, San Diego, CA, USA) to prepare a single cell suspension, and then cultured at a concentration of 1 × 10 ５The cells were seeded in 6-well dishes (Thermo Fisher Scientific, Waltham, MA, USA), and the compounds of the present invention were diluted in culture medium to final concentrations of 100 nM and 500 nM and treated for 72 hours. The proliferation of these cells was evaluated by staining with trypan blue (FUJIFILM Wako Pure Chemical Corporation, Japan) and counting the number of viable cells using a Countess II automated cell counter (Thermo Fisher Scientific, Waltham, MA). The compounds of the present invention used in the test were dissolved at 2 mM in dimethyl sulfoxide (Nacalai Tesque, Kyoto, Japan).

[0484] <Experimental Results> The evaluation results are shown in Figure 1. From the results in Figure 1, it was confirmed that the compounds of the present invention inhibit the proliferation of mouse glioblastoma stem cells.

[0485] Test Example 2: Enhancement effect of temozolomide on the growth inhibitory effect on human glioblastoma cells <Experimental method> According to the method described in the literature (Matsumura K, et al. BMC Cancer (2016) 16(1):748.), human glioblastoma cell line U251 was cultured in DMEM (FUJIFILM Wako Pure Chemical Corporation, Japan) supplemented with 10% fetal bovine serum (FBS, HyClone, GE Healthcare Life Sciences, Buckinghamshire, England) and 1% penicillin / streptomycin (FUJIFILM Wako Pure Chemical Corporation, Japan). The cells were cultured at 37°C in 5% CO using a medium supplemented with 100 units / mL and 100 μg / mL of 100% ethanol (Bio-Rad Corporation, 100 units / mL and 100 μg / mL, respectively). ２The cells were cultured in an incubator. Temozolomide (Sigma Chemical, St. Louis, MO, USA), a standard treatment for glioblastoma, was dissolved in dimethyl sulfoxide (Nacalai Tesque, Kyoto, Japan) to a concentration of 200 mM. U251 cells were suspended in trypsin (Lonza, Walkersville, MD, USA) and cultured at 2.5 × 10 ３ The cells were seeded in 6-well dishes (Thermo Fisher Scientific, Waltham, MA, USA). After 24 hours, temozolomide diluted with culture medium to final concentrations of 12.5, 25, and 50 μM, and the compound of the present invention (compound (I-5)) diluted with culture medium to final concentrations of 25, 50, and 100 nM, were treated alone or in combination for 6 days. The proliferation of these cells was assessed by counting the number of viable cells using trypan blue (FUJIFILM Wako Pure Chemical Corporation, Japan) staining and a Countess II automated cell counter (Thermo Fisher Scientific, Waltham, MA). The combination index (CI) values ​​of temozolomide and the compounds of the present invention were calculated using CalcuSyn 2.11 software (Biosoft, Cambridge, UK), and isobologram analysis was performed. A CI value of less than 0.9 was determined to indicate a synergistic effect, 0.9 to less than 1.1 to indicate an additive effect, and 1.1 or more to indicate an antagonistic effect.

[0486] <Experimental Results> The evaluation results are shown in Figure 2. From the results in Figure 2, it was confirmed that compound (I-5) of the present invention synergistically enhances the growth inhibitory effect of temozolomide on human glioblastoma U251 cells. In addition, after the compound (I-5) of the present invention was allowed to act alone for 6 days, the ED ５０ The value was 43.1 nM.

[0487] Test Example 3: In vivo antitumor effect in a mouse glioblastoma transplant model <Experimental method> According to the method described in the literature (Tanigawa S, et al. Cancer Gene Therapy (2021). https: / / doi.org / 10.1038 / s41417-020-00282-5), mouse glioblastoma stem cells transfected with the luciferase gene were established, and the cells were cultured in Neurobasal Medium containing B27 and N2 supplements (Gibco / Thermo Fisher Scientific, Waltham, MA, USA) and 10 ng / ml of EGF and bFGF (R&D Neurosphere cells were cultured in a neural stem cell culture medium supplemented with HCl (C1000) (C1000) (C1000) (C1000) at 37°C and 5% CO ２ The neurospheres were cultured in an incubator. The neurospheres were treated with Accutase (Innovative Cell Technologies, San Diego, CA, USA) to prepare a single-cell suspension, and then 1 × 10 cells were suspended in 2 μL of PBS. ３ The cells were transplanted into the cerebrum of 6-week-old male C57BL6J mice (Oriental Bioservice, Kyoto, Japan) immobilized on a Stereotaxic Instrument (51730D; Stoelting Co., Wood Dale, IL, USA) using a 30-gauge Hamilton syringe and an automatic injector (Legato 130; KD Scientific, Holliston, MA, USA). Immediately after transplantation, the compound of the present invention (compound (I-5)) was dissolved in 10% dimethyl sulfoxide (Nacalai Tesque, Kyoto, Japan), 10% Cremophor EL (Sigma Chemical, St. Louis, MO, USA), and 80% saline (Nacalai Tesque, Kyoto, Japan) and intraperitoneally administered at a dose of 10 mg / kg, three times a week. Three weeks after cell transplantation, D-luciferin was intraperitoneally administered at a dose of 150 mg / kg, and the size of the in vivo tumor was evaluated using an IVIS Lumina XR imaging system (Summit Pharmaceuticals International, Tokyo, Japan).

[0488] <Experimental Results> The evaluation results are shown in Figure 3. From the results in Figure 3, it was confirmed that compound (I-5) of the present invention inhibits the growth of glioblastoma tumors transplanted in vivo in mice.

[0489] Test Example 4: Growth inhibitory effect on human colon cancer SW48 cells <Experimental method> Human colon cancer SW48 cells were cultured in a medium containing DMEM (FUJIFILM Wako Pure Chemical Corporation, Japan) supplemented with 10% fetal bovine serum (FBS, HyClone, GE Healthcare Life Sciences, Buckinghamshire, England) and 1% penicillin / streptomycin (FUJIFILM Wako Pure Chemical Corporation, 100 units / mL and 100 μg / mL, respectively) at 37°C and 5% CO ２ SW48 cells were suspended in trypsin (Lonza, Walkersville, MD, USA) and cultured at 1 × 10 ５ The cells were seeded on a 6-well dish (TPP, Trasadingen, Switzerland), and after 24 hours, the compounds of the present invention (compounds (I-4), (I-5), and (I-10)) diluted with culture medium to a final concentration of 500 nM were treated for 3 days. The proliferation of these cells was evaluated by staining with trypan blue (FUJIFILM Wako Pure Chemical Corporation, Japan) and counting the number of viable cells using a Countess II automatic cell counter (Thermo Fisher Scientific, Waltham, MA).

[0490] <Experimental Results> The evaluation results are shown in Figure 4. From the results in Figure 4, it was confirmed that the compounds of the present invention inhibit the proliferation of human colon cancer cells SW48.

[0491] Test Example 5: Effect of increasing AMP / ATP ratio in human colon cancer SW48 cells <Experimental method> Human colon cancer SW48 cells were cultured in a medium containing DMEM (FUJIFILM Wako Pure Chemical Corporation, Japan) supplemented with 10% fetal bovine serum (FBS, HyClone, GE Healthcare Life Sciences, Buckinghamshire, England) and 1% penicillin / streptomycin (FUJIFILM Wako Pure Chemical Corporation, 100 units / mL and 100 μg / mL, respectively) at 37°C and 5% CO ２ SW48 cells were suspended in trypsin (Lonza, Walkersville, MD, USA) and cultured at 1 × 10 ５ The cells were seeded in a 6-well dish (TPP, Trasadingen, Switzerland), and 24 hours later, the cells were treated with the compound of the present invention (compound (I-5)) diluted with culture medium to final concentrations of 500 nM and 1 μM, and allowed to act for 2 days. Intracellular AMP was measured using the AMP Glo assay kit (Promega, Madison, WI, USA), and intracellular ATP was measured using the Cell Titer Glo Luminescent Cell Viability Assay Kit (Promega, Madison, WI, USA) on a SYNERGY HT (BioTek Instruments, Inc. Winooski, VT, USA), and the AMP / ATP ratio was calculated.

[0492] <Experimental Results> The evaluation results are shown in Figure 5. From the results in Figure 5, it was confirmed that compound (I-5) of the present invention has the effect of increasing the AMP / ATP ratio of human colon cancer cell SW48.

[0493] Test Example 6: Increasing effect of phosphorylated AMPK in human colon cancer SW48 cells <Experimental method> Human colon cancer SW48 cells were cultured in a medium containing DMEM (FUJIFILM Wako Pure Chemical Corporation, Japan) supplemented with 10% fetal bovine serum (FBS, HyClone, GE Healthcare Life Sciences, Buckinghamshire, England) and 1% penicillin / streptomycin (FUJIFILM Wako Pure Chemical Corporation, 100 units / mL and 100 μg / mL, respectively) at 37°C and 5% CO ２ SW48 cells were suspended in trypsin (Lonza, Walkersville, MD, USA) and cultured at 1 × 10 ５ The cells were seeded in a 6-well dish (TPP, Trasadingen, Switzerland). After 24 hours, the cells were treated with the compounds of the present invention (compounds (I-4), (I-5), and (I-10)) diluted with culture medium to a final concentration of 100 nM for 2 days. Cell proteins were dissolved in 1% SDS buffer containing protease inhibitor cocktail mix (Nacalai Tesque, Kyoto, Japan), and subjected to SDS-PAGE. After transferring the DNA to a PVDF membrane (Millipore, Billerica, MA, USA), Western blot analysis was performed using anti-phospho-AMPKα (Thr172, 1:1000, #2535; CST) antibody. GAPDH protein was analyzed as a loading control.

[0494] <Experimental Results> The evaluation results are shown in Figure 6. From the results in Figure 6, it was confirmed that the compounds of the present invention have the effect of increasing phosphorylated AMPK in human colon cancer cells SW48.

[0495] Test Example 7: In vivo antitumor effect in a transplant model of human colon cancer SW48 cells <Experimental method> According to the method described in the literature (Ii H, et al. ChemMedChem. (2018) 13(2): 155-163), human colon cancer SW48 cells were cultured in DMEM (FUJIFILM Wako Pure Chemical Corporation, Japan) supplemented with 10% fetal bovine serum (FBS, HyClone, GE Healthcare Life Sciences, Buckinghamshire, England) and 1% penicillin / streptomycin (FUJIFILM Wako Pure Chemical Corporation, Japan). The cells were cultured at 37°C in 5% CO using a medium supplemented with 100 units / mL and 100 μg / mL of 100% ethanol (Bio-Rad Corporation, 100 units / mL and 100 μg / mL, respectively). ２ SW48 cells were suspended in trypsin (Lonza, Walkersville, MD, USA) and cultured in an incubator at 3 × 10 ６ The cells were suspended in 100 μL of PBS / Matrigel (1:1, Corning, Corning, NY, USA) and subcutaneously injected into 6-week-old male or female CB17 SCID mice (Japan Clea, Osaka, Japan) to create a subcutaneously transplanted tumor model. Starting from 4 days after implantation, the compound of the present invention was dissolved in 10% ethanol (FUJIFILM Wako Pure Chemical Corporation, Japan), 10% dimethyl sulfoxide (Nacalai Tesque, Kyoto, Japan), 10% Cremophor EL (Sigma Chemical, St. Louis, MO, USA), and 70% saline (Nacalai Tesque, Kyoto, Japan) and intraperitoneally administered at a dose of 20 mg / kg every day. The major and minor diameters were measured twice weekly using calipers, and tumor volume was calculated as 0.5 × major diameter × minor diameter. ２ The tumor was excised and weighed 3.5 weeks after cell transplantation. The compound of the present invention (compound (I-5)) used in the test was dissolved at 10 mg / mL in dimethyl sulfoxide / ethanol (1:1) as a solvent.

[0496] <Experimental Results> The evaluation results are shown in Figures 7(A), (B), and (C). From the results in Figure 7, it was confirmed that compound (I-5) of the present invention inhibits the growth of human colon cancer SW48 tumors transplanted in vivo in mice. It was also confirmed that daily administration of 20 mg / kg of the compound of the present invention for 3.5 weeks did not cause significant changes in body weight.

[0497] Test Example 8: Growth inhibitory effect on human lung cancer A549 cells <Experimental method> According to the method described in the literature (Ii H, et al. ChemMedChem. (2018) 13(2): 155-163), human lung cancer A549 cells were cultured in DMEM (FUJIFILM Wako Pure Chemical Corporation, Japan) supplemented with 10% fetal bovine serum (FBS, HyClone, GE Healthcare Life Sciences, Buckinghamshire, England) and 1% penicillin / streptomycin (FUJIFILM Wako Pure Chemical Corporation, Japan). The cells were cultured at 37°C in 5% CO using a medium supplemented with 100 units / mL and 100 μg / mL of 100% ethanol (Bio-Rad Corporation, 100 units / mL and 100 μg / mL, respectively). ２ A549 cells were suspended in trypsin (Lonza, Walkersville, MD, USA) and cultured at 1 × 10 ３ Cells were seeded in 96-well dishes (TPP, Trasadingen, Switzerland). 24 hours later, the cells were treated with the compounds of the present invention diluted with culture medium to a final concentration of 500 nM for 3 days. Cell proliferation was assessed by WST-8 assay using Cell Count Reagent SF (Nacalai Tesque, Kyoto, Japan) and measuring absorbance at 450 nm with a SYNERGY HT (BioTek Instruments, Inc. Winooski, VT, USA). The compounds of the present invention were dissolved in dimethyl sulfoxide (Nacalai Tesque, Kyoto, Japan) at 2 mM.

[0498] <Experimental Results> The evaluation results are shown in Figure 8. From the results in Figure 8, it was confirmed that the compounds of the present invention inhibit the proliferation of human lung cancer A549 cells.

[0499] Test Example 9: Effect of increasing phosphorylated AMPK in human lung cancer A549 cells <Experimental method> Human lung cancer A549 cells were cultured in a 37°C, 5% CO2 incubator using a medium containing DMEM (FUJIFILM Wako Pure Chemical Corporation, Japan) supplemented with 10% fetal bovine serum (FBS, HyClone, GE Healthcare Life Sciences, Buckinghamshire, England) and 1% penicillin / streptomycin (FUJIFILM Wako Pure Chemical Corporation, 100 units / mL and 100 μg / mL, respectively). A549 cells were suspended in trypsin (Lonza, Walkersville, MD, USA) and cultured at 1 × 10 ５ Cells were seeded in 6-well dishes (TPP, Trasadingen, Switzerland) and treated with the compounds of the present invention diluted with culture medium to a final concentration of 100 nM to 1 μM for 24 hours. Cell proteins were dissolved in 1% SDS buffer containing protease inhibitor cocktail mix (Nacalai Tesque, Kyoto, Japan) and subjected to SDS-PAGE. After transferring the DNA to a PVDF membrane (Millipore, Billerica, MA, USA), Western blot analysis was performed using anti-phospho-AMPKα (Thr172, 1:1000, #2535; CST) antibody. GAPDH protein was analyzed as a loading control.

[0500] <Experimental Results> The evaluation results are shown in Figure 9. From the results in Figure 9, it was confirmed that the compounds of the present invention have the effect of increasing phosphorylated AMPK in human lung cancer A549 cells.

[0501] Formulation Example 1: Preparation of capsules 1) Compound (I-5) 50 mg 2) Microcrystalline cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0502] Preparation example 2: tablet preparation 1) compound (I-5) 50g 2) lactose 50g 3) corn starch 15g 4) carmellose calcium 44g 5) magnesium stearate 1g The total amount of 1), 2) and 3) and 30g of 4) are mixed with water, vacuum dried, and then sieved.This sieved powder is mixed with 14g of 4) and 1g of 5), and then tableted by tableting machine.In this way, obtain 1000 tablets, each containing 50mg of compound (I-5).

[0503] Since the compound of the present invention exhibits excellent AMP-activated protein kinase activating activity, a medicament (pharmaceutical composition) containing the compound of the present invention is useful for the prevention and / or treatment of diseases caused by decreased activity of AMP-activated protein kinase (e.g., diabetes, obesity, cancer, etc.), and in particular, can be an excellent agent for the prevention and / or treatment of solid cancers such as glioblastoma, gastric cancer, colon cancer, lung cancer, breast cancer, germ cell cancer, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, cervical cancer, ovarian cancer, etc. Furthermore, the compound of the present invention has the advantages of being easy to synthesize, stable, and easy to handle.

[0504] This application is based on Patent Application No. 2021-094481 filed in Japan on June 4, 2021, the contents of which are incorporated in their entirety herein.

Claims

1. Formula (I): [Formula 1] [In the formula, R １ is a hydroxy group or C ２－６ a propyl group or a C ８－１０ represents an alkyl group; R ２ each represents a halogen atom or an optionally substituted C １－６ Alkyl group, optionally substituted C ６－１０ Aryl group, cyano group, nitro group, carboxy group, C １－６ represents a thienyl group or a pyrazolyl group, which may be substituted by a substituent selected from the group consisting of an alkoxy-carbonyl group and an acyl group; L １ is C optionally substituted with a hydroxy group １－２０ represents an alkylene group; L ２ is the formula: [Case 2] Or the formula: [C3] (In the formula, ＊ L １ represents the bonding position with ＊＊ is R ２ represents the bonding position with represents a divalent group represented by the formula: n represents an integer of 1 to 8. or a pharma- ceutically acceptable salt thereof, or a hydrate thereof.

2. R １ C may be substituted with a hydroxy group or an ethynyl group ８－１０ is an alkyl group, R ２ are halogen atoms, C １－６ Alkyl group, cyano group, nitro group, carboxy group and C １－６a 2-thienyl group, a 3-thienyl group or a 5-pyrazolyl group, each of which may be substituted by a substituent selected from the group consisting of an alkoxy-carbonyl group; L １ But, C ６－１２ is an alkylene group, and n is an integer from 1 to 6; 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof.

3. The compound according to claim 1, wherein the compound represented by formula (I) is any one of the following a to k, or a pharma- ceutically acceptable salt thereof: a. N-(13,16,19,22-tetraoxapentacosan-1-yl)thiophene-3-carboxamide, b. N-(13,16,19,22-tetraoxahentriacontan-1-yl)thiophene-3-carboxamide, c. N-(13,16,19,22-tetraoxadotriacontan-1-yl)thiophene-3-carboxamide, d. N-(13,16,19,22-tetraoxa-33-tetratriacontin-1-yl)thiophene-3-carboxamide, e. N-(13,16,19,22-tetraoxa-32-tritriacontin-1-yl)thiophene-3-carboxamide, f. N-(13,16,19,22,25-pentaoxadotriacontan-1-yl)thiophene-3-carboxamide, g. N-(10,13,16,19,22-pentaoxadotriacontan-1-yl)thiophene-3-carboxamide, h. N-(13,16,19,22-tetraoxadotriacontan-1-yl)-1-methylpyrazole-5-carboxamide, i. N-(13,16,19,22-tetraoxadotriacontan-1-yl)thiophene-2-carboxamide, j. N-(13,16,19,22,25-pentaoxapentatriacontan-1-yl)thiophene-3-carboxamide, and k. N-(13,16,19,22,25,28-hexaoxaoctatriacontan-1-yl)thiophene-3-carboxamide.

4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, or a hydrate of either, and a pharma- ceutical acceptable carrier.

5. The pharmaceutical composition described in claim 4 for the prevention or treatment of a disease caused by decreased activity of AMP-activated protein kinase.

6. The pharmaceutical composition described in claim 5, wherein the disease caused by decreased activity of AMP-activated protein kinase is diabetes, obesity or cancer.

7. The pharmaceutical composition described in claim 5, wherein the disease caused by decreased activity of AMP-activated protein kinase is cancer.

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