WO2013129435A1 - Fused thiophene derivative - Google Patents

Fused thiophene derivative Download PDF

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WO2013129435A1
WO2013129435A1 PCT/JP2013/055041 JP2013055041W WO2013129435A1 WO 2013129435 A1 WO2013129435 A1 WO 2013129435A1 JP 2013055041 W JP2013055041 W JP 2013055041W WO 2013129435 A1 WO2013129435 A1 WO 2013129435A1
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compound
substituent
mmol
optionally substituted
optionally
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PCT/JP2013/055041
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French (fr)
Japanese (ja)
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勇樹 平田
慎太郎 細江
道寛 前本
正森 菅原
新 柳沢
潤 大内
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協和発酵キリン株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a fused thiophene derivative or a pharmaceutically acceptable salt thereof useful as a therapeutic and / or prophylactic agent for diseases (for example, hyperphosphatemia) affected by serum phosphorus concentration.
  • diseases for example, hyperphosphatemia
  • Serum phosphorus concentration is controlled by the balance of absorption of phosphorus from the intestinal tract, intracellular and bone accumulation, filtration into the original urine in the kidney and subsequent reabsorption in the tubule.
  • serum phosphorus concentration is 5.0 mg / dL or more, it is said to be hyperphosphatemia, which is a pathological condition that appears prominently in patients with end-stage renal disease or dialysis. Hyperphosphatemia secondarily leads to hypocalcemia and therefore induces secondary hyperparathyroidism, which is also a major factor in renal osteodystrophy.
  • a phosphate adsorbent having a function of adsorbing dietary phosphate with intake of food with a low phosphate content.
  • Use has been made.
  • diets with low phosphoric acid content cause malnutrition due to inadequate intake of other nutrients and are difficult to observe due to poor taste.
  • oral phosphate adsorbents include calcium preparations, magnesium preparations, and aluminum preparations, but calcium preparations and magnesium preparations induce hypercalcemia and hypermagnesemia, respectively, and aluminum preparations contain aluminum osteopathy. Induction of aluminum encephalopathy and dialysis dementia has been pointed out.
  • anion exchange resins have been developed as oral phosphate adsorbents, but these anion exchange resins have a lower phosphate adsorption capacity than the aforementioned phosphate adsorbents, and can be used at high doses. is necessary.
  • NaPi2b Sodium-dependent phosphorus transporter type 2b
  • CaPi2b knockout mice intestinal specific conditional knockout mice
  • a compound that inhibits NaPi2b can control serum phosphorus concentration, and is expected to be useful for the treatment of hyperphosphatemia in chronic kidney disease.
  • NaPi2b has been confirmed not only in the intestine but also in the lung and testis.
  • alveolar microlithiasis an inherited disorder with autosomal inferiority, in which minute stones are formed in the alveoli, it is thought to be caused by a defective phosphorus transport function on the alveoli due to NaPi2b dysfunction [Am J RespirCrit Care Med 175: 263-268, 2007].
  • a heterozygous gene mutation of NaPi2b has also been identified in patients with intratesticular microcalcification [Am. J. Hum. Genet. 79: 650-656, 2006].
  • NaPi2b inhibitor a compound that inhibits NaPi2b (NaPi2b inhibitor) is considered useful as a therapeutic and / or prophylactic agent for hyperphosphatemia, etc., while dysfunction in the lungs and testis occurs when NaPi2b inhibitor is systemically exposed. There is a risk. Therefore, there is a demand for a drug that inhibits NaPi2b in the intestinal tract and has reduced absorbability into blood (see Patent Document 1).
  • a compound that inhibits NaPi2b for example, a compound represented by the formula (A) (see Patent Document 2), a compound represented by the formula (B) (see Patent Document 1), and the like are known. Further, as a condensed thiophene derivative having a hydrazide at the 3-position, a compound represented by the formula (C) (see Non-Patent Document 1), a compound represented by the formula (D) (see Non-Patent Document 2), a formula (E) (See Non-Patent Document 3) and the like are known.
  • An object of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof that inhibits NaPi2b in the intestinal tract and is useful as a therapeutic and / or prophylactic agent for diseases (for example, hyperphosphatemia) affected by serum phosphorus concentration. Is to provide.
  • the present invention relates to the following (1) to (17).
  • R 1 and R 2 represents a hydrogen atom
  • the other represents an aryl which may have a substituent or an aromatic heterocyclic group which may have a substituent
  • L represents phenyl, an aromatic heterocyclic group or an aliphatic heterocyclic group
  • each of the phenyl, the aromatic heterocyclic group and the aliphatic heterocyclic group is represented by the following formula (II): -(CH 2 ) h -ABYDC (II) ⁇
  • h represents an integer of 0 to 3
  • C is a hydrogen atom, halogen, hydroxy, nitro, amino, cyano, carboxy, carbamoyl, optionally substituted lower alkyl, optionally substituted cycloalkyl, or optionally substituted.
  • R E is a hydrogen atom; halogen; carboxy; carboxylate (—COO ⁇ ); lower alkoxycarbonyl; or lower optionally substituted with hydroxy, lower alkoxy, carboxy or carboxylate (—COO ⁇ ).
  • X B represents a chlorine atom, a bromine atom, an iodine atom, or R DB SO 3 (wherein R DB has the same meaning as R DA ) (where R E is a carboxylate (—COO - ) Or carboxylate (—COO ⁇ ) in the case of substituted lower alkyl, X B— is missing)], or —OPO (OR E ) 2 (where R E is Represents a hydrogen atom or lower alkyl), D is (1) a bond, or (2) at least one CH 2 group is —O—, —S—, —SO 2 — and —NR 5 — (wherein R 5 is a hydrogen atom, lower Represents a linear C 3-30 alkylene optionally substituted with a group selected from alkyl, cycloalkyl, lower alkanoyl or lower alkoxycarbonyl), Y is (1) a bond, (2) -O-, (3) -S-
  • s3 and s4 are the same or different and each represents an integer of 0 to 2, and Y a represents a bond or —SO 2 —)]
  • the phenyl, the aromatic heterocyclic group and the aliphatic heterocyclic group may further have a substituent, n represents 1 or 2, m represents 1 or 2, Z is —CR 14 R 15 — ⁇ wherein R 14 and R 15 are the same or different and each has a hydrogen atom, halogen, carboxy, optionally substituted lower alkyl, or substituent.
  • Lower alkylcarbonyl which may be substituted, lower alkylcarbamoyl which may have a substituent, dilower alkylcarbamoyl which may have a substituent or aliphatic heterocyclic carbonyl which may have a substituent carded
  • B and / or D is at least one or more CH 2 groups -O -, - S- and -NR 5 - (wherein, R 5 is as defined above) or -NR 9 - (Wherein R 9 is as defined above) is a linear C 3-30 alkylene optionally substituted with a group selected from the above, and the total number of carbon atoms in the alkylene is 7 or less, Alternatively, when B and D are both bonds, R 14 and R 15 are simultaneously hydrogen atoms.
  • R 14 and R 15 together with adjacent carbon atoms form a cycloalkane, oxetane, oxolane or oxane ⁇ , —NR 16 —
  • R 16 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, Lower alkanoyl optionally having substituent, aroyl optionally having substituent, aliphatic heterocyclic carbonyl optionally having substituent, aromatic heterocyclic optionally having substituent Ring carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted A good arylsulfonyl, an optionally substituted aliphatic heterocyclic sulfonyl or an optionally substituted aromatic heterocyclic sulfonyl), Represents —O—, —S— or —SO 2 —
  • B is (1)-(CH 2 CH 2 W a ) qa- (CH 2 ) ra- (W a is -O-, -S-, -SO 2- , or -NR 9 -(Wherein R 9 is as defined above), qa represents an integer of 1 to 8, ra represents an integer of 0 to 3, and (2)-(CH 2 CH 2 CH 2 W aa ) ua — (CH 2 ) va — (wherein W aa is —O—, —S—, —SO 2 —, or —NR 9 — (wherein R 9 is as defined above).
  • Ua represents an integer of 1 to 6 and va represents an integer of 0 to 6), or (3) — (CH 2 ) ta — (where ta represents an integer of 1 to 30).
  • ta represents an integer of 1 to 30.
  • (9) D is (1)-(CH 2 CH 2 W b ) qb- (CH 2 ) rb- (where W b is -O-, -S-, -SO 2- , or -NR 5 -(Wherein R 5 is as defined above), qb represents an integer of 1 to 8, rb represents an integer of 0 to 3, and (2)-(CH 2 CH 2 CH 2 W bb ) ub- (CH 2 ) vb- (wherein W bb is -O-, -S-, -SO 2- , or -NR 5- (wherein R 5 is as defined above)).
  • Ub represents an integer of 1 to 6 and vb represents an integer of 0 to 6), or (3) — (CH 2 ) tb — (where tb represents an integer of 1 to 30).
  • An inhibitor of phosphorus uptake into blood comprising the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
  • a therapeutic and / or prophylactic agent for hyperphosphatemia comprising the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
  • a method for inhibiting the uptake of phosphorus into blood comprising a step of administering an effective amount of the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
  • a method for treating and / or preventing hyperphosphatemia comprising a step of administering an effective amount of the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
  • a fused-ring thiophene derivative useful as a therapeutic and / or preventive agent for a disease that inhibits NaPi2b in the intestinal tract and is affected by serum phosphorus concentration (for example, hyperphosphatemia) or a pharmaceutically acceptable product thereof Salt and the like are provided.
  • Lower alkyl, and lower alkanoyl, lower alkoxycarbonyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkoxy, lower alkanoyloxy, lower alkylsulfonyloxy, lower alkylthio, and lower alkyl moiety of lower alkylsulfonyl include, for example, linear or Examples include branched alkyl having 1 to 10 carbon atoms, and more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl , Nonyl,
  • Examples of cycloalkyl and the cycloalkyl portion of cycloalkylcarbonyl, cycloalkyloxycarbonyl, cycloalkyloxy, cycloalkylcarbonyloxy, and a cycloalkyl portion of a cycloalkane formed together with adjacent carbon atoms include, for example, 3 to 8 carbon atoms. More specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.
  • the straight chain C 3-30 alkylene means a straight chain alkylene having 3 to 30 carbon atoms, and more specifically, a general formula — (CH 2 ) m — (wherein m represents an integer of 3 to 30) ) Represents an alkylene represented by: That is, at least one CH 2 group defined by B and D is —O—, —S—, —SO 2 —, and —NR 9 — or —NR 5 — (wherein R 9 and R 5 They are each a hydrogen atom, a lower alkyl, cycloalkyl, the lower alkanoyl or lower alkoxy optionally a straight chain C 3-30 alkylene optionally substituted with a group selected from the a carbonyl), for example, the following equation (1) to And the group represented by (14).
  • Examples include methyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, anthrylmethyl, anthrylethyl and the like.
  • aryl and the aryl moiety of aroyl, aryloxycarbonyl, arylcarbamoyl, aryloxy, aroyloxy, arylsulfonyloxy, arylthio, and arylsulfonyl include aryl having 6 to 14 carbon atoms, and more specifically phenyl. , Naphthyl, azulenyl, anthryl and the like.
  • aliphatic heterocyclic group moiety of sulfonyl for example, a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, Bicyclic or tricyclic condensed rings containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom are included, and more specifically, aziridinyl and azetidinyl , Pyrrolidinyl, piperidino, piperidinyl, azepanyl, 1,2,5,6-te
  • aromatic heterocyclic group moiety of sulfonyl for example, a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom
  • Examples thereof include a condensed bicyclic or tricyclic condensed ring aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically furyl, thienyl.
  • Examples of the nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is , May contain other nitrogen atoms, oxygen atoms or sulfur atoms), condensed bicyclic or tricyclic condensed 3 to 8 membered rings and containing at least one nitrogen atom (
  • the condensed ring heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, pyrrolyl, imidazolidinyl, Imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl,
  • Halogen means each atom of fluorine, chlorine, bromine and iodine.
  • the substituents in sulfonyloxy, optionally substituted lower alkylthio, and optionally substituted lower alkylsulfonyl are the same or different, for example, halogen, hydroxy having 1 to 3 substituents , Sulfanyl, nitro, cyano, carboxy, carbamoyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic compound Heterocyclic
  • An arylsulfonyl which may have a substituent, an aralkyl which may have a substituent, an aromatic heterocyclic group which may have a substituent, an aromatic heterocyclic diyl which may have a substituent, a substituent
  • Cycloalkyl which may have a substituent, cycloalkylcarbonyl which may have a substituent, cycloalkyloxycarbonyl which may have a substituent, cycloalkyl which may have a substituent Oxy, optionally substituted cycloalkylcarbonyloxy, optionally substituted aliphatic heterocyclic group, optionally substituted aliphatic heterocyclic diyl, substituted An optionally substituted aliphatic heterocyclic carbonyl, an optionally substituted aliphatic heterocyclic oxycarbonyl, an optionally substituted aliphatic heterocyclic oxy, and optionally having a substituent Good aliphatic heterocyclic carbonyloxy, optionally substituted aliphatic heterocyclic thio, optionally substituted aliphatic heterocyclic sulfonyl, and optionally substituted adjacent Nitrogen field
  • C 1-10 alkyl as shown here and C 1-10 alkoxy, C 2-11 alkanoyloxy, C 1-10 alkylsulfanyl, C 2-11 alkanoyl, C 1-10 alkoxycarbonyl, C 1-10 alkylcarbamoyl and
  • Examples of the C 1-10 alkyl moiety of diC 1-10 alkylcarbamoyl include the groups exemplified above for the lower alkyl.
  • the two C 1-10 alkyl moieties in the diC 1-10 alkylcarbamoyl may be the same or different.
  • the C 3-8 cycloalkyl and C 3-8 cycloalkyl moiety cycloalkoxy, e.g. groups mentioned for illustrative said cycloalkyl is exemplified.
  • Examples of the aryl moiety of C 6-14 aryl and C 6-14 aryloxy, C 7-15 aroyl, C 7-15 aroyloxy and C 6-14 aryloxycarbonyl include the groups exemplified in the above aryl examples.
  • Examples of the aralkyl moiety of C 7-16 aralkyl and C 7-16 aralkyloxy and C 7-16 aralkyloxycarbonyl include the groups exemplified in the above examples of aralkyl.
  • the aliphatic heterocyclic group, aromatic heterocyclic group and halogen are as defined above.
  • Pharmaceutically acceptable salts of compound (I) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • Examples of the pharmaceutically acceptable acid addition salt of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, and maleic acid.
  • Organic salts such as salts, fumarate, citrate, benzoate, methanesulfonate and the like
  • pharmaceutically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt , Alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts and the like.
  • Examples of pharmaceutically acceptable ammonium salts include salts such as ammonium and tetramethylammonium.
  • organic amine addition salts examples include addition salts such as morpholine and piperidine, and examples of pharmaceutically acceptable amino acid addition salts include lysine. And addition salts of glycine, phenylalanine, aspartic acid, glutamic acid and the like.
  • Production method 1 Compound (I) can be produced by the following method.
  • Process 1 Compound (a-3) is compound (a-1) and preferably 1 to 30 equivalents of (a-2) in the absence of or in a solvent at a temperature between room temperature and the boiling point of the solvent used for 5 minutes. It can be produced by reacting for ⁇ 72 hours.
  • solvent examples include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dimethoxyethane (DME), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), 1,4 -Dioxane, tetrahydrofuran (THF), diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, N-methylpyrrolidone (NMP), water and the like are used, and these are used alone or in combination.
  • DME 1,2-dichloroethane
  • DME 1,2-dimethoxyethane
  • DMF N-dimethylformamide
  • DMA N-dimethylacetamide
  • THF tetrahydrofuran
  • diethyl ether diisopropyl ether
  • benzene toluene
  • xylene pyridine
  • Compound (a-1) is obtained as a commercial product.
  • Compound (a-2) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course, 4th edition, Volume 21, p. 1, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
  • Process 2 Compound (a-5) is compound (a-3) and preferably 1 to 30 equivalents of compound (a-4) in a solvent, preferably 1 to 30 equivalents of a sulfur introducing agent and a base at room temperature. And a reaction between 5 minutes and 72 hours at a temperature between the boiling points of the solvents to be used.
  • Examples of the sulfur introducing agent include sulfur, diphosphorus pentasulfide, Lawesson's reagent, and the like.
  • Examples of the base include diethylamine, triethylamine, ethyldiisopropylamine, morpholine, piperidine, L-proline, basic alumina and the like.
  • Examples of the solvent include methanol, ethanol, 2-propanol, tert-butyl alcohol, THF, dioxane, toluene, xylene, water and the like, and these can be used alone or in combination.
  • Compound (a-4) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course, 4th edition, Volume 21, p.149, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
  • Process 3 Compound (I) is compound (a-5), preferably 1 to 10 equivalents of compound (a-6), preferably 1 to 20 equivalents of a base in the presence of a solvent at ⁇ 10 ° C. It can be produced by reacting at a temperature between the boiling points for 5 minutes to 72 hours.
  • Examples of the base include potassium acetate, sodium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium phosphate, pyridine, triethylamine, N-methylmorpholine, N -Methylpiperidine, piperidine, piperazine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like.
  • DBU 1,8-diazabicyclo [5.4.0] -7-undecene
  • solvent examples include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, DME, DMF, DMA, 1,4-dioxane, THF, diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, NMP, water, and the like. These may be used alone or in combination.
  • Compound (a-6) can be obtained as a commercial product, or can be obtained by a known method [for example, New Experimental Chemistry Course, 4th edition, Volume 22, p. 115, Maruzen Co., Ltd. (1992)] or the like. It can be obtained accordingly.
  • compound (I) may be compound (a-5) and preferably 1 to 30 equivalents of (a-7) in the absence of a solvent or in a solvent, preferably 1 to 30 equivalents of a condensing agent. It can also be produced by reacting at a temperature between ⁇ 30 ° C. and 150 ° C. for 5 minutes to 72 hours, if necessary, preferably in the presence of 1 to 30 equivalents of an additive.
  • Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC), EDC hydrochloride, O- (benzotriazol-1-yl) 2 -N , N, N ', N'-Tetramethyluronium hexafluorophosphate (HATU), benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP), hexafluorophosphoric acid (benzotriazol-1-yloxy)
  • Examples include tripyrrolidinophosphonium (PyBOP) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBroP).
  • Examples of the additive include 1-hydroxybenzotriazole monohydrate (HOBt ⁇ H 2 O), triethylamine, 4-dimethylaminopyridine (DMAP), and the like are used alone or in combination.
  • Examples of the solvent include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, DME, DMF, DMA, 1,4-dioxane, THF, diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, NMP, water, and the like. These may be used alone or in combination.
  • Compound (a-7) can be obtained as a commercial product, or can be obtained by a known method [for example, New Experimental Chemistry Course, 4th edition, Volume 22, p. 1, Maruzen Co., Ltd. (1992)] or the like. It can be obtained similarly.
  • Manufacturing method 2 Compound (I) can also be produced according to the following steps.
  • R 20 represents a hydrogen atom or a protecting group for a carboxyl group such as methyl or ethyl
  • n, m, R 1 , R 2 , L, V 1 and Z are as defined above.
  • Compound (a-8) can be obtained as a commercial product.
  • Process 5 Compound (a-10) can be produced in the same manner as in production method 1, step 3 using compound (a-9) and compound (a-6) or compound (a-7).
  • Process 6 Compound (a-11) is obtained by reacting compound (a-10) without solvent or in a solvent in the presence of 1 to 100 equivalents of an aqueous hydrazine solution at a temperature between room temperature and 150 ° C. for 5 minutes to 72 hours. Can be manufactured.
  • Compound (a-11) can also be produced via compound (a-12).
  • Step 7a Compound (a-12) is obtained by reacting compound (a-10) in trifluoroacetic acid, preferably in the presence of 1 to 30 equivalents of trifluoroacetic anhydride, at a temperature between room temperature and 150 ° C. for 5 minutes to 72 hours. It can be manufactured by processing.
  • Compound (a-12) is also prepared using compound (a-10) according to the method described in WO2006 / 122200, Organic Letters, 16, 1013 (2006), Bioorganic Medicinal Chemistry, 18, 2803, (2000), etc. Can also be manufactured.
  • Step 7b Compound (a-11) can be produced in the same manner as in Step 6 above, using compound (a-12).
  • Process 8 Compound (I) can be produced in the same manner as in Step 1 above, using compound (a-11) and compound (a-2).
  • Production method 3 Among compounds (I), compound (Ib) in which A is an oxygen atom, B, Y and D are not simultaneously bonded and C is not a hydrogen atom can also be produced according to the following steps.
  • Step 9 Compound (Ib) is compound (Ia) obtained according to production method 1 or 2, preferably 1 to 30 equivalents of compound (a-13), without solvent or in a solvent, and preferably 1 to 30 equivalents. It can be produced by reacting at a temperature between ⁇ 10 ° C. and 150 ° C. for 5 minutes to 72 hours in the presence of a base.
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, N -Methylpiperidine, pyridine, DBU and the like.
  • solvent examples include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Water and the like, and these may be used alone or in combination.
  • Compound (a-13) can be obtained as a commercial product, or can be obtained by publicly known methods [for example, Experimental Chemistry Course, 4th edition, Volume 19, p.363, Maruzen Co., Ltd. (1992)] or the like. Obtainable. Production method 4 Among compounds (I), compounds (Id), (Ie) and (If) in which A is —NR 10 —, —S— and —SO 2 — can also be produced according to the following steps, respectively.
  • V 3 represents a leaving group such as chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, L A , m, n, h, R 1. , R 2 , R 10 , B, Y, C, D and Z are as defined above)
  • Process 10 Compound (Id) is compound (Ic) obtained according to production method 1 or 2, preferably 1 to 30 equivalents of compound (a-14), without solvent or in a solvent, and preferably 1 to 30 equivalents if necessary. It can be produced by reacting at a temperature between ⁇ 10 ° C. and 150 ° C. for 5 minutes to 72 hours in the presence of a base.
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, N -Methylpiperidine, pyridine, DBU and the like.
  • solvent examples include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Water and the like, and these may be used alone or in combination.
  • Compound (a-14) can be obtained as a commercial product, or can be obtained by publicly known methods [for example, Experimental Chemistry Course, 4th edition, Volume 20, p.279, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
  • Step 11 Compound (Ie) can be obtained in the same manner as in Step 10 above, using compound (Ic) and compound (a-15).
  • Compound (a-15) can be obtained as a commercial product, or can be obtained by publicly known methods [for example, Experimental Chemistry Course, 4th edition, Volume 24, p.319, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
  • Process 12 Compound (If) comprises compound (Ie) in a solvent in an amount of 1 equivalent to a large excess, preferably 1 to 10 equivalents of oxidizing agent, at a temperature between 0 ° C. and the boiling point of the solvent used for 5 minutes to 72 minutes. It can be manufactured by time processing.
  • Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, THF, 1,4-dioxane, dimethoxyethane, diethyl ether, diisopropyl ether, methanol, ethanol, 2-propanol, benzene, toluene, xylene, acetonitrile, ethyl acetate. , Water and the like, and these can be used alone or in combination. Preferred is dichloromethane.
  • oxidizing agent examples include metachloroperbenzoic acid, benzoyl peroxide, peracetic acid, hydrogen peroxide, sodium periodate, oxone, and the like, preferably metachloroperbenzoic acid.
  • Manufacturing method 5 Among compounds (I), compounds (Ii) and (Ij) in which Z is NR 11 can also be produced according to the following steps.
  • Process 13 Compound (Ii) can be obtained by using, for example, Protective Groups in Organic Synthesis, TW Greene, It can be produced according to the protecting group removal method described in, for example, John Wiley & Sons Inc. (1981).
  • the compound (Ii) is obtained by removing the compound (Ig) between -30 ° C. and 100 ° C. without solvent or in a solvent with 1 equivalent to a large excess of acid. It can be produced by treating at a temperature of 5 minutes to 72 hours.
  • the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and the like.
  • the solvent include methanol, ethanol, propanol, THF, 1,4-dioxane, DME, toluene, ethyl acetate, dichloromethane, DMF, water and the like, and these can be used alone or in combination.
  • Compound (Ij) is compound (Ii) and preferably 1 to 20 equivalents of compound (a-16) in a solvent, preferably in the presence of 1 to 20 equivalents of a base, at ⁇ 10 ° C. It can be produced by reacting at a temperature between the boiling points for 5 minutes to 72 hours.
  • Examples of the base include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, DBU and the like.
  • Examples of the solvent include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, DME, DMF, DMA, 1,4-dioxane, THF, diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, NMP, and the like. These are used alone or in combination.
  • Compound (a-16) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course, 4th edition, volume 19, p.363, Maruzen Co., Ltd. (1992), J. Am. Chem. Soc., 114, 1486, (1992), etc.] or the like.
  • the intermediates and target compounds in the above production methods are isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • Some compounds (I) may have stereoisomers such as geometric isomers and optical isomers, tautomers and the like, but the present invention includes all possible isomers including these. And mixtures thereof.
  • a part or all of each atom in the compound (I) may be replaced with a corresponding isotope atom, and the present invention also includes a compound replaced with these isotope atoms.
  • some or all of the hydrogen atoms in the compound (I) may be hydrogen atoms having an atomic weight of 2 (deuterium atoms).
  • a compound in which part or all of each atom in Compound (I) is replaced with a corresponding isotope atom can be produced by a method similar to each of the above production methods using a commercially available building block.
  • a compound in which some or all of the hydrogen atoms in the compound (I) are replaced with deuterium atoms is, for example, 1) a method of deuterating carboxylic acid under basic conditions using deuterium peroxide (See U.S. Pat. No. 3,849,458), 2) A method of deuterating alcohol, carboxylic acid, etc. using iridium complex as a catalyst and deuterium as a deuterium source (J. Am. Chem. Soc., 124).
  • compound (I) When it is desired to obtain a salt of compound (I), it can be purified as it is when compound (I) is obtained in the form of a salt. When it is obtained in a free form, compound (I) can be obtained in an appropriate solvent. It may be isolated or purified by dissolving or suspending and forming a salt by adding an acid or a base. Compound (I) and pharmaceutically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.
  • Test Example 1 [ 33 P] Phosphorus Uptake Assay of Human NaPi2b-Expressing Cells (1) Construction of Human NaPi2b-Induced Expression Cells Human NaPi2b-induced expression plasmids conform to known methods (Analytical Biochemistry, 400, 163, (2006)) Made. DNA encoding human NaPi2b was obtained by PCR. Using human kidney DNA (Clontech) as a template, human NaPi2b cDNA-specific primer and Pyrobest DNA Polymerase (Takara Bio) were used to obtain DNA encoding human NaPi2b by PCR.
  • PCR was performed at 95 ° C. for 2 minutes, followed by 35 cycles of 94 ° C. for 15 seconds, annealing temperature 60 ° C. for 15 seconds, and 72 ° C. for 2 minutes.
  • the amplified PCR fragment was cleaved with HindIII and NotI, and then a human NaPi2b DNA fragment was recovered by agarose gel electrophoresis.
  • the fragment was inserted between the corresponding restriction enzyme sites (HindIII-NotI) of the inducible expression vector to construct an inducible expression plasmid for human NaPi2b. It was confirmed that the sequence of the obtained human NaPi2b DNA matched the registered sequence of GenBank (NM_006424).
  • an inducible expression cell of human NaPi2b using KJMGER8 cells (a cell line derived from Namalwa cells) as a host was constructed.
  • the induced expression cells were prepared by introducing the human NaPi2b induced expression plasmid prepared above into KJMGER8 cells by electroporation (Cytotechnology, 3, 133 (1990)).
  • Inducible expression of human NaPi2b was performed by culturing human NaPi2b-expressing cells in the presence of 10 nmol / L ⁇ -estradiol (manufactured by Sigma) for 24 hours.
  • Ice-cooled buffer B (0.9 mmol / L CaCl 2 , 0.5 mmol / L MgCl 2 ⁇ 6H 2 O, 2.7 mmol / L KCl, 1.5 mmol / L KH 2 PO 4 , 138 mmol / L NaCl, 8.1 mmol / L Na 2 HPO 4 ⁇ 7H 2 O) was added to stop the reaction, followed by filtration while washing with a cell harvester with filter paper (Whatman GF / Bunifilter) set.
  • the washed filter paper was dried with a rapid dryer for 30 minutes, 30 ⁇ L of scintillation cocktail Microscint 20 was added, and the radioactivity of the filter paper was measured with a multiplate scintillation counter TopCount (Perkin Elmer Japan).
  • the inhibition rate was determined by the following formula. The results at a test compound concentration of 1 ⁇ mol / L are shown in Table 12.
  • Rats are housed in a metal cage in a breeding room with a temperature of 19 to 25 ° C, humidity of 30 to 70%, and 12 hours a day (7am to 7pm). Feed (FR-2; Funabashi Farm) and water were freely available. At the time of urine collection, one animal was housed in a metal cage for individual breeding, and it was fasted and allowed to drink freely. In the test, an individual having no abnormal appearance and no diarrhea on the day before and on the day of the test (no dirt around the anus) was used.
  • urinary phosphorus excretion at 6 hours after administration decreased at the doses of 10 mg / kg and 30 mg / kg as compared with the MC administration group.
  • the effect was similar to that of lanthanum carbonate hydrate 100 mg / kg. From these results, Compound 26 showed an action of suppressing urinary phosphorus excretion from a dose of 10 mg / kg.
  • compound 26 has an action of inhibiting phosphorus uptake via NaPi2b. That is, it was suggested that Compound 26 has an action of suppressing urinary phosphorus excretion based on inhibiting NaPi2b in the intestinal tract and inhibiting phosphorus absorption from the intestinal tract. Similarly, it was suggested that Compound (I) or its pharmaceutically acceptable salt, which has an inhibitory action on phosphorus uptake through NaPi2b, also has an inhibitory action on urinary phosphorus excretion based on an inhibitory action on phosphorus absorption in the intestine. .
  • Test Example 3 Membrane permeability test [Parallel Artificial Membrane Permeability Assay (PAMPA)] PAMPA plates were purchased from BD Gentest TM (cat # 353015). The test was conducted according to the attached instructions, and the “P e ” (effective permeability) value of compound (I) was calculated.
  • PAMPA Paraallel Artificial Membrane Permeability Assay
  • compound (I) or a pharmaceutically acceptable salt thereof is considered to have low membrane permeability and low absorption in vivo (in the blood), and the drug concentration does not increase even when administered orally. It was.
  • Compound (I) or a pharmaceutically acceptable salt thereof inhibits the uptake of phosphorus into the living body by inhibiting NaPi2b in the digestive tract (intestinal tract) when administered orally, but its absorbability is low. Therefore, the drug concentration in the blood is low, and the drug itself has little effect on other organs.
  • Compound (I) or a pharmaceutically acceptable salt thereof is a disease in which side effects are reduced by locally inhibiting NaPi2b in the intestinal tract, and a serum phosphorus concentration affects the disease (for example, hyperphosphatemia, etc.) It is useful as a therapeutic and / or prophylactic agent.
  • Test Example 4 Plasma concentration when compound (I) was orally administered Compound (I) or a pharmaceutically acceptable salt thereof was orally administered to Sprague-Dawley rats, and 0.5, 1, 2, 4, after administration Plasma is collected at 7 and 24 hours. After adding acetonitrile to the plasma sample and stirring, the centrifuged supernatant is analyzed using LC-MS / MS to determine the concentration of the administered compound.
  • Test Example 5 [ 33 P] Phosphorus Uptake Assay of Human NaPi2b Expressing Cells (2) The same test as in Test Example 1 was conducted, and the inhibitory action of phosphorus uptake via NaPi2b of compound (I) was confirmed. The results at a test compound concentration of 1 ⁇ mol / L are shown in Table 13.
  • Compound (I) or a pharmaceutically acceptable salt thereof can inhibit NaPi2b in the intestinal tract, suppress phosphorus absorption from the intestinal tract, and diseases in which serum phosphorus concentration affects (for example, It was considered useful as a therapeutic drug for hyperphosphatemia and the like. From the above, compound (I) or a pharmaceutically acceptable salt thereof can locally inhibit NaPi2b in the intestinal tract and suppress phosphorus absorption, thereby controlling the concentration of phosphorus in the blood. It was considered useful as a therapeutic and / or prophylactic agent for diseases such as hyperphosphatemia affected by serum phosphorus concentration. In addition, since compound (I) or a pharmaceutically acceptable salt thereof is poorly absorbed into the living body, it is considered that side effects (for example, calcification in the lungs and testis) associated with systemic exposure can be suppressed. It was.
  • Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.
  • the pharmaceutical preparation according to the present invention may contain Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment.
  • These pharmaceutical preparations are well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers (e.g., diluents, solvents, excipients, etc.). Manufactured by any method.
  • the administration route it is desirable to use one that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration.
  • examples of the dosage form include tablets and injections.
  • tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
  • an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution or a mixed solution of a saline solution and a glucose solution.
  • the dose and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of the condition to be treated, etc.
  • the dose is 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult, once to several times a day.
  • parenteral administration such as intravenous administration
  • 0.001 to 1000 mg preferably 0.01 to 100 mg per adult is administered once to several times a day.
  • the dose and the number of doses vary depending on the various conditions described above.
  • Step 2 (E) -N ′-(4-Chloro-3- (trifluoromethyl) benzylidene) -2-cyanocarbohydrazide (4.40 g, 15.2 mmol) and acetic acid (3.48 mL, 60.8) obtained in Step 1 mmol) was dissolved in THF (44 mL) and 1,1,1,3,3,3-hexamethyldisilazane (6.37 mL, 30.4 mmol) and 4,4-dimethylcyclohexanone (2.30 g, 18.2) were cooled with ice. mmol) and stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate.
  • Step 3 (E) -N ′-(4-Chloro-3- (trifluoromethyl) benzylidene) -2-cyano-2- (4,4-dimethylcyclohexylidene) acetohydrazide obtained in Step 2 ( 5.00 g, 12.6 mmol) was dissolved in THF (30 mL), triethylamine (3.50 mL, 25.1 mmol) and sulfur (0.403 g, 12.6 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 2 Methyl 3- (2,5,8,11,14,17,20,23-octoxapentacosan-25-yloxy) benzoate (2.70 g, 5.2 mmol) obtained in Step 1 was added to methanol ( 20 mL), 4 mol / L aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 3 hr. The mixture was washed with ethyl acetate, and then the pH of the aqueous layer was adjusted to about 2 with 6 mol / L hydrochloric acid and extracted with ethyl acetate.
  • Step 3 3- (2,5,8,11,14,17,20,23-octoxapentacosan-25-yloxy) benzoic acid (0.704 g, 1.40 mmol) and DMF (0.135) obtained in Step 2 mL) was dissolved in dichloromethane, thionyl chloride (0.51 mL, 7.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the mixture was dissolved in dichloromethane (5 mL), pyridine (1.13 mL, 14.0 mmol) and compound a (0.50 g, 1.16 mmol) obtained in Reference Example 1 were added, and the mixture was stirred at room temperature for 15 hours. Stir.
  • Carbodiimide hydrochloride (WSC ⁇ HCl) (10 mg, 0.053 mmol) and HOBt ⁇ H 2 O (HOBt ⁇ H 2 O) (8.0 mg, 0.053 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the mixture, and the resulting precipitate was collected by filtration to give compound 16 (10 mg, 23%).
  • Step 2 4- (2- (4-tert-Butoxycarbonyl) piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate benzyl (0.894 g, 1.80 mmol) obtained in Step 1 was added to THF (15 mL). ), Palladium hydroxide (0.253 g, 1.80 mmol) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After the mixture was filtered through celite, the solvent was evaporated under reduced pressure to give tert-butyl 4- (2- (piperazin-1-ylsulfonyl) ethyl) piperazine-1-carboxylate (0.594 g, 91%) Got.
  • Step 3 Compound 1 (0.313 g, 0.537 mmol) obtained in Example 1 was dissolved in DMF (5 mL), triethylamine (0.225 mL, 1.61 mmol) and 4- (2- (piperazine) obtained in Step 2 were used. -1-ylsulfonyl) ethyl) piperazine-1-carboxylate tert-butyl (0.292 g, 0.806 mmol) was added and stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 2 Benzyl 4- (2- (piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate (0.376 g, 0.948 mmol) obtained in Step 1 was dissolved in dichloromethane (15 mL) and triethylamine ( 0.397 mL, 2.84 mmol) and methanesulfonyl chloride (0.111 mL, 1.42 mmol) were added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 3 In the same manner as in Step 2 of Example 18, using benzyl 4- (2- (4- (methylsulfonyl) piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate obtained in Step 2.
  • Step 4 Compound 20 (80.0 mg) was prepared in the same manner as in Step 3 of Example 18 using 1- (methylsulfonyl) -4- (2- (piperazin-1-ylsulfonyl) ethyl) piperazine obtained in Step 3. , 68%).
  • Pentaacetic acid 13R, 14S, 15R, 16R
  • -1- (3-((E) -2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl -4,5,6,7-tetrahydrobenzo
  • Compound 25 50 mg, 0.063 mmol obtained in Example 25 was dissolved in dichloroethane (0.5 mL), trifluoroacetic acid (0.30 mL, 3.9 mmol) was added, and the mixture was stirred at 0 ° C.
  • Step 2 Dissolve methyl 2-(((3- (diethylamino) propyl) (methyl) amino) methyl) isonicotinate (390 mg, 1.33 mmol) obtained in Step 1 in 50% aqueous ethanol (4 mL) Lithium hydroxide monohydrate (112 mg, 2.66 mmol) was added, and the mixture was stirred overnight at room temperature. 3 mol / L hydrochloric acid was added to the mixture, and the mixture was extracted with chloroform / 2-propanol (6/1). The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 3 2-((((3- (Diethylamino) propyl) (methyl) amino) methyl) isonicotinic acid (180 mg, 0.644 mmol) obtained in Step 2 and compound a (100 mg) obtained in Reference Example 1 , 0.233 mmol) was dissolved in dichloromethane (3 mL) and 4-dimethylaminopyridine (56.8 mg, 0.465 mmol) and 2,4,6-trichlorobenzoic acid chloride (113 mg, 0.465 mmol) were added. Stir. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 2 Benzyl 1- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 1 (295 mg, 0.816 mmol) Was dissolved in DMF (5 mL), triethylamine (0.228 mL, 1.63 mol) and methanesulfonyl chloride (0.127 mL, 1.63 mmol) were added, and the mixture was stirred at room temperature overnight, and further stirred at 100 ° C. for 2 hr. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 3 Benzyl 1- (2- (2- (2-chloroethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 2 (223 mg, 0.587 mmol) was dissolved in DMF (5 mL), 2-diethylamine (1.84 mL, 17.6 mmol) was added, and the mixture was stirred at 100 ° C. overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 4 benzyl 1- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 3 (244 mg, 0.587 mmol) was dissolved in ethanol, palladium carbon (82.0 mg) was added, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The mixture was filtered and the filtrate's solvent was removed under reduced pressure to give 1- (2- (2- (2- (diethylaminoethoxy) ethoxy) ethyl-6-oxo-1,6-dihydropyridine-3- Carboxylic acid (158 mg, 82%) was obtained.
  • Step 5 Step of Example 6 using 1- (2- (2- (2- (diethylaminoethoxy) ethoxy) ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid) obtained in Step 4 In the same manner as in 3, compound 45 (67.0 mg, 38%) was obtained.
  • Step 2 Compound 46 (0.610 g, 31%) was obtained in the same manner as in Step 3 of Example 18 using benzyl 2- (3-hydroxypropylamino) acetate obtained in Step 1.
  • Step 2 4-bromo-2- (7-ethoxy-7-oxoheptyloxy) in the same manner as in Step 1 of Example 8 using methyl 4-bromo-2-hydroxybenzoate obtained in Step 1 Methyl benzoate (0.865 g, 86%) was obtained.
  • Step 3 Methyl 4-bromo-2- (7-ethoxy-7-oxoheptyloxy) benzoate (0.865 g, 2.23 mmol), 1,1'-bis (diphenylphosphino) ferrocene palladium obtained in Step 2 (II) Dichloride-dichloromethane complex (0.182 g, 0.232 mmol), 1,1'-bis (diphenylphosphino) ferrocene (0.124 g, 0.223 mmol) and potassium acetate (1.10 g, 11.2 mmol) in DMSO (15 mL) And stirred at 80 ° C. for 3 hours under a carbon monoxide atmosphere.
  • Step 4 In the same manner as in Step 3 of Example 6 using 3- (7-ethoxy-7-oxoheptyloxy) -4- (methoxycarbonyl) benzoic acid obtained in Step 3, compound 55 (0.654 g , Quantitative).
  • Step 2 4-Bromo-2-((3- (methoxycarbonyl) phenoxy) methyl) benzoic acid (4.1 g, 11.2 mmol) obtained in Step 1 was dissolved in DMF (20 mL), and potassium carbonate (3.1 g, 22.5 mmol) and methyl iodide (1.05 mL, 16.8 mmol) were added, and the mixture was stirred at 45 ° C. for 2 hours.
  • Step 3 Methyl 4-bromo-2-((3- (methoxycarbonyl) phenoxy) methyl) benzoate obtained in Step 2 (1.14 g, 3.0 mmol), 1,1′-bis (diphenylphosphino) ferrocene Palladium (II) dichloride dichloromethane complex (0.49 g, 0.60 mmol), 1,1'-bis (diphenylphosphino) ferrocene (0.167 g, 0.30 mmol) and potassium acetate (2.95 g, 30 mmol) are dissolved in DMSO, The mixture was stirred at 80 ° C. for 12 hours in a carbon monoxide atmosphere.
  • Step 4 4- (methoxycarbonyl) -3-((3- (methoxycarbonyl) phenoxy) benzoic acid (0.144 g, 0.42 mmol) obtained in Step 3 and compound a obtained in Reference Example 1 (0.15 g, 0.35 mmol) was dissolved in dichloromethane (2 mL) and 4-dimethylaminopyridine (0.043 g, 0.35 mmol), triethylamine (0.177 g, 1.75 mmol) and 2,4,6-trichlorobenzoic acid chloride (0.17 g, 0.70). mmol) and stirred for 2 hours at 0 ° C.
  • Step 2 Methyl 3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzoate (5.61 g, 19.7 mmol) obtained in Step 1 was dissolved in DMF (100 mL) and triethylamine (8.25 mL, 59.2 mol) and methanesulfonyl chloride (4.61 mL, 59.2 mmol) were added, and the mixture was stirred at room temperature overnight. Sodium iodide (5.91 g, 39.4 mmol) was added to the mixture, and the mixture was stirred at 100 ° C. for 2 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate.
  • Step 3 Methyl 3- (2- (2- (2-iodoethoxy) ethoxy) ethoxy) benzoate obtained in Step 2 (3.25 g, 8.24 mmol) was dissolved in DMF (60 mL), and potassium carbonate ( 5.70 g, 41.2 mol) and 2-diethylamine (18.1 g, 247 mmol) were added, and the mixture was stirred at 100 ° C. overnight. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 4 Dissolve methyl 3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxybenzoate (2.77 g, 8.16 mmol) obtained in Step 3 in 50% aqueous ethanol (60 mL). Lithium hydroxide monohydrate (685 mg, 16.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours, 3 mol / L hydrochloric acid was added to the mixture, and the mixture was extracted with chloroform / 2-propanol (6/1).
  • Step 5 Using the 3- (2- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzoic acid obtained in Step 4, in the same manner as in Step 2 of Example 6, compound 69 (45.0 mg, 20%).
  • Step 2 ((E) -2-amino-3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -4,5,6,7-dihydrothieno [ Compound 71 (8.83 g, 85%) was obtained in the same manner as in Example 1 using tert-butyl 2,3-c] pyridine-6 (7H) -carboxylate.
  • Step 2 tert-butyl 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (24.0 g, 85 mmol) obtained in Step 1 is replaced with dichloromethane (130 mL), 3- (chloromethyl) benzoyl chloride (12.38 mL, 87 mmol) and pyridine (7.0 mL, 87 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water was added to the mixture at room temperature, and the mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated.
  • Step 3 tert-butyl 2- (3- (chloromethyl) benzoylamino) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in step 2 (10.0 g, 23 mmol) was dissolved in dichloromethane (50 mL), 4-hydroxypiperidine (6.98 g, 69 mmol) and triethylamine (9.6 mL, 69 mmol) were added, and the mixture was stirred at room temperature for 20 hours.
  • Step 4 2- (3-((4-Hydroxypiperidin-1-yl) methyl) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene obtained in Step 3
  • Tert-Butyl-3-carboxylate (8.92 g, 18 mmol) was dissolved in trifluoroacetic acid (27.6 mL), trifluoroacetic anhydride (6.23 mL) was added, and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated, dropped into a saturated aqueous sodium hydrogen carbonate solution at 0 ° C. to neutralize, and extracted with chloroform.
  • Step 5 N- (3- (hydrazinocarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) -3-(( 4-Hydroxypiperidin-1-yl) methyl) benzamide (100 mg, 0.219 mmol) is dissolved in chloroform (2 mL), and 5,6-dichloronicotinaldehyde (77.0 mg, 0.438 mmol) is added. Stir for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 Performed using tert-butyl 2- (3-hydroxybenzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in Step 1 Similar to Example 8, 2- (3- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] Obtained tert-butyl thiophene-3-carboxylate (7.20 g, 90%).
  • Step 3 2- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo
  • b Dissolve tert-butyl thiophene-3-carboxylate (1.40 g, 2.62 mmol) in DMF (15 mL), add triethylamine (0.548 mL, 3.93 mmol) and methanesulfonyl chloride (0.307 mL, 3.93 mmol) at room temperature. And stirred overnight. After further stirring at 100 ° C. for 2 hours, water was added to the mixture, and the mixture was extracted with ethyl acetate.
  • Step 4 2- (3- (2- (2- (2-chloroethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] 2- (3- (2- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzamide) -6, as in Example 10, using tert-butyl thiophene-3-carboxylate 6-Dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (0.457 g, 82%) was obtained.
  • Step 5 2- (3- (2- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydro obtained in step 4 3- (2- (2- (2- (2- (2- (Diethylamino) ethoxy) ethoxy) ethoxy) -N-) using tert-butyl benzo [b] thiophene-3-carboxylate as in Step 4 of Example 86 (3- (hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide (59.0 mg, 64%) was obtained.
  • Step 6 2,1,3-Benzoxadiazole-5-carbaldehyde and 3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) -N- (3 obtained in Step 5
  • Compound 88 (25.0) was prepared in the same manner as in Step 5 of Example 86 using-(hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide. mg, 15%).
  • Step 2 Ethyl 2- (bromomethyl) thiazole-4-carboxylate (0.768 g, 3.07 mmol) obtained in Step 1 was dissolved in THF (10.0 mL), triethylamine (0.856 mL, 6.14 mmol) and N, N -Diethyl-N'-methylethane-1,2-diamine (0.745 mL, 4.61 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 5 2-((((2- (Diethylamino) ethyl) (methyl) amino) methyl) thiazole-4-carboxylic acid (60 mg, 2.7 mmol) obtained in Step 3 was dissolved in dichloromethane (1.0 mL).
  • Step 2 Example 1 using tert-butyl 2-amino-6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3-b] pyridine-3-carboxylate obtained in Step 1 In a similar manner to tert-butyl 2- (3- (chloromethyl) benzamido) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3-b] pyridine-3-carboxylate (10.8 g, 89%).
  • Step 3 2- (3- (Chloromethyl) benzamido) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3-b] pyridine-3-carboxylic acid tert obtained in Step 2 6-Cyclopropyl-2- (3-(((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide) -4,5,6,7 in the same manner as in Example 59.
  • Tert-butyl (5.86 g, 94%) of 4-tetrahydrothieno [2,3-c] pyridine-3-carboxylate was obtained.
  • Step 4 6-Cyclopropyl-2- (3-((((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide) -4,5,6,7-tetrahydrothieno obtained in Step 3 [ N- (6-Cyclopropyl-3- (hydrazinecarbonyl) -4,5,6, using tert-butyl 2,3-c] pyridine-3-carboxylate as in Step 5 of Example 88 7-tetrahydrothieno [2,3-c] pyridin-2-yl) -3-(((3-diethylamino) propyl) (methyl) amino) methyl) benzamide (1.22 g, 81%) was obtained.
  • Step 5 2,1,3-Benzoxadiazole-5-carbaldehyde and N- (6-cyclopropyl-3- (hydrazinecarbonyl) -4,5,6,7-tetrahydrothieno obtained in Step 4
  • Compound 90 [2,3-c] pyridin-2-yl) -3-(((3-diethylamino) propyl) (methyl) amino) methyl) benzamide was prepared in the same manner as in Step 5 of Example 86. 40.4 mg, 44%).
  • Step 2 (E) -2-amino-N ′-(4-chloro-3- (trifluoromethyl) benzylidene) -6-hydroxy-6-methyl-4,5,6,7 obtained in Step 1
  • Compound 91 (0.177 g, 87%) was obtained in the same manner as in Example 1 using -tetrahydrobenzo [b] thiophene-3-carbohydrazine.
  • Step 2 Lithium aluminum hydride (0.725 g, 19.1 mmol) suspended in THF (30 mL) and diethyl 4-dioxaspiro [4.5] decane-8,8-dicarboxylate obtained in Step 1 at 0 ° C (4.56 g, 15.9 mmol) was added. The mixture was stirred for 1 hour, lithium aluminum hydride (0.725 g, 19.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • Step 3 1,4-Dioxaspiro [4.5] decane-8,8-diyldimethanol (3.17 g, 15.7 mmol) obtained in Step 2 is dissolved in THF (150 mL) and n-butyllithium at 0 ° C. (2.76 mol / L THF solution; 6.81 mL, 18.8 mmol) was added. The mixture was stirred for 30 minutes, a THF solution (30 mL) of 4-toluenesulfonyl chloride (3.59 g, 18.8 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • Step 4 Dissolve 1,4,10-trioxaspiro [3.4.5] tridecane (0.20 g, 1.09 mmol) obtained in Step 3 in THF (5 mL) and add 10% hydrochloric acid (1 mL) at room temperature. ) And stirred overnight. Water was added to the mixture and extracted with ethyl acetate.
  • Step 5 Using 4-chloromethyl-4- (hydroxymethyl) cyclohexanone obtained in Step 4, in the same manner as in Step 1 of Example 86, 2-amino-6- (chloromethyl) -6- (hydroxymethyl) ) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (238 mg, 94%) was obtained.
  • 1 H-NMR (270 MHz, CDCl 3 , ⁇ ): 1.54 (s, 9H), 1.72 (t, J 6.6 Hz, 2H), 2.47 (s, 2H), 2.68-2.73 (m, 2H), 3.59 -3.67 (m, 4H), 5.91 (s, 2H).
  • Step 6 Using tert-butyl 2-amino-6- (chloromethyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in Step 5
  • 6- (chloromethyl) -2- (3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide) -6- ( Hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (1.68 g, 88%) was obtained.
  • Step 7 6- (Chloromethyl) -2- (3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide) -6- (hydroxymethyl) -4, obtained in Step 6 Using tert-butyl 5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate as in Step 4 of Example 86, N- (6- (chloromethyl) -3- (hydrazinecarbonyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide (0.62 g, 65%).
  • Step 8 N- (6- (chloromethyl) -3- (hydrazinecarbonyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl obtained in step 7 ) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide was used in the same manner as in Step 5 of Example 86 to give compound 93 (0.64 g, 76%).
  • Step 2 Using 2-oxaspiro [3.5] nonan-7-one obtained in Step 1, in the same manner as in Step 1 of Example 86, 2-amino-5,7-dihydro-4H-spiro [benzo [benzo [ b] tert-butyl thiophene-6,3′-oxetane] -3-carboxylate (10.5 g, 58%) was obtained.
  • Step 3 Example 86 using tert-butyl 2-amino-5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3′-oxetane] -3-carboxylate obtained in Step 2 2- (3- (chloromethyl) benzamido) -5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3′-oxetane] -3-carboxylic acid tert- Butyl (1.16 g, 76%) was obtained.
  • Step 4 2- (3- (Chloromethyl) benzamido) -5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3′-oxetane] -3-carboxylic acid tert obtained in Step 3 2- (3-(((2- (diethylamino) propyl) (methyl) amino) methyl) benzamido) -5,7-dihydro-4H-spiro in the same manner as Example 86, step 3 [Benzo [b] thiophene-6,3′-oxetane] -3-carboxylate tert-butyl (1.56 g, 77%) was obtained.
  • Step 5 2- (3-(((2- (Diethylamino) propyl) (methyl) amino) methyl) benzamido) -5,7-dihydro-4H-spiro [benzo [b] thiophene- obtained in Step 4 3-((((3- (diethylamino) propyl) (methyl) amino) methyl) -N using tert-butyl 6,3′-oxetane] -3-carboxylate as in Step 4 of Example 86 -(3- (hydrazinecarbonyl) -5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3'-oxetane] -2-yl) benzamide (79 mg, 70%) was obtained.
  • Step 6 3-((((3- (Diethylamino) propyl) (methyl) amino) methyl) -N- (3- (hydrazinecarbonyl) -5,7-dihydro-4H-spiro [benzo [ b] Thiophene-6,3′-oxetane] -2-yl) benzamide was used in the same manner as in Step 5 of Example 86 to give compound 94 (70 mg, 65%).
  • Compound 96 Compound 95 (1.96 g, 2.36 mmol) obtained in Example 95 was dissolved in dichloromethane (12 mL), and triethylamine (0.66 mL, 4.73 mmol) and mesyl chloride (0.277 mL, 3.55 mmol) were added at 0 ° C. The mixture was further stirred at room temperature for 1 hour. To the mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Compounds 99 to 104 Compounds 99 to 104 were obtained in the same manner as in Examples 97 and 98 using the corresponding benzyl 2-aminoacetate.
  • Compound 102 ESIMS m / z: 957 (M + H) + .
  • Compound 105 Compound 3 (7.00 g, 12.73 mmol) obtained in Example 3 was dissolved in DMF (50.0 mL), and cesium carbonate (8.29 g, 25.5 mmol) and 17-hydroxy-3,6,9,12, 15-Pentaoxaheptadecyl-4-methylbenzenesulfonate (11.11 g, 25.5 mmol) was added, and the mixture was stirred at 65 ° C. for 3 hours. Distilled water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Compounds 108 to 110 Compounds 108 to 110 were obtained in the same manner as in Example 102, using the corresponding amine instead of 3- (pyridin-3-yl) propanoic acid.
  • Compound 112 Compound 111 (0.749 g, 0.836 mmol) obtained in Example 104 was dissolved in ethanol (5.0 mL), and 4 mol / L aqueous sodium hydroxide solution (1.04 ml, 4.18 mmol) was added. Stir for hours. The mixture was neutralized with 1 mol / L hydrochloric acid, extracted with a mixed solvent of chloroform / methanol, and the organic layer was concentrated to obtain Compound 112 (0.685 g, 94%).
  • Compound 114 (0.800 g, 50%) was obtained in the same manner as in Example 12 using Compound 105 (1.50 g, 1.84 mmol) obtained in Example 100.
  • Compound 120 Compound 120 (0.384 g) in the same manner as in Example 13 using tert-butyl 3- (2- (2- (2-aminoethoxy) ethoxy) ethoxy) propanoate (0.939 g, 3.39 mmol). , 56%).
  • Compound 121 (0.389 g, ⁇ quantitative) was obtained in the same manner as in Example 25, using Compound 120 (0.384 g, 0.378 mmol) obtained in Example 113.
  • Compound 123 was obtained in the same manner as in Examples 108 and 109 using ethyl 3- (methylamino) propanoate.
  • Compound 131 was obtained in the same manner as in Examples 122 and 123 using ethyl 3- (methylamino) propanoate. ESIMS m / z: 899, 901 (M + H) + .
  • Step 2 In the same manner as in Example 16, using Compound 36 obtained in Example 36 and 3- (2- (2- (2-(-tosyloxyethoxy) ethoxy) ethoxy) propanoic acid obtained in Step 1 Compound 132 (580 mg, 60%) was obtained.
  • Compound 133 Compound 133 (296 mg, 36%) was obtained in the same manner as in Example 97, using Compound 132 obtained in Example 125 and the compound obtained in Step 1 of Example 46.
  • 1 H-NMR 300 MHz, CDCl 3 , ⁇ ): 1.07 (s, 6H), 1.61-1.70 (m, 4H), 2.52 (s, 2H), 2.67-2.90 (m, 8H), 2.96-2.98 ( m, 3H), 3.43-3.49 (m, 2H), 3.53-3.62 (m, 10H), 3.73-3.86 (m, 4H), 4.64-4.67 (m, 2H), 5.12-5.14 (m, 2H), 7.27-7.39 (m, 5H), 7.44-7.58 (m, 3H), 7.89-7.97 (m, 3H), 8.04-8.06 (m, 1H), 8.25-8.29 (m, 1H), 9.36 (s, 1H ), 12.89 (br s, 1H).
  • Compounds 140 to 144 Compounds 140 to 144 were obtained in the same manner as in Example 15, Example 52, or Example 127 using Compounds 135, 136, 137, 138, and 139.
  • Compound 140 ESIMS m / z: 852 (M + H) + .
  • Compound 141 ESIMS m / z: 866 (M + H) + .
  • Compound 142 ESIMS m / z: 910 (M + H) + .
  • Compound 144 ESIMS m / z: 910 (M + H) + .
  • Compound 145 Compound 140 was obtained in the same manner as in Example 127, using 3-amino-1-propanol and the compound obtained in the same manner as in Example 36.
  • Compound 146 was obtained in the same manner as in Example 127, using a compound obtained in the same manner as in Example 36 using 3-amino-1,2-propanediol. ESIMS m / z: 956 (M + H) + .
  • Compound 147 was obtained in the same manner as in Example 127, using a compound obtained in the same manner as in Example 36 using 2-amino-1,3-propanediol.
  • Compound 148 Compound 36 (280 mg, 0.485 mmol) obtained in Example 36 was dissolved in dichloromethane (5 mL), and pyridine (0.047 mL, 0.582 mmol) and chloroacetyl chloride (0.047 mL, 0.582 mmol) were cooled with ice. ) And stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Step 2 The crude 20-hydroxy-3,6,9,12,15,18-hexaoxaicosan-1-acid (0.253 g, 0.744 mmol) obtained in Step 1 was added to THF (1 mL) and DMF (0.1 In an ice bath, sodium hydride (0.104 g, 2.60 mmol) was added and stirred for 10 minutes.
  • Compound 150 was obtained in the same manner as in Example 130, using 3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) propanoic acid. ESIMS m / z: 837 (MH) + .
  • Compound 152 Compound 152 (1.67 g, 64%) was obtained in the same manner as in Example 96, using Compound 151 (2.4 g, 2.67 mmol) obtained in Example 136.
  • Compound 153 (0.089 g, 14%) was obtained in the same manner as in Example 126, using Compound 152 (0.550 g, 0.563 mmol) obtained in Example 137.
  • 1 H-NMR 400 MHz, CDCl 3 , ⁇ ): 1.07 (s, 6H), 1.61-1.70 (m, 4H), 2.53 (s, 2H), 2.80-2.98 (m, 9H), 3.47-3.77 ( m, 27H), 4.25-4.36 (m, 2H), 4.67 (s, 2H), 5.14 (s, 2H), 7.32-7.37 (m, 5H), 7.40-7.59 (m, 3H), 7.87-7.99 ( m, 3H), 8.27-8.31 (m, 1H), 9.38 (s, 1H), 12.94 (s, 1H).
  • Compound 154 (0.065 g, 80%) was obtained in the same manner as in Example 47, using Compound 153 (0.089 g, 0.081 mmol) obtained in Example 138.
  • Compound 161 Compound 1 (254 mg, 0.436 mmol) obtained in Example 1 was dissolved in DMF (5 mL), cesium carbonate (426 mg, 1.31 mmol) and 1-mercapto-3,6,9,12, 15,18,21,24-Octaheptacosane-27 acid (200 mg, 0.436 mmol) was added and stirred at 50 ° C. for 7 hours. Citric acid (335 mg, 1.75 mmol) and water were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography to give compound 161 (328 mg, 75%).
  • Step 2 Benzyl 1- (14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 1 1- (14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl) -6-oxo-1,6-dihydropyridine in the same manner as in Step 4 of Example 45. -3-carboxylic acid (1.29 g, 91%) was obtained.
  • Step 3 1- (14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl) -6-oxo-1,6-dihydropyridine-3-carboxylic acid obtained in Step 2 was used to give compound 162 (762 mg, 44%) in the same manner as in Step 3 of Example 6.
  • Compound 164 (125 mg, 55%) was obtained in the same manner as in Example 16 using Compound 158 obtained in Example 148.
  • Compound 166 Compound 105 (0.25 g, 0.31 mmol) obtained in Example 100 was dissolved in THF (10 mL), and 1H-tetrazole (0.043 g, 0.61 mmol) and di-tert-butyldiethyl phosphoramidite (0.128 mL, 0.46 mmol) was added and stirred at room temperature for 12 hours. Add 1H-tetrazole (0.034 g, 0.49 mmol) and di-tert-butyldiethyl phosphoramidite (0.10 mL, 0.37 mmol), then add m-chloroperbenzoic acid (0.16 g, 0.68 mmol) at room temperature. For 10 minutes.
  • Compound 169 Compound 169 (0.513 g, 0.706 mmol) obtained in Example 153 was dissolved in DMF (1.5 ml), sodium hydroxide (0.085 g, 2.1 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 10 minutes. did. Under ice cooling, propargyl bromide (0.115 ml, 1.060 mmol) was added and stirred for 1 hour. Water and saturated aqueous ammonium chloride solution were added to the mixture, and the mixture was extracted with ethyl acetate.
  • Compound 170 Compound 169 (0.136 g, 0.178 mmol) and 5-azidopentanoic acid (0.025 g, 0.178 mmol) obtained in Example 154 were dissolved in 1,4-dioxane (2.5 ml) and water (1 mL). , Sodium ascorbate (0.11 g, 0.53 mmol) and cupric sulfate pentahydrate (0.089 g, 0.36 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Aqueous ammonia was added to the mixture, and the mixture was extracted with ethyl acetate.
  • Compounds 171 and 172 were obtained in the same manner as in Example 155, using the corresponding azide compounds.
  • Compound 173 was obtained in the same manner as in Example 10 by using 4,4-difluorocyclohexanone in the same manner as in Reference Example 1, Examples 2, 3, 8 and 96 and morpholine. .
  • Compound 174 was obtained in the same manner as in Example 17 using the compound obtained in the same manner as in Reference Example 1, Example 2 and 3 using tetrahydro-4H-pyran-4-one.
  • Step 2 Methyl 3,5-dihydroxybenzoate (0.35 g, 2.082 mmol) was dissolved in DMF (10.0 mL) and cesium carbonate (2.035 g, 6.24 mmol) and 2- (2- (2 -Methoxyethoxy) ethoxy) ethyl-4-methylbenzenesulfonate (1.988 g, 6.24 mmol) was added and stirred at 100 ° C. for 2 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Step 3 Methyl 3,5-bis (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) benzoate (0.85 g, 1.846 mmol) obtained in Step 2 was added to 6 mol / L hydrochloric acid (9.23 mL). Dissolved and stirred at 100 ° C. overnight. By azeotroping with toluene, 3,5-bis (2- (2- (2-methoxyethoxy) ethoxy) benzoic acid (0.8 g, 97%) was obtained.
  • Step 4 Dissolve 3,5-bis (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) benzoic acid (0.433 g, 0.971 mmol) obtained in Step 3 in dichloromethane (4 mL), 4,6-trichlorobenzoyl chloride (0.233 mL, 1.493 mmol), triethylamine (0.52 mL, 3.73 mmol), 4-dimethylaminopyridine (0.182 g, 1.493 mmol) and synthesized in the same manner as Reference Example 1 (E)- Add 2-amino-N '-(4-chloro-3- (trifluoromethyl) benzylidene) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carbohydrazide (0.3 g, 0.747 mmol) And stirred at room temperature for 3 hours.
  • Step 2 tert-butyl 2- (3-hydroxybenzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in Step 1 (20.0 g, 49.8 2- (3- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamido) -6,6-dimethyl-4,5,6, in the same manner as in Example 8. 7-Tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (15.6 g, 59%) was obtained.
  • Step 3 2- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b ] 2- (3- (2- (2- (2- (2-oxirane-2-)-2- (3- (2- (2- (2-oxirane-2-) oxirane-2-tert-butyl] thiophene-3-carboxylate (5.00 g, 9.37 mmol) in the same manner as in Example 12.
  • Step 4 2- (3- (2- (2- (2- (2- (2-oxiran-2-ylmethoxy) ethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5, obtained in Step 3 2- (3- (13-Ethyl-11-hydroxy) as in Example 13 using tert-butyl 6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (3.16 g, 5.36 mmol) -3,6,9-trioxa-13-azapentadecyloxy) benzamide) tert-butyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (3.20 g , 90%).
  • Step 5 2- (3- (13-Ethyl-11-hydroxy-3,6,9-trioxa-13-azapentadecyloxy) benzamide) -6,6-dimethyl-4,5, obtained in Step 4 3- (13-Ethyl-11-hydroxy) as in Step 4 of Example 86 using tert-butyl 6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (2.00 g, 3.02 mmol) -3,6,9-trioxa-13-azazapentadecyloxy) -N- (3- (hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-2 -Yl) benzamide (1.50 g, 80%) was obtained.
  • Step 6 3- (13-Ethyl-11-hydroxy-3,6,9-trioxa-13-azazapentadecyloxy) -N- (3- (hydrazinecarbonyl) -6,6- Dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide (0.100 g, 0.161 mmol) and 4,5-dichlorothiazole-2-carbaldehyde synthesized by the method described in EP2080761 ( 0.040 g, 0.220 mmol), and in the same manner as in Step 5 of Example 86, compound 176 (E form) (19 mg, 15%) and compound 177 (Z form) (53 mg, 42%) were obtained. It was.
  • Compound 178 was obtained in the same manner as in Example 155, using 2-chloro-6- (trifluoromethyl) isonicotinaldehyde.
  • Tablet A tablet having the following composition is prepared by a conventional method.
  • Compound 26, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 10% aqueous solution of hydroxypropylcellulose 120 g is added thereto.
  • the obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
  • a condensed ring useful as a therapeutic and / or prophylactic agent for a disease that inhibits NaPi2b in the intestinal tract and has decreased absorbability into blood and is affected by serum phosphorus concentration (for example, hyperphosphatemia).
  • serum phosphorus concentration for example, hyperphosphatemia.
  • a thiophene derivative or a pharmaceutically acceptable salt thereof can be provided.

Abstract

Provided is a compound represented by formula (I) [wherein each of R1 and R2 represents a hydrogen atom or the like; L represents a phenyl group that is substituted by one or two groups represented by formula (II) -(CH2)h-A-B-Y-D-C (wherein h represents an integer of 0-3; C represents a hydrogen atom or the like; D represents a bond or the like; Y represents a bond or the like; B represents a bond or the like; and A represents a bond or the like) or the like; n is 1 or 2; m is 1 or 2; and Z represents -CR14R15- (wherein R14 and R15 may be the same or different and each represents a hydrogen atom or the like)] or a pharmaceutically acceptable salt thereof.

Description

縮環チオフェン誘導体Fused thiophene derivative
　本発明は、血清のリン濃度が影響する疾患（例えば、高リン血症など）の治療および／または予防剤として有用な縮環チオフェン誘導体またはその薬学的に許容される塩に関する。 The present invention relates to a fused thiophene derivative or a pharmaceutically acceptable salt thereof useful as a therapeutic and / or prophylactic agent for diseases (for example, hyperphosphatemia) affected by serum phosphorus concentration.
　血清リン濃度は、リンの腸管からの吸収、細胞内および骨への蓄積、腎臓での原尿へのろ過およびその後の尿細管での再吸収のバランスなどにより制御されている。血清リン濃度が5.0 mg/dL以上となる場合は高リン血症といわれ、主に末期腎不全や、透析期患者で顕著に表れてくる病態である。
　高リン血症は、二次的に低カルシウム血症を招くため、二次的な副甲状腺機能亢進症を誘発し、これはさらに腎性骨異栄養症の主要因ともなる。 Serum phosphorus concentration is controlled by the balance of absorption of phosphorus from the intestinal tract, intracellular and bone accumulation, filtration into the original urine in the kidney and subsequent reabsorption in the tubule. When the serum phosphorus concentration is 5.0 mg / dL or more, it is said to be hyperphosphatemia, which is a pathological condition that appears prominently in patients with end-stage renal disease or dialysis.
Hyperphosphatemia secondarily leads to hypocalcemia and therefore induces secondary hyperparathyroidism, which is also a major factor in renal osteodystrophy.
　従来、これら病態の改善には、腸管からのリン酸の吸収を減少させることを目的として、リン酸含有量の少ない食事の摂取や食物中のリン酸を吸着させる機能を有するリン酸吸着剤の使用が行われてきた。しかし、リン酸含有量の少ない食事は、他の栄養分の摂取不足による栄養障害を引き起こす、味覚が悪いため遵守することが難しいなどの問題が指摘されている。経口リン酸吸着剤としては、例えばカルシウム製剤やマグネシウム製剤、アルミウム製剤などがあるが、カルシウム製剤とマグネシウム製剤にはそれぞれ高カルシウム血症と高マグネシウム血症の誘発が、アルミニウム製剤にはアルミニウム骨症、アルミニウム脳症、透析痴呆の誘発が指摘されている。また、近年経口リン酸吸着剤として種々の陰イオン交換樹脂が開発されているが、これらの陰イオン交換樹脂は前記のリン酸吸着剤に比べてリン酸吸着能が低く、高用量の服用が必要である。 Conventionally, for the improvement of these pathological conditions, for the purpose of reducing the absorption of phosphate from the intestinal tract, a phosphate adsorbent having a function of adsorbing dietary phosphate with intake of food with a low phosphate content is proposed. Use has been made. However, it has been pointed out that diets with low phosphoric acid content cause malnutrition due to inadequate intake of other nutrients and are difficult to observe due to poor taste. Examples of oral phosphate adsorbents include calcium preparations, magnesium preparations, and aluminum preparations, but calcium preparations and magnesium preparations induce hypercalcemia and hypermagnesemia, respectively, and aluminum preparations contain aluminum osteopathy. Induction of aluminum encephalopathy and dialysis dementia has been pointed out. In recent years, various anion exchange resins have been developed as oral phosphate adsorbents, but these anion exchange resins have a lower phosphate adsorption capacity than the aforementioned phosphate adsorbents, and can be used at high doses. is necessary.
　腸管におけるリン吸収は、トランスポーター分子を介する能動輸送および細胞間隙を介する受動輸送が担っていると考えられている。トランスポーター分子として、ナトリウム依存性リントランスポータータイプ2b（NaPi2b）が報告されている［Pflugers Arch. 447: 763-767, 2004］。NaPi2bノックアウトマウス（腸管特異的コンディショナルノックアウト）に関する研究では、NaPi2bは40%程度の腸管リン吸収を担っていることが示唆されている［J. Am. Soc. Nephrol. 19: 78A, 2008］。従って、NaPi2bを阻害する化合物は、血清のリン濃度を制御でき、慢性腎臓病における高リン血症などの治療に有用であると期待される。しかしながら、NaPi2bは腸管以外に肺や精巣においても高い発現が確認されている。肺胞内に微小な結石が形成される常染色体劣勢の遺伝性疾患である肺胞微石症では、NaPi2b機能不全による肺胞上におけるリン輸送機能欠損がその原因と考えられている［Am J RespirCrit Care Med 175: 263-268, 2007］。さらに、精巣内微小石灰化患者においても、NaPi2bのヘテロ接合型遺伝子変異が同定されている［Am. J. Hum. Genet. 79: 650-656, 2006］。従って、高リン血症などの治療および／または予防薬としてNaPi2bを阻害する化合物（NaPi2b阻害剤）が有用と考えられる一方で、NaPi2b阻害剤が全身へ曝露されると肺や精巣における機能不全のリスクがある。そのため、腸管のNaPi2bを阻害し、血中への吸収性が低下した薬物が求められている（特許文献1参照）。 Phosphorus absorption in the intestinal tract is thought to be responsible for active transport via transporter molecules and passive transport via cell gaps. Sodium-dependent phosphorus transporter type 2b (NaPi2b) has been reported as a transporter molecule [Pflugers Arch. 447: 763-767, 2004]. Studies on NaPi2b knockout mice (intestinal specific conditional knockout) suggest that NaPi2b is responsible for about 40% intestinal phosphorus absorption [J. Am. Soc. Nephrol. 19: 78A, 2008]. Therefore, a compound that inhibits NaPi2b can control serum phosphorus concentration, and is expected to be useful for the treatment of hyperphosphatemia in chronic kidney disease. However, high expression of NaPi2b has been confirmed not only in the intestine but also in the lung and testis. In alveolar microlithiasis, an inherited disorder with autosomal inferiority, in which minute stones are formed in the alveoli, it is thought to be caused by a defective phosphorus transport function on the alveoli due to NaPi2b dysfunction [Am J RespirCrit Care Med 175: 263-268, 2007]. Furthermore, a heterozygous gene mutation of NaPi2b has also been identified in patients with intratesticular microcalcification [Am. J. Hum. Genet. 79: 650-656, 2006]. Therefore, a compound that inhibits NaPi2b (NaPi2b inhibitor) is considered useful as a therapeutic and / or prophylactic agent for hyperphosphatemia, etc., while dysfunction in the lungs and testis occurs when NaPi2b inhibitor is systemically exposed. There is a risk. Therefore, there is a demand for a drug that inhibits NaPi2b in the intestinal tract and has reduced absorbability into blood (see Patent Document 1).
　一方、NaPi2bを阻害する化合物として、例えば式（A）で表される化合物（特許文献2参照）、式（B）で表される化合物（特許文献1参照）などが知られている。また、3位にヒドラジドを有する縮環チオフェン誘導体として、式（C）で示される化合物（非特許文献1参照）、式（D）で示される化合物（非特許文献2参照）、式（E）で示される化合物（非特許文献3参照）などが知られている。 On the other hand, as a compound that inhibits NaPi2b, for example, a compound represented by the formula (A) (see Patent Document 2), a compound represented by the formula (B) (see Patent Document 1), and the like are known. Further, as a condensed thiophene derivative having a hydrazide at the 3-position, a compound represented by the formula (C) (see Non-Patent Document 1), a compound represented by the formula (D) (see Non-Patent Document 2), a formula (E) (See Non-Patent Document 3) and the like are known.
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
国際公開第2012/006475号パンフレットInternational Publication No. 2012/006475 Pamphlet 国際公開第2004/085382号パンフレットInternational Publication No. 2004/085382 Pamphlet
　本発明の目的は、腸管におけるNaPi2bを阻害し、血清のリン濃度が影響する疾患（例えば、高リン血症など）の治療および／または予防剤として有用な化合物またはその薬学的に許容される塩を提供することにある。 An object of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof that inhibits NaPi2b in the intestinal tract and is useful as a therapeutic and / or prophylactic agent for diseases (for example, hyperphosphatemia) affected by serum phosphorus concentration. Is to provide.
　本発明は、以下の（1）～（17）に関する。
(1)　下記式（I） The present invention relates to the following (1) to (17).
(1) The following formula (I)
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
＜式中、R1およびR2は、一方は水素原子を表し、他方は置換基を有していてもよいアリールまたは置換基を有していてもよい芳香族複素環基を表し、
Lは、フェニル、芳香族複素環基または脂肪族複素環基を表すが、該フェニル、該芳香族複素環基および該脂肪族複素環基はそれぞれ1～2個の下記式（II）
-(CH2)h-A-B-Y-D-C  (II)
｛式中、hは0～3の整数を表し、
Cは、水素原子、ハロゲン、ヒドロキシ、ニトロ、アミノ、シアノ、カルボキシ、カルバモイル、置換基を有していてもよい低級アルキル、置換基を有していてもよいシクロアルキル、置換基を有していてもよいアリール、置換基を有していてもよい脂肪族複素環基、置換基を有していてもよい芳香族複素環基、置換基を有していてもよいアラルキル、置換基を有していてもよい低級アルカノイル、置換基を有していてもよいシクロアルキルカルボニル、置換基を有していてもよいアロイル、置換基を有していてもよい脂肪族複素環カルボニル、置換基を有していてもよい芳香族複素環カルボニル、置換基を有していてもよい低級アルコキシカルボニル、置換基を有していてもよいシクロアルキルオキシカルボニル、置換基を有していてもよいアリールオキシカルボニル、置換基を有していてもよい脂肪族複素環オキシカルボニル、置換基を有していてもよい芳香族複素環オキシカルボニル、置換基を有していてもよい低級アルキルカルバモイル、置換基を有していてもよいジ低級アルキルカルバモイル、置換基を有していてもよいアリールカルバモイル、置換基を有していてもよい低級アルコキシ、置換基を有していてもよいシクロアルキルオキシ、置換基を有していてもよいアリールオキシ、置換基を有していてもよい脂肪族複素環オキシ、置換基を有していてもよい芳香族複素環オキシ、置換基を有していてもよい低級アルカノイルオキシ、置換基を有していてもよいシクロアルキルカルボニルオキシ、置換基を有していてもよいアロイルオキシ、置換基を有していてもよい脂肪族複素環カルボニルオキシ、置換基を有していてもよい芳香族複素環カルボニルオキシ、置換基を有していてもよい低級アルキルスルホニルオキシ、置換基を有していてもよいアリールスルホニルオキシ、置換基を有していてもよい低級アルキルチオ、置換基を有していてもよいアリールチオ、置換基を有していてもよい脂肪族複素環チオ、置換基を有していてもよい芳香族複素環チオ、置換基を有していてもよい低級アルキルスルホニル、置換基を有していてもよいアリールスルホニル、－NR3R4（式中、R3およびR4は、同一または異なって、水素原子、置換基を有していてもよい低級アルキル、置換基を有していてもよいシクロアルキル、置換基を有していてもよいアリール、置換基を有していてもよい脂肪族複素環基、置換基を有していてもよい芳香族複素環基、置換基を有していてもよい低級アルカノイル、置換基を有していてもよいシクロアルキルカルボニル、置換基を有していてもよいアロイル、置換基を有していてもよい脂肪族複素環カルボニル、置換基を有していてもよい芳香族複素環カルボニル、置換基を有していてもよい低級アルコキシカルボニル、置換基を有していてもよいシクロアルキルオキシカルボニル、置換基を有していてもよいアリールオキシカルボニル、置換基を有していてもよい低級アルキルスルホニル、置換基を有していてもよいアリールスルホニル、または置換基を有していてもよい芳香族複素環スルホニルを表すか、またはR3とR4が隣接する窒素原子と一緒になって置換基を有していてもよい含窒素複素環基を形成する）、－NRARBRC＋XA－［式中、RA、RBおよびRCは、同一または異なって、低級アルキル、シクロアルキルまたはアラルキルを表し、XAは、塩素原子、臭素原子、ヨウ素原子、またはRDASO3（式中、RDAはメチル、エチル、トリフルオロメチル、フェニルまたはトリルを表す）を表す］、下記式（A） <In the formula, one of R 1 and R 2 represents a hydrogen atom, and the other represents an aryl which may have a substituent or an aromatic heterocyclic group which may have a substituent,
L represents phenyl, an aromatic heterocyclic group or an aliphatic heterocyclic group, and each of the phenyl, the aromatic heterocyclic group and the aliphatic heterocyclic group is represented by the following formula (II):
-(CH 2 ) h -ABYDC (II)
{In the formula, h represents an integer of 0 to 3,
C is a hydrogen atom, halogen, hydroxy, nitro, amino, cyano, carboxy, carbamoyl, optionally substituted lower alkyl, optionally substituted cycloalkyl, or optionally substituted. Aryl which may have a substituent, an aliphatic heterocyclic group which may have a substituent, an aromatic heterocyclic group which may have a substituent, an aralkyl which may have a substituent, and a substituent. Lower alkanoyl which may be substituted, cycloalkylcarbonyl which may have substituent, aroyl which may have substituent, aliphatic heterocyclic carbonyl which may have substituent, substituent Aromatic heterocyclic carbonyl which may have, lower alkoxycarbonyl which may have a substituent, cycloalkyloxycarbonyl which may have a substituent, optionally having a substituent Aryloxycarbonyl, optionally substituted aliphatic heterocyclic oxycarbonyl, optionally substituted aromatic heterocyclic oxycarbonyl, optionally substituted lower alkylcarbamoyl, substituted Di-lower alkylcarbamoyl which may have a group, arylcarbamoyl which may have a substituent, lower alkoxy which may have a substituent, cycloalkyloxy which may have a substituent, Aryloxy optionally having substituent, aliphatic heterocyclic oxy optionally having substituent, aromatic heterocyclic oxy optionally having substituent, optionally having substituent Good lower alkanoyloxy, optionally substituted cycloalkylcarbonyloxy, optionally substituted aroyloxy, optionally substituted fat Aromatic heterocyclic carbonyloxy, optionally substituted aromatic heterocyclic carbonyloxy, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, substituted Lower alkylthio optionally having a group, arylthio optionally having a substituent, an aliphatic heterocyclic thio optionally having a substituent, an aromatic heterocyclic ring optionally having a substituent Thio, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, —NR 3 R 4 (wherein R 3 and R 4 are the same or different and represent a hydrogen atom , Lower alkyl optionally having substituents, cycloalkyl optionally having substituents, aryl optionally having substituents, aliphatic heterocyclic groups optionally having substituents Have a substituent Aromatic heterocyclic group which may have, lower alkanoyl which may have substituent, cycloalkylcarbonyl which may have substituent, aroyl which may have substituent, and substituent Aliphatic heterocyclic carbonyl which may have, aromatic heterocyclic carbonyl which may have a substituent, lower alkoxycarbonyl which may have a substituent, cycloalkyloxy which may have a substituent Carbonyl, aryloxycarbonyl optionally having substituent, lower alkylsulfonyl optionally having substituent, arylsulfonyl optionally having substituent, or optionally having substituent Represents an aromatic heterocyclic sulfonyl, or R 3 and R 4 together with the adjacent nitrogen atom form an optionally substituted nitrogen-containing heterocyclic group), —NR A R B R C + X A— [wherein R A , R B and R C are the same or different and each represents lower alkyl, cycloalkyl or aralkyl, and X A represents a chlorine atom, a bromine atom, an iodine atom, or R DA SO 3 (Wherein R DA represents methyl, ethyl, trifluoromethyl, phenyl or tolyl)], the following formula (A)
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
［式中、REは、水素原子；ハロゲン；カルボキシ；カルボキシレート(－COO-)；低級アルコキシカルボニル；またはヒドロキシ、低級アルコキシ、カルボキシまたはカルボキシレート(－COO-)で置換されていてもよい低級アルキルを表し、XBは、塩素原子、臭素原子、ヨウ素原子、またはRDBSO3（式中、RDBは、前記RDAと同義である）を表す（但しREがカルボキシレート(－COO-)またはカルボキシレート(－COO-)が置換した低級アルキルの場合、XB-は欠損している）］で表される基、または－OPO(ORE)2（式中、REは、水素原子または低級アルキルを表す）を表し、
Dは、(1) 結合、または(2) 少なくとも1つ以上のCH2基が－O－、－S－、－SO2－および－NR5－（式中、R5は、水素原子、低級アルキル、シクロアルキル、低級アルカノイルまたは低級アルコキシカルボニルを表す）から選ばれる基で置換されていてもよい直鎖C3-30アルキレンを表し、
Yは、(1) 結合、(2) －O－、(3) －S－、(4) －SO2－、(5) －NR6－（式中、R6は、－DY-CY（式中、DYおよびCYはそれぞれ前記DおよびCと同義である）を表す）、(6) 脂肪族複素環ジイル、(7) 芳香族複素環ジイル、(8) －Het-CONR7－（式中、Hetは芳香族複素環ジイルまたは脂肪族複素環ジイルを表し、R7は水素原子または低級アルキルを表す）または(9)－CH2CH(OH)CH2NR8－（式中、R8は水素原子または低級アルキルを表す）を表し、
Bは、(1) 結合、または(2) 少なくとも1つ以上のCH2基が－O－、－S－、－SO2－、および－NR9－（式中、R9は、水素原子、低級アルキル、シクロアルキル、低級アルカノイルまたは低級アルコキシカルボニルを表す）から選ばれる基で置換されていてもよい直鎖C3-30アルキレンを表し、
Aは、(1) 結合、(2) －O－、(3) －S－、(4) －SO2－、(5) －NR10－（式中、R10は、－BA1-YA1-DA1-CA1（式中、BA1、YA1、DA1およびCA1はそれぞれ前記B、Y、DおよびCと同義である）を表す）、(6) －CONR11－（式中、R11は、－BA2-YA2-DA2-CA2（式中、BA2、YA2、DA2およびCA2はそれぞれ前記B、Y、DおよびCと同義である）を表す）、(7) －NR12CO－（式中、R12は、－BA3-YA3-DA3-CA3（式中、BA3、YA3、DA3およびCA3はそれぞれ前記B、Y、DおよびCと同義である）を表す）、(8) －SO2NR13－（式中、R13は水素原子または置換基を有していてもよい低級アルキルを表す）、(9) 下記式(a1)で表される基 [Wherein R E is a hydrogen atom; halogen; carboxy; carboxylate (—COO − ); lower alkoxycarbonyl; or lower optionally substituted with hydroxy, lower alkoxy, carboxy or carboxylate (—COO − ). Represents an alkyl, and X B represents a chlorine atom, a bromine atom, an iodine atom, or R DB SO 3 (wherein R DB has the same meaning as R DA ) (where R E is a carboxylate (—COO - ) Or carboxylate (—COO − ) in the case of substituted lower alkyl, X B— is missing)], or —OPO (OR E ) 2 (where R E is Represents a hydrogen atom or lower alkyl),
D is (1) a bond, or (2) at least one CH 2 group is —O—, —S—, —SO 2 — and —NR 5 — (wherein R 5 is a hydrogen atom, lower Represents a linear C 3-30 alkylene optionally substituted with a group selected from alkyl, cycloalkyl, lower alkanoyl or lower alkoxycarbonyl),
Y is (1) a bond, (2) -O-, (3) -S-, (4) -SO 2- , (5) -NR 6- (wherein R 6 is -D Y -C Y (wherein D Y and C Y are as defined above for D and C), (6) aliphatic heterocyclic diyl, (7) aromatic heterocyclic diyl, (8) -Het-CONR 7 — (wherein Het represents an aromatic heterocyclic diyl or an aliphatic heterocyclic diyl, and R 7 represents a hydrogen atom or lower alkyl) or (9) —CH 2 CH (OH) CH 2 NR 8 — ( Wherein R 8 represents a hydrogen atom or lower alkyl)
B is (1) a bond, or (2) at least one CH 2 group is —O—, —S—, —SO 2 —, and —NR 9 — (wherein R 9 is a hydrogen atom, Represents a straight-chain C 3-30 alkylene optionally substituted with a group selected from: lower alkyl, cycloalkyl, lower alkanoyl or lower alkoxycarbonyl;
A is (1) a bond, (2) -O-, (3) -S-, (4) -SO 2- , (5) -NR 10- (wherein R 10 is -B A1 -Y A1 -D A1 -C A1 (wherein B A1 , Y A1 , D A1 and C A1 are as defined above for B, Y, D and C, respectively), (6) —CONR 11 — (formula Wherein R 11 represents -B A2 -Y A2 -D A2 -C A2 (wherein B A2 , Y A2 , D A2 and C A2 are as defined above for B, Y, D and C, respectively). ), (7) —NR 12 CO— (wherein R 12 is —B A3 —Y A3 —D A3 —C A3 (wherein B A3 , Y A3 , D A3 and C A3 are the aforementioned B, (Same as Y, D and C)), (8) —SO 2 NR 13 — (wherein R 13 represents a hydrogen atom or optionally substituted lower alkyl), (9 ) Group represented by the following formula (a1)
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
（式中、s1およびs2は、同一または異なって0～2の整数を表し、Qは酸素原子、硫黄原子またはメチレンを表す）または(10) 下記式(a2)で表される基 (Wherein s1 and s2 are the same or different and each represents an integer of 0 to 2, Q represents an oxygen atom, a sulfur atom or methylene) or (10) a group represented by the following formula (a2)
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（式中、s3およびs4は、同一または異なって0～2の整数を表し、Yaは結合または－SO2－を表す）を表す］を表す｝
で表される置換基を有しており、さらに該フェニル、該芳香族複素環基および該脂肪族複素環基はさらに置換基を有していてもよく、
nは、1または2を表し、mは、1または2を表し、
Zは、－CR14R15－｛式中、R14およびR15は、同一または異なって、水素原子、ハロゲン、カルボキシ、置換基を有していてもよい低級アルキル、置換基を有していてもよい低級アルコキシカルボニル、置換基を有していてもよい低級アルキルカルバモイル、置換基を有していてもよいジ低級アルキルカルバモイルまたは置換基を有していてもよい脂肪族複素環カルボニルを表すか［但し、Bおよび／またはDが、少なくとも1つ以上のCH2基が－O－、－S－および－NR5－（式中、R5は前記と同義である）または－NR9－（式中、R9は前記と同義である）から選ばれる基で置換されていてもよい直鎖C3-30アルキレンであり、該アルキレン中の炭素原子数の総和が７以下であるとき、あるいはBおよびDが共に結合であるとき、R14およびR15は同時に水素原子になることはない］、またはR14とR15が隣接する炭素原子と一緒になってシクロアルカン、オキセタン、オキソランまたはオキサンを形成する｝、
－NR16－（式中、R16は、水素原子、置換基を有していてもよい低級アルキル、置換基を有していてもよいシクロアルキル、置換基を有していてもよいアラルキル、置換基を有していてもよい低級アルカノイル、置換基を有していてもよいアロイル、置換基を有していてもよい脂肪族複素環カルボニル、置換基を有していてもよい芳香族複素環カルボニル、置換基を有していてもよい低級アルコキシカルボニル、置換基を有していてもよいアリールオキシカルボニル、置換基を有していてもよい低級アルキルスルホニル、置換基を有していてもよいアリールスルホニル、置換基を有していてもよい脂肪族複素環スルホニルまたは置換基を有していてもよい芳香族複素環スルホニルを表す）、
－O－、－S－または－SO2－を表す＞
で表される化合物またはその薬学的に許容される塩。
(2)　R1が水素原子であり、R2が置換基を有していてもよいアリールである(1)記載の化合物またはその薬学的に許容される塩。
(3)　Lが1個の式（II）で表される基で置換されたフェニルまたは芳香族複素環基である(1)または(2)記載の化合物またはその薬学的に許容される塩。
(4)　Lが表す芳香族複素環基がピリジルまたはチアゾリルである(1)～(3)のいずれかに記載の化合物またはその薬学的に許容される塩。
(5)　Lが下記式（La）～（Ld）のいずれかで表される基である(1)～(3)のいずれかに記載の化合物またはその薬学的に許容される塩。 (Wherein s3 and s4 are the same or different and each represents an integer of 0 to 2, and Y a represents a bond or —SO 2 —)]
The phenyl, the aromatic heterocyclic group and the aliphatic heterocyclic group may further have a substituent,
n represents 1 or 2, m represents 1 or 2,
Z is —CR 14 R 15 — {wherein R 14 and R 15 are the same or different and each has a hydrogen atom, halogen, carboxy, optionally substituted lower alkyl, or substituent. Lower alkylcarbonyl which may be substituted, lower alkylcarbamoyl which may have a substituent, dilower alkylcarbamoyl which may have a substituent or aliphatic heterocyclic carbonyl which may have a substituent carded [However, B and / or D is at least one or more CH 2 groups -O -, - S- and -NR 5 - (wherein, R 5 is as defined above) or -NR 9 - (Wherein R 9 is as defined above) is a linear C 3-30 alkylene optionally substituted with a group selected from the above, and the total number of carbon atoms in the alkylene is 7 or less, Alternatively, when B and D are both bonds, R 14 and R 15 are simultaneously hydrogen atoms. Or R 14 and R 15 together with adjacent carbon atoms form a cycloalkane, oxetane, oxolane or oxane},
—NR 16 — (wherein R 16 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, Lower alkanoyl optionally having substituent, aroyl optionally having substituent, aliphatic heterocyclic carbonyl optionally having substituent, aromatic heterocyclic optionally having substituent Ring carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted A good arylsulfonyl, an optionally substituted aliphatic heterocyclic sulfonyl or an optionally substituted aromatic heterocyclic sulfonyl),
Represents —O—, —S— or —SO 2 —>
Or a pharmaceutically acceptable salt thereof.
(2) The compound or a pharmaceutically acceptable salt thereof according to (1), wherein R 1 is a hydrogen atom, and R 2 is aryl optionally having substituent (s).
(3) The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof, wherein L is a phenyl or aromatic heterocyclic group substituted with one group represented by formula (II).
(4) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein the aromatic heterocyclic group represented by L is pyridyl or thiazolyl.
(5) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein L is a group represented by any of the following formulas (La) to (Ld).
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
（式中、h、A、B、Y、DおよびCは、それぞれ前記と同義である）
(6)　Zが－CR14R15－（式中、R14およびR15は、それぞれ前記と同義である）である(1)～(5)のいずれかに記載の化合物またはその薬学的に許容される塩。
(7)　Zが－NR16－（式中、R16は、前記と同義である）である(1)～(5)のいずれかに記載の化合物またはその薬学的に許容される塩。
(8)　Bが、(1) －(CH2CH2Wa)qa-(CH2)ra－（式中、Waは－O－、－S－、－SO2－、または－NR9－（式中、R9は前記と同義である）を表し、qaは1～8の整数を表し、raは0～3の整数を表す）、(2) －(CH2CH2CH2Waa)ua-(CH2)va－（式中、Waaは－O－、－S－、－SO2－、または－NR9－（式中、R9は前記と同義である）を表し、uaは1～6の整数を表し、vaは0～6の整数を表す）、または(3) －(CH2)ta－（式中、ta は1～30の整数を表す）である(1)～(7)のいずれかに記載の化合物またはその薬学的に許容される塩。
(9)　Dが、(1) －(CH2CH2Wb)qb-(CH2)rb－（式中、Wbは－O－、－S－、－SO2－、または－NR5－（式中、R5は前記と同義である）を表し、qbは1～8の整数を表し、rbは0～3の整数を表す）、(2) －(CH2CH2CH2Wbb)ub-(CH2)vb－（式中、Wbbは－O－、－S－、－SO2－、または－NR5－（式中、R5は前記と同義である）を表し、ubは1～6の整数を表し、vbは0～6の整数を表す）、または(3) －(CH2)tb－（式中、tb は1～30の整数を表す）である(1)～(8)のいずれかに記載の化合物またはその薬学的に許容される塩。
(10)　(1)～(9)のいずれかに記載の化合物またはその薬学的に許容される塩を含有する血中へのリンの取り込み阻害剤。
(11)　(1)～(9)のいずれかに記載の化合物またはその薬学的に許容される塩を含有する高リン血症の治療および／または予防剤。
(12)　(1)～(9)のいずれかに記載の化合物またはその薬学的に許容される塩の有効量を投与する工程を含む血中へのリンの取り込み阻害方法。
(13)　(1)～(9)のいずれかに記載の化合物またはその薬学的に許容される塩の有効量を投与する工程を含む高リン血症の治療および／または予防方法。
(14)　血中へのリンの取り込み阻害に使用するための(1)～(9)のいずれかに記載の化合物またはその薬学的に許容される塩。
(15)　高リン血症の治療および／または予防に使用するための(1)～(9)のいずれかに記載の化合物またはその薬学的に許容される塩。
(16)　血中へのリンの取り込み阻害剤の製造のための(1)～(9)のいずれかに記載の化合物またはその薬学的に許容される塩の使用。
(17)　高リン血症の治療および／または予防剤の製造のための(1)～(9)のいずれかに記載の化合物またはその薬学的に許容される塩の使用。 (Wherein h, A, B, Y, D and C are as defined above)
(6) The compound according to any one of (1) to (5) or a pharmaceutically acceptable salt thereof, wherein Z is —CR 14 R 15 — (wherein R 14 and R 15 are as defined above, respectively). Acceptable salt.
(7) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein Z is —NR 16 — (wherein R 16 has the same meaning as described above).
(8) B is (1)-(CH 2 CH 2 W a ) qa- (CH 2 ) ra- (W a is -O-, -S-, -SO 2- , or -NR 9 -(Wherein R 9 is as defined above), qa represents an integer of 1 to 8, ra represents an integer of 0 to 3, and (2)-(CH 2 CH 2 CH 2 W aa ) ua — (CH 2 ) va — (wherein W aa is —O—, —S—, —SO 2 —, or —NR 9 — (wherein R 9 is as defined above). , Ua represents an integer of 1 to 6 and va represents an integer of 0 to 6), or (3) — (CH 2 ) ta — (where ta represents an integer of 1 to 30). 1. The compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof.
(9) D is (1)-(CH 2 CH 2 W b ) qb- (CH 2 ) rb- (where W b is -O-, -S-, -SO 2- , or -NR 5 -(Wherein R 5 is as defined above), qb represents an integer of 1 to 8, rb represents an integer of 0 to 3, and (2)-(CH 2 CH 2 CH 2 W bb ) ub- (CH 2 ) vb- (wherein W bb is -O-, -S-, -SO 2- , or -NR 5- (wherein R 5 is as defined above)). , Ub represents an integer of 1 to 6 and vb represents an integer of 0 to 6), or (3) — (CH 2 ) tb — (where tb represents an integer of 1 to 30). 1) The compound according to any one of (8) or a pharmaceutically acceptable salt thereof.
(10) An inhibitor of phosphorus uptake into blood comprising the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
(11) A therapeutic and / or prophylactic agent for hyperphosphatemia comprising the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
(12) A method for inhibiting the uptake of phosphorus into blood, comprising a step of administering an effective amount of the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
(13) A method for treating and / or preventing hyperphosphatemia, comprising a step of administering an effective amount of the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
(14) The compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof for use in inhibiting phosphorus uptake into blood.
(15) The compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of hyperphosphatemia.
(16) Use of the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof for the manufacture of an inhibitor of phosphorus uptake into blood.
(17) Use of the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for hyperphosphatemia.
　本発明により、腸管におけるNaPi2bを阻害し、血清のリン濃度が影響する疾患（例えば、高リン血症など）の治療および／または予防剤として有用な縮環チオフェン誘導体またはその薬学的に許容される塩などが提供される。 According to the present invention, a fused-ring thiophene derivative useful as a therapeutic and / or preventive agent for a disease that inhibits NaPi2b in the intestinal tract and is affected by serum phosphorus concentration (for example, hyperphosphatemia) or a pharmaceutically acceptable product thereof Salt and the like are provided.
　以下、一般式（I）で表される化合物を化合物（I）という。他の式番号の化合物についても同様である。
　一般式（I）の各基の定義において、
　低級アルキル、ならびに低級アルカノイル、低級アルコキシカルボニル、低級アルキルカルバモイル、ジ低級アルキルカルバモイル、低級アルコキシ、低級アルカノイルオキシ、低級アルキルスルホニルオキシ、低級アルキルチオ、および低級アルキルスルホニルの低級アルキル部分としては、例えば直鎖または分岐状の炭素数1～10のアルキルがあげられ、より具体的にはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、ヘプチル、オクチル、ノニル、デシルなどがあげられる。ジ低級アルキルカルバモイルの2つの低級アルキル部分は、同一でも異なっていてもよい。 Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds of other formula numbers.
In the definition of each group of general formula (I):
Lower alkyl, and lower alkanoyl, lower alkoxycarbonyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkoxy, lower alkanoyloxy, lower alkylsulfonyloxy, lower alkylthio, and lower alkyl moiety of lower alkylsulfonyl include, for example, linear or Examples include branched alkyl having 1 to 10 carbon atoms, and more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl , Nonyl, decyl and the like. The two lower alkyl moieties of the di-lower alkylcarbamoyl may be the same or different.
　シクロアルキル、ならびにシクロアルキルカルボニル、シクロアルキルオキシカルボニル、シクロアルキルオキシ、シクロアルキルカルボニルオキシ、および隣接する炭素原子と一緒になって形成されるシクロアルカンのシクロアルキル部分としては、例えば炭素数3～8のシクロアルキルがあげられ、より具体的にはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチルなどがあげられる。 Examples of cycloalkyl and the cycloalkyl portion of cycloalkylcarbonyl, cycloalkyloxycarbonyl, cycloalkyloxy, cycloalkylcarbonyloxy, and a cycloalkyl portion of a cycloalkane formed together with adjacent carbon atoms include, for example, 3 to 8 carbon atoms. More specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.
　直鎖C3-30アルキレンは、炭素数3～30の直鎖のアルキレンを意味し、より具体的には一般式－(CH2)m－（式中、mは3～30の整数を表す）で表されるアルキレンを意味する。即ち、BおよびDで定義された少なくとも1つ以上のCH2基が－O－、－S－、－SO2－、および－NR9－または－NR5－（式中、R9およびR5は、それぞれ水素原子、低級アルキル、シクロアルキル、低級アルカノイルまたは低級アルコキシカルボニルを表す）から選ばれる基で置換されていてもよい直鎖C3-30アルキレンとしては、例えば以下の式(1)～(14)で表される基などがあげられる。
(1) －(CH2)n0－（式中、n0は3～30の整数を表す）
(2) －(CH2O)n1－（式中、n1は2～15の整数を表す）
(3) －(CH2CH2O)n2－（式中、n2は1～10の整数を表す）
(4) －(CH2CH2CH2O)n3－（式中、n3は1～7の整数を表す）
(5) －(CH2)n4(OCH2CH2)n5－（式中、n4は1～27の整数を表し、n5は1～9の整数を表す。但し、n4＋n5×3は30を超えない）
(6) －(CH2CH2O)n6(CH2)n7-（式中、n6は1～9の整数を表し、n7は1～27の整数を表す。但し、n6×3＋n7は30を超えない）
(7) －(CH2CH2S)n8－（式中、n8は1～10の整数を表す）
(8) －(CH2CH2CH2S)n9－（式中、n9は1～7の整数を表す）
(9) －(CH2CH2NCH3)n10－（式中、n10は1～10の整数を表す）
(10) －(CH2)n11O(CH2)n12－（式中、n11は1～28の整数を表し、n12は1～28の整数を表す。但し、n11＋n12は29を超えない）
(11) －(CH2)n13S(CH2)n14－（式中、n13は1～28の整数を表し、n14は1～28の整数を表す。但し、n13＋n14は29を超えない）
(12) －(CH2)n15NRw(CH2)n16－（式中、Rwは水素原子、低級アルキル、シクロアルキル、低級アルカノイルまたは低級アルコキシカルボニルを表し、n15は1～28の整数を表し、n16は1～28の整数を表す。但し、n15＋n16は29を超えない）
(13) －(CH2CH2W)q-(CH2)r－（式中、Wは－O－、－S－、－SO2－、または－NRw－（式中、Rwは前記と同義である）を表し、qは1～8の整数を表し、rは0～3の整数を表す）
(14) －(CH2CH2CH2W)u-(CH2)v－（式中、Wは－O－、－S－、－SO2－、または－NRW－（式中、Rwは前記と同義である）を表し、uは1～6の整数を表し、vは0～6の整数を表す）
　アラルキルとしては、例えば炭素数7～16のアラルキルがあげられ、より具体的にはベンジル、フェネチル、フェニルプロピル、フェニルブチル、フェニルペンチル、フェニルヘキシル、フェニルヘプチル、フェニルオクチル、フェニルノニル、フェニルデシル、ナフチルメチル、ナフチルエチル、ナフチルプロピル、ナフチルブチル、ナフチルペンチル、ナフチルヘキシル、アントリルメチル、アントリルエチルなどがあげられる。 The straight chain C 3-30 alkylene means a straight chain alkylene having 3 to 30 carbon atoms, and more specifically, a general formula — (CH 2 ) m — (wherein m represents an integer of 3 to 30) ) Represents an alkylene represented by: That is, at least one CH 2 group defined by B and D is —O—, —S—, —SO 2 —, and —NR 9 — or —NR 5 — (wherein R 9 and R 5 They are each a hydrogen atom, a lower alkyl, cycloalkyl, the lower alkanoyl or lower alkoxy optionally a straight chain C 3-30 alkylene optionally substituted with a group selected from the a carbonyl), for example, the following equation (1) to And the group represented by (14).
(1) — (CH 2 ) n0 — (where n0 represents an integer of 3 to 30)
(2) — (CH 2 O) n1 — (where n1 represents an integer of 2 to 15)
(3) — (CH 2 CH 2 O) n2 — (wherein n2 represents an integer of 1 to 10)
(4) — (CH 2 CH 2 CH 2 O) n3 — (where n3 represents an integer of 1 to 7)
(5) — (CH 2 ) n4 (OCH 2 CH 2 ) n5 — (where n4 represents an integer of 1 to 27 and n5 represents an integer of 1 to 9, provided that n4 + n5 × 3 exceeds 30) Absent)
(6) — (CH 2 CH 2 O) n6 (CH 2 ) n7 — (where n6 represents an integer of 1 to 9, n7 represents an integer of 1 to 27, provided that n6 × 3 + n7 represents 30) Not exceed)
(7) — (CH 2 CH 2 S) n8 — (where n8 represents an integer of 1 to 10)
(8) — (CH 2 CH 2 CH 2 S) n9 — (where n9 represents an integer of 1 to 7)
(9) — (CH 2 CH 2 NCH 3 ) n10 — (where n10 represents an integer of 1 to 10)
(10) — (CH 2 ) n11 O (CH 2 ) n12 — (wherein n11 represents an integer of 1 to 28, n12 represents an integer of 1 to 28, provided that n11 + n12 does not exceed 29)
(11) — (CH 2 ) n13 S (CH 2 ) n14 — (wherein n13 represents an integer of 1 to 28, n14 represents an integer of 1 to 28, provided that n13 + n14 does not exceed 29)
(12) — (CH 2 ) n15 NR w (CH 2 ) n16 — (wherein R w represents a hydrogen atom, lower alkyl, cycloalkyl, lower alkanoyl or lower alkoxycarbonyl, and n15 represents an integer of 1 to 28) N16 represents an integer of 1 to 28, provided that n15 + n16 does not exceed 29)
(13) — (CH 2 CH 2 W) q — (CH 2 ) r — (W is —O—, —S—, —SO 2 —, or —NR w — (where R w is As defined above, q represents an integer of 1 to 8, and r represents an integer of 0 to 3)
(14) — (CH 2 CH 2 CH 2 W) u — (CH 2 ) v — (W is —O—, —S—, —SO 2 —, or —NR W — (where R is w is as defined above), u represents an integer of 1 to 6, and v represents an integer of 0 to 6)
Examples of aralkyl include aralkyl having 7 to 16 carbon atoms, and more specifically, benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, phenyloctyl, phenylnonyl, phenyldecyl, naphthyl. Examples include methyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, anthrylmethyl, anthrylethyl and the like.
　アリール、ならびにアロイル、アリールオキシカルボニル、アリールカルバモイル、アリールオキシ、アロイルオキシ、アリールスルホニルオキシ、アリールチオ、およびアリールスルホニルのアリール部分としては、例えば炭素数6～14のアリールがあげられ、より具体的にはフェニル、ナフチル、アズレニル、アントリルなどがあげられる。
　脂肪族複素環基、ならびに脂肪族複素環ジイル、脂肪族複素環カルボニル、脂肪族複素環オキシカルボニル、脂肪族複素環オキシ、脂肪族複素環カルボニルオキシ、脂肪族複素環チオ、および脂肪族複素環スルホニルの脂肪族複素環基部分としては、例えば窒素原子、酸素原子および硫黄原子から選ばれる少なくとも1個の原子を含む5員または6員の単環性脂肪族複素環基、3～8員の環が縮合した二環または三環性で窒素原子、酸素原子および硫黄原子から選ばれる少なくとも1個の原子を含む縮環性脂肪族複素環基などがあげられ、より具体的にはアジリジニル、アゼチジニル、ピロリジニル、ピペリジノ、ピペリジニル、アゼパニル、1,2,5,6-テトラヒドロピリジル、イミダゾリジニル、ピラゾリジニル、ピペラジニル、ホモピペラジニル、ピラゾリニル、オキシラニル、テトラヒドロフラニル、テトラヒドロ-2H-ピラニル、5,6-ジヒドロ-2H-ピラニル、オキサゾリジニル、モルホリノ、モルホリニル、チオキサゾリジニル、チオモルホリニル、2H-オキサゾリル、2H-チオキサゾリル、ジヒドロインドリル、ジヒドロイソインドリル、ジヒドロベンゾフラニル、ベンゾイミダゾリジニル、ジヒドロベンゾオキサゾリル、ジヒドロベンゾチオキサゾリル、ベンゾジオキソリニル、テトラヒドロキノリル、テトラヒドロイソキノリル、ジヒドロ-2H-クロマニル、ジヒドロ-1H-クロマニル、ジヒドロ-2H-チオクロマニル、ジヒドロ-1H-チオクロマニル、テトラヒドロキノキサリニル、テトラヒドロキナゾリニル、ジヒドロベンゾジオキサニルなどがあげられる。 Examples of aryl and the aryl moiety of aroyl, aryloxycarbonyl, arylcarbamoyl, aryloxy, aroyloxy, arylsulfonyloxy, arylthio, and arylsulfonyl include aryl having 6 to 14 carbon atoms, and more specifically phenyl. , Naphthyl, azulenyl, anthryl and the like.
Aliphatic heterocyclic groups, and aliphatic heterocyclic diyls, aliphatic heterocyclic carbonyls, aliphatic heterocyclic oxycarbonyls, aliphatic heterocyclic oxys, aliphatic heterocyclic carbonyloxys, aliphatic heterocyclic thios, and aliphatic heterocyclic rings As the aliphatic heterocyclic group moiety of sulfonyl, for example, a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, Bicyclic or tricyclic condensed rings containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom are included, and more specifically, aziridinyl and azetidinyl , Pyrrolidinyl, piperidino, piperidinyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pipe Zolinyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, oxazolidinyl, morpholino, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydro Isoindolyl, dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydro-2H-chromanyl, dihydro- 1H-chromanyl, dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydrobenzodioxanyl and the like.
　芳香族複素環基、ならびに芳香族複素環ジイル、芳香族複素環カルボニル、芳香族複素環オキシカルボニル、芳香族複素環オキシ、芳香族複素環カルボニルオキシ、芳香族複素環チオ、および芳香族複素環スルホニルの芳香族複素環基部分としては、例えば窒素原子、酸素原子および硫黄原子から選ばれる少なくとも1個の原子を含む5員または6員の単環性芳香族複素環基、3～8員の環が縮合した二環または三環性で窒素原子、酸素原子および硫黄原子から選ばれる少なくとも1個の原子を含む縮環性芳香族複素環基などがあげられ、より具体的にはフリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアジニル、ベンゾフラニル、ベンゾチオフェニル、ベンゾオキサゾリル、ベンゾチアゾリル、イソインドリル、インドリル、インダゾリル、ベンゾイミダゾリル、ベンゾトリアゾリル、オキサゾロピリミジニル、チアゾロピリミジニル、ピロロピリジニル、ピロロピリミジニル、イミダゾピリジニル、プリニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル、ベンゾ[c][1,2,5]オキサジアゾリルなどがあげられる。 Aromatic heterocyclic groups, and aromatic heterocyclic diyls, aromatic heterocyclic carbonyls, aromatic heterocyclic oxycarbonyls, aromatic heterocyclic oxys, aromatic heterocyclic carbonyloxys, aromatic heterocyclic thios, and aromatic heterocyclics As the aromatic heterocyclic group moiety of sulfonyl, for example, a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, Examples thereof include a condensed bicyclic or tricyclic condensed ring aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically furyl, thienyl. , Pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl, benzoimidazolyl, benzotriazolyl, oxazopyrimidinyl, thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl Examples include pyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzo [c] [1,2,5] oxadiazolyl and the like.
　隣接する窒素原子と一緒になって形成される含窒素複素環基としては、例えば少なくとも1個の窒素原子を含む5員または6員の単環性複素環基(該単環性複素環基は、他の窒素原子、酸素原子または硫黄原子を含んでいてもよい)、3～8員の環が縮合した二環または三環性で少なくとも1個の窒素原子を含む縮環性複素環基(該縮環性複素環基は、他の窒素原子、酸素原子または硫黄原子を含んでいてもよい)などがあげられ、より具体的にはアジリジニル、アゼチジニル、ピロリジニル、ピペリジノ、アゼパニル、ピロリル、イミダゾリジニル、イミダゾリル、ピラゾリジニル、ピラゾリニル、ピラゾリル、ピペラジニル、ホモピペラジニル、オキサゾリジニル、2H-オキサゾリル、チオキサゾリジニル、2H-チオキサゾリル、モルホリノ、チオモルホリニル、ジヒドロインドリル、ジヒドロイソインドリル、インドリル、イソインドリル、テトラヒドロキノリル、テトラヒドロイソキノリル、ジヒドロベンゾオキサゾリル、ジヒドロベンゾチオキサゾリル、ベンゾイミダゾリジニル、ベンゾイミダゾリル、ジヒドロインダゾリル、インダゾリル、ベンゾトリアゾリル、ピロロピリジニル、ピロロピリミジニル、イミダゾピリジニル、プリニルなどがあげられる。 Examples of the nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is , May contain other nitrogen atoms, oxygen atoms or sulfur atoms), condensed bicyclic or tricyclic condensed 3 to 8 membered rings and containing at least one nitrogen atom ( The condensed ring heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, pyrrolyl, imidazolidinyl, Imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl, 2H-thioxazolyl, morpholino, thiomorpholine Linyl, dihydroindolyl, dihydroisoindolyl, indolyl, isoindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzoimidazolidinyl, benzoimidazolyl, dihydroindazolyl, indazolyl Benzotriazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl and the like.
　ハロゲンは、フッ素、塩素、臭素、ヨウ素の各原子を意味する。
　置換基を有していてもよい低級アルキル、置換基を有していてもよい低級アルカノイル、置換基を有していてもよい低級アルコキシカルボニル、置換基を有していてもよい低級アルキルカルバモイル、置換基を有していてもよいジ低級アルキルカルバモイル、置換基を有していてもよい低級アルコキシ、置換基を有していてもよい低級アルカノイルオキシ、置換基を有していてもよい低級アルキルスルホニルオキシ、置換基を有していてもよい低級アルキルチオ、および置換基を有していてもよい低級アルキルスルホニルにおける置換基としては、同一または異なって、例えば置換数1～3の、ハロゲン、ヒドロキシ、スルファニル、ニトロ、シアノ、カルボキシ、カルバモイル、C3-8シクロアルキル、C6-14アリール、脂肪族複素環基、芳香族複素環基、C1-10アルコキシ、C3-8シクロアルコキシ、C6-14アリールオキシ、C7-16アラルキルオキシ、C2-11アルカノイルオキシ、C7-15アロイルオキシ、C1-10アルキルスルファニル、-NRXRY(式中、RXおよびRYは同一または異なって、水素原子、C1-10アルキル、C3-8シクロアルキル、C6-14アリール、芳香族複素環基、C7-16アラルキル、C2-11アルカノイル、C7-15アロイル、C1-10アルコキシカルボニルまたはC7-16アラルキルオキシカルボニルを表す)、C2-11アルカノイル、C7-15アロイル、C1-10アルコキシカルボニル、C6-14アリールオキシカルボニル、C1-10アルキルカルバモイルおよびジC1-10アルキルカルバモイルなどからなる群から選ばれる置換基があげられる。 Halogen means each atom of fluorine, chlorine, bromine and iodine.
Lower alkyl optionally having substituent, lower alkanoyl optionally having substituent, lower alkoxycarbonyl optionally having substituent, lower alkylcarbamoyl optionally having substituent, Di-lower alkylcarbamoyl which may have a substituent, lower alkoxy which may have a substituent, lower alkanoyloxy which may have a substituent, lower alkyl which may have a substituent The substituents in sulfonyloxy, optionally substituted lower alkylthio, and optionally substituted lower alkylsulfonyl are the same or different, for example, halogen, hydroxy having 1 to 3 substituents , Sulfanyl, nitro, cyano, carboxy, carbamoyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic compound Heterocyclic group, C 1-10 alkoxy, C 3-8 cycloalkoxy, C 6-14 aryloxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10 alkylsulfanyl , -NR X R Y (wherein R X and R Y are the same or different and represent a hydrogen atom, C 1-10 alkyl, C 3-8 cycloalkyl, C 6-14 aryl, aromatic heterocyclic group, C 7-16 aralkyl, C 2-11 alkanoyl, C 7-15 aroyl, C 1-10 alkoxycarbonyl or C 7-16 aralkyloxycarbonyl), C 2-11 alkanoyl, C 7-15 aroyl, C 1- Examples thereof include a substituent selected from the group consisting of 10 alkoxycarbonyl, C 6-14 aryloxycarbonyl, C 1-10 alkylcarbamoyl, diC 1-10 alkylcarbamoyl and the like.
　置換基を有していてもよいアリール、置換基を有していてもよいアロイル、置換基を有していてもよいアリールオキシカルボニル、置換基を有していてもよいアリールカルバモイル、置換基を有していてもよいアリールオキシ、置換基を有していてもよいアロイルオキシ、置換基を有していてもよいアリールスルホニルオキシ、置換基を有していてもよいアリールチオ、置換基を有していてもよいアリールスルホニル、置換基を有していてもよいアラルキル、置換基を有していてもよい芳香族複素環基、置換基を有していてもよい芳香族複素環ジイル、置換基を有していてもよい芳香族複素環カルボニル、置換基を有していてもよい芳香族複素環オキシカルボニル、置換基を有していてもよい芳香族複素環オキシ、置換基を有していてもよい芳香族複素環カルボニルオキシ、置換基を有していてもよい芳香族複素環チオ、置換基を有していてもよい芳香族複素環スルホニル、置換基を有していてもよいフェニレン、置換基を有していてもよいピリジンジイル、および置換基を有していてもよいチアゾールジイルにおける置換基としては、同一または異なって例えば置換数1～3の、ハロゲン、ヒドロキシ、スルファニル、ニトロ、シアノ、カルボキシ、カルバモイル、C1-10アルキル、トリフルオロメチル、C3-8シクロアルキル、C6-14アリール、脂肪族複素環基、芳香族複素環基、C1-10アルコキシ、C3-8シクロアルコキシ、C6-14アリールオキシ、C7-16アラルキルオキシ、C2-11アルカノイルオキシ、C7-15アロイルオキシ、C1-10アルキルスルファニル、-NRXaRYa(式中、RXaおよびRYaは同一または異なって、水素原子、C1-10アルキル、C3-8シクロアルキル、C6-14アリール、芳香族複素環基、C7-16アラルキル、C2-11アルカノイル、C7-15アロイル、C1-10アルコキシカルボニルまたはC7-16アラルキルオキシカルボニルを表す)、C2-11アルカノイル、C7-15アロイル、C1-10アルコキシカルボニル、C6-14アリールオキシカルボニル、C1-10アルキルカルバモイルおよびジC1-10アルキルカルバモイルなどからなる群から選ばれる置換基があげられる。 Aryl optionally having substituents, aroyl optionally having substituents, aryloxycarbonyl optionally having substituents, arylcarbamoyl optionally having substituents, substituents Aryloxy which may have, aroyloxy which may have a substituent, arylsulfonyloxy which may have a substituent, arylthio which may have a substituent, having a substituent An arylsulfonyl which may have a substituent, an aralkyl which may have a substituent, an aromatic heterocyclic group which may have a substituent, an aromatic heterocyclic diyl which may have a substituent, a substituent An aromatic heterocyclic carbonyl that may have, an aromatic heterocyclic oxycarbonyl that may have a substituent, an aromatic heterocyclic oxy that may have a substituent, Good Aromatic heterocyclic carbonyloxy, optionally substituted aromatic heterocyclic thio, optionally substituted aromatic heterocyclic sulfonyl, optionally substituted phenylene, substituted As the substituents in pyridinediyl optionally having substituents and thiazolediyl optionally having substituents, for example, halogen, hydroxy, sulfanyl, nitro, cyano, Carboxy, carbamoyl, C 1-10 alkyl, trifluoromethyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, C 1-10 alkoxy, C 3-8 cyclo Alkoxy, C 6-14 aryloxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10 alkylsulfanyl, —NR Xa R Ya (where R Xa and R Ya Is the same or Different, hydrogen atom, C 1-10 alkyl, C 3-8 cycloalkyl, C 6-14 aryl, an aromatic heterocyclic group, C 7-16 aralkyl, C 2-11 alkanoyl, C 7-15 aroyl, C 1-10 alkoxycarbonyl or C 7-16 aralkyloxycarbonyl), C 2-11 alkanoyl, C 7-15 aroyl, C 1-10 alkoxycarbonyl, C 6-14 aryloxycarbonyl, C 1-10 alkylcarbamoyl And a substituent selected from the group consisting of di-C 1-10 alkylcarbamoyl and the like.
　置換基を有していてもよいシクロアルキル、置換基を有していてもよいシクロアルキルカルボニル、置換基を有していてもよいシクロアルキルオキシカルボニル、置換基を有していてもよいシクロアルキルオキシ、置換基を有していてもよいシクロアルキルカルボニルオキシ、置換基を有していてもよい脂肪族複素環基、置換基を有していてもよい脂肪族複素環ジイル、置換基を有していてもよい脂肪族複素環カルボニル、置換基を有していてもよい脂肪族複素環オキシカルボニル、置換基を有していてもよい脂肪族複素環オキシ、置換基を有していてもよい脂肪族複素環カルボニルオキシ、置換基を有していてもよい脂肪族複素環チオ、置換基を有していてもよい脂肪族複素環スルホニル、および置換基を有していてもよい隣接する窒素原子と一緒になって形成される含窒素複素環基における置換基としては、同一または異なって、例えば置換数1～3の、オキソ、ハロゲン、ヒドロキシ、スルファニル、ニトロ、シアノ、カルボキシ、カルバモイル、C1-10アルキル、トリフルオロメチル、C3-8シクロアルキル、C6-14アリール、脂肪族複素環基、芳香族複素環基、C1-10アルコキシ、C3-8シクロアルコキシ、C6-14アリールオキシ、C7-16アラルキルオキシ、C2-11アルカノイルオキシ、C7-15アロイルオキシ、C1-10アルキルスルファニル、－NRXbRYb(式中、RXbおよびRYbは同一または異なって、水素原子、C1-10アルキル、C3-8シクロアルキル、C6-14アリール、芳香族複素環基、C7-16アラルキル、C2-11アルカノイル、C7-15アロイル、C1-10アルコキシカルボニルまたはC7-16アラルキルオキシカルボニルを表す)、C2-11アルカノイル、C7-15アロイル、C1-10アルコキシカルボニル、C6-14アリールオキシカルボニル、C1-10アルキルカルバモイルおよびジC1-10アルキルカルバモイルなどからなる群から選ばれる置換基があげられる。 Cycloalkyl which may have a substituent, cycloalkylcarbonyl which may have a substituent, cycloalkyloxycarbonyl which may have a substituent, cycloalkyl which may have a substituent Oxy, optionally substituted cycloalkylcarbonyloxy, optionally substituted aliphatic heterocyclic group, optionally substituted aliphatic heterocyclic diyl, substituted An optionally substituted aliphatic heterocyclic carbonyl, an optionally substituted aliphatic heterocyclic oxycarbonyl, an optionally substituted aliphatic heterocyclic oxy, and optionally having a substituent Good aliphatic heterocyclic carbonyloxy, optionally substituted aliphatic heterocyclic thio, optionally substituted aliphatic heterocyclic sulfonyl, and optionally substituted adjacent Nitrogen field The substituent in the nitrogen-containing heterocyclic group formed together with the same or different, such as 1 to 3 substituents, oxo, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C 1 -10 alkyl, trifluoromethyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, C 1-10 alkoxy, C 3-8 cycloalkoxy, C 6-14 Aryloxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10 alkylsulfanyl, —NR Xb R Yb (wherein R Xb and R Yb are the same or different, Hydrogen atom, C 1-10 alkyl, C 3-8 cycloalkyl, C 6-14 aryl, aromatic heterocyclic group, C 7-16 aralkyl, C 2-11 alkanoyl, C 7-15 aroyl, C 1-10 alkoxycarbonyl or C 7-16 aralkyloxy carbonylation The represented), C 2-11 alkanoyl, C 7-15 aroyl, C 1-10 alkoxycarbonyl, C 6-14 aryloxycarbonyl, a C 1-10 group and the like alkylcarbamoyl and di C 1-10 alkylcarbamoyl Examples of the substituent are selected.
　ここで示したC1-10アルキルならびにC1-10アルコキシ、C2-11アルカノイルオキシ、C1-10アルキルスルファニル、C2-11アルカノイル、C1-10アルコキシカルボニル、C1-10アルキルカルバモイルおよびジC1-10アルキルカルバモイルのC1-10アルキル部分としては、例えば前記低級アルキルの例示であげた基が例示される。ジC1-10アルキルカルバモイルにおける2つのC1-10アルキル部分は同一でも異なっていてもよい。 C 1-10 alkyl as shown here and C 1-10 alkoxy, C 2-11 alkanoyloxy, C 1-10 alkylsulfanyl, C 2-11 alkanoyl, C 1-10 alkoxycarbonyl, C 1-10 alkylcarbamoyl and Examples of the C 1-10 alkyl moiety of diC 1-10 alkylcarbamoyl include the groups exemplified above for the lower alkyl. The two C 1-10 alkyl moieties in the diC 1-10 alkylcarbamoyl may be the same or different.
　C3-8シクロアルキルおよびC3-8シクロアルコキシのシクロアルキル部分としては、例えば前記シクロアルキルの例示であげた基が例示される。
　C6-14アリールならびにC6-14アリールオキシ、C7-15アロイル、C7-15アロイルオキシおよびC6-14アリールオキシカルボニルのアリール部分としては、例えば前記アリールの例示であげた基が例示される。 The C 3-8 cycloalkyl and C 3-8 cycloalkyl moiety cycloalkoxy, e.g. groups mentioned for illustrative said cycloalkyl is exemplified.
Examples of the aryl moiety of C 6-14 aryl and C 6-14 aryloxy, C 7-15 aroyl, C 7-15 aroyloxy and C 6-14 aryloxycarbonyl include the groups exemplified in the above aryl examples. The
　C7-16アラルキルならびにC7-16アラルキルオキシおよびC7-16アラルキルオキシカルボニルのアラルキル部分としては、例えば前記アラルキルの例示であげた基が例示される。
　脂肪族複素環基、芳香族複素環基およびハロゲンは、それぞれ前記と同義である。
　化合物（I）の薬学的に許容される塩は、例えば薬学的に許容される酸付加塩、金属塩、アンモニウム塩、有機アミン付加塩、アミノ酸付加塩などを包含する。化合物（I）の薬学的に許容される酸付加塩としては、例えば塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩などの無機酸塩、酢酸塩、シュウ酸塩、マレイン酸塩、フマル酸塩、クエン酸塩、安息香酸塩、メタンスルホン酸塩などの有機酸塩などがあげられ、薬学的に許容される金属塩としては、例えばナトリウム塩、カリウム塩などのアルカリ金属塩、マグネシウム塩、カルシウム塩などのアルカリ土類金属塩、アルミニウム塩、亜鉛塩などがあげられ、薬学的に許容されるアンモニウム塩としては、例えばアンモニウム、テトラメチルアンモニウムなどの塩があげられ、薬学的に許容される有機アミン付加塩としては、例えばモルホリン、ピペリジンなどの付加塩があげられ、薬学的に許容されるアミノ酸付加塩としては、例えばリジン、グリシン、フェニルアラニン、アスパラギン酸、グルタミン酸などの付加塩があげられる。 Examples of the aralkyl moiety of C 7-16 aralkyl and C 7-16 aralkyloxy and C 7-16 aralkyloxycarbonyl include the groups exemplified in the above examples of aralkyl.
The aliphatic heterocyclic group, aromatic heterocyclic group and halogen are as defined above.
Pharmaceutically acceptable salts of compound (I) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. Examples of the pharmaceutically acceptable acid addition salt of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, and maleic acid. Organic salts such as salts, fumarate, citrate, benzoate, methanesulfonate and the like, and pharmaceutically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt , Alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts and the like. Examples of pharmaceutically acceptable ammonium salts include salts such as ammonium and tetramethylammonium. Examples of acceptable organic amine addition salts include addition salts such as morpholine and piperidine, and examples of pharmaceutically acceptable amino acid addition salts include lysine. And addition salts of glycine, phenylalanine, aspartic acid, glutamic acid and the like.
　次に化合物（I）の製造法について説明する。
　なお、以下に示す製造法において、定義した基が該製造法の条件下で変化するかまたは該製造法を実施するのに不適切な場合、有機合成化学で常用される保護基の導入および除去方法[例えば、プロテクティブ・グループス・イン・オーガニック・シンセシス第3版(Protective Groups in Organic Synthesis, third edition)、グリーン(T. W. Greene)著、John Wiley & Sons Inc.(1999年)などに記載の方法]などを用いることにより、目的化合物を製造することができる。また、必要に応じて置換基導入などの反応工程の順序を変えることもできる。 Next, the manufacturing method of compound (I) is demonstrated.
In addition, in the production method shown below, when a defined group changes under the conditions of the production method or is inappropriate for carrying out the production method, introduction and removal of a protective group commonly used in organic synthetic chemistry Methods [e.g., Protective Groups in Organic Synthesis, third edition, by TW Greene, John Wiley & Sons Inc. (1999), etc. ] Can be used to produce the target compound. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
　製造法1
　化合物（I）は以下の方法によって製造することができる。 Production method 1
Compound (I) can be produced by the following method.
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
（式中、V1は、塩素原子、臭素原子、ヨウ素原子などの脱離基を表し、n、m、R1、R2、LおよびZはそれぞれ前記と同義である）
工程１
化合物（a-3）は、化合物（a-1）と好ましくは1～30当量の（a-2）を、無溶媒でまたは溶媒中、室温と用いる溶媒の沸点の間の温度で、5分間～72時間反応させることにより製造することができる。 (In the formula, V 1 represents a leaving group such as a chlorine atom, a bromine atom, and an iodine atom, and n, m, R 1 , R 2 , L, and Z are as defined above.)
Process 1
Compound (a-3) is compound (a-1) and preferably 1 to 30 equivalents of (a-2) in the absence of or in a solvent at a temperature between room temperature and the boiling point of the solvent used for 5 minutes. It can be produced by reacting for ~ 72 hours.
　溶媒としては、例えばアセトニトリル、ジクロロメタン、1,2-ジクロロエタン、クロロホルム、1,2-ジメトキシエタン（DME）、N,N-ジメチルホルムアミド（DMF）、N,N-ジメチルアセトアミド（DMA）、1,4-ジオキサン、テトラヒドロフラン（THF）、ジエチルエーテル、ジイソプロピルエーテル、ベンゼン、トルエン、キシレン、ピリジン、N-メチルピロリドン（NMP）、水などがあげられ、これらは単独でまたは混合して用いられる。 Examples of the solvent include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dimethoxyethane (DME), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), 1,4 -Dioxane, tetrahydrofuran (THF), diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, N-methylpyrrolidone (NMP), water and the like are used, and these are used alone or in combination.
　化合物（a-1）は、市販品として得られる。
　化合物（a-2）は、市販品として得られるか、あるいは公知の方法［例えば、実験化学講座、第4版、21巻、p. 1、丸善株式会社（1992年）など］またはそれらに準じて得ることができる。
工程2
　化合物（a-5）は、化合物（a-3）と好ましくは1～30当量の化合物（a-4）を、溶媒中、好ましくは1～30当量の硫黄導入剤および塩基の存在下、室温と用いる溶媒の沸点の間の温度で、5分間～72時間反応させることにより製造することができる。 Compound (a-1) is obtained as a commercial product.
Compound (a-2) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course, 4th edition, Volume 21, p. 1, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
Process 2
Compound (a-5) is compound (a-3) and preferably 1 to 30 equivalents of compound (a-4) in a solvent, preferably 1 to 30 equivalents of a sulfur introducing agent and a base at room temperature. And a reaction between 5 minutes and 72 hours at a temperature between the boiling points of the solvents to be used.
　硫黄導入剤としては、例えば硫黄、五硫化二リン、ローソン試薬（Lawesson’s試薬）などがあげられる。塩基としては、例えばジエチルアミン、トリエチルアミン、エチルジイソプロピルアミン、モルホリン、ピペリジン、L-プロリン、塩基性アルミナなどがあげられる。溶媒としては、例えばメタノール、エタノール、2-プロパノール、tert-ブチルアルコール、THF、ジオキサン、トルエン、キシレン、水などがあげられ、これらは単独でまたは混合して用いられる。 Examples of the sulfur introducing agent include sulfur, diphosphorus pentasulfide, Lawesson's reagent, and the like. Examples of the base include diethylamine, triethylamine, ethyldiisopropylamine, morpholine, piperidine, L-proline, basic alumina and the like. Examples of the solvent include methanol, ethanol, 2-propanol, tert-butyl alcohol, THF, dioxane, toluene, xylene, water and the like, and these can be used alone or in combination.
　化合物（a-4）は、市販品として得られるか、あるいは公知の方法［例えば、実験化学講座、第4版、21巻、p.149、丸善株式会社（1992年）など］またはそれらに準じて得ることができる。
工程3
　化合物（I）は、化合物（a-5）と好ましくは1～10当量の化合物（a-6）を、好ましくは1～20当量の塩基の存在下、溶媒中、-10℃と用いる溶媒の沸点の間の温度で、5分間～72時間反応させることにより製造することができる。 Compound (a-4) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course, 4th edition, Volume 21, p.149, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
Process 3
Compound (I) is compound (a-5), preferably 1 to 10 equivalents of compound (a-6), preferably 1 to 20 equivalents of a base in the presence of a solvent at −10 ° C. It can be produced by reacting at a temperature between the boiling points for 5 minutes to 72 hours.
　塩基としては、例えば酢酸カリウム、酢酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸ナトリウム、炭酸水素ナトリウム、水酸化ナトリウム、水酸化リチウム、水酸化カリウム、リン酸カリウム、ピリジン、トリエチルアミン、N-メチルモルホリン、N-メチルピペリジン、ピペリジン、ピペラジン、ジイソプロピルエチルアミン、1,8-ジアザビシクロ[5.4.0]-7-ウンデセン(DBU)などがあげられる。溶媒としては、例えばアセトニトリル、ジクロロメタン、1,2-ジクロロエタン、クロロホルム、DME、DMF、DMA、1,4-ジオキサン、THF、ジエチルエーテル、ジイソプロピルエーテル、ベンゼン、トルエン、キシレン、ピリジン、NMP、水などがあげられ、これらは単独でまたは混合して用いられる。
化合物（a-6）は、市販品として得られるか、あるいは公知の方法［例えば、新実験化学講座、第4版、22巻、p. 115、丸善株式会社（1992年）など］またはそれらに準じて得ることができる。 Examples of the base include potassium acetate, sodium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium phosphate, pyridine, triethylamine, N-methylmorpholine, N -Methylpiperidine, piperidine, piperazine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like. Examples of the solvent include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, DME, DMF, DMA, 1,4-dioxane, THF, diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, NMP, water, and the like. These may be used alone or in combination.
Compound (a-6) can be obtained as a commercial product, or can be obtained by a known method [for example, New Experimental Chemistry Course, 4th edition, Volume 22, p. 115, Maruzen Co., Ltd. (1992)] or the like. It can be obtained accordingly.
　また別法として、化合物（I）は、化合物（a-5）と好ましくは1～30当量の（a-7）を、無溶媒でまたは溶媒中、好ましくは1～30当量の縮合剤の存在下、必要により好ましくは1～30当量の添加剤の存在下、-30℃と150℃の間の温度で、5分間～72時間反応させることにより製造することもできる。
　縮合剤としては、例えばジシクロヘキシルカルボジイミド（DCC）、ジイソプロピルカルボジイミド、N-(3-ジメチルアミノプロピル)-N’-エチルカルボジイミド（EDC）、EDC塩酸塩、O-(ベンゾトリアゾール-1-イル) -N,N,N',N'-テトラメチルウロニウムヘキサフルオロリン酸塩（HATU）、ベンゾトリアゾール-1-イルオキシ-トリスジメチルアミノホスホニウム塩（BOP）、ヘキサフルオロリン酸（ベンゾトリアゾール-1-イルオキシ）トリピロリジノホスホニウム（PyBOP）、ブロモ－トリス－ピロリジノホスホニウムヘキサフルオロリン酸塩（PyBroP）などがあげられる。添加剤としては、例えば1-ヒドロキシベンゾトリアゾール・1水和物（HOBt・H2O）、トリエチルアミン、4-ジメチルアミノピリジン（DMAP）などがあげられ、これらは単独でまたは混合して用いられる。溶媒としては、例えばアセトニトリル、ジクロロメタン、1,2-ジクロロエタン、クロロホルム、DME、DMF、DMA、1,4-ジオキサン、THF、ジエチルエーテル、ジイソプロピルエーテル、ベンゼン、トルエン、キシレン、ピリジン、NMP、水などがあげられ、これらは単独でまたは混合して用いられる。 Alternatively, compound (I) may be compound (a-5) and preferably 1 to 30 equivalents of (a-7) in the absence of a solvent or in a solvent, preferably 1 to 30 equivalents of a condensing agent. It can also be produced by reacting at a temperature between −30 ° C. and 150 ° C. for 5 minutes to 72 hours, if necessary, preferably in the presence of 1 to 30 equivalents of an additive.
Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC), EDC hydrochloride, O- (benzotriazol-1-yl) 2 -N , N, N ', N'-Tetramethyluronium hexafluorophosphate (HATU), benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP), hexafluorophosphoric acid (benzotriazol-1-yloxy) Examples include tripyrrolidinophosphonium (PyBOP) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBroP). Examples of the additive include 1-hydroxybenzotriazole monohydrate (HOBt · H 2 O), triethylamine, 4-dimethylaminopyridine (DMAP), and the like are used alone or in combination. Examples of the solvent include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, DME, DMF, DMA, 1,4-dioxane, THF, diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, NMP, water, and the like. These may be used alone or in combination.
　化合物（a-7）は、市販品として得られるか、あるいは公知の方法［例えば、新実験化学講座、第4版、22巻、p. 1、丸善株式会社（1992年）など］またはそれらに準じて得ることができる。
製造法２
　化合物（I）は以下の工程に従い製造することもできる。 Compound (a-7) can be obtained as a commercial product, or can be obtained by a known method [for example, New Experimental Chemistry Course, 4th edition, Volume 22, p. 1, Maruzen Co., Ltd. (1992)] or the like. It can be obtained similarly.
Manufacturing method 2
Compound (I) can also be produced according to the following steps.
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
（式中、R20は、水素原子またはメチル、エチルなどのカルボキシル基の保護基を表し、n、m、R1、R2、L、V1およびZはそれぞれ前記と同義である）
工程4
　化合物（a-9）は、化合物（a-4）および化合物（a-8）を用い、製造法1の工程2と同様にして製造することができる。 (In the formula, R 20 represents a hydrogen atom or a protecting group for a carboxyl group such as methyl or ethyl, and n, m, R 1 , R 2 , L, V 1 and Z are as defined above.)
Process 4
Compound (a-9) can be produced in the same manner as in production method 1, step 2 using compound (a-4) and compound (a-8).
　化合物（a-8）は、市販品として得ることができる。
工程5
　化合物（a-10）は、化合物（a-9）および化合物（a-6）または化合物（a-7）を用い、製造法1の工程3と同様にして製造することができる。
工程6
　化合物（a-11）は、化合物（a-10）を、無溶媒でまたは溶媒中、１～100当量のヒドラジン水溶液存在下、室温と150℃の間の温度で、5分間から72時間反応させることにより製造することができる。 Compound (a-8) can be obtained as a commercial product.
Process 5
Compound (a-10) can be produced in the same manner as in production method 1, step 3 using compound (a-9) and compound (a-6) or compound (a-7).
Process 6
Compound (a-11) is obtained by reacting compound (a-10) without solvent or in a solvent in the presence of 1 to 100 equivalents of an aqueous hydrazine solution at a temperature between room temperature and 150 ° C. for 5 minutes to 72 hours. Can be manufactured.
　溶媒としては、例えばメタノール、エタノール、2-プロパノール、tert-ブチルアルコール、1,4-ジオキサン、THF、DMF、水などがあげられ、これらは単独でまたは混合して用いられる。
　また、化合物（a-11）は化合物（a-12）を経由して製造することもできる。
工程7a
　化合物（a-12）は、化合物（a-10）を、トリフルオロ酢酸中、好ましくは1～30当量の無水トリフルオロ酢酸存在下、室温と150℃の間の温度で、5分間～72時間処理することにより製造することができる。 Examples of the solvent include methanol, ethanol, 2-propanol, tert-butyl alcohol, 1,4-dioxane, THF, DMF, water and the like, and these can be used alone or in combination.
Compound (a-11) can also be produced via compound (a-12).
Step 7a
Compound (a-12) is obtained by reacting compound (a-10) in trifluoroacetic acid, preferably in the presence of 1 to 30 equivalents of trifluoroacetic anhydride, at a temperature between room temperature and 150 ° C. for 5 minutes to 72 hours. It can be manufactured by processing.
　化合物（a-12）はまた、化合物（a-10）を用い、WO2006/122200、Organic Letters, 16, 1013 (2006）、Bioorganic Medicinal Chemistry, 18, 2803, (2000)などに記載の方法に準じて製造することもできる。
工程7b
　化合物（a-11）は、化合物（a-12）を用い、上記工程6と同様にして製造することができる。
工程8
　化合物（I）は、化合物（a-11）および化合物（a-2）を用い、上記工程１と同様にして製造することができる。
製造法3
　化合物（I）のうち、Aが酸素原子であり、B, YおよびDが同時に結合でなく、Cが水素原子でない化合物（I-b）は以下の工程に従い製造することもできる。 Compound (a-12) is also prepared using compound (a-10) according to the method described in WO2006 / 122200, Organic Letters, 16, 1013 (2006), Bioorganic Medicinal Chemistry, 18, 2803, (2000), etc. Can also be manufactured.
Step 7b
Compound (a-11) can be produced in the same manner as in Step 6 above, using compound (a-12).
Process 8
Compound (I) can be produced in the same manner as in Step 1 above, using compound (a-11) and compound (a-2).
Production method 3
Among compounds (I), compound (Ib) in which A is an oxygen atom, B, Y and D are not simultaneously bonded and C is not a hydrogen atom can also be produced according to the following steps.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
（式中、V2は、塩素原子、臭素原子、ヨウ素原子、トリフルオロメタンスルホニルオキシ、メタンスルホニルオキシ、p-トルエンスルホニルオキシなどの脱離基を表し、LAは、Lが表すフェニル基、芳香族複素環基または脂肪族複素環基を表し、m、n、h、R1、R2、B、Y、C、DおよびZはそれぞれ前記と同義である）
工程9
　化合物（I-b）は、製造法1または2に従い得られる化合物（I-a）を好ましくは1～30当量の化合物（a-13）と、無溶媒でまたは溶媒中、必要により好ましくは1～30当量の塩基の存在下、-10℃と150℃の間の温度で5分間～72時間反応させることにより製造することができる。 (In the formula, V 2 represents a leaving group such as chlorine atom, bromine atom, iodine atom, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy, L A represents a phenyl group represented by L, aromatic Represents an aromatic heterocyclic group or an aliphatic heterocyclic group, and m, n, h, R 1 , R 2 , B, Y, C, D and Z are as defined above)
Step 9
Compound (Ib) is compound (Ia) obtained according to production method 1 or 2, preferably 1 to 30 equivalents of compound (a-13), without solvent or in a solvent, and preferably 1 to 30 equivalents. It can be produced by reacting at a temperature between −10 ° C. and 150 ° C. for 5 minutes to 72 hours in the presence of a base.
　塩基としては、例えば炭酸カリウム、炭酸ナトリウム、炭酸セシウム、水酸化リチウム、水酸化カリウム、水酸化ナトリウム、水素化ナトリウム、ナトリウムメトキシド、カリウム tert-ブトキシド、トリエチルアミン、ジイソプロピルエチルアミン、N-メチルモルホリン、N-メチルピペリジン、ピリジン、DBUなどがあげられる。溶媒としては、例えばメタノール、エタノール、ジクロロメタン、クロロホルム、1,2-ジクロロエタン、トルエン、キシレン、酢酸エチル、アセトニトリル、ジエチルエーテル、THF、DME、1,4-ジオキサン、DMF、DMA、NMP、DMSO、ピリジン、水などがあげられ、これらは単独でまたは混合して用いられる。 Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, N -Methylpiperidine, pyridine, DBU and the like. Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Water and the like, and these may be used alone or in combination.
　化合物（a-13）は市販品として得られるか、あるいは公知の方法［例えば、実験化学講座、第4版、19巻、p.363、丸善株式会社（1992年）など］またはそれらに準じて得ることができる。
製造法4
　化合物（I）のうち、Aが－NR10－、－S－および－SO2－である化合物（I-d）、（I-e）および（I-f）は、それぞれ以下の工程に従い製造することもできる。 Compound (a-13) can be obtained as a commercial product, or can be obtained by publicly known methods [for example, Experimental Chemistry Course, 4th edition, Volume 19, p.363, Maruzen Co., Ltd. (1992)] or the like. Obtainable.
Production method 4
Among compounds (I), compounds (Id), (Ie) and (If) in which A is —NR 10 —, —S— and —SO 2 — can also be produced according to the following steps, respectively.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
（式中、V3は、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ、トリフルオロメタンスルホニルオキシ、p-トルエンスルホニルオキシなどの脱離基を表し、LA、m、n、h、R1、R2、R10、B、Y、C、DおよびZはそれぞれ前記と同義である）
工程10
　化合物（I-d）は、製造法1または2に従い得られる化合物（I-c）を好ましくは1～30当量の化合物（a-14）と、無溶媒でまたは溶媒中、必要により好ましくは1～30当量の塩基の存在下、-10℃と150℃の間の温度で5分間～72時間反応させることにより製造することができる。 (In the formula, V 3 represents a leaving group such as chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, L A , m, n, h, R 1. , R 2 , R 10 , B, Y, C, D and Z are as defined above)
Process 10
Compound (Id) is compound (Ic) obtained according to production method 1 or 2, preferably 1 to 30 equivalents of compound (a-14), without solvent or in a solvent, and preferably 1 to 30 equivalents if necessary. It can be produced by reacting at a temperature between −10 ° C. and 150 ° C. for 5 minutes to 72 hours in the presence of a base.
　塩基としては、例えば炭酸カリウム、炭酸ナトリウム、炭酸セシウム、水酸化リチウム、水酸化カリウム、水酸化ナトリウム、水素化ナトリウム、ナトリウムメトキシド、カリウム tert-ブトキシド、トリエチルアミン、ジイソプロピルエチルアミン、N-メチルモルホリン、N-メチルピペリジン、ピリジン、DBUなどがあげられる。溶媒としては、例えばメタノール、エタノール、ジクロロメタン、クロロホルム、1,2-ジクロロエタン、トルエン、キシレン、酢酸エチル、アセトニトリル、ジエチルエーテル、THF、DME、1,4-ジオキサン、DMF、DMA、NMP、DMSO、ピリジン、水などがあげられ、これらは単独でまたは混合して用いられる。 Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, N -Methylpiperidine, pyridine, DBU and the like. Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Water and the like, and these may be used alone or in combination.
　化合物（a-14）は、市販品として得られるか、あるいは公知の方法［例えば、実験化学講座、第4版、20巻、p.279、丸善株式会社（1992年）など］またはそれらに準じて得ることができる。
工程11
　化合物（I-e）は、化合物（I-c）と化合物（a-15）を用いて、上記工程10と同様にして得ることができる。 Compound (a-14) can be obtained as a commercial product, or can be obtained by publicly known methods [for example, Experimental Chemistry Course, 4th edition, Volume 20, p.279, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
Step 11
Compound (Ie) can be obtained in the same manner as in Step 10 above, using compound (Ic) and compound (a-15).
　化合物（a-15）は、市販品として得られるか、あるいは公知の方法［例えば、実験化学講座、第4版、24巻、p.319、丸善株式会社（1992年）など］またはそれらに準じて得ることができる。
工程12
　化合物（I-f）は、化合物（I-e）を、溶媒中、1当量から大過剰量、好ましくは1～10当量の酸化剤で、0℃と用いる溶媒の沸点の間の温度で、5分間から72時間処理することにり製造することができる。
溶媒としては、例えばジクロロメタン、クロロホルム、1,2-ジクロロエタン、THF、1,4-ジオキサン、ジメトキシエタン、ジエチルエーテル、ジイソプロピルエーテル、メタノール、エタノール、2-プロパノール、ベンゼン、トルエン、キシレン、アセトニトリル、酢酸エチル、水などがあげられ、これらは単独でまたは混合して用いることができる。好ましくは、ジクロロメタンなどがあげられる。酸化剤としては、例えばメタクロロ過安息香酸、過酸化ベンゾイル、過酢酸、過酸化水素、過ヨウ素酸ナトリウム、オキソンなどがあげられ、好ましくはメタクロロ過安息香酸などがあげられる。
製造法5
　化合物（I）のうち、ZがNR11である化合物（I-i）および（I-j）は以下の工程に従い製造することもできる。 Compound (a-15) can be obtained as a commercial product, or can be obtained by publicly known methods [for example, Experimental Chemistry Course, 4th edition, Volume 24, p.319, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
Process 12
Compound (If) comprises compound (Ie) in a solvent in an amount of 1 equivalent to a large excess, preferably 1 to 10 equivalents of oxidizing agent, at a temperature between 0 ° C. and the boiling point of the solvent used for 5 minutes to 72 minutes. It can be manufactured by time processing.
Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, THF, 1,4-dioxane, dimethoxyethane, diethyl ether, diisopropyl ether, methanol, ethanol, 2-propanol, benzene, toluene, xylene, acetonitrile, ethyl acetate. , Water and the like, and these can be used alone or in combination. Preferred is dichloromethane. Examples of the oxidizing agent include metachloroperbenzoic acid, benzoyl peroxide, peracetic acid, hydrogen peroxide, sodium periodate, oxone, and the like, preferably metachloroperbenzoic acid.
Manufacturing method 5
Among compounds (I), compounds (Ii) and (Ij) in which Z is NR 11 can also be produced according to the following steps.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
（式中、Pは、tert-ブトキシカルボニル、ベンジルなどのアミノ基の保護基を表し、R11aは前記R11の定義のうちの水素原子以外の基を表し、n、m、R1、R2、LおよびV2はそれぞれ前記と同義である）
工程13
　化合物（I-i）は、製造法1～4に従い得られる化合物（I-g）を用いて、例えばプロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）、グリーン（T. W. Greene）著、ジョン・ワイリー・アンド・サンズ・インコーポレイテッド（JohnWiley & Sons Inc.）（1981年）などに記載の保護基の除去方法に従い製造することができる。 (Wherein P represents an amino-protecting group such as tert-butoxycarbonyl, benzyl, etc., R 11a represents a group other than a hydrogen atom in the definition of R 11 , and n, m, R 1 , R 2 , L and V 2 are as defined above)
Process 13
Compound (Ii) can be obtained by using, for example, Protective Groups in Organic Synthesis, TW Greene, It can be produced according to the protecting group removal method described in, for example, John Wiley & Sons Inc. (1981).
　例えば、Pがtert-ブトキシカルボニル基である場合、化合物（I-i）は、化合物（I-g）を、無溶媒でまたは溶媒中、1当量～大過剰量の酸で、-30℃と100℃の間の温度で、5分間～72時間処理することにより製造することができる。
　酸としては、例えば塩酸、硫酸、トリフルオロ酢酸、メタンスルホン酸などがあげられる。溶媒としては、例えばメタノール、エタノール、プロパノール、THF、1,4-ジオキサン、DME、トルエン、酢酸エチル、ジクロロメタン、DMF、水などがあげられ、これらは単独でまたは混合して用いられる。
工程14
　化合物（I-j）は、化合物（I-i）と好ましくは1～20当量の化合物（a-16）を、溶媒中、必要により好ましくは1～20当量の塩基の存在下、-10℃と用いる溶媒の沸点の間の温度で、5分間～72時間反応させることにより製造することができる。 For example, when P is a tert-butoxycarbonyl group, the compound (Ii) is obtained by removing the compound (Ig) between -30 ° C. and 100 ° C. without solvent or in a solvent with 1 equivalent to a large excess of acid. It can be produced by treating at a temperature of 5 minutes to 72 hours.
Examples of the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and the like. Examples of the solvent include methanol, ethanol, propanol, THF, 1,4-dioxane, DME, toluene, ethyl acetate, dichloromethane, DMF, water and the like, and these can be used alone or in combination.
Process 14
Compound (Ij) is compound (Ii) and preferably 1 to 20 equivalents of compound (a-16) in a solvent, preferably in the presence of 1 to 20 equivalents of a base, at −10 ° C. It can be produced by reacting at a temperature between the boiling points for 5 minutes to 72 hours.
　塩基としては、例えば、炭酸カリウム、炭酸ナトリウム、炭酸水素カリウム、炭酸水素ナトリウム、トリエチルアミン、ジイソプロピルエチルアミン、N-メチルモルホリン、ピリジン、DBUなどがあげられる。溶媒としては、例えばアセトニトリル、ジクロロメタン、1,2-ジクロロエタン、クロロホルム、DME、DMF、DMA、1,4-ジオキサン、THF、ジエチルエーテル、ジイソプロピルエーテル、ベンゼン、トルエン、キシレン、ピリジン、NMPなどがあげられ、これらは単独でまたは混合して用いられる。 Examples of the base include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, DBU and the like. Examples of the solvent include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, DME, DMF, DMA, 1,4-dioxane, THF, diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, NMP, and the like. These are used alone or in combination.
　化合物（a-16）は市販品として得られるか、あるいは公知の方法［例えば、実験化学講座、第4版、19巻、p.363、丸善株式会社（1992年）、J. Am. Chem. Soc., 114, 1486, (1992）など］またはそれらに準じて得ることができる。
　上記各製造法における中間体および目的化合物は、有機合成化学で常用される分離精製法、例えば、ろ過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィーなどに付して単離精製することができる。また、中間体においては特に精製することなく次の反応に供することも可能である。 Compound (a-16) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course, 4th edition, volume 19, p.363, Maruzen Co., Ltd. (1992), J. Am. Chem. Soc., 114, 1486, (1992), etc.] or the like.
The intermediates and target compounds in the above production methods are isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to. The intermediate can be subjected to the next reaction without any particular purification.
　化合物（I）の中には、幾何異性体、光学異性体などの立体異性体、互変異性体などが存在し得るものもあるが、本発明は、これらを含め、全ての可能な異性体およびそれらの混合物を包含する。
　化合物（I） 中の各原子の一部またはすべては、それぞれ対応する同位体原子で置き換わっていてもよく、本発明は、これら同位体原子で置き換わった化合物も包含する。例えば、化合物（I） 中の水素原子の一部またはすべては、原子量2の水素原子（重水素原子）であってもよい。 Some compounds (I) may have stereoisomers such as geometric isomers and optical isomers, tautomers and the like, but the present invention includes all possible isomers including these. And mixtures thereof.
A part or all of each atom in the compound (I) may be replaced with a corresponding isotope atom, and the present invention also includes a compound replaced with these isotope atoms. For example, some or all of the hydrogen atoms in the compound (I) may be hydrogen atoms having an atomic weight of 2 (deuterium atoms).
　化合物（I） 中の各原子の一部またはすべてが、それぞれ対応する同位体原子で置き換わった化合物は、市販のビルディングブロックを用いて、上記各製造法と同様な方法で製造することができる。また、化合物（I） 中の水素原子の一部またはすべてが重水素原子で置き換わった化合物は、例えば、1）過酸化重水素を用い、塩基性条件下にカルボン酸などを重水素化する方法（米国特許第3849458号明細書参照）、2）イリジウム錯体を触媒として用い、重水を重水素源として用いてアルコール、カルボン酸などを重水素化する方法(J．Am．Chem．Soc., 124(10)，2092 (2002))、3）パラジウムカーボンを触媒として用い、重水素源として重水素ガスのみを用いて脂肪酸を重水素化する方法(LIPIDS，Vol．9，No．11, 913 (1974))、4）白金、パラジウム、ロジウム、ルテニウム、イリジウムなどの金属を触媒として用い、重水または重水および重水素ガスを重水素源として用いてアクリル酸、アクリル酸メチル、メタクリル酸、メタクリル酸メチルなどを重水素化する方法（特公平5－19536号公報、特開昭61－277648号公報、特開昭61－275241号公報）、5）パラジウム、ニッケル、銅または亜クロム酸銅などの触媒を用い、重水を重水素源として用いて、アクリル酸、メタクリル酸メチルなどを重水素化する方法（特開昭63－198638号公報）などを用いて合成することもできる。 A compound in which part or all of each atom in Compound (I) is replaced with a corresponding isotope atom can be produced by a method similar to each of the above production methods using a commercially available building block. In addition, a compound in which some or all of the hydrogen atoms in the compound (I) are replaced with deuterium atoms is, for example, 1) a method of deuterating carboxylic acid under basic conditions using deuterium peroxide (See U.S. Pat. No. 3,849,458), 2) A method of deuterating alcohol, carboxylic acid, etc. using iridium complex as a catalyst and deuterium as a deuterium source (J. Am. Chem. Soc., 124). (10), 2092 (2002)), 3) Deuteration of fatty acids using palladium carbon as a catalyst and only deuterium gas as a deuterium source (LIPIDS, Vol. 9, No. 11, 913 ( 1974)), 4) Using metals such as platinum, palladium, rhodium, ruthenium, iridium as catalysts and using heavy water or heavy water and deuterium gas as deuterium sources, acrylic acid, methyl acrylate, methacrylic acid, methyl methacrylate Deuterium etc. (Japanese Patent Publication No. 5-19536, JP 61-277648, JP 61-275241), 5) Heavy water using a catalyst such as palladium, nickel, copper or copper chromite Can also be synthesized by using a method for deuterating acrylic acid, methyl methacrylate, etc., using as a deuterium source (JP-A 63-198638).
　化合物（I）の塩を取得したいとき、化合物（I）が塩の形で得られるときはそのまま精製すればよく、また、遊離の形で得られるときは、化合物（I）を適当な溶媒に溶解または懸濁し、酸または塩基を加えることにより塩を形成させて単離、精製すればよい。
　また、化合物（I）およびその薬学的に許容される塩は、水または各種溶媒との付加物の形で存在することもあるが、これらの付加物も本発明に包含される。 When it is desired to obtain a salt of compound (I), it can be purified as it is when compound (I) is obtained in the form of a salt. When it is obtained in a free form, compound (I) can be obtained in an appropriate solvent. It may be isolated or purified by dissolving or suspending and forming a salt by adding an acid or a base.
Compound (I) and pharmaceutically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.
　本発明によって得られる化合物（I）の具体例を第1～11表に示す。ただし、本発明の化合物はこれらに限定されるものではない。 Specific examples of the compound (I) obtained by the present invention are shown in Tables 1 to 11. However, the compound of the present invention is not limited to these.
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
　次に、代表的な化合物（I）の薬理作用について試験例により具体的に説明する。
試験例１：ヒトNaPi2b発現細胞の[33P]リン取り込みアッセイ
（1）ヒトNaPi2b誘導発現細胞の造成
　ヒトNaPi2b誘導発現プラスミドは、公知の方法（Analytical Biochemistry, 400, 163, (2006)）に準じて作製した。ヒトNaPi2bをコードするDNAはPCRで取得した。ヒト腎臓DNA（クロンテック社製）を鋳型として、ヒトNaPi2b cDNA特異的プライマーと、Pyrobest DNA Polymerase（タカラバイオ社製）を用いて、PCRによりヒトNaPi2bをコードするDNAを取得した。PCRは、95℃で2分間の処理後、94℃で15秒間、アニール温度60℃で15秒間、72℃で2分間からなる反応を35サイクル行った。増幅されたPCR断片をHindIIIとNotIで切断後、アガロースゲル電気泳動法によりヒトNaPi2b DNA断片を回収した。該断片を、誘導発現ベクターの対応する制限酵素サイト（HindIII-NotI）間へ組み込むことにより、ヒトNaPi2bの誘導発現プラスミドを構築した。取得したヒトNaPi2b DNAの配列は、GenBankの登録配列（NM_006424）と一致することを確認した。 Next, the pharmacological action of a representative compound (I) will be specifically described with reference to test examples.
Test Example 1: [ 33 P] Phosphorus Uptake Assay of Human NaPi2b-Expressing Cells (1) Construction of Human NaPi2b-Induced Expression Cells Human NaPi2b-induced expression plasmids conform to known methods (Analytical Biochemistry, 400, 163, (2006)) Made. DNA encoding human NaPi2b was obtained by PCR. Using human kidney DNA (Clontech) as a template, human NaPi2b cDNA-specific primer and Pyrobest DNA Polymerase (Takara Bio) were used to obtain DNA encoding human NaPi2b by PCR. PCR was performed at 95 ° C. for 2 minutes, followed by 35 cycles of 94 ° C. for 15 seconds, annealing temperature 60 ° C. for 15 seconds, and 72 ° C. for 2 minutes. The amplified PCR fragment was cleaved with HindIII and NotI, and then a human NaPi2b DNA fragment was recovered by agarose gel electrophoresis. The fragment was inserted between the corresponding restriction enzyme sites (HindIII-NotI) of the inducible expression vector to construct an inducible expression plasmid for human NaPi2b. It was confirmed that the sequence of the obtained human NaPi2b DNA matched the registered sequence of GenBank (NM_006424).
　公知の方法（Analytical Biochemistry, 400, 163, (2006)）に準じて、KJMGER8細胞（Namalwa細胞由来の細胞株）を宿主とするヒトNaPi2bの誘導発現細胞を造成した。該誘導発現細胞は、KJMGER8細胞に、上記にて作製したヒトNaPi2bの誘導発現プラスミドをエレクトロポレーション法（Cytotechnology, 3, 133 (1990)）にて導入することにより作製した。ヒトNaPi2bの誘導発現は、ヒトNaPi2b発現細胞を10 nmol/L β-estradiol（シグマ社製）存在下で24時間培養することにより行った。
（2）ヒトNaPi2b発現細胞を用いた[33P]リン取り込みアッセイ
　上記の方法にてヒトNaPi2bの発現を誘導した細胞をバッファーA （115 mmol/L NaCl、5.4 mmol/L KCl、0.8 mmol/L MgCl2・6H2O、1.8 mmol/L CaCl2、10 mmol/L 4-(2-ヒドロキシエチル)-1-ピペラジンエタンスルホン酸（HEPES）、pH 7.0）にて懸濁し、1.0×106個/mLの細胞密度に調整した。これを96ウェルプレート（コーニング社製）に70 μL/ウェル分注した。このプレートに、バッファーAで調製した最終濃度の10倍濃い被験化合物溶液を10 μL添加した。室温で30分間静置後、5 μCi/mL H2[33P]O4を含む4.5 μmol/L Na2HPO4/NaH2PO4（pH 7.0）を20 μL添加し、取り込み反応を30分間行った。氷冷したバッファーB （0.9 mmol/L CaCl2、0.5 mmol/L MgCl2・6H2O、2.7 mmol/L KCl、1.5 mmol/L KH2PO4、138 mmol/L NaCl、8.1 mmol/L Na2HPO4・7H2O）を添加することで反応を停止し、ろ紙（Whatman GF/B unifilter）をセットしたセルハーベスターで洗浄しながらろ過した。洗浄したろ紙を迅速乾燥機で30分間乾燥させた後、シンチレーションカクテルMicroscint 20を30 μL添加し、ろ紙の放射活性をマルチプレートシンチレーションカウンターTopCount（パーキンエルマージャパン）で測定した。 According to a known method (Analytical Biochemistry, 400, 163, (2006)), an inducible expression cell of human NaPi2b using KJMGER8 cells (a cell line derived from Namalwa cells) as a host was constructed. The induced expression cells were prepared by introducing the human NaPi2b induced expression plasmid prepared above into KJMGER8 cells by electroporation (Cytotechnology, 3, 133 (1990)). Inducible expression of human NaPi2b was performed by culturing human NaPi2b-expressing cells in the presence of 10 nmol / L β-estradiol (manufactured by Sigma) for 24 hours.
(2) [ 33 P] phosphorus uptake assay using human NaPi2b-expressing cells Buffer A (115 mmol / L NaCl, 5.4 mmol / L KCl, 0.8 mmol / L) MgCl 2 · 6H 2 O, 1.8 mmol / L CaCl 2 , 10 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), pH 7.0) suspended in 1.0 × 10 6 The cell density was adjusted to / mL. This was dispensed into a 96-well plate (Corning) at 70 μL / well. To this plate, 10 μL of a test compound solution having a concentration 10 times the final concentration prepared with Buffer A was added. After standing at room temperature for 30 minutes, add 20 μL of 4.5 μmol / L Na 2 HPO 4 / NaH 2 PO 4 (pH 7.0) containing 5 μCi / mL H 2 [ 33 P] O 4 and allow the uptake reaction for 30 minutes. went. Ice-cooled buffer B (0.9 mmol / L CaCl 2 , 0.5 mmol / L MgCl 2 · 6H 2 O, 2.7 mmol / L KCl, 1.5 mmol / L KH 2 PO 4 , 138 mmol / L NaCl, 8.1 mmol / L Na 2 HPO 4 · 7H 2 O) was added to stop the reaction, followed by filtration while washing with a cell harvester with filter paper (Whatman GF / Bunifilter) set. The washed filter paper was dried with a rapid dryer for 30 minutes, 30 μL of scintillation cocktail Microscint 20 was added, and the radioactivity of the filter paper was measured with a multiplate scintillation counter TopCount (Perkin Elmer Japan).
　阻害率は、以下の式で求めた。被験化合物濃度1μmol/Lでの結果を第12表に示した。 The inhibition rate was determined by the following formula. The results at a test compound concentration of 1 μmol / L are shown in Table 12.
Figure JPOXMLDOC01-appb-M000028
Figure JPOXMLDOC01-appb-M000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
　本試験により、化合物（I）はNaPi2bを介したリンの取り込みを阻害することが確かめられた。即ち、化合物（I）またはその薬学的に許容される塩は、腸管のNaPi2bを阻害し、腸管からのリンの吸収を抑制することができ、血清のリン濃度が影響する疾患（例えば、高リン血症など）などの治療薬として有用であると考えられた。
試験例2：ラット尿中リン***量への作用
　試験には、雄性Crl:CD（SD） ラット（日本チャールス・リバー、神奈川）を用いた。6週齢で購入し1週間以上の馴化の後、7週齢で使用した。ラットは温度19～25°C、湿度30～70%、１日12時間照明（午前7時～午後7時）の飼育室にて、金属ケージに5-6匹ずつ収容し、市販の固型飼料（FR-2; 船橋農場）と水を自由に摂取させた。採尿の際には、個別飼育用の金属ケージに1匹ずつ収容し、絶食下・自由飲水とした。試験には外見上に異常が認められず、試験の前日および当日に下痢が認められない（肛門周囲に汚れがない）個体を使用した。 This test confirmed that Compound (I) inhibited the uptake of phosphorus via NaPi2b. That is, Compound (I) or a pharmaceutically acceptable salt thereof can inhibit NaPi2b in the intestinal tract, suppress absorption of phosphorus from the intestinal tract, and diseases (for example, high phosphorus levels) affected by serum phosphorus concentration. It was thought that it was useful as a therapeutic drug for blood pressure.
Test Example 2: Effects on rat urinary phosphorus excretion The male Crl: CD (SD) rat (Nippon Charles River, Kanagawa) was used for the test. Purchased at 6 weeks of age and used at 7 weeks of age after acclimatization for over 1 week. Rats are housed in a metal cage in a breeding room with a temperature of 19 to 25 ° C, humidity of 30 to 70%, and 12 hours a day (7am to 7pm). Feed (FR-2; Funabashi Farm) and water were freely available. At the time of urine collection, one animal was housed in a metal cage for individual breeding, and it was fasted and allowed to drink freely. In the test, an individual having no abnormal appearance and no diarrhea on the day before and on the day of the test (no dirt around the anus) was used.
　試験前日、各個体の体重を測定し、群間で体重に有意差がないように群分けした。試験当日の朝、前日の体重をもとに、0.5 w/v% メチルセルロール（MC）（MC投与群）、化合物26（10および30 mg/kg）（化合物投与群）のMC溶液および陽性対照として炭酸ランタン水和物（陽性対照群）のMC溶液の適当量をそれぞれ経口投与した。いずれの投与液も注射筒およびゾンデを用いて、強制経口投与した。投与後、ラットを個別飼育用のケージに移して採尿を開始し、6時間後に尿を採集した。採集した尿中のリン濃度をホスファC-テストワコーを用いて測定した。 The day before the test, the weight of each individual was measured and divided into groups so that there was no significant difference in weight between groups. On the morning of the test, based on the previous day's body weight, 0.5 w / v% methylcellulose (MC) (MC administration group), compound 26 (10 and 30 mg / kg) (compound administration group) MC solution and positive As a control, an appropriate amount of MC solution of lanthanum carbonate hydrate (positive control group) was orally administered. All the administration solutions were forcibly administered orally using a syringe and a sonde. After administration, the rats were transferred to individual cages and urine collection was started, and urine was collected 6 hours later. The phosphorus concentration in the collected urine was measured using Phospha C-Test Wako.
　化合物26を投与した群では、10 mg/kgおよび30 mg/kgの用量で、MC投与群と比較して、投与後6時間の尿中リン***量が低減した。その作用は、炭酸ランタン水和物 100 mg/kgと同程度であった。
　これらの結果から、化合物26は、10 mg/kgの用量から尿中リン***量を抑制する作用を示した。 In the group administered with Compound 26, urinary phosphorus excretion at 6 hours after administration decreased at the doses of 10 mg / kg and 30 mg / kg as compared with the MC administration group. The effect was similar to that of lanthanum carbonate hydrate 100 mg / kg.
From these results, Compound 26 showed an action of suppressing urinary phosphorus excretion from a dose of 10 mg / kg.
　試験例1の結果から、化合物26はNaPi2bを介したリンの取り込み阻害作用を有している。即ち、化合物26は、腸管におけるNaPi2bを阻害し腸管からのリン吸収を阻害することに基づく尿中リン***量抑制作用を有することが示唆された。同様にNaPi2bを介したリンの取り込み阻害作用を有する化合物（I）またはその薬学的に許容される塩も、腸管におけるリン吸収阻害作用に基づく尿中リン***量抑制作用を有することが示唆された。
試験例3：膜透過性試験［Parallel Artificial Membrane Permeability Assay (PAMPA)］
　PAMPAプレートはBD GentestTM (cat ＃353015)から購入した。付属する説明書に準じて試験を行い、化合物（I）の“Pe”（effective permeability）値を算出した。 From the results of Test Example 1, compound 26 has an action of inhibiting phosphorus uptake via NaPi2b. That is, it was suggested that Compound 26 has an action of suppressing urinary phosphorus excretion based on inhibiting NaPi2b in the intestinal tract and inhibiting phosphorus absorption from the intestinal tract. Similarly, it was suggested that Compound (I) or its pharmaceutically acceptable salt, which has an inhibitory action on phosphorus uptake through NaPi2b, also has an inhibitory action on urinary phosphorus excretion based on an inhibitory action on phosphorus absorption in the intestine. .
Test Example 3: Membrane permeability test [Parallel Artificial Membrane Permeability Assay (PAMPA)]
PAMPA plates were purchased from BD Gentest ™ (cat # 353015). The test was conducted according to the attached instructions, and the “P e ” (effective permeability) value of compound (I) was calculated.
　本試験の結果、例えば化合物3、5、6、26、41、52などは小さいPe値を示した。即ち、化合物（I）またはその薬学的に許容される塩は膜透過性が小さく生体内（血中）への吸収性が低いと考えられ、経口投与しても薬物の濃度が上昇しないと考えられた。
　化合物（I）またはその薬学的に許容される塩は、経口投与されると消化管（腸管）のNaPi2bを阻害することで生体内へのリンの取り込みを阻害するが、その吸収性の低さから血中での薬物濃度が低く、薬物そのものによる他臓器への影響が少ない。即ち、化合物（I）またはその薬学的に許容される塩は、腸管におけるNaPi2bを局所的に阻害することで副作用が低減し、血清のリン濃度が影響する疾患（例えば、高リン血症など）などの治療および／または予防薬として有用である。
試験例4：化合物（I）を経口投与したときの血漿中濃度
　化合物（I）またはその薬学的に許容される塩をSprague-Dawleyラットに経口投与し、投与後0.5、1、2、4、7および24時間に血漿を採取する。血漿試料にアセトニトリルを添加し攪拌した後、遠心分離した上清をLC-MS/MSを用いて分析し、投与した化合物濃度を求める。 As a result of this test, for example, compounds 3, 5, 6, 26, 41, and 52 showed a small Pe value. That is, compound (I) or a pharmaceutically acceptable salt thereof is considered to have low membrane permeability and low absorption in vivo (in the blood), and the drug concentration does not increase even when administered orally. It was.
Compound (I) or a pharmaceutically acceptable salt thereof inhibits the uptake of phosphorus into the living body by inhibiting NaPi2b in the digestive tract (intestinal tract) when administered orally, but its absorbability is low. Therefore, the drug concentration in the blood is low, and the drug itself has little effect on other organs. That is, Compound (I) or a pharmaceutically acceptable salt thereof is a disease in which side effects are reduced by locally inhibiting NaPi2b in the intestinal tract, and a serum phosphorus concentration affects the disease (for example, hyperphosphatemia, etc.) It is useful as a therapeutic and / or prophylactic agent.
Test Example 4: Plasma concentration when compound (I) was orally administered Compound (I) or a pharmaceutically acceptable salt thereof was orally administered to Sprague-Dawley rats, and 0.5, 1, 2, 4, after administration Plasma is collected at 7 and 24 hours. After adding acetonitrile to the plasma sample and stirring, the centrifuged supernatant is analyzed using LC-MS / MS to determine the concentration of the administered compound.
　本試験により、経口投与された化合物（I）またはその薬学的に許容される塩の低い血中濃度が確認できる。
試験例5：ヒトNaPi2b発現細胞の[33P]リン取り込みアッセイ(2)
　試験例1と同様の試験を行い、化合物（I）のNaPi2bを介したリンの取り込みの阻害作用を確認した。被験化合物濃度1μmol/Lでの結果を第13表に示した。 This test confirms a low blood concentration of orally administered compound (I) or a pharmaceutically acceptable salt thereof.
Test Example 5: [ 33 P] Phosphorus Uptake Assay of Human NaPi2b Expressing Cells (2)
The same test as in Test Example 1 was conducted, and the inhibitory action of phosphorus uptake via NaPi2b of compound (I) was confirmed. The results at a test compound concentration of 1 μmol / L are shown in Table 13.
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
　本試験により、化合物（I）またはその薬学的に許容される塩は、腸管のNaPi2bを阻害し、腸管からのリンの吸収を抑制することができ、血清のリン濃度が影響する疾患（例えば、高リン血症など）などの治療薬として有用であると考えられた。
　以上より、化合物（I）またはその薬学的に許容される塩は、腸管におけるNaPi2bを局所的に阻害し、リンの吸収を抑制することで、血中のリンの濃度を制御することができ、血清のリン濃度が影響する疾患（例えば、高リン血症など）などの治療および／または予防剤として有用であると考えられた。また、化合物（I）またはその薬学的に許容される塩は生体内への吸収性が小さいために、全身暴露に伴う副作用（例えば肺や精巣における石灰化）を抑制することができると考えられた。 According to this test, Compound (I) or a pharmaceutically acceptable salt thereof can inhibit NaPi2b in the intestinal tract, suppress phosphorus absorption from the intestinal tract, and diseases in which serum phosphorus concentration affects (for example, It was considered useful as a therapeutic drug for hyperphosphatemia and the like.
From the above, compound (I) or a pharmaceutically acceptable salt thereof can locally inhibit NaPi2b in the intestinal tract and suppress phosphorus absorption, thereby controlling the concentration of phosphorus in the blood. It was considered useful as a therapeutic and / or prophylactic agent for diseases such as hyperphosphatemia affected by serum phosphorus concentration. In addition, since compound (I) or a pharmaceutically acceptable salt thereof is poorly absorbed into the living body, it is considered that side effects (for example, calcification in the lungs and testis) associated with systemic exposure can be suppressed. It was.
　化合物（I）またはその薬学的に許容される塩は、そのまま単独で投与することも可能であるが、通常各種の医薬製剤として提供するのが望ましい。また、それら医薬製剤は、動物または人に使用されるものである。
　本発明に係わる医薬製剤は、活性成分として化合物（I）またはその薬学的に許容される塩を単独で、または任意の他の治療のための有効成分との混合物として含有することができる。また、それら医薬製剤は、活性成分を薬学的に許容される一種またはそれ以上の担体(例えば、希釈剤、溶剤、賦形剤など)と一緒に混合し、製剤学の技術分野においてよく知られている任意の方法により製造される。 Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.
The pharmaceutical preparation according to the present invention may contain Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment. These pharmaceutical preparations are well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers (e.g., diluents, solvents, excipients, etc.). Manufactured by any method.
　投与経路としては、治療に際し最も効果的なものを使用するのが望ましく、経口または、例えば静脈内などの非経口をあげることができる。
　投与形態としては、例えば錠剤、注射剤などがあげられる。
　経口投与に適当な、例えば錠剤などは、乳糖などの賦形剤、澱粉などの崩壊剤、ステアリン酸マグネシウムなどの滑沢剤、ヒドロキシプロピルセルロースなどの結合剤などを用いて製造できる。 As the administration route, it is desirable to use one that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration.
Examples of the dosage form include tablets and injections.
For example, tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
　非経口投与に適当な、例えば注射剤などは、塩溶液、ブドウ糖溶液または塩水とブドウ糖溶液の混合液などの希釈剤または溶剤などを用いて製造できる。
　化合物（I）またはその薬学的に許容される塩の投与量および投与回数は、投与形態、患者の年齢、体重、治療すべき症状の性質もしくは重篤度などにより異なるが、通常経口の場合、成人一人あたり、0.01～1000mg、好ましくは0.05～100mgの範囲で、1日1回ないし数回投与する。静脈内投与などの非経口投与の場合、成人一人あたり0.001～1000mg、好ましくは0.01～100mgを1日1回ないし数回投与する。しかしながら、これら投与量および投与回数に関しては、前述の種々の条件により変動する。 For example, an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution or a mixed solution of a saline solution and a glucose solution.
The dose and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of the condition to be treated, etc. The dose is 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult, once to several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 1000 mg, preferably 0.01 to 100 mg per adult is administered once to several times a day. However, the dose and the number of doses vary depending on the various conditions described above.
　以下、本発明を実施例および参考例によりさらに具体的に説明するが、本発明の範囲はこれらの実施例に限定されることはない。
　なお、実施例および参考例で用いられるプロトン核磁気共鳴スペクトル(1H-NMR)では、化合物および測定条件によって交換性プロトンが明瞭には観測されないことがある。また、シグナルの多重度の表記としては通常用いられるものを用いるが、brとは見かけ上幅広いシグナルであることを表す。また、各化合物の命名には必要によりChemBioDraw Ultra ver. 11.0.1を用いた。
参考例1　(E)-2-アミノ-N’-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)-6,6-ジメチル-3-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボヒドラジド（化合物a）
工程1：2-シアノアセトヒドラジド（4.28 g, 43.2 mmol）を酢酸エチル（150 mL）に溶解し、2-クロロ-3-(トリフルオロメチル)ベンズアルデヒド（9.90 g, 47.5 mmol）を加え、50℃で2時間攪拌した。混合物を氷冷後、析出した結晶をろ過することにより、(E)-N’-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)-2-シアノカルボヒドラジド（10.7 g, 86%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 3.93 (s, 2H), 7.58 (d, J = 8.6 Hz, 1H), 7.80 (dd, J = 1.6, 8.6 Hz, 1H), 7.92 (s, 1H), 7.97 (d, J = 1.6 Hz, 1H), 9.83 (br s, 1H).
工程2：工程１で得られた(E)-N’-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)-2-シアノカルボヒドラジド（4.40g, 15.2 mmol）および酢酸（3.48 mL, 60.8 mmol）をTHF（44 mL）に溶解し、氷冷下1,1,1,3,3,3-ヘキサメチルジシラザン（6.37 mL, 30.4 mmol）および4,4-ジメチルシクロヘキサノン（2.30  g, 18.2 mmol）を加え、室温で終夜攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。得られた残渣にメタノールを加え析出した固体をろ取することにより、(E)-N’-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)-2-シアノ-2-(4,4-ジメチルシクロヘキシリデン)アセトヒドラジド（5.00 g, 83%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 1.03 (s, 6H), 1.50-1.64 (m, 4H), 2.54-2.59 (m, 1H), 2.68-2.76 (m, 2H), 3.03-3.09 (m, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.80-8.27 (m, 3H), 9.25 (br s, 1H).
工程3：工程2で得られた(E)-N’-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)-2-シアノ-2-(4,4-ジメチルシクロヘキシリデン)アセトヒドラジド（5.00 g, 12.6 mmol）をTHF（30 mL）に溶解し、トリエチルアミン（3.50 mL, 25.1 mmol）および硫黄（0.403 g, 12.6 mmol）を加え室温で終夜攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、溶媒を減圧下で留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝90／10）で精製することにより化合物a（2.92 g, 54%）を得た。
1H-NMR（300 MHz, DMSO-d6, δ）: 0.99 (s, 6H), 1.17 (t, J = 6.0 Hz, 2H), 2.27 (s, 2H), 2.60 (t, J = 6.0 Hz, 2H), 6.68 (br s, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.95 (dd, J = 2.0, 8.2 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.30 (s, 1H), 10.77 (br s, 1H).
参考例2　(E)-2-アミノ-N’-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-3-カルボヒドラジド（化合物b）
　Ｎ-シクロプロピルピペリジン-4-オンを用い、参考例1と同様にして化合物bを得た。
1H-NMR (300 MHz, CDCl3, δ): 0.55-0.57 (m, 4H), 1.89-1.92 (m, 1H), 2.85-2.86 (m, 2H), 2.99 (t, J= 5.9 Hz, 2H), 3.65 (s, 2H), 6.11 (s, 2H), 7.53 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 6.8 Hz, 1H), 7.99 (s, 1H), 8.14 (s, 1H), 8.89 (s, 1H). EXAMPLES Hereinafter, although an Example and a reference example demonstrate this invention further more concretely, the scope of the present invention is not limited to these Examples.
In the proton nuclear magnetic resonance spectrum ( 1 H-NMR) used in Examples and Reference Examples, exchangeable protons may not be clearly observed depending on the compound and measurement conditions. In addition, as a notation of signal multiplicity, a commonly used one is used, and br represents an apparently wide signal. Further, ChemBioDraw Ultra ver. 11.0.1 was used for naming each compound as necessary.
Reference Example 1 (E) -2-Amino-N '-(4-chloro-3- (trifluoromethyl) benzylidene) -6,6-dimethyl-3-4,5,6,7-tetrahydrobenzo [b] Thiophene-3-carbohydrazide (compound a)
Step 1: 2-Cyanoacetohydrazide (4.28 g, 43.2 mmol) is dissolved in ethyl acetate (150 mL), 2-chloro-3- (trifluoromethyl) benzaldehyde (9.90 g, 47.5 mmol) is added, and 50 ° C. For 2 hours. The mixture was ice-cooled, and the precipitated crystals were filtered to obtain (E) -N ′-(4-chloro-3- (trifluoromethyl) benzylidene) -2-cyanocarbohydrazide (10.7 g, 86%). Obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 3.93 (s, 2H), 7.58 (d, J = 8.6 Hz, 1H), 7.80 (dd, J = 1.6, 8.6 Hz, 1H), 7.92 (s , 1H), 7.97 (d, J = 1.6 Hz, 1H), 9.83 (br s, 1H).
Step 2: (E) -N ′-(4-Chloro-3- (trifluoromethyl) benzylidene) -2-cyanocarbohydrazide (4.40 g, 15.2 mmol) and acetic acid (3.48 mL, 60.8) obtained in Step 1 mmol) was dissolved in THF (44 mL) and 1,1,1,3,3,3-hexamethyldisilazane (6.37 mL, 30.4 mmol) and 4,4-dimethylcyclohexanone (2.30 g, 18.2) were cooled with ice. mmol) and stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. Methanol was added to the resulting residue, and the precipitated solid was collected by filtration to give (E) -N ′-(4-chloro-3- (trifluoromethyl) benzylidene) -2-cyano-2- (4,4 -Dimethylcyclohexylidene) acetohydrazide (5.00 g, 83%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.03 (s, 6H), 1.50-1.64 (m, 4H), 2.54-2.59 (m, 1H), 2.68-2.76 (m, 2H), 3.03- 3.09 (m, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.80-8.27 (m, 3H), 9.25 (br s, 1H).
Step 3: (E) -N ′-(4-Chloro-3- (trifluoromethyl) benzylidene) -2-cyano-2- (4,4-dimethylcyclohexylidene) acetohydrazide obtained in Step 2 ( 5.00 g, 12.6 mmol) was dissolved in THF (30 mL), triethylamine (3.50 mL, 25.1 mmol) and sulfur (0.403 g, 12.6 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 90/10) to obtain Compound a (2.92 g, 54%).
1 H-NMR (300 MHz, DMSO-d 6 , δ): 0.99 (s, 6H), 1.17 (t, J = 6.0 Hz, 2H), 2.27 (s, 2H), 2.60 (t, J = 6.0 Hz , 2H), 6.68 (br s, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.95 (dd, J = 2.0, 8.2 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.30 (s, 1H), 10.77 (br s, 1H).
Reference Example 2 (E) -2-Amino-N '-(4-chloro-3- (trifluoromethyl) benzylidene) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3-c ] Pyridine-3-carbohydrazide (Compound b)
Compound b was obtained in the same manner as in Reference Example 1 using N-cyclopropylpiperidin-4-one.
1 H-NMR (300 MHz, CDCl 3 , δ): 0.55-0.57 (m, 4H), 1.89-1.92 (m, 1H), 2.85-2.86 (m, 2H), 2.99 (t, J = 5.9 Hz, 2H), 3.65 (s, 2H), 6.11 (s, 2H), 7.53 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 6.8 Hz, 1H), 7.99 (s, 1H), 8.14 ( s, 1H), 8.89 (s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(クロロメチル)ベンズアミド（化合物1）
　参考例1で得られる化合物ａ（0.843 g, 1.96 mmol）をジクロロメタン（20 mL）に溶解し、3-クロロメチルベンゾイルクロリド（0.418 mL, 2.94 mmol）およびピリジン（0.238 mL, 2.94 mmol）を加え室温で2時間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。得られた固体をメタノールでリスラリーすることにより、化合物1（1.04 g, 91%）を得た。
1H-NMR（400 MHz, CDCl3, δ）: 1.08 (s, 6H), 1.71 (t, J = 5.9 Hz, 2H), 1.89 (t, J = 5.9 Hz, 2H), 2.55 (s, 2H), 4.68 (s, 2H), 7.51-7.65 (m, 3H), 7.98-8.03 (m, 4H), 8.23 (s, 1H), 9.24 (s, 1H), 13.02 (br s, 1H). (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3- (chloromethyl) benzamide (Compound 1)
Compound a (0.843 g, 1.96 mmol) obtained in Reference Example 1 is dissolved in dichloromethane (20 mL), and 3-chloromethylbenzoyl chloride (0.418 mL, 2.94 mmol) and pyridine (0.238 mL, 2.94 mmol) are added to room temperature. For 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained solid was reslurried with methanol to obtain Compound 1 (1.04 g, 91%).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.71 (t, J = 5.9 Hz, 2H), 1.89 (t, J = 5.9 Hz, 2H), 2.55 (s, 2H ), 4.68 (s, 2H), 7.51-7.65 (m, 3H), 7.98-8.03 (m, 4H), 8.23 (s, 1H), 9.24 (s, 1H), 13.02 (br s, 1H).
酢酸　(E)-3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェニル（化合物2）
　3-アセトキシ安息香酸（0.629 g, 3.49 mmol）をジクロロメタン（15 mL）に溶解し、塩化チオニル（1.02 mL, 14.0 mmol）およびDMF（0.180 mL, 2.33 mmol）を加え、室温で終夜攪拌した。混合物を減圧下で濃縮した後、トルエンを加え溶媒を共沸した。得られた残渣をジクロロメタン（15 mL）に溶解し、化合物ａ（1.00 g, 2.33 mmol）およびピリジン（0.282 mL, 3.49 mmol）を加え、室温で3時間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝95／1）で精製することにより、化合物2（1.30 g, 94%）を得た。
1H-NMR（400 MHz, DMSO-d6, δ）: 1.03 (s, 6H), 1.53 (t, J = 6.3 Hz, 2H), 2.45-2.54 (m, 5H), 2.78 (t, J = 6.3 Hz, 2H), 7.01-7.02 (m, 1H), 7.27-7.37 (m, 3H), 7.75-7.77 (m, 1H), 7.95-7.97 (m, 1H), 8.10 (s, 1H), 8.48 (s, 1H), 9.69 (br s, 1H), 11.22 (br s, 1H). Acetic acid (E) -3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] Thiophen-2-ylcarbamoyl) phenyl (compound 2)
3-acetoxybenzoic acid (0.629 g, 3.49 mmol) was dissolved in dichloromethane (15 mL), thionyl chloride (1.02 mL, 14.0 mmol) and DMF (0.180 mL, 2.33 mmol) were added, and the mixture was stirred at room temperature overnight. After the mixture was concentrated under reduced pressure, toluene was added and the solvent was azeotroped. The obtained residue was dissolved in dichloromethane (15 mL), compound a (1.00 g, 2.33 mmol) and pyridine (0.282 mL, 3.49 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 95/1) to obtain Compound 2 (1.30 g, 94%).
1 H-NMR (400 MHz, DMSO-d 6 , δ): 1.03 (s, 6H), 1.53 (t, J = 6.3 Hz, 2H), 2.45-2.54 (m, 5H), 2.78 (t, J = 6.3 Hz, 2H), 7.01-7.02 (m, 1H), 7.27-7.37 (m, 3H), 7.75-7.77 (m, 1H), 7.95-7.97 (m, 1H), 8.10 (s, 1H), 8.48 (s, 1H), 9.69 (br s, 1H), 11.22 (br s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-ヒドロキシベンズアミド（化合物3）
　実施例2で得られた化合物2（1.30 g, 2.20 mmool）をメタノール（50 mL）に溶解し、炭酸カリウム（1.52 g, 11.0 mmol）を加えて還流下2時間攪拌した。放冷後、混合物に1 mol/L塩酸を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。得られた固体をメタノールでリスラリーすることにより、化合物3（1.11 g, 92%）を得た。
1H-NMR（300 MHz, DMSO-d6, δ）: 1.03 (s, 6H), 1.53 (t, J = 6.0 Hz, 1H), 2.76 (t, J = 6.0 Hz, 2H), 3.18-3.19 (m, 2H), 3.81 (br s, 1H), 6.99-7.01 (m, 1H), 7.30-7.36(m, 3H), 7.75-7.78 (m, 1H), 7.95-7.98 (m, 1H), 8.10 (s, 1H), 8.43 (s, 1H), 9.64 (br s, 1H), 11.12 (br s, 1H). (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3-hydroxybenzamide (compound 3)
Compound 2 (1.30 g, 2.20 mmol) obtained in Example 2 was dissolved in methanol (50 mL), potassium carbonate (1.52 g, 11.0 mmol) was added, and the mixture was stirred for 2 hours under reflux. After allowing to cool, 1 mol / L hydrochloric acid was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained solid was reslurried with methanol to obtain Compound 3 (1.11 g, 92%).
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.03 (s, 6H), 1.53 (t, J = 6.0 Hz, 1H), 2.76 (t, J = 6.0 Hz, 2H), 3.18-3.19 (m, 2H), 3.81 (br s, 1H), 6.99-7.01 (m, 1H), 7.30-7.36 (m, 3H), 7.75-7.78 (m, 1H), 7.95-7.98 (m, 1H), 8.10 (s, 1H), 8.43 (s, 1H), 9.64 (br s, 1H), 11.12 (br s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(クロロメチル)ベンズアミド（化合物4）
　参考例2で得られる化合物bを用い、実施例1と同様にして化合物4を得た。
1H-NMR (300 MHz, CDCl3, δ): 0.56-0.63 (m, 4H), 1.90-1.97 (m, 1H), 2.99-3.09 (m, 4H), 3.83 (s, 2H), 4.67 (s, 2H), 7.49-7.65 (m, 3H), 7.97-8.04 (m, 4H), 8.19 (s, 1H), 9.11 (s, 1H), 12.86 (s, 1H). (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3- c] Pyridin-2-yl) -3- (chloromethyl) benzamide (compound 4)
Using compound b obtained in Reference Example 2, compound 4 was obtained in the same manner as Example 1.
1 H-NMR (300 MHz, CDCl 3 , δ): 0.56-0.63 (m, 4H), 1.90-1.97 (m, 1H), 2.99-3.09 (m, 4H), 3.83 (s, 2H), 4.67 ( s, 2H), 7.49-7.65 (m, 3H), 7.97-8.04 (m, 4H), 8.19 (s, 1H), 9.11 (s, 1H), 12.86 (s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-ヒドロキシベンズアミド（化合物5）
　参考例2で得られる化合物bを用い、実施例2および3と同様にして化合物5を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 0.43-0.75 (m, 4H), 1.22-1.30 (m, 1H), 2.82-3.08 (m, 4H), 3.28-3.47 (m, 2H), 6.99-7.03 (m, 1H), 7.26-7.35 (m, 3H), 7.76-8.14 (m, 3H), 8.43 (s, 1H), 9.95 (s, 1H), 11.72 (br s, 1H).  (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3- c] Pyridin-2-yl) -3-hydroxybenzamide (Compound 5)
Compound 5 was obtained in the same manner as in Examples 2 and 3 using Compound b obtained in Reference Example 2.
1 H-NMR (300 MHz, DMSO-d 6 , δ): 0.43-0.75 (m, 4H), 1.22-1.30 (m, 1H), 2.82-3.08 (m, 4H), 3.28-3.47 (m, 2H ), 6.99-7.03 (m, 1H), 7.26-7.35 (m, 3H), 7.76-8.14 (m, 3H), 8.43 (s, 1H), 9.95 (s, 1H), 11.72 (br s, 1H) .
(E)-3-(2,5,8,11,14,17,20,23-オクタペンタコサン-25-イルオキシ)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)ベンズアミド（化合物6）
工程1：3-ヒドロキシ安息香酸メチル（0.79 g, 5.2 mmol）、ヘプタエチレングリコールモノメチルエーテル（2.0 g, 5.2 mmol）およびポリマー担持トリフェニルホスフィン（2.6 g, 7.8 mmol）をジクロロメタン（25 mL）に懸濁させ、氷冷下でジtert-ブチルアゾジカルボキシレート（1.68 g, 7.3 mmol）を加え、室温で15時間攪拌した。混合物をセライトでろ過した後、ろ液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝90／10）で精製することにより、3-(2,5,8,11,14,17,20,23-オクタオキサペンタコサン-25-イルオキシ)安息香酸メチル（2.81 g, 定量的）を得た。
1H-NMR (270 MHz, CDCl3, δ): 3.38 (s, 3H), 3.63-3.75 (m, 26H), 3.87 (dd, J = 5.7, 4.2 Hz, 2H), 3.91 (s, 3H), 4.17 (dd, J = 5.5, 4.0 Hz, 2H), 7.12 (ddd, J = 8.2, 2.7, 1.2 Hz, 1H), 7.33 (dd, J = 8.2, 7.6 Hz, 1H), 7.57 (dd, J = 2.7, 1.2 Hz, 1H), 7.63 (dt, J = 7.6, 1.2 Hz, 1H).
工程2：工程1で得られた3-(2,5,8,11,14,17,20,23-オクタオキサペンタコサン-25-イルオキシ)安息香酸メチル（2.70 g, 5.2 mmol）をメタノール（20 mL）に溶解し、4 mol/L水酸化ナトリウム水溶液（4 mL）を加え、室温で3時間攪拌した。混合物を酢酸エチルで洗浄した後、水層のpHをを6 mol/L塩酸で約2とし、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下で濃縮することにより、3-(2,5,8,11,14,17,20,23-オクタオキサペンタコサン-25-イルオキシ)安息香酸（2.25 g, 86%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 3.38 (s, 3H), 3.55-3.58 (m, 2H), 3.63-3.74 (m, 26H), 3.88 (dd, J = 5.4, 4.1 Hz, 2H), 4.20 (dd, J = 5.4, 4.1 Hz, 2H), 7.16 (ddd, J = 7.9, 2.5, 1.2 Hz, 1H), 7.36 (dd, J = 7.9, 7.6 Hz, 1H), 7.63 (dd, J = 2.5, 1.2 Hz, 1H), 7.69 (dt, J = 7.6, 1.2 Hz, 1H).
工程3：工程2で得られた3-(2,5,8,11,14,17,20,23-オクタオキサペンタコサン-25-イルオキシ)安息香酸（0.704 g, 1.40 mmol）およびDMF（0.135 mL）をジクロロメタンに溶解し、塩化チオニル（0.51 mL，7.0 mmol）を加え、室温で2時間攪拌した。混合物を濃縮して得られた残渣をジクロロメタン（5 mL）に溶解し、ピリジン（1.13 mL, 14.0 mmol）および参考例1で得られる化合物a（0.50 g, 1.16 mmol）を加え、室温で15時間攪拌した。混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下で濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝96／4）で精製することにより、化合物6（0.517 g, 49%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 1.07 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 2.53 (br s, 2H), 2.88 (t, J = 6.0 Hz, 2H), 3.37 (s, 3H), 3.52-3.56 (m, 2H), 3.61-3.75 (m, 26H), 3.89 (t, J = 4.8 Hz, 2H), 4.21 (t, J = 4.8 Hz, 2H), 7.13 (dd, J = 8.1, 2.1 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.55-7.63 (m, 3H), 7.97 (dd, J = 8.4, 1.8 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 8.25 (s, 1H), 9.24 (br s, 1H), 12.88 (br s, 1H).  ESI-MS m/z： 916, 918 (M+H)+. (E) -3- (2,5,8,11,14,17,20,23-octapentacosane-25-yloxy) -N- (3- (2- (4-chloro-3- (trifluoro Methyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide (Compound 6)
Step 1: Methyl 3-hydroxybenzoate (0.79 g, 5.2 mmol), heptaethylene glycol monomethyl ether (2.0 g, 5.2 mmol) and polymer-supported triphenylphosphine (2.6 g, 7.8 mmol) are suspended in dichloromethane (25 mL). Di-tert-butyl azodicarboxylate (1.68 g, 7.3 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. The mixture was filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol = 90/10) to give 3- (2,5,8,11,14,17, 20,23-octaoxapentacosan-25-yloxy) benzoic acid methyl ester (2.81 g, quantitative) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 3.38 (s, 3H), 3.63-3.75 (m, 26H), 3.87 (dd, J = 5.7, 4.2 Hz, 2H), 3.91 (s, 3H) , 4.17 (dd, J = 5.5, 4.0 Hz, 2H), 7.12 (ddd, J = 8.2, 2.7, 1.2 Hz, 1H), 7.33 (dd, J = 8.2, 7.6 Hz, 1H), 7.57 (dd, J = 2.7, 1.2 Hz, 1H), 7.63 (dt, J = 7.6, 1.2 Hz, 1H).
Step 2: Methyl 3- (2,5,8,11,14,17,20,23-octoxapentacosan-25-yloxy) benzoate (2.70 g, 5.2 mmol) obtained in Step 1 was added to methanol ( 20 mL), 4 mol / L aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 3 hr. The mixture was washed with ethyl acetate, and then the pH of the aqueous layer was adjusted to about 2 with 6 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3- (2,5,8,11,14,17,20,23-octoxapentacosan-25-yloxy) benzoic acid ( 2.25 g, 86%).
1 H-NMR (270 MHz, CDCl 3 , δ): 3.38 (s, 3H), 3.55-3.58 (m, 2H), 3.63-3.74 (m, 26H), 3.88 (dd, J = 5.4, 4.1 Hz, 2H), 4.20 (dd, J = 5.4, 4.1 Hz, 2H), 7.16 (ddd, J = 7.9, 2.5, 1.2 Hz, 1H), 7.36 (dd, J = 7.9, 7.6 Hz, 1H), 7.63 (dd , J = 2.5, 1.2 Hz, 1H), 7.69 (dt, J = 7.6, 1.2 Hz, 1H).
Step 3: 3- (2,5,8,11,14,17,20,23-octoxapentacosan-25-yloxy) benzoic acid (0.704 g, 1.40 mmol) and DMF (0.135) obtained in Step 2 mL) was dissolved in dichloromethane, thionyl chloride (0.51 mL, 7.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the mixture was dissolved in dichloromethane (5 mL), pyridine (1.13 mL, 14.0 mmol) and compound a (0.50 g, 1.16 mmol) obtained in Reference Example 1 were added, and the mixture was stirred at room temperature for 15 hours. Stir. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 96/4) to obtain Compound 6 (0.517 g, 49%). .
1 H-NMR (270 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 2.53 (br s, 2H), 2.88 (t, J = 6.0 Hz, 2H), 3.37 (s, 3H), 3.52-3.56 (m, 2H), 3.61-3.75 (m, 26H), 3.89 (t, J = 4.8 Hz, 2H), 4.21 (t, J = 4.8 Hz, 2H ), 7.13 (dd, J = 8.1, 2.1 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.55-7.63 (m, 3H), 7.97 (dd, J = 8.4, 1.8 Hz, 1H) , 8.04 (d, J = 1.8 Hz, 1H), 8.25 (s, 1H), 9.24 (br s, 1H), 12.88 (br s, 1H). ESI-MS m / z: 916, 918 (M + H ) + .
(E)-3-(2,5,8,11-テトラオキサトリデカン-13-イルオキシ)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)ベンズアミド（化合物7）
　テトラエチレングリコールモノメチルエーテルを用い、実施例6と同様にして化合物7を得た。
ESI-MS m/z：740 (M+H)+. (E) -3- (2,5,8,11-Tetraoxatridecan-13-yloxy) -N- (3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-Dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide (Compound 7)
Compound 7 was obtained in the same manner as in Example 6 using tetraethylene glycol monomethyl ether.
ESI-MS m / z: 740 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)ベンズアミド（化合物8）
　実施例3で得られる化合物3（3.00 g, 5.45 mmol）をDMF（30 mL）に溶解し、炭酸カリウム（1.81 g, 16.4 mol）および2-(2-(2-クロロエトキシ)エトキシ)エタノール（2.76 g, 13.1 mmol）を加え、100℃で6時間攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。得られた固体をメタノールでリスラリーすることにより、化合物8（2.01 g, 54%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.11 (s, 6H), 1.73 (t, J = 5.7 Hz, 2H), 2.48 (d, J = 5.9 Hz, 1H), 2.57 (s, 2H), 2.91 (s, 2H), 3.65-3.70 (m, 2H), 3.74-3.77 (m, 6H), 3.93 (dd, J = 5.1, 4.0 Hz, 2H), 4.26 (t, J = 4.6 Hz, 2H), 7.17-7.18 (m, 1H), 7.41-7.45 (m, 1H), 7.61-7.66 (m, 3H), 8.01 (d, J = 8.1 Hz, 1H), 8.08 (s, 1H), 8.26 (d, J = 5.1 Hz, 1H), 9.25 (s, 1H), 12.94 (s, 1H). (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamide (Compound 8)
Compound 3 (3.00 g, 5.45 mmol) obtained in Example 3 was dissolved in DMF (30 mL), and potassium carbonate (1.81 g, 16.4 mol) and 2- (2- (2-chloroethoxy) ethoxy) ethanol ( 2.76 g, 13.1 mmol) was added, and the mixture was stirred at 100 ° C. for 6 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained solid was reslurried with methanol to obtain Compound 8 (2.01 g, 54%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.11 (s, 6H), 1.73 (t, J = 5.7 Hz, 2H), 2.48 (d, J = 5.9 Hz, 1H), 2.57 (s, 2H ), 2.91 (s, 2H), 3.65-3.70 (m, 2H), 3.74-3.77 (m, 6H), 3.93 (dd, J = 5.1, 4.0 Hz, 2H), 4.26 (t, J = 4.6 Hz, 2H), 7.17-7.18 (m, 1H), 7.41-7.45 (m, 1H), 7.61-7.66 (m, 3H), 8.01 (d, J = 8.1 Hz, 1H), 8.08 (s, 1H), 8.26 (d, J = 5.1 Hz, 1H), 9.25 (s, 1H), 12.94 (s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(2-(2-(2-ヨードエトキシ)エトキシ)エトキシ)ベンズアミド（化合物9）
　実施例8で得られた化合物8（1.50 g, 2.20 mmol）をDMF（15 mL）に溶解し、トリエチルアミン（0.460 mL, 3.30 mol）およびメタンスルホニルクロリド（0.257 mL, 3.30 mmol）を加え、室温で終夜攪拌した。混合物にヨウ化ナトリウム（0.659 g, 4.40 mmol）を加え、100℃で2時間攪拌した後、水を加えて酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝1／1）で精製することにより、化合物9（1.29 g, 74%）を得た。
1H-NMR (270 MHz, DMSO-d6, δ): 1.02 (s, 6H), 1.53 (t, J = 6.3 Hz, 2H), 2.74 (s, 2H), 3.00 (s, 3H), 3.59-3.61 (m, 4H), 3.63-3.69 (m, 3H), 3.76 (t, J = 4.9 Hz, 2H), 4.16 (t, J = 4.9 Hz, 2H), 7.19 (s, 1H), 7.44 (d, J = 5.9 Hz, 3H), 7.75 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 6.8 Hz, 1H), 8.09 (s, 1H), 8.41 (s, 1H), 11.18 (s, 1H), 11.41 (s, 1H). (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3- (2- (2- (2-iodoethoxy) ethoxy) ethoxy) benzamide (Compound 9)
Compound 8 (1.50 g, 2.20 mmol) obtained in Example 8 was dissolved in DMF (15 mL), triethylamine (0.460 mL, 3.30 mol) and methanesulfonyl chloride (0.257 mL, 3.30 mmol) were added, and at room temperature. Stir overnight. Sodium iodide (0.659 g, 4.40 mmol) was added to the mixture, and the mixture was stirred at 100 ° C. for 2 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give Compound 9 (1.29 g, 74%).
1 H-NMR (270 MHz, DMSO-d 6 , δ): 1.02 (s, 6H), 1.53 (t, J = 6.3 Hz, 2H), 2.74 (s, 2H), 3.00 (s, 3H), 3.59 -3.61 (m, 4H), 3.63-3.69 (m, 3H), 3.76 (t, J = 4.9 Hz, 2H), 4.16 (t, J = 4.9 Hz, 2H), 7.19 (s, 1H), 7.44 ( d, J = 5.9 Hz, 3H), 7.75 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 6.8 Hz, 1H), 8.09 (s, 1H), 8.41 (s, 1H), 11.18 ( s, 1H), 11.41 (s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エトキシ)ベンズアミド（化合物10）
　実施例9で得られた化合物9（0.800 g, 1.01 mmol）をDMF（15 mL）に溶解し、炭酸カリウム（0.698 g, 5.05 mol）および2-ジエチルアミン（2.22 g, 30.3 mmol）を加え、100℃で5時間攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、化合物10（0.648 g, 87%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 1.02 (s, 6H), 1.07 (s, 6H), 1.69 (t, J = 6.3 Hz, 2H), 2.54-2.56 (m, 6H), 2.67 (t, J = 5.9 Hz, 2H), 2.87 (t, J= 5.9 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H), 3.65 (dd, J = 5.4, 3.4 Hz, 2H), 3.73 (dd, J = 5.4, 3.4 Hz, 2H), 3.88 (t, J = 4.4 Hz, 2H), 4.21 (t, J = 4.4 Hz, 2H), 7.13 (dd, J = 8.3, 2.5 Hz, 1H), 7.39 (t, J = 8.3 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.61 (t, J= 2.5 Hz, 2H), 7.97 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 8.24 (s, 1H).  ESI-MS m/z：739 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzamide (Compound 10)
Compound 9 (0.800 g, 1.01 mmol) obtained in Example 9 was dissolved in DMF (15 mL), and potassium carbonate (0.698 g, 5.05 mol) and 2-diethylamine (2.22 g, 30.3 mmol) were added. Stir at 5 ° C. for 5 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to give compound 10 (0.648 g, 87%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.02 (s, 6H), 1.07 (s, 6H), 1.69 (t, J = 6.3 Hz, 2H), 2.54-2.56 (m, 6H), 2.67 (t, J = 5.9 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H), 3.65 (dd, J = 5.4, 3.4 Hz, 2H), 3.73 (dd, J = 5.4, 3.4 Hz, 2H), 3.88 (t, J = 4.4 Hz, 2H), 4.21 (t, J = 4.4 Hz, 2H), 7.13 (dd, J = 8.3, 2.5 Hz, 1H) , 7.39 (t, J = 8.3 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.61 (t, J = 2.5 Hz, 2H), 7.97 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 8.24 (s, 1H). ESI-MS m / z: 739 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(2,6-ジメチル-9,12-ジオキサ-2,6-ジアザトリデカン-14-イルオキシ)ベンズアミド（化合物11）
　N,N,N’-トリメチル-1,3-プロパンジアミンを用い、実施例10と同様にして化合物11を得た。
ESI-MS m/z：780 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3- (2,6-dimethyl-9,12-dioxa-2,6-diazatridecan-14-yloxy) benzamide (compound 11)
Compound 11 was obtained in the same manner as in Example 10 using N, N, N′-trimethyl-1,3-propanediamine.
ESI-MS m / z: 780 (M + H) + .
(R,E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(2-(2-(2-(オキシラン-2-イルメトキシ)エトキシ)エトキシ)エトキシ)ベンズアミド（化合物12）
　実施例8で得られる化合物8（50.0 mg，0.0733 mmol）をDMF（1.5 mL）に溶解し、水素化ナトリウム（4.40 mg，0.110 mmol）および(S)-(+)-エピクロロヒドリン（0.0136 mg，0.147 mmol）を加え、室温で終夜攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘプタン／酢酸エチル＝9／1）で精製することにより、化合物12（16.0 mg, 29%）を得た。
1H-NMR (300 MHz，CDCl3，δ): 1.07 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 2.53 (s, 2H), 2.60 (dd, J = 5.0, 2.9 Hz, 1H), 2.78 (dd, J = 5.0, 4.2 Hz, 1H), 2.87 (t,  J = 6.0 Hz, 2H), 3.13-3.19 (m, 1H), 3.43 (dd, J = 11.4, 5.9 Hz，1H), 3.61-3.82 (m, 9H), 3.89 (t, J = 4.8 Hz，2H), 4.21 (t, J = 4.8 Hz, 2H)， 7.13 (dd, J = 8.0, 2.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.55-7.63 (m, 3H), 7.94-7.99 (m, 1H), 8.04 (s, 1H), 8.23 (s, 1H), 9.24 (br s, 1H), 12.89 (br s, 1H). (R, E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b ] Thiophen-2-yl) -3- (2- (2- (2- (oxiran-2-ylmethoxy) ethoxy) ethoxy) ethoxy) benzamide (Compound 12)
Compound 8 (50.0 mg, 0.0733 mmol) obtained in Example 8 was dissolved in DMF (1.5 mL), sodium hydride (4.40 mg, 0.110 mmol) and (S)-(+)-epichlorohydrin (0.0136 mg, 0.147 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (heptane / ethyl acetate = 9/1) to give Compound 12 (16.0 mg, 29%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 2.53 (s, 2H), 2.60 (dd, J = 5.0, 2.9 Hz , 1H), 2.78 (dd, J = 5.0, 4.2 Hz, 1H), 2.87 (t, J = 6.0 Hz, 2H), 3.13-3.19 (m, 1H), 3.43 (dd, J = 11.4, 5.9 Hz, 1H), 3.61-3.82 (m, 9H), 3.89 (t, J = 4.8 Hz, 2H), 4.21 (t, J = 4.8 Hz, 2H), 7.13 (dd, J = 8.0, 2.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.55-7.63 (m, 3H), 7.94-7.99 (m, 1H), 8.04 (s, 1H), 8.23 (s, 1H), 9.24 (br s, 1H ), 12.89 (br s, 1H).
(R,E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(13-エチル-11-ヒドロキシ-3,6,9-トリオキサ-13-アザペンタデシルオキシ)ベンズアミド（化合物13）
　実施例12で得られる化合物12（20 mg, 0.027 mmol）をTHF（1.0 mL）に溶解し、ジエチルアミン（20 mg, 0.27 mmol）を加え、室温で終夜攪拌した。混合物を濃縮し、残渣をシリカゲルカラムクロマトグラフィ－（クロロホルム／メタノ－ル＝4／1）で精製することにより、化合物13（4.0 mg, 18%）を得た。
1H-NMR (300 MHz,CDCl3, δ): 1.08 (s, 6H), 1.17 (t, J = 7.2 Hz, 6H), 1.63 (t, J = 6.0 Hz, 2H), 2.67-2.94 (m, 7H), 3.44-3.55 (m, 2H), 3.63-3.75 (m, 9H), 3.88 (t, J= 4.8 Hz, 2H), 4.01-4.10 (m, 1H), 4.22 (t, J = 4.8 Hz, 2H), 7.13 (dd, J= 8.2, 2.4 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.55-7.64 (m, 3H), 7.94-7.99 (m, 1H), 8.06-8.28 (s, 2H).  ESI-MS m/z: 811, 813 (M+H)+. (R, E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b ] Thiophen-2-yl) -3- (13-ethyl-11-hydroxy-3,6,9-trioxa-13-azapentadecyloxy) benzamide (Compound 13)
Compound 12 (20 mg, 0.027 mmol) obtained in Example 12 was dissolved in THF (1.0 mL), diethylamine (20 mg, 0.27 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol = 4/1) to give Compound 13 (4.0 mg, 18%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.17 (t, J = 7.2 Hz, 6H), 1.63 (t, J = 6.0 Hz, 2H), 2.67-2.94 (m , 7H), 3.44-3.55 (m, 2H), 3.63-3.75 (m, 9H), 3.88 (t, J = 4.8 Hz, 2H), 4.01-4.10 (m, 1H), 4.22 (t, J = 4.8 Hz, 2H), 7.13 (dd, J = 8.2, 2.4 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.55-7.64 (m, 3H), 7.94-7.99 (m, 1H), 8.06 -8.28 (s, 2H). ESI-MS m / z: 811, 813 (M + H) + .
(E)-3-(2-(2-(2-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェノキシ)エトキシ)エトキシ)エトキシ)プロパン酸tert-ブチル
工程1：3-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)プロパン酸tert-ブチル（2.85 mL, 10.8 mmol）をジクロロメタン（20 mL）に溶解し、トリエチルアミン（8.71 mL, 62.5 mmol）およびp-トルエンスルホニルクロリド（3.08 g, 16.2 mmol）を加え、室温で3時間攪拌した。混合物に10%塩酸を加え、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（ヘキサン／酢酸エチル＝5／1）で精製することにより3-(2-(2-(2-トシロキシエトキシ)エトキシ)エトキシ)プロパン酸tert-ブチル（4.15 g, 89%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.44 (s, 9H), 2.45 (s, 3H), 2.50 (t, J = 6.4 Hz, 2H), 3.58-3.60 (m, 8H), 3.67-3.72 (m, 4H), 4.16 (t, J = 4.8 Hz, 2H), 7.34 (d, J= 8.2 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H). 
工程2：実施例3で得られる化合物3（1.76 g, 3.20 mmol）をDMF（15.0 mL）に溶解し、工程1で得られた3-(2-(2-(2-トシロキシエトキシ)エトキシ)エトキシ)プロパン酸tert-ブチル（4.15 g, 9.60 mmol）、炭酸カリウム（1.78 g, 12.8 mmol）およびヨウ化ナトリウム （0.240 g, 1.60 mmol）を加え、100℃で2時間攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（クロロホルム／メタノ－ル＝99／1）で精製することにより、化合物14（1.65 g, 64%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.08 (s, 6H), 1.45 (s, 9H), 1.69 (d, J = 5.7 Hz, 2H), 2.49-2.55 (m, 2H), 3.46-3.51 (m, 2H), 3.60-3.76 (m, 12H), 3.89 (d, J = 4.8 Hz, 2H), 4.21 (d, J = 4.8 Hz, 2H), 7.14 (m, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.56-7.64 (m, 3H), 7.99-8.06 (m, 2H), 8.24 (s, 1H), 9.24 (s, 1H), 12.89 (s, 1H).  (E) -3- (2- (2- (2- (3- (3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4, 5,6,7-Tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) phenoxy) ethoxy) ethoxy) ethoxy) tert-butyl propanoate Step 1: 3- (2- (2- (2-hydroxyethoxy) ethoxy) Dissolve tert-butyl ethoxy) propanoate (2.85 mL, 10.8 mmol) in dichloromethane (20 mL), add triethylamine (8.71 mL, 62.5 mmol) and p-toluenesulfonyl chloride (3.08 g, 16.2 mmol) at room temperature. Stir for 3 hours. 10% hydrochloric acid was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give tert-butyl 3- (2- (2- (2-tosyloxyethoxy) ethoxy) ethoxy) propanoate (4.15 g, 89 %).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.44 (s, 9H), 2.45 (s, 3H), 2.50 (t, J = 6.4 Hz, 2H), 3.58-3.60 (m, 8H), 3.67 -3.72 (m, 4H), 4.16 (t, J = 4.8 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H).
Step 2: Compound 3 (1.76 g, 3.20 mmol) obtained in Example 3 was dissolved in DMF (15.0 mL), and 3- (2- (2- (2-tosyloxyethoxy) ethoxy obtained in Step 1 was obtained. ) Ethoxy) tert-butyl propanoate (4.15 g, 9.60 mmol), potassium carbonate (1.78 g, 12.8 mmol) and sodium iodide (0.240 g, 1.60 mmol) were added, and the mixture was stirred at 100 ° C for 2 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 99/1) to obtain Compound 14 (1.65 g, 64%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.45 (s, 9H), 1.69 (d, J = 5.7 Hz, 2H), 2.49-2.55 (m, 2H), 3.46 -3.51 (m, 2H), 3.60-3.76 (m, 12H), 3.89 (d, J = 4.8 Hz, 2H), 4.21 (d, J = 4.8 Hz, 2H), 7.14 (m, 1H), 7.40 ( d, J = 8.2 Hz, 1H), 7.56-7.64 (m, 3H), 7.99-8.06 (m, 2H), 8.24 (s, 1H), 9.24 (s, 1H), 12.89 (s, 1H).
(E)-3-(2-(2-(2-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェノキシ)エトキシ)エトキシ)エトキシ)プロパン酸（化合物15）
　実施例14で得られた化合物14（0.80 g, 9.87 mmol）に0℃にてトリフルオロ酢酸（1.5 mL）を加え、30分間攪拌した。混合物をジクロロエタンで希釈し、溶媒を減圧下で留去した。得られた残渣をシリカゲルカラムクロマトグラフィ－（クロロホルム／メタノ－ル＝99／1）で精製することにより、化合物15（0.235 g, 32%）を得た。
1H-NMR (400 MHz, DMSO-d6, δ): 1.02 (s, 6H), 1.53 (d, J = 6.3 Hz, 2H), 2.39-2.44 (m, 2H), 3.46-3.62 (m, 14H), 3.75 (d, J = 4.4 Hz, 2H), 4.13-4.17 (m, 2H), 7.19 (br s, 1H), 7.41-7.48 (m, 3H), 7.74-7.77 (m, 2H), 7.95 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 8.41 (s, 1H), 11.21 (s, 1H), 11.42 (s, 1H). (E) -3- (2- (2- (2- (3- (3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4, 5,6,7-Tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) phenoxy) ethoxy) ethoxy) ethoxy) propanoic acid (compound 15)
Trifluoroacetic acid (1.5 mL) was added to Compound 14 (0.80 g, 9.87 mmol) obtained in Example 14 at 0 ° C., and the mixture was stirred for 30 minutes. The mixture was diluted with dichloroethane and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 99/1) to give Compound 15 (0.235 g, 32%).
1 H-NMR (400 MHz, DMSO-d 6 , δ): 1.02 (s, 6H), 1.53 (d, J = 6.3 Hz, 2H), 2.39-2.44 (m, 2H), 3.46-3.62 (m, 14H), 3.75 (d, J = 4.4 Hz, 2H), 4.13-4.17 (m, 2H), 7.19 (br s, 1H), 7.41-7.48 (m, 3H), 7.74-7.77 (m, 2H), 7.95 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 8.41 (s, 1H), 11.21 (s, 1H), 11.42 (s, 1H).
N-(3-((E)-2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((15S, 16R, 17R, 18R)-15,16,17-18,19-ペンタヒドロキシ-12-オキソ-3,6,9-トリオキサ-13-アザノナデシルオキシ)ベンズアミド（化合物16）
　実施例15で得られた化合物15（36 mg, 0.048 mmol）をDMF（1.0 mL）に溶解し、D-グルカミン（9.51 mg,0.053 mmol）、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩（WSC・HCl）（10 mg, 0.053 mmol）およびHOBt・H2O（HOBt・H2O）（8.0 mg, 0.053 mmol）を加えて、室温で終夜攪拌した。混合物に水を加え、生じた沈殿物をろ取することにより、化合物16（10 mg, 23%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.01 (s, 6H), 1.61 (br s, 2H), 2.39-2.48 (m, 4H), 2.78-2.87 (m, 2H), 3.52-3.87 (m, 18H), 4.13 (br s, 2H), 7.01-7.08 (m, 1H), 7.31-7.36 (m, 1H), 7.47-7.55 (m, 3H), 7.90 (d, J = 6.8 Hz, 1H), 7.99 (s, 1H) 8.23 (s, 1H), 9.50 (s, 1H), 12.70 (s, 1H).  ESI-MS m/z: 917, 919 (M+H)+. N- (3-((E) -2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3-((15S, 16R, 17R, 18R) -15,16,17-18,19-pentahydroxy-12-oxo-3,6,9-trioxa-13-azanonadecyloxy Benzamide (Compound 16)
Compound 15 (36 mg, 0.048 mmol) obtained in Example 15 was dissolved in DMF (1.0 mL), D-glucamine (9.51 mg, 0.053 mmol), 1- (3-dimethylaminopropyl) -3-ethyl. Carbodiimide hydrochloride (WSC · HCl) (10 mg, 0.053 mmol) and HOBt · H 2 O (HOBt · H 2 O) (8.0 mg, 0.053 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the mixture, and the resulting precipitate was collected by filtration to give compound 16 (10 mg, 23%).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.01 (s, 6H), 1.61 (br s, 2H), 2.39-2.48 (m, 4H), 2.78-2.87 (m, 2H), 3.52-3.87 (m, 18H), 4.13 (br s, 2H), 7.01-7.08 (m, 1H), 7.31-7.36 (m, 1H), 7.47-7.55 (m, 3H), 7.90 (d, J = 6.8 Hz, 1H), 7.99 (s, 1H) 8.23 (s, 1H), 9.50 (s, 1H), 12.70 (s, 1H). ESI-MS m / z: 917, 919 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(15-ヒドロキシ-14,14-ビス(ヒドロキシメチル)-12-オキソ-3,6,9-トリオキサ-13-アザペンタデシルオキシ)ベンズアミド（化合物17）
　トリス(ヒドロキシメチル)アミノメタンを用い、実施例16と同様にして化合物17を得た。
ESI-MS m/z：857, 859 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3- (15-hydroxy-14,14-bis (hydroxymethyl) -12-oxo-3,6,9-trioxa-13-azapentadecyloxy) benzamide (Compound 17)
Compound 17 was obtained in the same manner as in Example 16 using tris (hydroxymethyl) aminomethane.
ESI-MS m / z: 857, 859 (M + H) + .
(E)-4-(2-(4-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)ベンジル)ピペラジン-1-イルスルホニル)エチル)ピペラジン-1-カルボン酸tert-ブチル（化合物18）
工程1：ピペラジン-1-カルボン酸ベンジル（0.914 g, 4.15 mmol）をジクロロメタン（20 mL）に溶解し、トリエチルアミン（1.16 mL, 8.30 mmol）を加え、氷冷下2-クロロエタンスルホニルクロリド（0.523 mL, 4.98 mmol）を滴下した。混合物を氷冷下で30分間攪拌した後、ピペラジン-1-カルボン酸tert-ブチル（1.16 g, 6.22 mmol）を加え、室温で終夜攪拌した。混合物に水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝95／5）で精製することにより、4-(2-(4-tert-ブトキシカルボニル)ピペラジン-1-イル)エチルスルホニル)ピペラジン-1-カルボン酸ベンジル（2.00 g, 97%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 1.46 (s, 9H), 2.41 (t, J = 4.9 Hz, 4H), 2.82 (dt, J = 9.2, 3.0 Hz, 2H), 3.09 (dd, J = 8.6, 6.0 Hz, 2H), 3.25 (d, J = 4.8 Hz, 4H), 3.41 (dd, J = 9.5, 4.4 Hz, 4H), 3.60 (t, J= 4.9 Hz, 4H), 5.14 (s, 2H), 7.35 (dd, J = 10.8, 5.3 Hz, 5H).
工程2：工程１で得られた4-(2-(4-tert-ブトキシカルボニル)ピペラジン-1-イル)エチルスルホニル)ピペラジン-1-カルボン酸ベンジル（0.894 g, 1.80 mmol）をTHF（15 mL）に溶解し、水酸化パラジウム（0.253 g, 1.80 mmol）を加え、水素雰囲気下、室温で終夜攪拌した。混合物をセライトを通してろ過した後、溶媒を減圧下で留去することにより、4-(2-(ピペラジン-1-イルスルホニル)エチル)ピペラジン-1-カルボン酸tert-ブチル（0.594 g, 91%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 1.46 (s, 9H), 2.43 (t, J = 5.1 Hz, 4H), 2.82-2.87 (m, 2H), 2.98 (dd, J = 6.0, 3.8 Hz, 4H), 3.10 (dd, J = 6.0, 3.8 Hz, 4H), 3.30 (t, J = 5.1 Hz, 4H), 3.43 (dd, J = 9.7, 4.2 Hz, 4H).
工程3：実施例1で得られる化合物1（0.313 g, 0.537 mmol）をDMF（5 mL）に溶解し、トリエチルアミン（0.225 mL, 1.61 mmol）および工程2で得られた4-(2-(ピペラジン-1-イルスルホニル)エチル)ピペラジン-1-カルボン酸tert-ブチル（0.292 g, 0.806 mmol）を加え、室温で終夜攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、化合物18（0.246 g, 50%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 1.08 (s, 6H), 1.46 (s, 9H), 1.70 (t, J = 6.0 Hz, 2H), 2.42 (t, J = 4.9 Hz, 2H), 2.56 (d, J = 8.1 Hz, 2H), 2.86 (dq, J = 16.0, 4.0 Hz, 6H), 3.10 (dd, J = 9.0, 6.0 Hz, 4H), 3.24 (t, J = 4.9 Hz, 2H), 3.32 (t, J= 4.4 Hz, 4H), 3.42 (t, J = 4.9 Hz, 2H), 3.52 (t, J = 4.9 Hz, 2H), 3.64 (s, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.52-7.53 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.94-7.99 (m, 2H), 8.04 (s, 2H), 8.22 (d, J = 4.4 Hz, 1H), 9.23 (s, 1H), 12.95 (s, 1H). (E) -4- (2- (4- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6 , 7-Tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) benzyl) piperazin-1-ylsulfonyl) ethyl) piperazine-1-carboxylate tert-butyl (compound 18)
Step 1: Benzyl piperazine-1-carboxylate (0.914 g, 4.15 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.16 mL, 8.30 mmol) was added, and 2-chloroethanesulfonyl chloride (0.523 mL, 4.98 mmol) was added dropwise. The mixture was stirred for 30 minutes under ice-cooling, piperazine-1-carboxylate tert-butyl (1.16 g, 6.22 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the mixture and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 95/5) to give 4- (2- (4-tert-butoxycarbonyl) piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate benzyl (2.00 g, 97%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.46 (s, 9H), 2.41 (t, J = 4.9 Hz, 4H), 2.82 (dt, J = 9.2, 3.0 Hz, 2H), 3.09 (dd , J = 8.6, 6.0 Hz, 2H), 3.25 (d, J = 4.8 Hz, 4H), 3.41 (dd, J = 9.5, 4.4 Hz, 4H), 3.60 (t, J = 4.9 Hz, 4H), 5.14 (s, 2H), 7.35 (dd, J = 10.8, 5.3 Hz, 5H).
Step 2: 4- (2- (4-tert-Butoxycarbonyl) piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate benzyl (0.894 g, 1.80 mmol) obtained in Step 1 was added to THF (15 mL). ), Palladium hydroxide (0.253 g, 1.80 mmol) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After the mixture was filtered through celite, the solvent was evaporated under reduced pressure to give tert-butyl 4- (2- (piperazin-1-ylsulfonyl) ethyl) piperazine-1-carboxylate (0.594 g, 91%) Got.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.46 (s, 9H), 2.43 (t, J = 5.1 Hz, 4H), 2.82-2.87 (m, 2H), 2.98 (dd, J = 6.0, 3.8 Hz, 4H), 3.10 (dd, J = 6.0, 3.8 Hz, 4H), 3.30 (t, J = 5.1 Hz, 4H), 3.43 (dd, J = 9.7, 4.2 Hz, 4H).
Step 3: Compound 1 (0.313 g, 0.537 mmol) obtained in Example 1 was dissolved in DMF (5 mL), triethylamine (0.225 mL, 1.61 mmol) and 4- (2- (piperazine) obtained in Step 2 were used. -1-ylsulfonyl) ethyl) piperazine-1-carboxylate tert-butyl (0.292 g, 0.806 mmol) was added and stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to give compound 18 (0.246 g, 50%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.46 (s, 9H), 1.70 (t, J = 6.0 Hz, 2H), 2.42 (t, J = 4.9 Hz, 2H ), 2.56 (d, J = 8.1 Hz, 2H), 2.86 (dq, J = 16.0, 4.0 Hz, 6H), 3.10 (dd, J = 9.0, 6.0 Hz, 4H), 3.24 (t, J = 4.9 Hz , 2H), 3.32 (t, J = 4.4 Hz, 4H), 3.42 (t, J = 4.9 Hz, 2H), 3.52 (t, J = 4.9 Hz, 2H), 3.64 (s, 2H), 7.46 (t , J = 7.5 Hz, 1H), 7.52-7.53 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.94-7.99 (m, 2H), 8.04 (s, 2H), 8.22 (d, J = 4.4 Hz, 1H), 9.23 (s, 1H), 12.95 (s, 1H).
(E)-N-3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((4-(2-(ピペラジン-1-イル)エチルスルホニル)ピペラジン-1-イル)メチル)ベンズアミド（化合物19）
　実施例18で得られる化合物18（0.440 g, 0.484 mmol）をジクロロメタン（10 mL）に溶解し、トリフルオロ酢酸（1.87 mL. 24.2 mmol）を加え室温で2時間攪拌した。混合物に1 mol/L水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をアミノカラムクロマトグラフィー（クロロホルム／メタノール＝98／2）で精製することにより、化合物19（0.217 g,  55%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 1.08 (s, 6H), 1.70 (t, J = 6.0 Hz, 2H), 2.45 (s, 4H), 2.55 (br s, 6H), 2.81 (t, J = 7.6 Hz, 2H), 2.88-2.90 (m, 6H), 3.11 (t, J = 7.3 Hz, 2H), 3.33 (s, 4H), 3.64 (s, 2H), 7.44-7.54 (m, 2H), 7.59 (d, J = 8.6 Hz, 1H), 7.96 (t, J = 9.4 Hz, 2H), 8.05 (s, 2H), 8.21 (s, 1H), 9.24 (s, 1H), 12.94 (s, 1H).  ESI-MS m/z：808 (M+H)+. (E) -N-3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene- 2-yl) -3-((4- (2- (piperazin-1-yl) ethylsulfonyl) piperazin-1-yl) methyl) benzamide (Compound 19)
Compound 18 (0.440 g, 0.484 mmol) obtained in Example 18 was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1.87 mL. 24.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A 1 mol / L aqueous sodium hydroxide solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by amino column chromatography (chloroform / methanol = 98/2) to obtain Compound 19 (0.217 g, 55%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.70 (t, J = 6.0 Hz, 2H), 2.45 (s, 4H), 2.55 (br s, 6H), 2.81 ( t, J = 7.6 Hz, 2H), 2.88-2.90 (m, 6H), 3.11 (t, J = 7.3 Hz, 2H), 3.33 (s, 4H), 3.64 (s, 2H), 7.44-7.54 (m , 2H), 7.59 (d, J = 8.6 Hz, 1H), 7.96 (t, J = 9.4 Hz, 2H), 8.05 (s, 2H), 8.21 (s, 1H), 9.24 (s, 1H), 12.94 (s, 1H). ESI-MS m / z: 808 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((4-(2-(4-(メチルスルホニル)ピペラジン-1-イル)エチルスルホニル)ピペラジン-1-イル)メチル)ベンズアミド（化合物20）
工程1：実施例18の工程１で得られた4-(2-(4-tert-ブトキシカルボニル)ピペラジン-1-イル)エチルスルホニル)ピペラジン-1-カルボン酸ベンジルを用い、実施例19と同様にして、4-(2-(ピペラジン-1-イル)エチルスルホニル)ピペラジン-1-カルボン酸ベンジル（0.376 g, 35%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 2.44 (br s, 1H), 2.76 (t, J = 4.8 Hz, 4H), 2.93-2.95 (m, 2H), 3.04-3.09 (m, 2H), 3.18 (t, J = 4.8 Hz, 4H), 3.25 (s, 4H), 3.61 (t, J = 4.8 Hz, 4H), 5.14 (s, 2H), 7.34-7.38 (m, 5H).
工程2：工程１で得られた4-(2-(ピペラジン-1-イル)エチルスルホニル)ピペラジン-1-カルボン酸ベンジル（0.376 g, 0.948 mmol）をジクロロメタン（15 mL）に溶解し、トリエチルアミン（0.397 mL, 2.84 mmol）およびメタンスルホニルクロリド（0.111 mL, 1.42 mmol）を加え、室温で終夜攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。得られた固体をエタノールでリスラリーすることにより、4-(2-(4-(メチルスルホニル)ピペラジン-1-イル)エチルスルホニル)ピペラジン-1-カルボン酸ベンジル（0.0880 g, 20%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 2.59 (t, J= 4.9 Hz, 4H), 2.78 (s, 3H), 2.89 (dd, J = 8.6, 5.7 Hz, 2H), 3.07 (dd, J= 8.6, 5.7 Hz, 2H), 3.23-3.25 (m, 8H), 3.61 (t, J = 4.9 Hz, 4H), 5.15 (s, 2H), 7.33-7.39 (m, 5H).
工程3：工程2で得られた4-(2-(4-(メチルスルホニル)ピペラジン-1-イル)エチルスルホニル)ピペラジン-1-カルボン酸ベンジルを用い、実施例18の工程2と同様にして、1-(メチルスルホニル)-4-(2-(ピペラジン-1-イルスルホニル)エチル)ピペラジン（59.0 mg, 93%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 2.60-2.61 (m, 4H), 2.77-2.80 (dd, J= 9.3, 5.7 Hz, 2H), 2.92-2.95 (m, 8H), 3.08 (dd, J = 9.3, 5.7 Hz, 2H), 3.16-3.26 (m, 8H).
工程4：工程3で得られる1-(メチルスルホニル)-4-(2-(ピペラジン-1-イルスルホニル)エチル)ピペラジンを用い、実施例18の工程3と同様にして、化合物20（80.0 mg, 68%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 1.03 (s, 8H), 1.54 (t, J = 5.9 Hz, 2H), 2.51-2.55 (m, 2H), 2.75 (t, J = 7.1 Hz, 4H), 2.83 (s, 3H), 3.01-3.04 (m, 6H), 3.11 (t, J = 4.8 Hz, 4H), 3.19-3.21 (m, 6H), 3.61 (s, 2H), 7.49-7.52 (m, 2H), 7.74-7.77 (m, 2H), 7.86 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 8.09 (s, 1H), 8.42 (s, 1H), 11.15 (s, 1H), 11.49 (s, 1H).  ESI-MS m/z：886 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3-((4- (2- (4- (methylsulfonyl) piperazin-1-yl) ethylsulfonyl) piperazin-1-yl) methyl) benzamide (Compound 20)
Step 1: Similar to Example 19 using benzyl 4- (2- (4-tert-butoxycarbonyl) piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate obtained in Step 1 of Example 18. To give benzyl 4- (2- (piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate (0.376 g, 35%).
1 H-NMR (270 MHz, CDCl 3 , δ): 2.44 (br s, 1H), 2.76 (t, J = 4.8 Hz, 4H), 2.93-2.95 (m, 2H), 3.04-3.09 (m, 2H ), 3.18 (t, J = 4.8 Hz, 4H), 3.25 (s, 4H), 3.61 (t, J = 4.8 Hz, 4H), 5.14 (s, 2H), 7.34-7.38 (m, 5H).
Step 2: Benzyl 4- (2- (piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate (0.376 g, 0.948 mmol) obtained in Step 1 was dissolved in dichloromethane (15 mL) and triethylamine ( 0.397 mL, 2.84 mmol) and methanesulfonyl chloride (0.111 mL, 1.42 mmol) were added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting solid was reslurried with ethanol to give benzyl 4- (2- (4- (methylsulfonyl) piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate (0.0880 g, 20%). .
1 H-NMR (270 MHz, CDCl 3 , δ): 2.59 (t, J = 4.9 Hz, 4H), 2.78 (s, 3H), 2.89 (dd, J = 8.6, 5.7 Hz, 2H), 3.07 (dd , J = 8.6, 5.7 Hz, 2H), 3.23-3.25 (m, 8H), 3.61 (t, J = 4.9 Hz, 4H), 5.15 (s, 2H), 7.33-7.39 (m, 5H).
Step 3: In the same manner as in Step 2 of Example 18, using benzyl 4- (2- (4- (methylsulfonyl) piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate obtained in Step 2. 1- (methylsulfonyl) -4- (2- (piperazin-1-ylsulfonyl) ethyl) piperazine (59.0 mg, 93%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 2.60-2.61 (m, 4H), 2.77-2.80 (dd, J = 9.3, 5.7 Hz, 2H), 2.92-2.95 (m, 8H), 3.08 ( dd, J = 9.3, 5.7 Hz, 2H), 3.16-3.26 (m, 8H).
Step 4: Compound 20 (80.0 mg) was prepared in the same manner as in Step 3 of Example 18 using 1- (methylsulfonyl) -4- (2- (piperazin-1-ylsulfonyl) ethyl) piperazine obtained in Step 3. , 68%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.03 (s, 8H), 1.54 (t, J = 5.9 Hz, 2H), 2.51-2.55 (m, 2H), 2.75 (t, J = 7.1 Hz , 4H), 2.83 (s, 3H), 3.01-3.04 (m, 6H), 3.11 (t, J = 4.8 Hz, 4H), 3.19-3.21 (m, 6H), 3.61 (s, 2H), 7.49- 7.52 (m, 2H), 7.74-7.77 (m, 2H), 7.86 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 8.09 (s, 1H), 8.42 (s, 1H), 11.15 (s, 1H), 11.49 (s, 1H). ESI-MS m / z: 886 (M + H) + .
(E)-3-((3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)ベンジル)(メチル)アミノ)プロピルカルバミン酸tert-ブチル
　3-(メチルアミノ)プロピルカルバミン酸tert-ブチルを用い、実施例18の工程3と同様にして化合物21（1.02 g, 81%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.08 (s, 6H), 1.41 (s, 9H), 1.67-1.75 (m, 4H), 2.20 (s, 3H), 2.48 (t, J = 6.6 Hz, 2H), 2.54 (s, 2H), 2.84-2.91 (m, 2H), 3.18-3.22 (m, 2H), 3.58 (s, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.56-7.59 (m, 2H), 7.94-7.96 (m, 3H), 8.05 (s, 1H), 8.22 (s, 1H).  (E) -3-((3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] Thiophen-2-ylcarbamoyl) benzyl) (methyl) amino) propylcarbamate tert-butyl 3- (methylamino) propylcarbamate tert-butyl (1.02 g, 81%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.41 (s, 9H), 1.67-1.75 (m, 4H), 2.20 (s, 3H), 2.48 (t, J = 6.6 Hz, 2H), 2.54 (s, 2H), 2.84-2.91 (m, 2H), 3.18-3.22 (m, 2H), 3.58 (s, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.56-7.59 (m, 2H), 7.94-7.96 (m, 3H), 8.05 (s, 1H), 8.22 (s, 1H).
(E)-3-(((3-アミノプロピル)(メチル)アミノ)メチル)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)ベンズアミド（化合物22）
　実施例21で得られる化合物21を用い、実施例19と同様にして化合物22（0.799 g, 91%）を得た。
1H-NMR (270 MHz, DMSO-d6, δ): 1.04 (s, 6H), 1.51 (t, J = 6.4 Hz, 2H), 1.69-1.78 (m, 2H), 2.14 (s, 3H), 2.43-2.50 (m, 4H), 2.82-2.87 (m, 4H), 3.59 (s, 2H), 7.45-7.49 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.84-7.89 (m, 2H), 7.94-7.97 (m, 1H), 8.10 (d, J = 1.5 Hz, 1H), 8.46 (s, 1H).  (E) -3-(((3-Aminopropyl) (methyl) amino) methyl) -N- (3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6, 6-Dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide (Compound 22)
Using Compound 21 obtained in Example 21, Compound 22 (0.799 g, 91%) was obtained in the same manner as Example 19.
1 H-NMR (270 MHz, DMSO-d 6 , δ): 1.04 (s, 6H), 1.51 (t, J = 6.4 Hz, 2H), 1.69-1.78 (m, 2H), 2.14 (s, 3H) , 2.43-2.50 (m, 4H), 2.82-2.87 (m, 4H), 3.59 (s, 2H), 7.45-7.49 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.84-7.89 (m, 2H), 7.94-7.97 (m, 1H), 8.10 (d, J = 1.5 Hz, 1H), 8.46 (s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(((3-(3-ヒドロキシ-2-(ヒドロキシメチル)-2-メチルプロパンアミド)プロピル)(メチル)アミノ)メチル)ベンズアミド（化合物23）
　実施例22で得られた化合物22（150 mg, 0.237 mmol）をDMF（6 mL）に溶解し、3-ヒドロキシ-2-(ヒドロキシメチル)-2-メチルプロピオン酸（63.4 mg, 0.473 mmol）、EDC塩酸塩（90.7 mg, 0.473 mmol）およびHOBt・H2O（71.5 mg, 0.473 mmol）を加えて、室温で終夜攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をNHシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、化合物23（53.0 mg, 30%）を得た。
1H-NMR (270 MHz, DMSO-d6, δ): 0.96 (s, 3H), 1.03 (s, 6H), 1.54 (t, J = 6.2 Hz, 2H), 1.61-1.78 (m, 2H), 2.70-2.78 (m, 2H), 3.09-3.16 (m, 10H), 3.41-3.53 (m, 5H), 4.44 (br s, 2H), 7.33-7.44 (m, 1H), 7.49-7.53 (m, 2H), 7.75-7.90 (m, 4H), 7.96 (d, J = 8.1 Hz, 1H), 8.10 (s, 1H), 8.43 (s, 1H), 11.21 (br s, 1H), 11.48 (br s, 1H).  ESI-MS m/z: 750, 752 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3-(((3- (3-hydroxy-2- (hydroxymethyl) -2-methylpropanamido) propyl) (methyl) amino) methyl) benzamide (Compound 23)
Compound 22 (150 mg, 0.237 mmol) obtained in Example 22 was dissolved in DMF (6 mL), 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid (63.4 mg, 0.473 mmol), EDC hydrochloride (90.7 mg, 0.473 mmol) and HOBt · H 2 O (71.5 mg, 0.473 mmol) were added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by NH silica gel column chromatography (chloroform / methanol = 9/1) to obtain Compound 23 (53.0 mg, 30%).
1 H-NMR (270 MHz, DMSO-d 6 , δ): 0.96 (s, 3H), 1.03 (s, 6H), 1.54 (t, J = 6.2 Hz, 2H), 1.61-1.78 (m, 2H) , 2.70-2.78 (m, 2H), 3.09-3.16 (m, 10H), 3.41-3.53 (m, 5H), 4.44 (br s, 2H), 7.33-7.44 (m, 1H), 7.49-7.53 (m , 2H), 7.75-7.90 (m, 4H), 7.96 (d, J = 8.1 Hz, 1H), 8.10 (s, 1H), 8.43 (s, 1H), 11.21 (br s, 1H), 11.48 (br s, 1H). ESI-MS m / z: 750, 752 (M + H) + .
(E)-2-(2-(2-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)ベンジルアミノ)エトキシ)エトキシ)エチルカルバミン酸tert-ブチル（化合物24）
　実施例1で得られる化合物1（0.300 g, 0.515 mmol）をアセトニトリル（3 mL）に溶解し、50%KFセライト（0.349 g,3.00 mmol）および2-(2-(2-アミノエトキシ)エトキシ)エチルカルバミン酸tert-ブチル（0.320 g, 1.29 mmol）を加え、80℃で2時間攪拌した。混合物に水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（クロロホルム／メタノ－ル＝9／1）で精製することにより、化合物24（0.187 g, 46%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.08 (s, 6H), 1.43 (s, 9H), 1.69 (t, J = 5.9 Hz, 2H), 2.54 (s, 2H), 2.83 (t, J = 5.4 Hz, 2H), 2.88 (t, J = 5.9 Hz, 2H), 3.30 (t, J= 4.9 Hz, 2H), 3.53 (t, J = 5.4 Hz, 2H), 3.60-3.64 (m, 7H), 3.92 (s, 2H), 5.14 (s, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.56-7.61 (m, 2H), 7.92-8.06 (m, 4H), 8.23 (m, 1H), 9.27 (br s, 1H), 12.91 (br s, 1H). (E) -2- (2- (2- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6 , 7-Tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) benzylamino) ethoxy) ethoxy) ethylcarbamate tert-butyl (compound 24)
Compound 1 (0.300 g, 0.515 mmol) obtained in Example 1 was dissolved in acetonitrile (3 mL), 50% KF Celite (0.349 g, 3.00 mmol) and 2- (2- (2-aminoethoxy) ethoxy) Tert-Butyl ethylcarbamate (0.320 g, 1.29 mmol) was added, and the mixture was stirred at 80 ° C. for 2 hr. Water was added to the mixture and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to give Compound 24 (0.187 g, 46%).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.43 (s, 9H), 1.69 (t, J = 5.9 Hz, 2H), 2.54 (s, 2H), 2.83 (t , J = 5.4 Hz, 2H), 2.88 (t, J = 5.9 Hz, 2H), 3.30 (t, J = 4.9 Hz, 2H), 3.53 (t, J = 5.4 Hz, 2H), 3.60-3.64 (m , 7H), 3.92 (s, 2H), 5.14 (s, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.56-7.61 (m, 2H), 7.92-8.06 (m, 4H), 8.23 ( m, 1H), 9.27 (br s, 1H), 12.91 (br s, 1H).
(E)-2-(2-(2-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)ベンジル(メチル)アミノ)エトキシ)エトキシ)エチルカルバミン酸tert-ブチル（化合物25）
　実施例24で得られた化合物24（0.210 g, 0.264 mmol）をジクロロエタン（2 mL）およびメタノ－ル（2 mL）に溶解し、ホルムアルデヒド37%水溶液（0.197 mL, 2.64 mmol）、およびトリアセトキシ水素化ホウ素ナトリウム（0.280 g, 1.32 mmol）を加え、室温で10分間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下で留去することにより、化合物25（0.169 g, 79%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.43 (s, 9H), 1.69 (t, J = 5.9 Hz, 2H), 2.28 (s, 3H), 2.54 (s, 2H), 2.66 (t, J = 5.9 Hz, 2H), 2.88 (t, J = 5.9 Hz, 2H), 3.27-3.32 (m, 2H), 3.53 (d, J = 4.9 Hz, 2H), 3.58-3.67 (m, 9H), 7.46 (d, J = 7.3 Hz, 1H), 7.56-7.62 (m, 2H), 7.91-8.07 (m, 4H), 8.23 (s, 1H), 9.27 (s, 1H), 12.88 (s, 1H). (E) -2- (2- (2- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6 , 7-Tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) benzyl (methyl) amino) ethoxy) ethoxy) ethylcarbamate tert-butyl (compound 25)
Compound 24 (0.210 g, 0.264 mmol) obtained in Example 24 was dissolved in dichloroethane (2 mL) and methanol (2 mL), 37% aqueous formaldehyde solution (0.197 mL, 2.64 mmol), and triacetoxyhydrogen Sodium borohydride (0.280 g, 1.32 mmol) was added and stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 25 (0.169 g, 79%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.43 (s, 9H), 1.69 (t, J = 5.9 Hz, 2H), 2.28 (s, 3H), 2.54 (s , 2H), 2.66 (t, J = 5.9 Hz, 2H), 2.88 (t, J = 5.9 Hz, 2H), 3.27-3.32 (m, 2H), 3.53 (d, J = 4.9 Hz, 2H), 3.58 -3.67 (m, 9H), 7.46 (d, J = 7.3 Hz, 1H), 7.56-7.62 (m, 2H), 7.91-8.07 (m, 4H), 8.23 (s, 1H), 9.27 (s, 1H ), 12.88 (s, 1H).
ペンタ酢酸　(13R,14S,15R,16R)-1-(3-(3-((E)-2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェニル)-2-メチル-12-オキソ-5,8-ジオキサ-2,11-ヘプタデカン-13,14,15,16,17-ペンタイル（化合物26）
　実施例25で得られた化合物25（50 mg, 0.063 mmol）をジクロロエタン（0.5 mL）に溶解し、トリフルオロ酢酸（0.30 mL, 3.9 mmol）を加え、0℃で10分間攪拌した。混合物を減圧下で濃縮し、得られた残渣をジクロロメタン(1 mL）に溶解し、トリエチルアミン（0.021 mL, 0.15 mmol）を加えた。続いて、WO2010/078449に記載されている方法で調製したペンタ酢酸　(2R,3R,4S,5R)-6-クロロ-6-オキソヘキサン-1,2,3,4,5-ペンタイル（49 mg, 0.12 mmol）を加え、0℃で30分間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（クロロホルム／メタノ－ル＝9／1）で精製することにより化合物26（41 mg, 48%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.69 (t, J = 5.9 Hz, 2H), 2.04 (s, 3H), 2.04 (s, 3H), 2.08 (s, 3H), 2.09 (s, 3H), 2.18 (s, 3H), 2.28 (s, 3H), 2.53 (s, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.88 (t, J = 5.9 Hz, 2H), 3.39-3.52 (m, 4H), 3.58-3.67 (m, 8H), 4.11 (dd, J = 12.2, 5.5 Hz, 1H), 4.30 (dd, J = 12.2, 4.2 Hz, 1H), 5.05 (dd, J = 10.1, 5.5 Hz, 1H), 5.33 (d, J = 4.8 Hz, 1H), 5.46 (d, J = 5.5 Hz, 1H), 5.66 (dd, J = 4.8 Hz, 1H), 6.64 (s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.56-7.61 (m, 2H), 7.90-8.07 (m, 4H), 8.23 (s, 1H), 9.03 (s, 1H), 12.85 (s, 1H). Pentaacetic acid (13R, 14S, 15R, 16R) -1- (3- (3-((E) -2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl -4,5,6,7-tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) phenyl) -2-methyl-12-oxo-5,8-dioxa-2,11-heptadecane-13,14,15, 16,17-Pentile (Compound 26)
Compound 25 (50 mg, 0.063 mmol) obtained in Example 25 was dissolved in dichloroethane (0.5 mL), trifluoroacetic acid (0.30 mL, 3.9 mmol) was added, and the mixture was stirred at 0 ° C. for 10 minutes. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (1 mL), and triethylamine (0.021 mL, 0.15 mmol) was added. Subsequently, pentaacetic acid (2R, 3R, 4S, 5R) -6-chloro-6-oxohexane-1,2,3,4,5-pentyl (49 mg) prepared by the method described in WO2010 / 078449 , 0.12 mmol) and stirred at 0 ° C. for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to obtain Compound 26 (41 mg, 48%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.69 (t, J = 5.9 Hz, 2H), 2.04 (s, 3H), 2.04 (s, 3H), 2.08 (s , 3H), 2.09 (s, 3H), 2.18 (s, 3H), 2.28 (s, 3H), 2.53 (s, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.88 (t, J = 5.9 Hz, 2H), 3.39-3.52 (m, 4H), 3.58-3.67 (m, 8H), 4.11 (dd, J = 12.2, 5.5 Hz, 1H), 4.30 (dd, J = 12.2, 4.2 Hz, 1H ), 5.05 (dd, J = 10.1, 5.5 Hz, 1H), 5.33 (d, J = 4.8 Hz, 1H), 5.46 (d, J = 5.5 Hz, 1H), 5.66 (dd, J = 4.8 Hz, 1H) ), 6.64 (s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.56-7.61 (m, 2H), 7.90-8.07 (m, 4H), 8.23 (s, 1H), 9.03 (s, 1H), 12.85 (s, 1H).
N-(3-((E)-2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((13R,14S,15R,16R)-15,16,17,18,19-ペンタヒドロキシ-2-メチル-12-オキソ-5,8-ジオキサ-2,11-ジアザヘプタデシル)ベンズアミド（化合物27）
　実施例26で得られた化合物26（40 mg, 0.037 mmol）をメタノ－ル（1.0 mL）および水（0.050 mL）の混合溶媒に溶解し、水酸化リチウム・一水和物（6.2 mg,0.15 mmol）を加え、0℃で30分間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム／メタノ－ル＝9／1の混合溶媒で抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（クロロホルム／メタノ－ル＝4／1）で精製することにより化合物27（13 mg, 38%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.00 (s, 6H), 1.60 (br s, 2H), 2.21 (s, 3H), 2.44  (s, 2H), 2.57 (br s, 2H), 2.84 (br s, 2H), 3.34-3.80 (m, 16H), 4.07-4.13 (m, 1H), 4.23-4.28 (m, 1H), 7.40 (t, J= 7.7 Hz, 1H), 7.46-7.53 (m, 2H), 7.56-7.62 (m, 1H), 7.81-7.99 (m, 4H), 8.26 (s, 1H), 9.64 (s, 1H), 12.67 (s, 1H).  ESI-MS m/z: 886, 888 (M+H)+. N- (3-((E) -2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3-((13R, 14S, 15R, 16R) -15,16,17,18,19-pentahydroxy-2-methyl-12-oxo-5,8-dioxa-2,11- Diazaheptadecyl) benzamide (Compound 27)
Compound 26 (40 mg, 0.037 mmol) obtained in Example 26 was dissolved in a mixed solvent of methanol (1.0 mL) and water (0.050 mL), and lithium hydroxide monohydrate (6.2 mg, 0.15). mmol) and stirred at 0 ° C. for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with a mixed solvent of chloroform / methanol = 9/1. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 4/1) to give compound 27 (13 mg, 38%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.00 (s, 6H), 1.60 (br s, 2H), 2.21 (s, 3H), 2.44 (s, 2H), 2.57 (br s, 2H) , 2.84 (br s, 2H), 3.34-3.80 (m, 16H), 4.07-4.13 (m, 1H), 4.23-4.28 (m, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.46- 7.53 (m, 2H), 7.56-7.62 (m, 1H), 7.81-7.99 (m, 4H), 8.26 (s, 1H), 9.64 (s, 1H), 12.67 (s, 1H). ESI-MS m / z: 886, 888 (M + H) + .
(E)-1-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェニル)-5,8,11-トリオキサ-2-アザテトラデカン-14-酸tert-ブチル（化合物28）
　実施例1で得られる化合物1（0.700 g, 1.20 mmol）および3-(2-(2-(2-アミノエトキシ)エトキシ)エトキシ)プロパン酸tert-ブチル（0.833 g, 3.00 mmol）を用い、実施例24と同様にして、化合物28（0.475 g, 48%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.00 (s, 6H), 1.43 (s, 9H), 1.69 (t, J = 5.9 Hz, 2H), 2.44 (s, 2H), 2.48 (t, J = 6.8 Hz, 2H), 2.81 (t, J = 4.9 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 3.57-3.71 (m, 12H), 3.88 (s, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.51-7.58 (m, 2H), 7.87-7.91 (m, 2H), 7.98 (t, J = 8.8 Hz, 2H), 8.27 (s, 1H), 9.54 (br s, 1H), 12.67 (br s, 1H).  (E) -1- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] thiophen-2-ylcarbamoyl) phenyl) -5,8,11-trioxa-2-azatetradecane-14-acid tert-butyl (compound 28)
Using compound 1 obtained in Example 1 (0.700 g, 1.20 mmol) and tert-butyl 3- (2- (2- (2-aminoethoxy) ethoxy) ethoxy) propanoate (0.833 g, 3.00 mmol) Analogously to Example 24, compound 28 (0.475 g, 48%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.00 (s, 6H), 1.43 (s, 9H), 1.69 (t, J = 5.9 Hz, 2H), 2.44 (s, 2H), 2.48 (t , J = 6.8 Hz, 2H), 2.81 (t, J = 4.9 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 3.57-3.71 (m, 12H), 3.88 (s, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.51-7.58 (m, 2H), 7.87-7.91 (m, 2H), 7.98 (t, J = 8.8 Hz, 2H), 8.27 (s, 1H), 9.54 ( br s, 1H), 12.67 (br s, 1H).
(E)-1-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェニル)-2-メチル-5,8,11-トリオキサ-2-アザテトラデカン-14-酸tert-ブチル（化合物29）
　実施例25と同様にして、実施例28で得られる化合物28（1.00 g, 1.22 mmol）を用い、化合物29（1.00 g, 98%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.08 (s, 6H), 1.44 (s, 9H), 1.69 (t, J = 6.0 Hz, 2H), 2.28 (s, 3H), 2.48 (t, J = 6.6 Hz, 2H), 2.54 (s, 2H), 2.65 (t, J = 5.6 Hz, 2H), 2.88 (t, J = 6.0 Hz, 2H), 3.57-3.72 (m, 14H), 7.46 (t, J = 7.6 Hz, 1H), 7.56-7.65 (m, 2H), 7.90-8.07 (m, 4H), 8.23 (s, 1H), 9.25 (br s, 1H), 12.88 (br s, 1H). (E) -1- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] thiophen-2-ylcarbamoyl) phenyl) -2-methyl-5,8,11-trioxa-2-azatetradecane-14-acid tert-butyl (compound 29)
In the same manner as in Example 25, Compound 29 (1.00 g, 98%) was obtained using Compound 28 (1.00 g, 1.22 mmol) obtained in Example 28.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.44 (s, 9H), 1.69 (t, J = 6.0 Hz, 2H), 2.28 (s, 3H), 2.48 (t , J = 6.6 Hz, 2H), 2.54 (s, 2H), 2.65 (t, J = 5.6 Hz, 2H), 2.88 (t, J = 6.0 Hz, 2H), 3.57-3.72 (m, 14H), 7.46 (t, J = 7.6 Hz, 1H), 7.56-7.65 (m, 2H), 7.90-8.07 (m, 4H), 8.23 (s, 1H), 9.25 (br s, 1H), 12.88 (br s, 1H ).
(E)-1-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェニル)-2-メチル-5,8,11-トリオキサ-2-アザテトラデカン-14-酸（化合物30）
　実施例15と同様にして、実施例29で得られた化合物29（1.00 g, 1.19 mmol）を用い、化合物30（0.45 g, 48%）を得た。 (E) -1- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] thiophen-2-ylcarbamoyl) phenyl) -2-methyl-5,8,11-trioxa-2-azatetradecane-14-acid (compound 30)
In the same manner as in Example 15, Compound 30 (0.45 g, 48%) was obtained using Compound 29 (1.00 g, 1.19 mmol) obtained in Example 29.
(E)-1-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェニル)-N-(1,3-ジヒドロキシ-2-(ヒドロキシメチル)プロパン-2-イル)-2-メチル-5,8,11-トリオキサ-2-アザテトラデカン-14-アミド（化合物31）
　実施例16と同様にして、実施例30で得られた化合物30（0.150 g, 0.192 mmol）を用い、化合物31（30.0 mg, 18%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.07 (s, 6H), 1.68 (t, J = 5.9 Hz, 2H), 2.28 (s, 3H), 2.49-2.55 (m, 4H), 2.65 (t, J = 6.6 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H),  3.58-3.76 (m, 20H), 7.43-7.51 (m, 2H), 7.55-7.61 (m, 2H), 7.92-8.07 (m, 4H),  8.21 (s, 1H), 9.40 (br s, 1H), 12.83 (br s, 1H).  ESI-MS m/z: 884, 886 (M+H)+. (E) -1- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] thiophen-2-ylcarbamoyl) phenyl) -N- (1,3-dihydroxy-2- (hydroxymethyl) propan-2-yl) -2-methyl-5,8,11-trioxa-2-azatetradecane -14-amide (compound 31)
In the same manner as in Example 16, using Compound 30 (0.150 g, 0.192 mmol) obtained in Example 30, Compound 31 (30.0 mg, 18%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.68 (t, J = 5.9 Hz, 2H), 2.28 (s, 3H), 2.49-2.55 (m, 4H), 2.65 (t, J = 6.6 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 3.58-3.76 (m, 20H), 7.43-7.51 (m, 2H), 7.55-7.61 (m, 2H), 7.92-8.07 (m, 4H), 8.21 (s, 1H), 9.40 (br s, 1H), 12.83 (br s, 1H). ESI-MS m / z: 884, 886 (M + H) + .
(E)-1-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェニル)-N-(2,3-ジヒドロキシプロピル)-2-メチル-5,8,11-トリオキサ-2-アザテトラデカン-14-アミド（化合物32）
　3-アミノ-1,2-プロパンジオールを用い、実施例31と同様にして化合物32を得た。
ESI-MS m/z: 854, 856 (M+H)+. (E) -1- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] thiophen-2-ylcarbamoyl) phenyl) -N- (2,3-dihydroxypropyl) -2-methyl-5,8,11-trioxa-2-azatetradecan-14-amide (compound 32)
Compound 32 was obtained in the same manner as in Example 31 using 3-amino-1,2-propanediol.
ESI-MS m / z: 854, 856 (M + H) + .
(E)-1-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェニル)-5,8,11-トリオキサ-2-アザテトラデカン-14-酸（化合物33）
　実施例15と同様にして、実施例28で得られた化合物28（0.475 g, 0.580 mmol）を用い、化合物33（0.375 g, 85%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.08 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 2.54 (s, 2H), 2.58 (t, J= 5.3 Hz, 2H), 2.88 (t, J = 6.0 Hz, 2H), 3.10 (t, J = 4.8 Hz, 2H), 3.58-3.78 (m, 12H), 4.34 (s, 2H), 7.54-7.61 (m, 2H), 7.79 (t, J = 7.7 Hz, 1H), 7.96 (t, J = 8.1 Hz, 1H), 8.05-8.11 (m, 3H), 8.24 (s, 1H), 9.39 (br s, 1H), 12.95 (br s, 1H).  (E) -1- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] thiophen-2-ylcarbamoyl) phenyl) -5,8,11-trioxa-2-azatetradecane-14-acid (compound 33)
In the same manner as in Example 15, Compound 33 (0.375 g, 85%) was obtained using Compound 28 (0.475 g, 0.580 mmol) obtained in Example 28.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 2.54 (s, 2H), 2.58 (t, J = 5.3 Hz, 2H ), 2.88 (t, J = 6.0 Hz, 2H), 3.10 (t, J = 4.8 Hz, 2H), 3.58-3.78 (m, 12H), 4.34 (s, 2H), 7.54-7.61 (m, 2H) , 7.79 (t, J = 7.7 Hz, 1H), 7.96 (t, J = 8.1 Hz, 1H), 8.05-8.11 (m, 3H), 8.24 (s, 1H), 9.39 (br s, 1H), 12.95 (br s, 1H).
((E)-1-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェニル)-N-(1,3-ジヒドロキシ-2-(ヒドロキシメチル)プロパン-2-イル)-5,8,11-トリオキサ-2-アザテトラデカン-14-アミド（化合物34）
　実施例16と同様にして、実施例33で得られた化合物33（70 mg, 0.091 mmol）を用い、化合物34（4.3 mg, 5%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.08 (s, 6H), 1.59-1.73 (m, 2H), 2.48-2.54 (m, 2H), 2.54 (s, 2H), 2.79-2.94 (m, 2H), 3.00-3.05 (m, 2H), 3.56-3.75 (m, 18H), 4.17 (s, 2H), 7.51-7.73 (m, 3H), 7.85-8.10 (m, 4H), 8.17-8.23 (m, 1H), 9.39 (br s, 1H), 12.94 (br s, 1H).  ESI-MS m/z: 870, 872 (M+H)+. ((E) -1- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) phenyl) -N- (1,3-dihydroxy-2- (hydroxymethyl) propan-2-yl) -5,8,11-trioxa-2-azatetradecane-14- Amide (Compound 34)
In the same manner as in Example 16, Compound 34 (4.3 mg, 5%) was obtained using Compound 33 (70 mg, 0.091 mmol) obtained in Example 33.
1 H-NMR (400 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.59-1.73 (m, 2H), 2.48-2.54 (m, 2H), 2.54 (s, 2H), 2.79-2.94 ( m, 2H), 3.00-3.05 (m, 2H), 3.56-3.75 (m, 18H), 4.17 (s, 2H), 7.51-7.73 (m, 3H), 7.85-8.10 (m, 4H), 8.17- 8.23 (m, 1H), 9.39 (br s, 1H), 12.94 (br s, 1H). ESI-MS m / z: 870, 872 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((2-(2-(2-((2-ジエチルアミノエチル)(メチル)アミノカルボニル)エトキシ)エトキシ)エトキシ)(メチル)アミノ)メチル)ベンズアミド（化合物35）
　N,N-ジエチル-N’-メチルエチレンジアミンを用い、実施例31と同様にして、化合物35を得た。
ESI-MS m/z: 893, 895 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3-((2- (2- (2-((2-diethylaminoethyl) (methyl) aminocarbonyl) ethoxy) ethoxy) ethoxy) (methyl) amino) methyl) benzamide (Compound 35)
Compound 35 was obtained in the same manner as in Example 31 using N, N-diethyl-N′-methylethylenediamine.
ESI-MS m / z: 893, 895 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((メチルアミノ)メチル)ベンズアミド（化合物36）
　実施例1で得られる化合物1およびメチルアミンを用い、実施例24と同様にして、化合物36（190 mg, 19%）を得た。
1H-NMR（270 MHz, CDCl3, δ）: 1.07 (s, 6H), 1.69 (t, J = 6.3 Hz, 2H), 2.49-2.53 (m, 5H), 2.88 (t, J = 6.3 Hz, 2H), 3.88 (s, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.56-7.59 (m, 2H), 7.93-8.04 (m, 4H), 8.23 (s, 1H).  (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3-((methylamino) methyl) benzamide (Compound 36)
Using Compound 1 obtained in Example 1 and methylamine, Compound 36 (190 mg, 19%) was obtained in the same manner as Example 24.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.69 (t, J = 6.3 Hz, 2H), 2.49-2.53 (m, 5H), 2.88 (t, J = 6.3 Hz , 2H), 3.88 (s, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.56-7.59 (m, 2H), 7.93-8.04 (m, 4H), 8.23 (s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((N-メチル-3-ピペリジン-1-イル)プロパンアミド)メチル)ベンズアミド（化合物37）
　実施例36で得られる化合物36を用い、実施例23と同様にして、化合物37（160 mg, 81%）を得た。
1H-NMR（300 MHz, CDCl3, δ）: 1.07 (s, 6H), 1.40-1.58 (m, 6H), 1.66-1.71 (m, 2H), 2.35 (s, 2H), 2.36-2.44 (m, 4H), 2.53-2.81 (m, 4H), 2.86-2.91 (m, 2H), 2.97-2.98 (m, 3H), 4.65-4.68 (m, 2H), 7.46-7.59 (m, 3H), 7.90-7.98 (m, 3H), 8.04-8.06 (m, 1H), 8.25-8.29 (m, 1H).  ESI-MS m/z: 716, 718 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3-((N-methyl-3-piperidin-1-yl) propanamido) methyl) benzamide (Compound 37)
Using Compound 36 obtained in Example 36, Compound 37 (160 mg, 81%) was obtained in the same manner as Example 23.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.40-1.58 (m, 6H), 1.66-1.71 (m, 2H), 2.35 (s, 2H), 2.36-2.44 ( m, 4H), 2.53-2.81 (m, 4H), 2.86-2.91 (m, 2H), 2.97-2.98 (m, 3H), 4.65-4.68 (m, 2H), 7.46-7.59 (m, 3H), 7.90-7.98 (m, 3H), 8.04-8.06 (m, 1H), 8.25-8.29 (m, 1H). ESI-MS m / z: 716, 718 (M + H) + .
(E)-3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)安息香酸（化合物38）
　参考例1で得られる化合物ａ（1.00 g, 2.33 mmol）をジクロロメタン（25 mL）に懸濁させ、ピリジン（0.376 mL, 4.65 mmol）および3-(クロロカルボニル)安息香酸メチル（0.693 g, 3.49 mmol）を加え、室温で1時間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。得られた固体をメタノール（20 mL）およびTHF（8 mL）に懸濁させ、氷冷下2 mol/L 水酸化ナトリウム水溶液（5.91 mL, 11.8 mmol）を加え、室温で5時間攪拌した。溶媒を減圧下で留去し、水を加えた後、1 mol/L塩酸を用いて中和し、析出した固体をろ取することにより、化合物38（0.770 g, 57%）を得た。
1H-NMR（300 MHz, DMSO-d6, δ）: 1.07 (s, 6H), 1.51-1.56 (m, 2H), 2.51-2.55 (m, 2H), 2.72-2.77 (m, 2H), 7.61-7.75 (m, 2H), 7.92-7.96 (m, 1H), 8.09-8.16 (m, 3H), 8.41-8.47 (m, 2H).  (E) -3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-ylcarbamoyl) benzoic acid (Compound 38)
Compound a (1.00 g, 2.33 mmol) obtained in Reference Example 1 was suspended in dichloromethane (25 mL), and pyridine (0.376 mL, 4.65 mmol) and methyl 3- (chlorocarbonyl) benzoate (0.693 g, 3.49 mmol). ) And stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained solid was suspended in methanol (20 mL) and THF (8 mL), 2 mol / L aqueous sodium hydroxide solution (5.91 mL, 11.8 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 5 hr. The solvent was distilled off under reduced pressure, water was added, neutralized with 1 mol / L hydrochloric acid, and the precipitated solid was collected by filtration to give compound 38 (0.770 g, 57%).
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.07 (s, 6H), 1.51-1.56 (m, 2H), 2.51-2.55 (m, 2H), 2.72-2.77 (m, 2H), 7.61-7.75 (m, 2H), 7.92-7.96 (m, 1H), 8.09-8.16 (m, 3H), 8.41-8.47 (m, 2H).
(E)-N1-(2-(2-(2-(2-アミノエトキシ)エトキシ)エトキシ)エチル)-N3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)イソフタルアミド（化合物39）
　実施例38で得られる化合物38および1,11-ジアミノ-3,6,9-トリオキサウンデカンを用い、実施例16と同様にして、化合物39（12.0 mg, 9%）を得た。
1H-NMR（400 MHz, CDCl3, δ）: 1.06 (s, 6H), 1.66 (t, J = 6.2 Hz, 2H), 2.50 (s, 2H), 2.81 (t, J = 4.9 Hz, 2H), 2.87 (t, J = 6.2 Hz, 2H), 3.46-3.49 (m, 2H), 3.57-3.76 (m, 12H), 7.52-7.57 (m, 2H), 7.94 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 8.09 (t, J = 8.0 Hz, 2H), 8.26 (s, 1H), 8.47 (s, 1H).  ESI-MS m/z: 752 (M+H)+. (E) -N 1 - (2- (2- (2- (2- aminoethoxy) ethoxy) ethoxy) ethyl) -N 3 - (3- (2- (4- chloro-3- (trifluoromethyl) Benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) isophthalamide (Compound 39)
Compound 39 (12.0 mg, 9%) was obtained in the same manner as in Example 16 using Compound 38 obtained in Example 38 and 1,11-diamino-3,6,9-trioxaundecane.
1 H-NMR (400 MHz, CDCl 3 , δ): 1.06 (s, 6H), 1.66 (t, J = 6.2 Hz, 2H), 2.50 (s, 2H), 2.81 (t, J = 4.9 Hz, 2H ), 2.87 (t, J = 6.2 Hz, 2H), 3.46-3.49 (m, 2H), 3.57-3.76 (m, 12H), 7.52-7.57 (m, 2H), 7.94 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 8.09 (t, J = 8.0 Hz, 2H), 8.26 (s, 1H), 8.47 (s, 1H). ESI-MS m / z: 752 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((3-ヒドロキシプロピルチオ)メチル)ベンズアミド（化合物40）
　実施例1で得られる化合物1（1.83 g, 3.14 mmol）をDMF（10 mL）に溶解し、トリエチルアミン（1.01 mL, 7.23 mmol）、3-メルカプトプロパン-1-オ－ル（0.62 mL, 7.23 mmol）およびヨウ化ナトリウム（0.42 g, 3.14 mmol）を加え、室温で終夜攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（ヘプタン／酢酸エチル＝5／1）で精製することにより、化合物40（0.863 g, 43%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.04 (s, 6H), 1.65 (t, J = 5.9 Hz, 2H), 1.90-1.97 (m, 2H), 2.48 (s, 2H), 2.53 (t, J = 7.3 Hz, 2H), 2.85 (t, J = 5.9 Hz, 2H), 3.13 (br s, 1H), 3.74 (t, J = 6.8 Hz, 2H), 3.80 (s, 2H), 7.47 (t, J = 7.3 Hz, 1H), 7.52-7.56 (m, 2H), 7.86 (s, 1H), 7.91-7.95 (m, 2H), 8.07 (s, 1H), 8.14 (s, 1H), 9.36 (br s, 1H), 12.85 (br s, 1H). (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3-((3-hydroxypropylthio) methyl) benzamide (Compound 40)
Compound 1 (1.83 g, 3.14 mmol) obtained in Example 1 was dissolved in DMF (10 mL), triethylamine (1.01 mL, 7.23 mmol), 3-mercaptopropan-1-ol (0.62 mL, 7.23 mmol). ) And sodium iodide (0.42 g, 3.14 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (heptane / ethyl acetate = 5/1) to give Compound 40 (0.863 g, 43%).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.04 (s, 6H), 1.65 (t, J = 5.9 Hz, 2H), 1.90-1.97 (m, 2H), 2.48 (s, 2H), 2.53 (t, J = 7.3 Hz, 2H), 2.85 (t, J = 5.9 Hz, 2H), 3.13 (br s, 1H), 3.74 (t, J = 6.8 Hz, 2H), 3.80 (s, 2H), 7.47 (t, J = 7.3 Hz, 1H), 7.52-7.56 (m, 2H), 7.86 (s, 1H), 7.91-7.95 (m, 2H), 8.07 (s, 1H), 8.14 (s, 1H) , 9.36 (br s, 1H), 12.85 (br s, 1H).
(E)-3-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)ベンジルチオ)プロピル　4-メチルベンゼンスルフォナート（化合物41）
　実施例40で得られた化合物40（0.40 g,0.63 mmol）をピリジン（4 mL）に溶解し、p-トルエンスルホニルクロリド（0.155 g, 0.82 mmol）を加えて、0℃で2時間攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を10%塩酸で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（ヘプタン／酢酸エチル＝5／1）で精製することにより、化合物41（0.435 g, 88%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.07 (s, 6H), 1.68 (t, J = 5.9 Hz, 2H), 1.84-1.91 (m, 2H), 2.46-2.89 (m, 5H), 2.50-2.54 (m, 2H), 2.84-2.90 (m, 2H), 3.71 (s, 2H), 4.06-4.17 (m, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.42-7.52 (m, 2H), 7.54-7.59 (m, 1H), 7.76 (t, J = 7.8 Hz, 2H), 7.90-7.97 (m, 3H), 8.03 (s, 1H), 8.22 (s, 1H), 9.27 (br s, 1H), 12.94 (br s, 1H). (E) -3- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] thiophen-2-ylcarbamoyl) benzylthio) propyl 4-methylbenzenesulfonate (compound 41)
Compound 40 (0.40 g, 0.63 mmol) obtained in Example 40 was dissolved in pyridine (4 mL), p-toluenesulfonyl chloride (0.155 g, 0.82 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with 10% hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (heptane / ethyl acetate = 5/1) to give Compound 41 (0.435 g, 88%).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.68 (t, J = 5.9 Hz, 2H), 1.84-1.91 (m, 2H), 2.46-2.89 (m, 5H) , 2.50-2.54 (m, 2H), 2.84-2.90 (m, 2H), 3.71 (s, 2H), 4.06-4.17 (m, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.42-7.52 (m, 2H), 7.54-7.59 (m, 1H), 7.76 (t, J = 7.8 Hz, 2H), 7.90-7.97 (m, 3H), 8.03 (s, 1H), 8.22 (s, 1H), 9.27 (br s, 1H), 12.94 (br s, 1H).
(E)-3-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)ベンジルスルフォニル)プロピル　4-メチルベンゼンスルフォナート（化合物42）
　実施例41で得られた化合物41（0.215 g, 0.271 mmol）をジクロロメタン(2 mL）に溶解し、メタクロロ過安息香酸（0.155 g, 0.651 mmol）を加え、0℃で終夜攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を10%塩酸で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣を2-プロパノールとジイソプロピルエ－テルの混合溶媒で洗浄することにより、化合物42（0.150 g, 67%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.08 (s, 6H), 1.70 (t, J = 5.9 Hz, 2H), 2.11-2.15 (m, 2H), 2.43 (s, 3H), 2.55 (s, 2H), 2.88 (t, J = 5.9 Hz, 2H), 2.96 (t, J = 7.8 Hz, 2H), 4.14 (t, J = 5.9 Hz, 2H), 4.32 (s, 2H), 7.33 (t, J = 8.3 Hz, 2H), 7.55-7.67 (m, 3H), 7.74 (t, J = 8.3 Hz, 2H), 7.95-8.11 (m, 4H), 8.22 (s, 1H), 9.25 (br s, 1H), 13.05 (br s, 1H). (E) -3- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] thiophen-2-ylcarbamoyl) benzylsulfonyl) propyl 4-methylbenzenesulfonate (compound 42)
Compound 41 (0.215 g, 0.271 mmol) obtained in Example 41 was dissolved in dichloromethane (2 mL), metachloroperbenzoic acid (0.155 g, 0.651 mmol) was added, and the mixture was stirred at 0 ° C. overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with 10% hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with a mixed solvent of 2-propanol and diisopropyl ether to obtain Compound 42 (0.150 g, 67%).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.70 (t, J = 5.9 Hz, 2H), 2.11-2.15 (m, 2H), 2.43 (s, 3H), 2.55 (s, 2H), 2.88 (t, J = 5.9 Hz, 2H), 2.96 (t, J = 7.8 Hz, 2H), 4.14 (t, J = 5.9 Hz, 2H), 4.32 (s, 2H), 7.33 (t, J = 8.3 Hz, 2H), 7.55-7.67 (m, 3H), 7.74 (t, J = 8.3 Hz, 2H), 7.95-8.11 (m, 4H), 8.22 (s, 1H), 9.25 ( br s, 1H), 13.05 (br s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((3-(ジメチルアミノ)プロピルスルフォニル)メチル)ベンズアミド（化合物43）
　実施例42で得られた化合物42（50 mg,　0.061 mmol）をDMF（1 mL）に溶解し、ジエチルアミン（0.094 mL, 0.91 mmol）を加えて、50℃で終夜攪拌した。混合物を濃縮し、残渣をシリカゲルカラムクロマトグラフィ－（クロロホルム／メタノ－ル＝5／1）で精製することにより、化合物43（35 mg, 80%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 0.98 (t, J = 7.1 Hz, 6H), 1.07 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 1.93-2.04 (m, 2H), 2.47-2.58 (m, 8H), 2.88 (t, J = 5.9 Hz, 2H), 2.95-3.01 (m, 2H), 4.34 (s, 2H), 7.53-7.59 (m, 2H), 7.67-7.71 (m, 1H), 7.93-7.99 (m, 1H), 8.03-8.09 (m, 3H), 8.23 (s, 1H), 9.30 (br s, 1H), 13.00 (br s, 1H).
ESI-MS m/z: 725, 727 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3-((3- (dimethylamino) propylsulfonyl) methyl) benzamide (Compound 43)
Compound 42 (50 mg, 0.061 mmol) obtained in Example 42 was dissolved in DMF (1 mL), diethylamine (0.094 mL, 0.91 mmol) was added, and the mixture was stirred at 50 ° C. overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol = 5/1) to give compound 43 (35 mg, 80%).
1 H-NMR (400 MHz, CDCl 3 , δ): 0.98 (t, J = 7.1 Hz, 6H), 1.07 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 1.93-2.04 (m , 2H), 2.47-2.58 (m, 8H), 2.88 (t, J = 5.9 Hz, 2H), 2.95-3.01 (m, 2H), 4.34 (s, 2H), 7.53-7.59 (m, 2H), 7.67-7.71 (m, 1H), 7.93-7.99 (m, 1H), 8.03-8.09 (m, 3H), 8.23 (s, 1H), 9.30 (br s, 1H), 13.00 (br s, 1H).
ESI-MS m / z: 725, 727 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-2-(((3-(ジメチルアミノ)プロピル)(メチル)アミノ)メチル)イソニコチンアミド（化合物44）
工程1：WO03/043636に記載の方法で得た2-(クロロメチル)イソニコチン酸メチル（300 mg, 1.62 mmol）をTHF（20 mL）に溶解し、(3-(ジエチルアミノ)プロピル)(メチル)アミン（466 mg, 3.23 mmol）を加え、還流下、5時間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、2-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)イソニコチン酸メチル（396 mg, 84%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.01 (t, J = 7.1 Hz, 6H), 1.64-1.75 (m, 2H), 2.22 (s, 3H), 2.43-2.56 (m, 8H), 3.71 (s, 2H), 3.95 (s, 3H), 7.71 (dd, J = 5.3, 1.6 Hz, 1H), 7.97 (s, 1H), 8.69 (dd, J = 5.3, 0.8 Hz, 1H).
工程2：工程1で得られた2-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)イソニコチン酸メチル（390 mg, 1.33 mmol）を50%エタノール水溶液（4 mL）に溶解し、水酸化リチウム・一水和物（112 mg, 2.66 mmol）を加え、室温で終夜撹拌した。混合物に3 mol/L塩酸を加え、クロロホルム／2-プロパノール（6／1）で抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、2-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)イソニコチン酸（371 mg, 定量的）を得た。
1H-NMR (270 MHz, CDCl3, δ): 0.89 (t, J= 7.1 Hz, 6H), 1.52-1.63 (m, 2H), 2.03 (s, 3H), 2.29-2.43 (m, 8H), 3.47 (s, 2H), 4.18 (br s, 1H), 7.58-7.63 (m, 1H), 7.82 (br s, 1H), 8.27-8.31 (m, 1H).
工程3：工程2で得られた2-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)イソニコチン酸（180 mg, 0.644 mmol）と参考例1で得られる化合物ａ（100 mg, 0.233 mmol）をジクロロメタン（3 mL）に溶解し、4-ジメチルアミノピリジン（56.8 mg, 0.465 mmol）および2,4,6-トリクロロ安息香酸クロリド（113 mg, 0.465 mmol）を加え、室温で終夜攪拌した。混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下で留去し、残渣をNHシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、化合物44（81.3 mg, 51%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.01 (t, J = 7.1 Hz, 6H), 1.07 (s, 6H), 1.66-1.76 (m, 4H), 2.28 (s, 3H), 2.46-2.63 (m, 10H), 2.90 (t, J = 5.7 Hz, 2H), 3.75 (s, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.71 (dd, J= 5.1, 1.8 Hz, 1H), 7.94-8.03 (m, 3H), 8.27 (s, 1H), 8.73 (d, J = 5.1 Hz, 1H).  ESI-MS m/z: 691, 693 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -2-(((3- (dimethylamino) propyl) (methyl) amino) methyl) isonicotinamide (Compound 44)
Step 1: Methyl 2- (chloromethyl) isonicotinate (300 mg, 1.62 mmol) obtained by the method described in WO03 / 043636 is dissolved in THF (20 mL), and (3- (diethylamino) propyl) (methyl ) Amine (466 mg, 3.23 mmol) was added and stirred under reflux for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain methyl 2-(((3- (diethylamino) propyl) (methyl) amino) methyl) isonicotinate (396 mg, 84%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.01 (t, J = 7.1 Hz, 6H), 1.64-1.75 (m, 2H), 2.22 (s, 3H), 2.43-2.56 (m, 8H) , 3.71 (s, 2H), 3.95 (s, 3H), 7.71 (dd, J = 5.3, 1.6 Hz, 1H), 7.97 (s, 1H), 8.69 (dd, J = 5.3, 0.8 Hz, 1H).
Step 2: Dissolve methyl 2-(((3- (diethylamino) propyl) (methyl) amino) methyl) isonicotinate (390 mg, 1.33 mmol) obtained in Step 1 in 50% aqueous ethanol (4 mL) Lithium hydroxide monohydrate (112 mg, 2.66 mmol) was added, and the mixture was stirred overnight at room temperature. 3 mol / L hydrochloric acid was added to the mixture, and the mixture was extracted with chloroform / 2-propanol (6/1). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to give 2-(((3- (diethylamino) propyl) (methyl) amino) methyl) isonicotinic acid (371 mg, quantitative) Got.
1 H-NMR (270 MHz, CDCl 3 , δ): 0.89 (t, J = 7.1 Hz, 6H), 1.52-1.63 (m, 2H), 2.03 (s, 3H), 2.29-2.43 (m, 8H) , 3.47 (s, 2H), 4.18 (br s, 1H), 7.58-7.63 (m, 1H), 7.82 (br s, 1H), 8.27-8.31 (m, 1H).
Step 3: 2-((((3- (Diethylamino) propyl) (methyl) amino) methyl) isonicotinic acid (180 mg, 0.644 mmol) obtained in Step 2 and compound a (100 mg) obtained in Reference Example 1 , 0.233 mmol) was dissolved in dichloromethane (3 mL) and 4-dimethylaminopyridine (56.8 mg, 0.465 mmol) and 2,4,6-trichlorobenzoic acid chloride (113 mg, 0.465 mmol) were added. Stir. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (chloroform / methanol = 9/1) to obtain Compound 44 (81.3 mg, 51%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.01 (t, J = 7.1 Hz, 6H), 1.07 (s, 6H), 1.66-1.76 (m, 4H), 2.28 (s, 3H), 2.46 -2.63 (m, 10H), 2.90 (t, J = 5.7 Hz, 2H), 3.75 (s, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 5.1, 1.8 Hz, 1H), 7.94-8.03 (m, 3H), 8.27 (s, 1H), 8.73 (d, J = 5.1 Hz, 1H). ESI-MS m / z: 691, 693 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-1-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エチル)-6-オキソ-1,6-ジヒドロピリジン-3-カルボキサミド（化合物45）
工程1：6-ヒドロキシイソニコチン酸ベンジル（608 mg, 2.65 mmol）をDMF（20 mL）に溶解し、水素化ナトリウム（138 mg, 3.45 mol）および2-(2-(2-クロロエトキシ)エトキシ)エタノール（894 mg, 5.30 mmol）を加え、50℃で5時間攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、1-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エチル)-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸ベンジル（296 mg, 31%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 3.49-3.53 (m, 2H), 3.56-3.60 (m, 4H), 3.63-3.71 (m, 2H), 3.80 (t, J = 4.9 Hz, 2H), 4.17 (t, J = 4.9 Hz, 2H), 5.30 (s, 2H), 6.52 (d, J = 9.5 Hz, 1H), 7.33-7.43 (m, 5H), 7.88 (dd, J = 9.5, 2.6 Hz, 1H), 8.33 (d, J = 2.6 Hz, 1H).
工程2：工程１で得られた1-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エチル)-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸ベンジル（295 mg, 0.816 mmol）をDMF（5 mL）に溶解し、トリエチルアミン（0.228 mL, 1.63 mol）およびメタンスルホニルクロリド（0.127 mL, 1.63 mmol）を加え、室温で終夜攪拌した後、100℃でさらに2時間攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、1-(2-(2-(2-クロロエトキシ)エトキシ)エチル)-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸ベンジル（223 mg, 72%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 3.51-3.58 (m, 6H), 3.62-3.66 (m, 2H), 3.78 (t, J = 4.9 Hz, 2H), 4.17 (t, J = 4.9 Hz, 2H), 5.30 (s, 2H), 6.52 (d, J = 9.5 Hz, 1H), 7.33-7.43 (m, 5H), 7.88 (dd, J = 9.5, 2.6 Hz, 1H), 8.29 (d, J = 2.6 Hz, 1H).
工程3：工程2で得られた1-(2-(2-(2-クロロエトキシ)エトキシ)エチル)-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸ベンジル（223 mg, 0.587 mmol）をDMF（5 mL）に溶解し、2-ジエチルアミン（1.84 mL, 17.6 mmol）を加え、100℃で終夜攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、1-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エチル)-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸ベンジル（245 mg, 定量的）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.01 (t, J= 7.1 Hz, 6H), 2.50-2.62 (m, 6H), 3.46-3.59 (m, 6H), 3.77 (t, J = 4.9 Hz, 2H), 4.16 (t, J = 4.9 Hz, 2H), 5.30 (s, 2H), 6.52 (d, J = 9.5 Hz, 1H), 7.32-7.42 (m, 5H), 7.88 (dd, J = 9.5, 2.6 Hz, 1H), 8.30 (d, J = 2.6 Hz, 1H).
工程4：工程3で得られた1-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エチル)-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸ベンジル（244 mg, 0.587 mmol）をエタノールに溶解し、パラジウム炭素（82.0 mg）を加え、水素雰囲気下室温で2時間攪拌した。混合物をろ過し、ろ液の溶媒を減圧下で留去することにより、1-(2-(2-(2-(ジエチルアミノエトキシ)エトキシ)エチル-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸（158 mg, 82%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.31 (t, J= 7.1 Hz, 6H), 3.11-3.19 (m, 6H), 3.54-3.60 (m, 4H), 3.75 (t, J = 4.6 Hz, 2H), 3.85 (t, J = 5.1 Hz, 2H), 4.17 (t, J = 4.6 Hz, 2H), 5.11 (br s, 1H), 6.49 (d, J = 9.2 Hz, 1H), 7.97 (dd, J = 9.2, 2.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H).
工程5：工程4で得られた1-(2-(2-(2-(ジエチルアミノエトキシ)エトキシ)エチル-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸を用い、実施例6の工程3と同様にして化合物45（67.0 mg, 38%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.04 (t, J = 7.1 Hz, 6H), 1.07 (s, 6H), 1.68 (t, J = 6.0 Hz, 2H), 2.51 (s, 2H), 2.57-2.72 (m, 8H), 3.49-3.59 (m, 6H), 3.77-3.86 (m, 2H), 4.23 (t, J = 4.8 Hz, 2H), 6.61 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.83-7.98 (m, 2H), 8.06 (d, J = 2.2 Hz, 1H), 8.26-8.33 (m, 2H).  ESI-MS m/z: 738, 740 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -1- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxamide (Compound 45)
Step 1: Benzyl 6-hydroxyisonicotinate (608 mg, 2.65 mmol) is dissolved in DMF (20 mL), sodium hydride (138 mg, 3.45 mol) and 2- (2- (2-chloroethoxy) ethoxy ) Ethanol (894 mg, 5.30 mmol) was added and stirred at 50 ° C. for 5 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give benzyl 1- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxylate (296 mg, 31%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 3.49-3.53 (m, 2H), 3.56-3.60 (m, 4H), 3.63-3.71 (m, 2H), 3.80 (t, J = 4.9 Hz, 2H), 4.17 (t, J = 4.9 Hz, 2H), 5.30 (s, 2H), 6.52 (d, J = 9.5 Hz, 1H), 7.33-7.43 (m, 5H), 7.88 (dd, J = 9.5 , 2.6 Hz, 1H), 8.33 (d, J = 2.6 Hz, 1H).
Step 2: Benzyl 1- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 1 (295 mg, 0.816 mmol) Was dissolved in DMF (5 mL), triethylamine (0.228 mL, 1.63 mol) and methanesulfonyl chloride (0.127 mL, 1.63 mmol) were added, and the mixture was stirred at room temperature overnight, and further stirred at 100 ° C. for 2 hr. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to give 1- (2- (2- (2-chloroethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine- Benzyl 3-carboxylate (223 mg, 72%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 3.51-3.58 (m, 6H), 3.62-3.66 (m, 2H), 3.78 (t, J = 4.9 Hz, 2H), 4.17 (t, J = 4.9 Hz, 2H), 5.30 (s, 2H), 6.52 (d, J = 9.5 Hz, 1H), 7.33-7.43 (m, 5H), 7.88 (dd, J = 9.5, 2.6 Hz, 1H), 8.29 ( d, J = 2.6 Hz, 1H).
Step 3: Benzyl 1- (2- (2- (2-chloroethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 2 (223 mg, 0.587 mmol) Was dissolved in DMF (5 mL), 2-diethylamine (1.84 mL, 17.6 mmol) was added, and the mixture was stirred at 100 ° C. overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give 1- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxylic acid Benzyl acid (245 mg, quantitative) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.01 (t, J = 7.1 Hz, 6H), 2.50-2.62 (m, 6H), 3.46-3.59 (m, 6H), 3.77 (t, J = 4.9 Hz, 2H), 4.16 (t, J = 4.9 Hz, 2H), 5.30 (s, 2H), 6.52 (d, J = 9.5 Hz, 1H), 7.32-7.42 (m, 5H), 7.88 (dd, J = 9.5, 2.6 Hz, 1H), 8.30 (d, J = 2.6 Hz, 1H).
Step 4: benzyl 1- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 3 (244 mg, 0.587 mmol) was dissolved in ethanol, palladium carbon (82.0 mg) was added, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The mixture was filtered and the filtrate's solvent was removed under reduced pressure to give 1- (2- (2- (2- (diethylaminoethoxy) ethoxy) ethyl-6-oxo-1,6-dihydropyridine-3- Carboxylic acid (158 mg, 82%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.31 (t, J = 7.1 Hz, 6H), 3.11-3.19 (m, 6H), 3.54-3.60 (m, 4H), 3.75 (t, J = 4.6 Hz, 2H), 3.85 (t, J = 5.1 Hz, 2H), 4.17 (t, J = 4.6 Hz, 2H), 5.11 (br s, 1H), 6.49 (d, J = 9.2 Hz, 1H), 7.97 (dd, J = 9.2, 2.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H).
Step 5: Step of Example 6 using 1- (2- (2- (2- (diethylaminoethoxy) ethoxy) ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid) obtained in Step 4 In the same manner as in 3, compound 45 (67.0 mg, 38%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.04 (t, J = 7.1 Hz, 6H), 1.07 (s, 6H), 1.68 (t, J = 6.0 Hz, 2H), 2.51 (s, 2H ), 2.57-2.72 (m, 8H), 3.49-3.59 (m, 6H), 3.77-3.86 (m, 2H), 4.23 (t, J = 4.8 Hz, 2H), 6.61 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.83-7.98 (m, 2H), 8.06 (d, J = 2.2 Hz, 1H), 8.26-8.33 (m, 2H). ESI-MS m / z: 738, 740 (M + H) + .
(E)-2-((3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)ベンジル)(3-ヒドロキシプロピル)アミノ)酢酸ベンジル（化合物46）
工程１：3-アミノプロパン-1-オール（24.6 g, 327 mmol）をジクロロメタン（30 mL）に溶解し、氷冷下ジクロロメタン（50 mL）に溶解した2-ブロモ酢酸ベンジル（5.00 g, 21.8 mmol）を滴下した。室温で30分間攪拌した後、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下で留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、2-(3-ヒドロキシプロピルアミノ)酢酸ベンジル（2.23 g, 46%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.67-1.75 (m, 2H), 2.86 (t, J = 5.9 Hz, 2H), 3.46 (s, 2H), 3.80 (t, J = 5.9 Hz, 2H), 5.17 (s, 2H), 7.33-7.41(m, 5H).
工程2：工程1で得られた2-(3-ヒドロキシプロピルアミノ)酢酸ベンジルを用い、実施例18の工程3と同様にして、化合物46（0.610 g, 31%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.08 (s, 6H), 1.52 (t, J = 1.0 Hz, 2H), 1.70 (t, J = 5.8 Hz, 2H), 1.80 (t, J = 5.8 Hz, 2H), 2.54 (s, 2H), 2.80-2.90 (m, 4H), 3.36 (s, 2H), 3.83 (s, 2H), 4.18 (s, 1H), 5.15 (s, 2H), 7.31-7.33 (m, 5H), 7.45 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 8.7 Hz, 2H), 7.97-8.00 (m, 3H), 8.10 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 3.9 Hz, 1H), 9.22 (s, 1H), 12.93 (s, 1H). (E) -2-((3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] Thiophen-2-ylcarbamoyl) benzyl) (3-hydroxypropyl) amino) acetic acid benzyl (compound 46)
Step 1: 3-Aminopropan-1-ol (24.6 g, 327 mmol) dissolved in dichloromethane (30 mL) and 2-bromobenzyl acetate (5.00 g, 21.8 mmol) dissolved in dichloromethane (50 mL) under ice cooling ) Was added dropwise. After stirring at room temperature for 30 minutes, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to give benzyl 2- (3-hydroxypropylamino) acetate (2.23 g, 46% )
1 H-NMR (270 MHz, CDCl 3 , δ): 1.67-1.75 (m, 2H), 2.86 (t, J = 5.9 Hz, 2H), 3.46 (s, 2H), 3.80 (t, J = 5.9 Hz , 2H), 5.17 (s, 2H), 7.33-7.41 (m, 5H).
Step 2: Compound 46 (0.610 g, 31%) was obtained in the same manner as in Step 3 of Example 18 using benzyl 2- (3-hydroxypropylamino) acetate obtained in Step 1.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.52 (t, J = 1.0 Hz, 2H), 1.70 (t, J = 5.8 Hz, 2H), 1.80 (t, J = 5.8 Hz, 2H), 2.54 (s, 2H), 2.80-2.90 (m, 4H), 3.36 (s, 2H), 3.83 (s, 2H), 4.18 (s, 1H), 5.15 (s, 2H) , 7.31-7.33 (m, 5H), 7.45 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 8.7 Hz, 2H), 7.97-8.00 (m, 3H), 8.10 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 3.9 Hz, 1H), 9.22 (s, 1H), 12.93 (s, 1H).
(E)-2-((3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)ベンジル)(3-ヒドロキシプロピル)アミノ)酢酸（化合物47）
　実施例46で得られる化合物46を用い、実施例18の工程2と同様にして、化合物47（0.328 mg, 61%）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 1.02 (s, 6H), 1.53 (t, J = 6.0 Hz, 2H), 1.60 (t, J = 7.0 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.76 (s, 2H), 3.22 (s, 4H), 3.43 (t, J = 6.4 Hz, 3H), 3.81 (s, 2H), 7.47 (t, J= 7.7 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.73-7.76 (m, 2H), 7.85 (s, 1H), 7.96 (d, J = 6.6 Hz, 1H), 8.10 (s, 1H), 8.42 (s, 1H).  ESI-MS m/z: 679 (M+H)+. (E) -2-((3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) benzyl) (3-hydroxypropyl) amino) acetic acid (compound 47)
Using Compound 46 obtained in Example 46, Compound 47 (0.328 mg, 61%) was obtained in the same manner as in Step 2 of Example 18.
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.02 (s, 6H), 1.53 (t, J = 6.0 Hz, 2H), 1.60 (t, J = 7.0 Hz, 2H), 2.66 (t , J = 7.0 Hz, 2H), 2.76 (s, 2H), 3.22 (s, 4H), 3.43 (t, J = 6.4 Hz, 3H), 3.81 (s, 2H), 7.47 (t, J = 7.7 Hz , 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.73-7.76 (m, 2H), 7.85 (s, 1H), 7.96 (d, J = 6.6 Hz, 1H), 8.10 (s, 1H) , 8.42 (s, 1H). ESI-MS m / z: 679 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((2-(ジエチルアミノ)エチルアミノ)メチル)ベンズアミド（化合物48）
　N,N-ジエチルエチレンジアミンを用い、実施例24と同様にして、化合物48（0.125 mg, 55%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.00 (t, J = 7.1 Hz, 6H), 1.08 (s, 6H), 1.70 (t, J = 6.3 Hz, 2H), 2.47-2.56 (m, 7H), 2.59 (d, J = 5.5 Hz, 2H), 2.69 (dd, J = 9.5, 3.3 Hz, 2H), 2.88 (t, J = 6.0 Hz, 2H), 3.90 (s, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.57-7.57 (m, 1H), 7.59-7.61 (m, 1H), 7.91-7.97 (m, 2H), 7.99 (s, 1H), 8.05 (d, J = 1.8 Hz, 1H), 8.23 (s, 1H), 9.23 (s, 1H), 12.92 (s, 1H). (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-yl) -3-((2- (diethylamino) ethylamino) methyl) benzamide (Compound 48)
Compound 48 (0.125 mg, 55%) was obtained in the same manner as in Example 24 using N, N-diethylethylenediamine.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.00 (t, J = 7.1 Hz, 6H), 1.08 (s, 6H), 1.70 (t, J = 6.3 Hz, 2H), 2.47-2.56 (m , 7H), 2.59 (d, J = 5.5 Hz, 2H), 2.69 (dd, J = 9.5, 3.3 Hz, 2H), 2.88 (t, J = 6.0 Hz, 2H), 3.90 (s, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.57-7.57 (m, 1H), 7.59-7.61 (m, 1H), 7.91-7.97 (m, 2H), 7.99 (s, 1H), 8.05 (d, J = 1.8 Hz, 1H), 8.23 (s, 1H), 9.23 (s, 1H), 12.92 (s, 1H).
(E)-2-((3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)ベンジル)(2-(ジエチルアミノ)エチル)アミノ)酢酸ベンジル（化合物49）
　実施例48で得られた化合物48（0.123 g, 0.186 mmol）をDMF（5 mL）に溶解し、炭酸カリウム（0.051 g, 0.371 mmol）および2-ブロモ酢酸ベンジル（0.035 mL, 0.223 mmol）を加え、室温で1時間攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝90／10）で精製することにより化合物49（0.083 g, 55%）を得た。
ESI-MS m/z: 810 (M+H)+. (E) -2-((3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] Thiophen-2-ylcarbamoyl) benzyl) (2- (diethylamino) ethyl) amino) acetic acid benzyl (Compound 49)
Compound 48 (0.123 g, 0.186 mmol) obtained in Example 48 was dissolved in DMF (5 mL), and potassium carbonate (0.051 g, 0.371 mmol) and benzyl 2-bromoacetate (0.035 mL, 0.223 mmol) were added. And stirred at room temperature for 1 hour. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 90/10) to obtain Compound 49 (0.083 g, 55%).
ESI-MS m / z: 810 (M + H) + .
(E)-2-((3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)ベンジル)(2-(ジエチルアミノ)エチル)アミノ)酢酸（化合物50）
　実施例49で得られる化合物49を用い、実施例18の工程2と同様にして、化合物50（0.042 g, 57%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.08 (s, 6H), 1.22 (t, J = 7.2 Hz, 6H), 1.68 (t, J = 6.3 Hz, 2H), 2.54 (s, 2H), 2.70 (t, J = 4.9 Hz, 2H), 2.83-2.98 (m, 8H), 3.31 (s, 2H), 3.87 (s, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.94 (t, J = 6.9 Hz, 3H), 8.06 (s, 1H), 8.27 (d, J = 3.9 Hz, 1H), 9.56 (s, 1H).  ESI-MS m/z: 679 (M+H)+. (E) -2-((3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) benzyl) (2- (diethylamino) ethyl) amino) acetic acid (compound 50)
Using compound 49 obtained in Example 49, compound 50 (0.042 g, 57%) was obtained in the same manner as in Step 2 of Example 18.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.22 (t, J = 7.2 Hz, 6H), 1.68 (t, J = 6.3 Hz, 2H), 2.54 (s, 2H ), 2.70 (t, J = 4.9 Hz, 2H), 2.83-2.98 (m, 8H), 3.31 (s, 2H), 3.87 (s, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.94 (t, J = 6.9 Hz, 3H), 8.06 (s, 1H), 8.27 (d, J = 3.9 Hz, 1H), 9.56 (s, 1H). ESI -MS m / z: 679 (M + H) + .
(E)-2-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェノキシ)酢酸メチル（化合物51）
　クロロ酢酸メチルを用い、実施例8と同様にして、化合物51（0.733 g, 65%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.08 (s, 6H), 1.70 (t, J = 6.3 Hz, 2H), 2.54 (s, 2H), 2.88 (t, J = 5.4 Hz, 2H), 3.83 (s, 3H), 4.73 (s, 2H), 7.16 (dd, J = 8.2, 2.6 Hz, 1H), 7.43 (t, J = 8.2 Hz, 1H), 7.58 (d, J= 8.6 Hz, 2H), 7.67 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 8.05 (s, 1H), 8.26 (s, 1H), 9.20 (s, 1H), 12.95 (s, 1H). (E) -2- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] Methylthiophen-2-ylcarbamoyl) phenoxy) methyl acetate (compound 51)
Compound 51 (0.733 g, 65%) was obtained in the same manner as Example 8 using methyl chloroacetate.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.70 (t, J = 6.3 Hz, 2H), 2.54 (s, 2H), 2.88 (t, J = 5.4 Hz, 2H ), 3.83 (s, 3H), 4.73 (s, 2H), 7.16 (dd, J = 8.2, 2.6 Hz, 1H), 7.43 (t, J = 8.2 Hz, 1H), 7.58 (d, J = 8.6 Hz , 2H), 7.67 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 8.05 (s, 1H), 8.26 (s, 1H), 9.20 (s, 1H), 12.95 (s, 1H).
(E)-2-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェノキシ)酢酸（化合物52）
　実施例51で得られた化合物51（0.400 g, 0.643 mmol）をメタノール（8 mL）に懸濁させ、氷冷下で2 mol/L 水酸化ナトリウム水溶液（1.61 mL, 3.22 mmol）を加え、室温で30分間攪拌した。混合物を1 mol/L塩酸を用いて中和し、析出した固体をろ取することにより、化合物52（0.319 g, 82%）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 1.02 (s, 6H), 1.53 (t, J = 6.2 Hz, 2H), 2.74 (t, J = 6.4 Hz, 2H), 4.70 (s, 3H), 7.15-7.18 (m, 1H), 7.43-7.46 (m, 4H), 7.75 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 9.5 Hz, 1H), 8.09 (s, 1H), 8.41 (s, 1H), 11.21 (s, 1H), 11.44 (s, 1H).  (E) -2- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] thiophen-2-ylcarbamoyl) phenoxy) acetic acid (compound 52)
Compound 51 (0.400 g, 0.643 mmol) obtained in Example 51 was suspended in methanol (8 mL), 2 mol / L aqueous sodium hydroxide solution (1.61 mL, 3.22 mmol) was added under ice cooling, and room temperature was added. For 30 minutes. The mixture was neutralized with 1 mol / L hydrochloric acid, and the precipitated solid was collected by filtration to give compound 52 (0.319 g, 82%).
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.02 (s, 6H), 1.53 (t, J = 6.2 Hz, 2H), 2.74 (t, J = 6.4 Hz, 2H), 4.70 (s , 3H), 7.15-7.18 (m, 1H), 7.43-7.46 (m, 4H), 7.75 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 9.5 Hz, 1H), 8.09 (s, 1H), 8.41 (s, 1H), 11.21 (s, 1H), 11.44 (s, 1H).
(E)-2-(2-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェノキシ)アセトアミド)酢酸tert-ブチル（化合物53）
　実施例52で得られる化合物52を用い、実施例16と同様にして、化合物53（0.222 g, 85%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.08 (s, 6H), 1.48 (s, 9H), 1.70 (t, J = 6.3 Hz, 2H), 2.54 (s, 2H), 2.88 (t, J = 5.9 Hz, 2H), 4.06 (d, J = 5.6 Hz, 2H), 4.61 (s, 2H), 7.11 (s, 1H), 7.16 (dd, J = 8.2, 2.6 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.66 (t, J= 2.0 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.98 (dd, J = 8.4, 1.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 4.9 Hz, 1H), 9.22 (s, 1H), 12.96 (s, 1H). (E) -2- (2- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7- Tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) phenoxy) acetamido) acetic acid tert-butyl (compound 53)
Using compound 52 obtained in Example 52, compound 53 (0.222 g, 85%) was obtained in the same manner as Example 16.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.48 (s, 9H), 1.70 (t, J = 6.3 Hz, 2H), 2.54 (s, 2H), 2.88 (t , J = 5.9 Hz, 2H), 4.06 (d, J = 5.6 Hz, 2H), 4.61 (s, 2H), 7.11 (s, 1H), 7.16 (dd, J = 8.2, 2.6 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.66 (t, J = 2.0 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.98 (dd , J = 8.4, 1.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 4.9 Hz, 1H), 9.22 (s, 1H), 12.96 (s, 1H).
(E)-2-(2-(3-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)フェノキシ)アセトアミド)酢酸（化合物54）
　実施例53で得られる化合物53を用い、実施例15と同様にして、化合物54（0.161 g, 定量的）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 1.02 (s, 6H), 1.52 (t, J = 6.2 Hz, 2H), 2.75-2.78 (m, 3H), 3.80 (d, J = 5.9 Hz, 2H), 4.58 (s, 2H), 7.20 (d, J= 6.2 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 7.7 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.09 (s, 2H), 8.42 (s, 1H).  ESI-MS m/z: 663 (M+H)+. (E) -2- (2- (3- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7- Tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) phenoxy) acetamido) acetic acid (compound 54)
Compound 54 (0.161 g, quantitative) was obtained in the same manner as Example 15 using Compound 53 obtained in Example 53.
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.02 (s, 6H), 1.52 (t, J = 6.2 Hz, 2H), 2.75-2.78 (m, 3H), 3.80 (d, J = 5.9 Hz, 2H), 4.58 (s, 2H), 7.20 (d, J = 6.2 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 7.7 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.09 (s, 2H), 8.42 (s, 1H). ESI-MS m / z: 663 (M + H) + .
(E)-4-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)-2-(7-エトキシ-7-オキソヘプチルオキシ)安息香酸メチル（化合物55）
工程1：4-ブロモ-2-ヒドロキシ安息香酸（3.00 g,  13.8 mmol）をトルエン（30 mL）およびメタノール（30 mL）に懸濁させ、氷冷下2.0 mol/Lトリメチルシリルジアゾメタンヘキサン溶液（17.3 mL, 34.6 mmol）を滴下し、2時間攪拌した。減圧下で溶媒を留去した後、2 mol/L 水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化アンモニウムおよび飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝4／1）で精製することにより、4-ブロモ-2-ヒドロキシ安息香酸メチル（1.67 g, 52%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 3.95 (s, 3H), 7.03 (dd, J = 8.6, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 10.83 (s, 1H).
工程2：工程1で得られた4-ブロモ-2-ヒドロキシ安息香酸メチルを用い、実施例8の工程1と同様にして、4-ブロモ-2-(7-エトキシ-7-オキソヘプチルオキシ)安息香酸メチル（0.865 g, 86%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.25 (t, J = 7.1 Hz, 3H), 1.38-1.43 (m, 2H), 1.49-1.54 (m, 2H), 1.62-1.72 (m, 2H), 1.79-1.89 (m, 2H), 2.31 (t, J = 7.5 Hz, 2H), 3.87 (s, 3H), 4.01 (t, J = 6.4 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 7.09-7.12 (m, 2H), 7.66 (dd, J = 6.6, 2.2 Hz, 1H).
工程3：工程2で得られた4-ブロモ-2-(7-エトキシ-7-オキソヘプチルオキシ)安息香酸メチル（0.865 g, 2.23 mmol）、1,1’-ビス(ジフェニルホスフィノ)フェロセン　パラジウム(II)ジクロリド-ジクロロメタン錯体（0.182 g, 0.232 mmol）、1,1’-ビス(ジフェニルホスフィノ）フェロセン（0.124 g, 0.223 mmol）および酢酸カリウム（1.10 g, 11.2 mmol）をDMSO（15 mL）に溶解し、一酸化炭素雰囲気下、80℃で3時間攪拌した。混合物を塩酸で酸性とした後、水およびメタノールを加えて析出した固体をろ取した。得られた固体をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝95／5）で精製することにより、3-(7-エトキシ-7-オキソヘプチルオキシ)-4-(メトキシカルボニル)安息香酸（0.604 g, 77%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.25 (dd, J = 7.6, 6.6 Hz, 3H), 1.42-1.45 (m, 2H), 1.50-1.55 (m, 2H), 1.62-1.73 (m, 2H), 1.81-1.91 (m, 2H), 2.32 (t, J = 7.4 Hz, 2H), 3.92 (s, 3H), 4.08-4.17 (m, 4H), 7.66-7.69 (m, 2H), 7.81 (d, J = 7.9 Hz, 1H).
工程4：工程3で得られた3-(7-エトキシ-7-オキソヘプチルオキシ)-4-(メトキシカルボニル)安息香酸を用い、実施例6の工程3と同様にして、化合物55（0.654 g, 定量的）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.08 (s, 6H), 1.25 (t, J = 7.3 Hz, 3H), 1.42 (q, J = 7.8 Hz, 2H), 1.51-1.55 (m, 2H), 1.60-1.72 (m, 2H), 1.83-1.90 (m, 2H), 2.31 (t, J = 7.8 Hz, 2H), 2.55 (s, 2H), 2.89 (t, J = 6.3 Hz, 2H), 3.49 (d, J = 5.9 Hz, 2H), 3.92 (s, 3H), 4.10-4.16 (m, 4H), 7.58 (d, J = 8.8 Hz, 2H), 7.69 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 9.8 Hz, 1H), 8.04 (s, 1H), 8.24 (s, 1H), 9.23 (s, 1H), 13.04 (s, 1H). (E) -4- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-ylcarbamoyl) -2- (7-ethoxy-7-oxoheptyloxy) methyl benzoate (compound 55)
Step 1: Suspend 4-bromo-2-hydroxybenzoic acid (3.00 g, 13.8 mmol) in toluene (30 mL) and methanol (30 mL), and add 2.0 mol / L trimethylsilyldiazomethanehexane solution (17.3 mL) under ice-cooling. , 34.6 mmol) was added dropwise and stirred for 2 hours. The solvent was distilled off under reduced pressure, 2 mol / L aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give methyl 4-bromo-2-hydroxybenzoate (1.67 g, 52%).
1 H-NMR (300 MHz, CDCl 3 , δ): 3.95 (s, 3H), 7.03 (dd, J = 8.6, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.69 (d , J = 8.6 Hz, 1H), 10.83 (s, 1H).
Step 2: 4-bromo-2- (7-ethoxy-7-oxoheptyloxy) in the same manner as in Step 1 of Example 8 using methyl 4-bromo-2-hydroxybenzoate obtained in Step 1 Methyl benzoate (0.865 g, 86%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.25 (t, J = 7.1 Hz, 3H), 1.38-1.43 (m, 2H), 1.49-1.54 (m, 2H), 1.62-1.72 (m, 2H), 1.79-1.89 (m, 2H), 2.31 (t, J = 7.5 Hz, 2H), 3.87 (s, 3H), 4.01 (t, J = 6.4 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 7.09-7.12 (m, 2H), 7.66 (dd, J = 6.6, 2.2 Hz, 1H).
Step 3: Methyl 4-bromo-2- (7-ethoxy-7-oxoheptyloxy) benzoate (0.865 g, 2.23 mmol), 1,1'-bis (diphenylphosphino) ferrocene palladium obtained in Step 2 (II) Dichloride-dichloromethane complex (0.182 g, 0.232 mmol), 1,1'-bis (diphenylphosphino) ferrocene (0.124 g, 0.223 mmol) and potassium acetate (1.10 g, 11.2 mmol) in DMSO (15 mL) And stirred at 80 ° C. for 3 hours under a carbon monoxide atmosphere. The mixture was acidified with hydrochloric acid, water and methanol were added, and the precipitated solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (chloroform / methanol = 95/5) to give 3- (7-ethoxy-7-oxoheptyloxy) -4- (methoxycarbonyl) benzoic acid (0.604 g, 77%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.25 (dd, J = 7.6, 6.6 Hz, 3H), 1.42-1.45 (m, 2H), 1.50-1.55 (m, 2H), 1.62-1.73 ( m, 2H), 1.81-1.91 (m, 2H), 2.32 (t, J = 7.4 Hz, 2H), 3.92 (s, 3H), 4.08-4.17 (m, 4H), 7.66-7.69 (m, 2H) , 7.81 (d, J = 7.9 Hz, 1H).
Step 4: In the same manner as in Step 3 of Example 6 using 3- (7-ethoxy-7-oxoheptyloxy) -4- (methoxycarbonyl) benzoic acid obtained in Step 3, compound 55 (0.654 g , Quantitative).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.25 (t, J = 7.3 Hz, 3H), 1.42 (q, J = 7.8 Hz, 2H), 1.51-1.55 (m , 2H), 1.60-1.72 (m, 2H), 1.83-1.90 (m, 2H), 2.31 (t, J = 7.8 Hz, 2H), 2.55 (s, 2H), 2.89 (t, J = 6.3 Hz, 2H), 3.49 (d, J = 5.9 Hz, 2H), 3.92 (s, 3H), 4.10-4.16 (m, 4H), 7.58 (d, J = 8.8 Hz, 2H), 7.69 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 9.8 Hz, 1H), 8.04 (s, 1H), 8.24 (s, 1H), 9.23 (s, 1H), 13.04 (s, 1H ).
(E)-2-(6-カルボキシヘキシルオキシ)-4-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)安息香酸（化合物56）
　実施例55で得られる化合物55を用い、実施例52と同様にして化合物56（0.270 g, 44%）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 1.02 (s, 6H), 1.35-1.40 (m, 5H), 1.53-1.54 (m, 5H), 1.67-1.69 (m, 2H), 2.18 (t, J = 7.3 Hz, 2H), 2.73 (t, J = 6.2 Hz, 2H), 4.05 (t, J = 6.4 Hz, 2H), 7.46 (d, J= 7.7 Hz, 1H), 7.52 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.74 (d, J= 8.8 Hz, 1H), 7.93 (d, J = 9.9 Hz, 1H), 8.07 (s, 1H), 8.40 (s, 1H).  ESI-MS m/z: 722 (M+H)+. (E) -2- (6-Carboxyhexyloxy) -4- (3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5, 6,7-Tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) benzoic acid (Compound 56)
Compound 56 (0.270 g, 44%) was obtained in the same manner as in Example 52, using Compound 55 obtained in Example 55.
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.02 (s, 6H), 1.35-1.40 (m, 5H), 1.53-1.54 (m, 5H), 1.67-1.69 (m, 2H), 2.18 (t, J = 7.3 Hz, 2H), 2.73 (t, J = 6.2 Hz, 2H), 4.05 (t, J = 6.4 Hz, 2H), 7.46 (d, J = 7.7 Hz, 1H), 7.52 ( s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 9.9 Hz, 1H), 8.07 (s, 1H), 8.40 ( s, 1H). ESI-MS m / z: 722 (M + H) + .
(E)-4-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)-2-((3-(メトキシカルボニル)フェノキシ)メチル)安息香酸メチル（化合物57）
工程１：5-ブロモフタラジド（4.26 g, 20 mmol）および3-ヒドロキシ安息香酸メチル（3.04 g, 20 mmol）をDMF（4.3 mL）に溶解し、120℃でナトリウムメトキシド（28%メタノール溶液, 3.86 g, 20 mmol）を滴下した。反応液からメタノールを留去しつつ120℃で5時間攪拌した。混合物に水とトルエンを加え抽出した。水層を6 mol/L塩酸で酸性とし、析出した固体をろ取することにより、4-ブロモ-2-((3-(メトキシカルボニル)フェノキシ)メチル)安息香酸を得た（4.19 g, 57%）。
1H-NMR (270 MHz, DMSO-d6, δ): 3.86 (s, 3H), 5.50 (s, 2H), 7.27-7.34 (m, 1H), 7.43-7.61 (m, 3H), 7.69 (d, J = 8.8 Hz, 1H), 7.87-7.89 (m, 2H).
工程2：工程1で得られた4-ブロモ-2-((3-(メトキシカルボニル)フェノキシ)メチル)安息香酸（4.1 g, 11.2 mmol）をDMF（20 mL）に溶解し、炭酸カリウム（3.1 g, 22.5 mmol）およびヨウ化メチル（1.05 mL, 16.8 mmol）を加え、45℃で2時間攪拌した。混合物に水およびメタノールを加え、析出した固体をろ取することにより、4-ブロモ-2-((3-(メトキシカルボニル)フェノキシ)メチル)安息香酸メチルを得た（3.23 g, 76%）
1H-NMR (270 MHz, CDCl3, δ): 3.91 (s, 3H), 3.92 (s, 3H), 5.50 (s, 2H), 7.22 (d, J = 8.8 Hz, 1H), 7.38 (t, J = 8.3 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.67-7.69 (m, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H).
工程3：工程2で得られた4-ブロモ-2-((3-(メトキシカルボニル)フェノキシ)メチル)安息香酸メチル（1.14 g, 3.0 mmol）、1,1’-ビス(ジフェニルホスフィノ)フェロセン　パラジウム(II)ジクロリド　ジクロロメタン錯体（0.49 g, 0.60 mmol）、1,1’-ビス(ジフェニルホスフィノ)フェロセン（0.167 g, 0.30 mmol）および酢酸カリウム（2.95 g, 30 mmol）をDMSOに溶解し、一酸化炭素雰囲気下、80℃で12時間攪拌した。混合物を塩酸で酸性とした後、水およびメタノールを加えて析出した固体をろ取した。得られた固体をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝95／5）で精製することにより、4-(メトキシカルボニル)-3-((3-(メトキシカルボニル)フェノキシ)安息香酸を得た（0.60 g, 58%）。
1H-NMR (270 MHz, CDCl3, δ): 3.92 (s, 3H), 3.94 (s, 3H), 5.53 (s, 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.67-7.69 (m, 2H), 8.10 (s, 2H), 8.47 (s, 1H). 
工程4：工程3で得られた4-(メトキシカルボニル)-3-((3-(メトキシカルボニル)フェノキシ)安息香酸（0.144 g, 0.42 mmol）および参考例1で得られる化合物ａ（0.15 g, 0.35 mmol）をジクロロメタン（2 mL）に溶解し、4-ジメチルアミノピリジン（0.043 g, 0.35 mmol）、トリエチルアミン（0.177 g, 1.75 mmol）および2,4,6-トリクロロ安息香酸クロリド（0.17 g, 0.70 mmol）を加え、0℃で2時間攪拌した。混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下で留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム）で精製し、さらにメタノール中でリスラリーすることにより、化合物57を得た（0.10 g, 38%）。
1H-NMR (270 MHz, CDCl3, δ): 1.08 (br s, 6H), 1.70 (s, 2H), 2.55 (s, 2H), 2.89 (br s, 2H), 3.91 (s, 3H), 3.94 (s, 3H), 5.56 (s, 2H), 7.29-7.31 (m, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 8.03-8.06 (m, 2H), 8.14 (d, J = 7.8 Hz, 1H), 8.27 (s, 1H), 8.52 (s, 1H), 9.26 (br s, 1H), 13.16 (br s, 1H). (E) -4- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene -2-ylcarbamoyl) -2-((3- (methoxycarbonyl) phenoxy) methyl) methyl benzoate (Compound 57)
Step 1: 5-Bromophthalazide (4.26 g, 20 mmol) and methyl 3-hydroxybenzoate (3.04 g, 20 mmol) were dissolved in DMF (4.3 mL) and sodium methoxide (28% methanol solution, 3.86) at 120 ° C. g, 20 mmol) was added dropwise. The mixture was stirred at 120 ° C. for 5 hours while removing methanol from the reaction solution. Water and toluene were added to the mixture for extraction. The aqueous layer was acidified with 6 mol / L hydrochloric acid, and the precipitated solid was collected by filtration to give 4-bromo-2-((3- (methoxycarbonyl) phenoxy) methyl) benzoic acid (4.19 g, 57 %).
1 H-NMR (270 MHz, DMSO-d 6 , δ): 3.86 (s, 3H), 5.50 (s, 2H), 7.27-7.34 (m, 1H), 7.43-7.61 (m, 3H), 7.69 ( d, J = 8.8 Hz, 1H), 7.87-7.89 (m, 2H).
Step 2: 4-Bromo-2-((3- (methoxycarbonyl) phenoxy) methyl) benzoic acid (4.1 g, 11.2 mmol) obtained in Step 1 was dissolved in DMF (20 mL), and potassium carbonate (3.1 g, 22.5 mmol) and methyl iodide (1.05 mL, 16.8 mmol) were added, and the mixture was stirred at 45 ° C. for 2 hours. Water and methanol were added to the mixture, and the precipitated solid was collected by filtration to give methyl 4-bromo-2-((3- (methoxycarbonyl) phenoxy) methyl) benzoate (3.23 g, 76%)
1 H-NMR (270 MHz, CDCl 3 , δ): 3.91 (s, 3H), 3.92 (s, 3H), 5.50 (s, 2H), 7.22 (d, J = 8.8 Hz, 1H), 7.38 (t , J = 8.3 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.67-7.69 (m, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H).
Step 3: Methyl 4-bromo-2-((3- (methoxycarbonyl) phenoxy) methyl) benzoate obtained in Step 2 (1.14 g, 3.0 mmol), 1,1′-bis (diphenylphosphino) ferrocene Palladium (II) dichloride dichloromethane complex (0.49 g, 0.60 mmol), 1,1'-bis (diphenylphosphino) ferrocene (0.167 g, 0.30 mmol) and potassium acetate (2.95 g, 30 mmol) are dissolved in DMSO, The mixture was stirred at 80 ° C. for 12 hours in a carbon monoxide atmosphere. The mixture was acidified with hydrochloric acid, water and methanol were added, and the precipitated solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (chloroform / methanol = 95/5) to obtain 4- (methoxycarbonyl) -3-((3- (methoxycarbonyl) phenoxy) benzoic acid (0.60 g, 58%).
1 H-NMR (270 MHz, CDCl 3 , δ): 3.92 (s, 3H), 3.94 (s, 3H), 5.53 (s, 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.38 (t , J = 7.8 Hz, 1H), 7.67-7.69 (m, 2H), 8.10 (s, 2H), 8.47 (s, 1H).
Step 4: 4- (methoxycarbonyl) -3-((3- (methoxycarbonyl) phenoxy) benzoic acid (0.144 g, 0.42 mmol) obtained in Step 3 and compound a obtained in Reference Example 1 (0.15 g, 0.35 mmol) was dissolved in dichloromethane (2 mL) and 4-dimethylaminopyridine (0.043 g, 0.35 mmol), triethylamine (0.177 g, 1.75 mmol) and 2,4,6-trichlorobenzoic acid chloride (0.17 g, 0.70). mmol) and stirred for 2 hours at 0 ° C. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (chloroform), and further reslurried in methanol to obtain Compound 57 (0.10 g, 38%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.08 (br s, 6H), 1.70 (s, 2H), 2.55 (s, 2H), 2.89 (br s, 2H), 3.91 (s, 3H) , 3.94 (s, 3H), 5.56 (s, 2H), 7.29-7.31 (m, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.67 ( d, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 8.03-8.06 (m, 2H), 8.14 (d, J = 7.8 Hz, 1H), 8.27 (s, 1H), 8.52 (s, 1H), 9.26 (br s, 1H), 13.16 (br s, 1H).
(E)-2-((3-カルボキシフェノキシ)メチル)-4-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イルカルバモイル)安息香酸（化合物58）
　実施例57で得られた化合物57（0.090 g, 0.12 mmol）をメタノール（2 mL）-THF（1 mL）に溶解し、4 mol/L水酸化ナトリウム水溶液（1 mL）を加え、室温で4時間攪拌した。混合物を塩酸で酸性とし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、濃縮した。残渣をメタノール中でリスラリーすることにより、化合物58（0.077 g, 89%）を得た。
1H-NMR（270 MHz, DMSO-d6, δ）: 1.02 (s, 6H), 1.54 (br s, 2H), 2.47 (s, 2H), 2.74 (br s, 2H), 5.50 (s, 2H), 7.20-7.41 (m, 2H), 7.46-7.57 (m, 2H), 7.70 (d, J = 8.9 Hz, 1H), 7.83-8.08 (m, 4H), 8.19 (s, 1H), 8.40 (s, 1H).  ESI-MS m/z： 728 (M+H)+，750 (M+Na)+. (E) -2-((3-carboxyphenoxy) methyl) -4- (3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl-4, 5,6,7-Tetrahydrobenzo [b] thiophen-2-ylcarbamoyl) benzoic acid (Compound 58)
Compound 57 (0.090 g, 0.12 mmol) obtained in Example 57 was dissolved in methanol (2 mL) -THF (1 mL), and 4 mol / L aqueous sodium hydroxide solution (1 mL) was added. Stir for hours. The mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated. The residue was reslurried in methanol to give Compound 58 (0.077 g, 89%).
1 H-NMR (270 MHz, DMSO-d 6 , δ): 1.02 (s, 6H), 1.54 (br s, 2H), 2.47 (s, 2H), 2.74 (br s, 2H), 5.50 (s, 2H), 7.20-7.41 (m, 2H), 7.46-7.57 (m, 2H), 7.70 (d, J = 8.9 Hz, 1H), 7.83-8.08 (m, 4H), 8.19 (s, 1H), 8.40 (s, 1H). ESI-MS m / z: 728 (M + H) + , 750 (M + Na) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6,6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド（化合物59）
　実施例4で得られる化合物4（1.15 g、1.93 mmol）をTHF（20.0 mL）に溶解し、トリエチルアミン（0.404 mL、2.90 mmol）およびN1,N1-ジエチル-N3-メチルプロパン-1,3-ジアミン（0.334 g、2.32 mmol）を加え、室温で終夜撹拌した。混合物を減圧下で濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝4／1）で精製することにより化合物59（0.707 g, 52 %）を得た。
1H-NMR (400 MHz, CDCl3, δ): 0.55-0.60 (m, 4H), 1.02 (t, J = 7.1 Hz, 6H), 1.64-1.74 (m, 2H), 1.91-1.95 (m, 1H), 2.19 (s, 3H), 2.48 (m, 8H), 2.98-3.07 (m, 4H), 3.57 (s, 2H), 3.82 (s, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.57-7.58 (m, 2H), 7.90-8.04 (m, 4H), 8.20 (s, 1H).  ESI-MS m/z: 703 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-cyclopropyl-4,5,6,7-tetrahydrothieno [2, 3-c] pyridin-2-yl) -3-(((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide (Compound 59)
Compound 4 (1.15 g, 1.93 mmol) obtained in Example 4 was dissolved in THF (20.0 mL), triethylamine (0.404 mL, 2.90 mmol) and N 1 , N 1 -diethyl-N 3 -methylpropane-1, 3-Diamine (0.334 g, 2.32 mmol) was added and stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 4/1) to give Compound 59 (0.707 g, 52%).
1 H-NMR (400 MHz, CDCl 3 , δ): 0.55-0.60 (m, 4H), 1.02 (t, J = 7.1 Hz, 6H), 1.64-1.74 (m, 2H), 1.91-1.95 (m, 1H), 2.19 (s, 3H), 2.48 (m, 8H), 2.98-3.07 (m, 4H), 3.57 (s, 2H), 3.82 (s, 2H), 7.45 (t, J = 7.7 Hz, 1H ), 7.57-7.58 (m, 2H), 7.90-8.04 (m, 4H), 8.20 (s, 1H). ESI-MS m / z: 703 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-((4-(2-(ジメチルアミノ)エチル)ピペラジン-1-イル)メチル)ベンズアミド（化合物60）
　1-(2-ジメチルアミノエチル)ピペラジンを用い、実施例59と同様にして化合物60を得た。
ESI-MS m/z: 716 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3- c] Pyridin-2-yl) -3-((4- (2- (dimethylamino) ethyl) piperazin-1-yl) methyl) benzamide (Compound 60)
Compound 60 was obtained in the same manner as in Example 59, using 1- (2-dimethylaminoethyl) piperazine.
ESI-MS m / z: 716 (M + H) + .
(E)-3-(1,4’-ビピペリジン-1’-イルメチル)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)ベンズアミド（化合物61）
　4-ピペリジノピペリジンを用い、実施例59と同様にして化合物61を得た。
ESI-MS m/z: 727 (M+H)+. (E) -3- (1,4'-bipiperidin-1'-ylmethyl) -N- (3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-cyclopropyl -4,5,6,7-Tetrahydrothieno [2,3-c] pyridin-2-yl) benzamide (Compound 61)
Compound 61 was obtained in the same manner as in Example 59, using 4-piperidinopiperidine.
ESI-MS m / z: 727 (M + H) + .
(E)-(4-(3-(3-(2-(4-クロロ-3-(トリフルオロ)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イルカルバモイル)ベンジル)モルホリン-2-イル)メチルカルバミン酸tert-ブチル（化合物62）
　(モルホリン-2-イルメチル)カルバミン酸tert-ブチルを用い、実施例59と同様にして、化合物62（130 mg, 定量的）を得た。
1H-NMR (270 MHz, CDCl3, δ): 0.55-0.60 (m, 4H), 1.41 (s, 9H), 1.92-1.99 (m, 2H), 2.17-2.27 (m, 1H), 2.54-2.67 (m, 2H), 2.73-2.90 (m, 4H), 2.98-3.08 (m, 3H), 3.24-3.35 (m, 1H), 3.50-3.72 (m, 3H), 3.83-3.87 (m, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.54-7.61 (m, 2H), 7.92-8.03 (m, 4H), 8.19 (s, 1H).  ESI-MS m/z: 775, 777 (M+H)+. (E)-(4- (3- (3- (2- (4-Chloro-3- (trifluoro) benzylidene) hydrazinecarbonyl) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2 , 3-c] Pyridin-2-ylcarbamoyl) benzyl) morpholin-2-yl) methylcarbamate tert-butyl (Compound 62)
Compound 62 (130 mg, quantitative) was obtained in the same manner as in Example 59, using tert-butyl (morpholin-2-ylmethyl) carbamate.
1 H-NMR (270 MHz, CDCl 3 , δ): 0.55-0.60 (m, 4H), 1.41 (s, 9H), 1.92-1.99 (m, 2H), 2.17-2.27 (m, 1H), 2.54- 2.67 (m, 2H), 2.73-2.90 (m, 4H), 2.98-3.08 (m, 3H), 3.24-3.35 (m, 1H), 3.50-3.72 (m, 3H), 3.83-3.87 (m, 2H ), 7.46 (t, J = 7.6 Hz, 1H), 7.54-7.61 (m, 2H), 7.92-8.03 (m, 4H), 8.19 (s, 1H). ESI-MS m / z: 775, 777 ( M + H) + .
(E)-3-((2-(アミノメチル)モルホリノ)メチル)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)ベンズアミド（化合物63）
　実施例62で得られた化合物62（120 mg, 0.155 mmol）をクロロホルム（2 mL）に溶解し、トリフルオロ酢酸（0.5 mL）を加え、室温で30分間攪拌した。溶媒を減圧下で留去した後、残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥し、濃縮した。残渣をNHシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、化合物63（69.0 mg, 66%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 0.49-0.60 (m, 4H), 1.89-2.04 (m, 3H), 2.17-2.25 (m, 1H), 2.70-2.72 (m, 3H), 2.98-3.06 (m, 4H), 3.54-3.90 (m, 7H), 7.46 (t, J = 7.7 Hz, 1H), 7.56-7.61 (m, 2H), 7.91-8.03 (m, 4H), 8.20-8.21 (m, 1H).  ESI-MS m/z: 675, 677 (M+H)+. (E) -3-((2- (aminomethyl) morpholino) methyl) -N- (3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-cyclopropyl- 4,5,6,7-Tetrahydrothieno [2,3-c] pyridin-2-yl) benzamide (Compound 63)
Compound 62 (120 mg, 0.155 mmol) obtained in Example 62 was dissolved in chloroform (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 30 min. After the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by NH silica gel column chromatography (chloroform / methanol = 9/1) to give Compound 63 (69.0 mg, 66%).
1 H-NMR (300 MHz, CDCl 3 , δ): 0.49-0.60 (m, 4H), 1.89-2.04 (m, 3H), 2.17-2.25 (m, 1H), 2.70-2.72 (m, 3H), 2.98-3.06 (m, 4H), 3.54-3.90 (m, 7H), 7.46 (t, J = 7.7 Hz, 1H), 7.56-7.61 (m, 2H), 7.91-8.03 (m, 4H), 8.20- 8.21 (m, 1H). ESI-MS m / z: 675, 677 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-((2-((ジエチルアミノ)メチル)モルホリノ)メチル)ベンズアミド（化合物64）
　実施例63で得られた化合物63（32.0 mg, 0.0474 mmol）を1,2-ジクロロエタン（3 mL）に溶解し、アセトアルデヒド（20.1 mg, 0.474 mmol）および水素化ホウ素ナトリウム（30.1 mg, 0.142 mmol）を加え、室温で2時間攪拌した。溶媒を減圧下で留去し、得られた残渣をNHシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、化合物64（6.90 mg, 20%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 0.56-0.60 (m, 4H), 1.00 (t, J = 7.1 Hz, 6H), 1.86-1.97 (m, 2H), 2.14-2.36 (m, 2H), 2.52-2.88 (m, 7H), 2.98-3.07 (m, 4H), 3.52-3.71 (m, 4H), 3.83-3.87 (m, 3H), 7.46 (t, J = 7.7 Hz, 1H), 7.56-7.59 (m, 2H), 7.91-8.04 (m, 4H), 8.20 (s, 1H), 9.07 (br s, 1H), 12.8 (br s, 1H).  ESI-MS m/z: 731, 733 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3- c] Pyridin-2-yl) -3-((2-((diethylamino) methyl) morpholino) methyl) benzamide (Compound 64)
Compound 63 (32.0 mg, 0.0474 mmol) obtained in Example 63 was dissolved in 1,2-dichloroethane (3 mL), acetaldehyde (20.1 mg, 0.474 mmol) and sodium borohydride (30.1 mg, 0.142 mmol). And stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (chloroform / methanol = 9/1) to obtain Compound 64 (6.90 mg, 20%).
1 H-NMR (300 MHz, CDCl 3 , δ): 0.56-0.60 (m, 4H), 1.00 (t, J = 7.1 Hz, 6H), 1.86-1.97 (m, 2H), 2.14-2.36 (m, 2H), 2.52-2.88 (m, 7H), 2.98-3.07 (m, 4H), 3.52-3.71 (m, 4H), 3.83-3.87 (m, 3H), 7.46 (t, J = 7.7 Hz, 1H) , 7.56-7.59 (m, 2H), 7.91-8.04 (m, 4H), 8.20 (s, 1H), 9.07 (br s, 1H), 12.8 (br s, 1H). ESI-MS m / z: 731 , 733 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-((3-(ジエチルアミノ)プロピルアミノ)メチル)ベンズアミド（化合物65）
　実施例4で得られる化合物4（0.0313 g, 0.0530 mmol）をアセトニトリル（1.00 mL）に溶解し、フッ化カリウム（0.0150 g, 0.131 mmol）およびN1,N1-ジエチルプロパン-1,3-ジアミン（0.0200 mL, 0.126 mmol）を加え、5時間還流した。反応液をセライトを通してろ過し、ろ液を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／4% アンモニア含有メタノール＝4／1）で精製することにより、化合物65（0.0270 g, 75%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 0.53-0.58 (m, 4H), 1.01 (t, J = 7.1 Hz, 6H), 1.64-1.73 (m, 2H), 1.88-1.95 (m, 1H), 2.48-2.54 (m, 6H), 2.68 (t, J = 6.8 Hz, 2H), 2.98-3.03 (m, 4H), 3.80 (s, 2H), 3.87 (s, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.56 (dd, J = 8.0, 3.2 Hz, 2H), 7.92-7.95 (m, 3H), 8.02 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H).  (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3- c] Pyridin-2-yl) -3-((3- (diethylamino) propylamino) methyl) benzamide (Compound 65)
Compound 4 (0.0313 g, 0.0530 mmol) obtained in Example 4 was dissolved in acetonitrile (1.00 mL), and potassium fluoride (0.0150 g, 0.131 mmol) and N 1 , N 1 -diethylpropane-1,3-diamine were dissolved. (0.0200 mL, 0.126 mmol) was added and refluxed for 5 hours. The reaction solution was filtered through celite, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / 4% ammonia-containing methanol = 4/1) to obtain Compound 65 (0.0270 g, 75%).
1 H-NMR (300 MHz, CDCl 3 , δ): 0.53-0.58 (m, 4H), 1.01 (t, J = 7.1 Hz, 6H), 1.64-1.73 (m, 2H), 1.88-1.95 (m, 1H), 2.48-2.54 (m, 6H), 2.68 (t, J = 6.8 Hz, 2H), 2.98-3.03 (m, 4H), 3.80 (s, 2H), 3.87 (s, 2H), 7.45 (t , J = 7.6 Hz, 1H), 7.56 (dd, J = 8.0, 3.2 Hz, 2H), 7.92-7.95 (m, 3H), 8.02 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H) .
(E)-3-((ベンジル(3-(ジエチルアミノ)プロピル)アミノ)メチル)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)ベンズアミド（化合物66）
　実施例65で得られる化合物65（0.100 g、0.145 mmol）を1,2-ジクロロエタン（1.00 mL）-メタノール（1.00 mL）に溶解し、ベンズアルデヒド（0.0740 mL、0.725 mmol）、およびトリアセトキシ水素化ホウ素ナトリウム（0.0920 g、0.435 mmol）を加え、室温で5時間撹拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／4%アンモニア含有メタノール＝6／1）で精製することにより、化合物66（0.0340 g, 30%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 0.54-0.58 (m, 4H), 0.97 (t, J = 6.8 Hz, 6H), 1.64-1.72 (m, 2H), 1.89-1.94 (m, 1H), 2.43-2.47 (m, 8H), 2.97-3.05 (m, 4H), 3.59 (s, 2H), 3.63 (s, 2H), 3.80 (s, 2H), 7.21 (t, J = 6.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 2H), 7.40 (d, J= 7.8 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.91 (t, J = 9.3 Hz, 2H), 8.02 (d, J = 2.0 Hz, 2H), 8.23 (s, 1H).  ESI-MS m/z: 779 (M+H)+. (E) -3-((Benzyl (3- (diethylamino) propyl) amino) methyl) -N- (3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6- Cyclopropyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl) benzamide (Compound 66)
Compound 65 (0.100 g, 0.145 mmol) obtained in Example 65 was dissolved in 1,2-dichloroethane (1.00 mL) -methanol (1.00 mL), benzaldehyde (0.0740 mL, 0.725 mmol), and triacetoxyborohydride Sodium (0.0920 g, 0.435 mmol) was added and stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / 4% ammonia-containing methanol = 6/1) to obtain Compound 66 (0.0340 g, 30%).
1 H-NMR (400 MHz, CDCl 3 , δ): 0.54-0.58 (m, 4H), 0.97 (t, J = 6.8 Hz, 6H), 1.64-1.72 (m, 2H), 1.89-1.94 (m, 1H), 2.43-2.47 (m, 8H), 2.97-3.05 (m, 4H), 3.59 (s, 2H), 3.63 (s, 2H), 3.80 (s, 2H), 7.21 (t, J = 6.8 Hz , 1H), 7.32 (t, J = 7.8 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H ), 7.62 (d, J = 6.8 Hz, 1H), 7.91 (t, J = 9.3 Hz, 2H), 8.02 (d, J = 2.0 Hz, 2H), 8.23 (s, 1H). ESI-MS m / z: 779 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-((メチル-(3-(メチルアミノ)プロピル)アミノ)メチル)ベンズアミド（化合物67）
　N,N’-ジメチル-1,3-プロパンジアミンを用い、実施例59と同様にして、化合物67（295 mg, 53%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 0.56-0.60 (m, 4H), 1.66-1.77 (m, 3H), 1.92-1.95 (m ,1H), 2.21 (s, 3H), 2.42-2.80 (m, 4H), 2.62-2.67 (m, 2H), 2.97-3.09 (m, 4H), 3.57 (s, 2H), 3.83 (s, 2H), 7.46 (t, J= 7.7 Hz, 1H), 7.52-7.61 (m, 2H), 7.92-7.97 (m, 3H), 8.05 (d, J = 1.8 Hz, 1H), 8.19 (s, 1H).  (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3- c] Pyridin-2-yl) -3-((methyl- (3- (methylamino) propyl) amino) methyl) benzamide (Compound 67)
Compound 67 (295 mg, 53%) was obtained in the same manner as in Example 59 using N, N′-dimethyl-1,3-propanediamine.
1 H-NMR (270 MHz, CDCl 3 , δ): 0.56-0.60 (m, 4H), 1.66-1.77 (m, 3H), 1.92-1.95 (m, 1H), 2.21 (s, 3H), 2.42- 2.80 (m, 4H), 2.62-2.67 (m, 2H), 2.97-3.09 (m, 4H), 3.57 (s, 2H), 3.83 (s, 2H), 7.46 (t, J = 7.7 Hz, 1H) , 7.52-7.61 (m, 2H), 7.92-7.97 (m, 3H), 8.05 (d, J = 1.8 Hz, 1H), 8.19 (s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(8,12-ジメチル-2,5-ジオキサ-8,12-ジアザトリデカン-13-イル)ベンズアミド（化合物68）
　実施例67で得られた化合物67（50.0 mg, 0.076 mmol）をDMF（3 mL）に溶解し、炭酸カリウム（31.4 mg, 0.227 mmol）および1-ブロモ-2-(メトキシエトキシ)エタン（20.8 mg, 0.113 mmol）を加え、80℃で3時間攪拌した。混合物に飽和炭酸カリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し濃縮した。残渣をNHシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、化合物68（35.3 mg, 61%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 0.56-0.60 (m, 4H), 1.68-1.81 (m, 4H), 1.91-1.95 (m, 1H), 2.19 (s, 3H), 2.31 (s, 3H), 2.42 (t, J= 7.2 Hz, 2H), 2.61-2.67 (m, 2H), 2.97-3.06 (m, 4H), 3.36 (s, 3H), 3.51-3.61 (m, 8H), 3.83 (s, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.91-7.97 (m, 3H), 8.04 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H).  ESI-MS m/z: 661, 663 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3- c] Pyridin-2-yl) -3- (8,12-dimethyl-2,5-dioxa-8,12-diazatridecan-13-yl) benzamide (Compound 68)
Compound 67 (50.0 mg, 0.076 mmol) obtained in Example 67 was dissolved in DMF (3 mL), and potassium carbonate (31.4 mg, 0.227 mmol) and 1-bromo-2- (methoxyethoxy) ethane (20.8 mg) were dissolved. , 0.113 mmol) and stirred at 80 ° C. for 3 hours. Saturated aqueous potassium carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by NH silica gel column chromatography (chloroform / methanol = 9/1) to give Compound 68 (35.3 mg, 61%).
1 H-NMR (300 MHz, CDCl 3 , δ): 0.56-0.60 (m, 4H), 1.68-1.81 (m, 4H), 1.91-1.95 (m, 1H), 2.19 (s, 3H), 2.31 ( s, 3H), 2.42 (t, J = 7.2 Hz, 2H), 2.61-2.67 (m, 2H), 2.97-3.06 (m, 4H), 3.36 (s, 3H), 3.51-3.61 (m, 8H) , 3.83 (s, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.91-7.97 (m, 3H), 8.04 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H). ESI-MS m / z: 661, 663 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エトキシ)ベンズアミド（化合物69）
工程1：3-ヒドロキシ安息香酸メチル（3.00 g, 19.7 mmol）をDMF（30 mL）に溶解し、炭酸カリウム（6.54 g, 47.3 mol）および2-(2-(2-クロロエトキシ)エトキシ)エタノール（9.97 g, 59.2 mmol）を加え、100℃で3時間攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝1／1）で精製することにより、3-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)安息香酸メチル（5.61 g, 定量的）を得た。
1H-NMR (270 MHz, CDCl3, δ): 3.61-3.79 (m, 8H), 3.87-3.91 (m, 5H), 4.17-4.20 (m, 2H), 7.11-7.15 (m, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.57-7.58 (m, 1H), 7.64 (dt, J = 7.7, 1.2 Hz, 1H). 
工程2：工程１で得られた3-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)安息香酸メチル（5.61 g, 19.7 mmol）をDMF（100 mL）に溶解し、トリエチルアミン（8.25 mL, 59.2 mol）およびメタンスルホニルクロリド（4.61 mL, 59.2 mmol）を加え、室温で終夜攪拌した。混合物にヨウ化ナトリウム（5.91 g, 39.4 mmol）を加え、100℃で2時間攪拌した。混合物に水を加えて酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、3-(2-(2-(2-ヨードエトキシ)エトキシ)エトキシ)安息香酸メチル（3.25 g, 42%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 3.63 (t, J= 5.8 Hz, 2H), 3.69-3.79 (m, 6H), 3.87-3.91 (m, 5H), 4.18 (t, J = 4.8 Hz, 2H), 7.10-7.15 (m, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.57-7.58 (m, 1H), 7.62-8.65 (m, 1H).
工程3：工程2で得られた3-(2-(2-(2-ヨードエトキシ)エトキシ)エトキシ)安息香酸メチル（3.25 g, 8.24 mmol）をDMF（60 mL）に溶解し、炭酸カリウム（5.70 g, 41.2 mol）および2-ジエチルアミン（18.1 g, 247 mmol）を加え、100℃で終夜攪拌した。混合物に水を加えて酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、3-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エトキシ安息香酸メチル（2.77 g, 99%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.02 (t, J= 7.1 Hz, 6H), 2.56 (q, J = 7.1 Hz, 4H), 2.66 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 6.4 Hz, 2H), 3.63-3.67 (m ,2H), 3.71-3.75 (m, 2H), 3.86-3.89 (m, 2H), 3.91 (s, 3H), 4.16-4.19 (m, 2H), 7.11-7.15 (m, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.56-7.58 (m, 1H), 7.62-7.65 (m, 1H).
工程4：工程3で得られた3-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エトキシ安息香酸メチル（2.77 g, 8.16 mmol）を50%エタノール水溶液（60 mL）に溶解し、水酸化リチウム・一水和物（685 mg, 16.3 mmol）を加え、室温で3時間撹拌した。混合物に3 mol/L塩酸を加え、クロロホルム／2-プロパノール（6／1）で抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製することにより、3-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エトキシ)安息香酸（1.97 g, 74%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.37 (t, J= 7.2 Hz, 6H), 3.10-3.26 (m, 6H), 3.65-3.72 (m, 4H), 3.83-3.85 (m, 2H), 3.99-4.02 (m, 2H), 4.18-4.21 (m, 2H), 7.11-7.15 (m, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.64-7.71 (m, 2H). 
工程5：工程4で得られた3-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エトキシ)安息香酸を用い、実施例6の工程2と同様にして化合物69（45.0 mg, 20%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 0.55-0.59 (m, 4H), 1.02 (t, J = 7.2 Hz, 6H), 1.89-1.94 (m, 1H), 2.57 (q, J = 7.2 Hz, 4H), 2.67 (t, J = 6.4 Hz, 2H), 2.97-3.05 (m, 4H), 3.58 (t, J = 6.4 Hz, 2H), 3.63-3.67 (m, 2H), 3.72-3.81 (m, 2H), 3.81 (s, 2H), 3.87-3.91 (m, 2H), 4.19-4.23 (m, 2H), 7.11-7.15 (m, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.55-7.61 (m, 3H), 7.95 (dd, J = 8.6, 2.0 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H).  ESI-MS m/z: 750, 752 (M+H)+ (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3- c] pyridin-2-yl) -3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzamide (Compound 69)
Step 1: Dissolve methyl 3-hydroxybenzoate (3.00 g, 19.7 mmol) in DMF (30 mL), potassium carbonate (6.54 g, 47.3 mol) and 2- (2- (2-chloroethoxy) ethoxy) ethanol (9.97 g, 59.2 mmol) was added, and the mixture was stirred at 100 ° C. for 3 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give methyl 3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzoate (5.61 g, quantitative) Got.
1 H-NMR (270 MHz, CDCl 3 , δ): 3.61-3.79 (m, 8H), 3.87-3.91 (m, 5H), 4.17-4.20 (m, 2H), 7.11-7.15 (m, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.57-7.58 (m, 1H), 7.64 (dt, J = 7.7, 1.2 Hz, 1H).
Step 2: Methyl 3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzoate (5.61 g, 19.7 mmol) obtained in Step 1 was dissolved in DMF (100 mL) and triethylamine (8.25 mL, 59.2 mol) and methanesulfonyl chloride (4.61 mL, 59.2 mmol) were added, and the mixture was stirred at room temperature overnight. Sodium iodide (5.91 g, 39.4 mmol) was added to the mixture, and the mixture was stirred at 100 ° C. for 2 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to give methyl 3- (2- (2- (2-iodoethoxy) ethoxy) ethoxy) benzoate (3.25 g, 42%). Obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 3.63 (t, J = 5.8 Hz, 2H), 3.69-3.79 (m, 6H), 3.87-3.91 (m, 5H), 4.18 (t, J = 4.8 Hz, 2H), 7.10-7.15 (m, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.57-7.58 (m, 1H), 7.62-8.65 (m, 1H).
Step 3: Methyl 3- (2- (2- (2-iodoethoxy) ethoxy) ethoxy) benzoate obtained in Step 2 (3.25 g, 8.24 mmol) was dissolved in DMF (60 mL), and potassium carbonate ( 5.70 g, 41.2 mol) and 2-diethylamine (18.1 g, 247 mmol) were added, and the mixture was stirred at 100 ° C. overnight. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give methyl 3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxybenzoate (2.77 g, 99%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.02 (t, J = 7.1 Hz, 6H), 2.56 (q, J = 7.1 Hz, 4H), 2.66 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 6.4 Hz, 2H), 3.63-3.67 (m, 2H), 3.71-3.75 (m, 2H), 3.86-3.89 (m, 2H), 3.91 (s, 3H), 4.16-4.19 ( m, 2H), 7.11-7.15 (m, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.56-7.58 (m, 1H), 7.62-7.65 (m, 1H).
Step 4: Dissolve methyl 3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxybenzoate (2.77 g, 8.16 mmol) obtained in Step 3 in 50% aqueous ethanol (60 mL). Lithium hydroxide monohydrate (685 mg, 16.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours, 3 mol / L hydrochloric acid was added to the mixture, and the mixture was extracted with chloroform / 2-propanol (6/1). The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to give 3- (2- (2- (2- (diethylamino) ethoxy) Ethoxy) ethoxy) benzoic acid (1.97 g, 74%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.37 (t, J = 7.2 Hz, 6H), 3.10-3.26 (m, 6H), 3.65-3.72 (m, 4H), 3.83-3.85 (m, 2H), 3.99-4.02 (m, 2H), 4.18-4.21 (m, 2H), 7.11-7.15 (m, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.64-7.71 (m, 2H) .
Step 5: Using the 3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzoic acid obtained in Step 4, in the same manner as in Step 2 of Example 6, compound 69 (45.0 mg, 20%).
1 H-NMR (270 MHz, CDCl 3 , δ): 0.55-0.59 (m, 4H), 1.02 (t, J = 7.2 Hz, 6H), 1.89-1.94 (m, 1H), 2.57 (q, J = 7.2 Hz, 4H), 2.67 (t, J = 6.4 Hz, 2H), 2.97-3.05 (m, 4H), 3.58 (t, J = 6.4 Hz, 2H), 3.63-3.67 (m, 2H), 3.72- 3.81 (m, 2H), 3.81 (s, 2H), 3.87-3.91 (m, 2H), 4.19-4.23 (m, 2H), 7.11-7.15 (m, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.55-7.61 (m, 3H), 7.95 (dd, J = 8.6, 2.0 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H). ESI-MS m / z: 750, 752 (M + H) +
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(15-ヒドロキシ-14,14-ビス(ヒドロキシメチル)-12-オキソ-3,6,9-トリオキサ-13-アザペンタデシロキシ)ベンズアミド（化合物70）
　実施例5で得られる化合物5およびトリス（ヒドロキシメチル）アミノメタンを用い、実施例14～16と同様にして化合物70を得た。
ESI-MS m/z: 870, 872 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3- c] pyridin-2-yl) -3- (15-hydroxy-14,14-bis (hydroxymethyl) -12-oxo-3,6,9-trioxa-13-azapentadecyloxy) benzamide (Compound 70)
Compound 70 was obtained in the same manner as in Examples 14 to 16 using Compound 5 obtained in Example 5 and tris (hydroxymethyl) aminomethane.
ESI-MS m / z: 870, 872 (M + H) + .
(E)-3-(2-(4-クロロ-3-(トリフルオロメチル)ベンズアミド)-4,5-ジヒドロチエノ[2,3-c]ピリジン-6-(7H)-カルボン酸tert-ブチル（化合物71）
工程1：N-tert-ブトキシカルボニル-ピペリジン-4-オンを用い、参考例１と同様にして、(E)-2-アミノ-3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-4,5,6,7-ジヒドロチエノ[2,3-c]ピリジン-6(7H)-カルボン酸tert-ブチル（7.84 g, 93%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.50 (s, 9H), 2.82 (t, J = 5.5 Hz, 2H), 3.69 (t, J= 5.5 Hz, 2H), 4.41 (s, 2H), 6.09 (br s, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.88 (dd, J= 8.4, 1.8 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 8.15 (br s, 1H), 8.85 (br s, 1H).
工程2：工程1で得られる((E)-2-アミノ-3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-4,5,6,7-ジヒドロチエノ[2,3-c]ピリジン-6(7H)-カルボン酸tert-ブチルを用い、実施例1と同様にして化合物71（8.83 g, 85%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.51 (s, 9H), 2.96 (s, 2H), 3.78 (t, J = 4.9 Hz, 2H), 4.60 (s, 2H), 4.67 (s, 2H), 7.51-7.65 (m, 3H), 7.94-8.06 (m, 4H), 8.21 (s, 1H), 9.05 (s, 1H), 12.79 (br s, 1H). (E) -3- (2- (4-Chloro-3- (trifluoromethyl) benzamide) -4,5-dihydrothieno [2,3-c] pyridine-6- (7H) -tert-butyl carboxylate ( Compound 71)
Step 1: Using (E) -2-amino-3- (2- (4-chloro-3- (trifluoromethyl) in the same manner as in Reference Example 1 using N-tert-butoxycarbonyl-piperidin-4-one ) Benzylidene) hydrazinecarbonyl) -4,5,6,7-dihydrothieno [2,3-c] pyridine-6 (7H) -carboxylate tert-butyl (7.84 g, 93%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.50 (s, 9H), 2.82 (t, J = 5.5 Hz, 2H), 3.69 (t, J = 5.5 Hz, 2H), 4.41 (s, 2H ), 6.09 (br s, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.88 (dd, J = 8.4, 1.8 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 8.15 ( br s, 1H), 8.85 (br s, 1H).
Step 2: ((E) -2-amino-3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -4,5,6,7-dihydrothieno [ Compound 71 (8.83 g, 85%) was obtained in the same manner as in Example 1 using tert-butyl 2,3-c] pyridine-6 (7H) -carboxylate.
1 H-NMR (400 MHz, CDCl 3 , δ): 1.51 (s, 9H), 2.96 (s, 2H), 3.78 (t, J = 4.9 Hz, 2H), 4.60 (s, 2H), 4.67 (s , 2H), 7.51-7.65 (m, 3H), 7.94-8.06 (m, 4H), 8.21 (s, 1H), 9.05 (s, 1H), 12.79 (br s, 1H).
(E)-3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-2-(3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド-4,5-ジヒドロチエノ[2,3-c]ピリジン-6(7H)-カルボン酸tert-ブチル（化合物72）
　実施例71で得られる化合物71を用い、実施例59と同様にして、化合物72（1.98 g, 90%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.06 (t, J= 6.8 Hz, 6H), 1.48 (s, 9H), 1.67-1.75 (m, 2H), 2.19 (s, 3H), 2.40 (t, J= 7.3 Hz, 2H), 2.60-2.62 (m, 6H), 2.96 (s, 2H), 3.55 (s, 2H), 3.71 (s, 2H), 4.55 (s, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 7.8 Hz, 2H), 7.94 (s, 1H), 8.01 (s, 1H), 8.29 (s, 1H).  ESI-MS m/z: 763 (M+H)+. (E) -3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -2- (3-(((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide Tert-Butyl-4,5-dihydrothieno [2,3-c] pyridine-6 (7H) -carboxylate (Compound 72)
Compound 72 (1.98 g, 90%) was obtained in the same manner as in Example 59, using Compound 71 obtained in Example 71.
1 H-NMR (400 MHz, CDCl 3 , δ): 1.06 (t, J = 6.8 Hz, 6H), 1.48 (s, 9H), 1.67-1.75 (m, 2H), 2.19 (s, 3H), 2.40 (t, J = 7.3 Hz, 2H), 2.60-2.62 (m, 6H), 2.96 (s, 2H), 3.55 (s, 2H), 3.71 (s, 2H), 4.55 (s, 2H), 7.44 ( t, J = 7.3 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 7.8 Hz, 2H), 7.94 (s, 1H), 8.01 (s, 1H), 8.29 ( s, 1H). ESI-MS m / z: 763 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド（化合物73）
　実施例72で得られる化合物72を用い、実施例19と同様にして、化合物73（1.56 g, 91%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.01 (t, J= 7.2 Hz, 6H), 1.63-1.74 (m, 2H), 2.20 (s, 3H), 2.44-2.51 (m, 8H), 2.89 (s, 2H), 3.23 (t, J = 5.4 Hz, 2H), 3.58 (s, 2H), 4.02 (s, 2H), 7.46 (t, J= 7.6 Hz, 1H), 7.58 (dd, J = 8.1, 2.8 Hz, 2H), 7.90-7.97 (m, 3H), 8.05 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H).  (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -4,5,6,7-tetrahydrothieno [2,3-c] pyridine-2 -Yl) -3-(((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide (Compound 73)
Compound 73 (1.56 g, 91%) was obtained in the same manner as in Example 19 using Compound 72 obtained in Example 72.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.01 (t, J = 7.2 Hz, 6H), 1.63-1.74 (m, 2H), 2.20 (s, 3H), 2.44-2.51 (m, 8H) , 2.89 (s, 2H), 3.23 (t, J = 5.4 Hz, 2H), 3.58 (s, 2H), 4.02 (s, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.58 (dd, J = 8.1, 2.8 Hz, 2H), 7.90-7.97 (m, 3H), 8.05 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H).
(E)-3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-2-(3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド)-4,5-ジヒドロチエノ[2,3-c]ピリジン-6(7H)-カルボン酸　1,1,1-トリフルオロ-2-メチルプロパン-2-イル（化合物74）
　実施例73で得られた化合物73（300 mg, 0.452 mmol）をジクロロメタン（15 mL）に溶解し、トリエチルアミン（0.126 mL, 0.905 mmol）およびBioorganic & Medicinal Chemistry, 19, 1580-1593, 2011に記載の方法で得た3-メチル-1-((1,1,1-トリフルオロ-2-メチルプロパン-2-イルオキシ)カルボニル)-1H-イミダゾール-3-イウム　ヨージド（181 mg, 0.498 mmol）を加え、室温で1時間攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝85／1）で精製することにより、化合物74（163 mg, 44%）を得た。
1H-NMR (400 MHz, DMSO-d6, δ): 1.05 (t, J = 7.1 Hz, 6H), 1.67 (s, 8H), 2.16 (s, 3H), 2.42 (t, J = 6.8 Hz, 2H), 2.78-2.81 (br m, 4H), 2.90-2.94 (br m, 4H), 3.57 (s, 2H), 3.61 (t, J = 5.9 Hz, 2H), 4.50 (s, 2H), 7.46 (d, J = 4.8 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.84-7.87 (m, 1H), 7.91 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H), 8.45 (s, 1H).  ESI-MS m/z: 817 (M+H)+. (E) -3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -2- (3-(((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide ) -4,5-Dihydrothieno [2,3-c] pyridine-6 (7H) -carboxylic acid 1,1,1-trifluoro-2-methylpropan-2-yl (compound 74)
Compound 73 (300 mg, 0.452 mmol) obtained in Example 73 was dissolved in dichloromethane (15 mL) and described in Triethylamine (0.126 mL, 0.905 mmol) and Bioorganic & Medicinal Chemistry, 19, 1580-1593, 2011 Add 3-methyl-1-((1,1,1-trifluoro-2-methylpropan-2-yloxy) carbonyl) -1H-imidazol-3-ium iodide (181 mg, 0.498 mmol) obtained by the method And stirred at room temperature for 1 hour. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 85/1) to give Compound 74 (163 mg, 44%).
1 H-NMR (400 MHz, DMSO-d 6 , δ): 1.05 (t, J = 7.1 Hz, 6H), 1.67 (s, 8H), 2.16 (s, 3H), 2.42 (t, J = 6.8 Hz , 2H), 2.78-2.81 (br m, 4H), 2.90-2.94 (br m, 4H), 3.57 (s, 2H), 3.61 (t, J = 5.9 Hz, 2H), 4.50 (s, 2H), 7.46 (d, J = 4.8 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.84-7.87 (m, 1H), 7.91 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H ), 8.10 (s, 1H), 8.45 (s, 1H). ESI-MS m / z: 817 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-(1-フェニルエチル)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド（化合物75）
　(1-ブロモエチル)ベンゼンを用い、実施例74と同様にして化合物75を得た。
ESI-MS m/z: 766 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6- (1-phenylethyl) -4,5,6,7-tetrahydrothieno [ 2,3-c] pyridin-2-yl) -3-(((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide (Compound 75)
Compound 75 was obtained in the same manner as in Example 74, using (1-bromoethyl) benzene.
ESI-MS m / z: 766 (M + H) + .
(E)-3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-2-(3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド-4,5-ジヒドロチエノ[2,3-c]ピリジン-6(7H)-カルボン酸tert-ブチル（化合物76）
　N,N-ジエチル-N’-メチルエチレンジアミンを用い、実施例72と同様にして、化合物76を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.03 (t, J = 7.1 Hz, 6H), 1.47 (s, 9H), 2.22 (s, 3H), 2.58-2.65 (m, 8H), 2.94 (s, 2H), 3.59 (s, 2H), 3.72 (t, J = 5.1 Hz, 2H), 4.55 (s, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.54-7.55 (m, 2H), 7.87-8.01 (m, 4H), 8.26 (s, 1H).  (E) -3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -2- (3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide Tert-Butyl-4,5-dihydrothieno [2,3-c] pyridine-6 (7H) -carboxylate (Compound 76)
Compound 76 was obtained in the same manner as in Example 72, using N, N-diethyl-N′-methylethylenediamine.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.03 (t, J = 7.1 Hz, 6H), 1.47 (s, 9H), 2.22 (s, 3H), 2.58-2.65 (m, 8H), 2.94 (s, 2H), 3.59 (s, 2H), 3.72 (t, J = 5.1 Hz, 2H), 4.55 (s, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.54-7.55 (m, 2H), 7.87-8.01 (m, 4H), 8.26 (s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド（化合物77）
　実施例76で得られる化合物76を用い、実施例19と同様にして、化合物77（0.0228 mg, 62%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.01 (t, J = 7.1 Hz, 6H), 2.24 (s, 3H), 2.50-2.57 (m, 6H), 2.62-2.64 (m, 2H), 2.85 (s, 2H), 3.16 (t, J = 5.5 Hz, 2H), 3.61 (s, 2H), 3.97 (s, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 9.0 Hz, 2H), 7.94-7.99 (m, 4H), 8.22 (s, 1H).  (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -4,5,6,7-tetrahydrothieno [2,3-c] pyridine-2 -Yl) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide (Compound 77)
Compound 77 (0.0228 mg, 62%) was obtained in the same manner as in Example 19 using Compound 76 obtained in Example 76.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.01 (t, J = 7.1 Hz, 6H), 2.24 (s, 3H), 2.50-2.57 (m, 6H), 2.62-2.64 (m, 2H) , 2.85 (s, 2H), 3.16 (t, J = 5.5 Hz, 2H), 3.61 (s, 2H), 3.97 (s, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 9.0 Hz, 2H), 7.94-7.99 (m, 4H), 8.22 (s, 1H).
(E)-3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-2-(3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド)-4,5-ジヒドロチエノ[2,3-c]ピリジン-6(7H)-カルボン酸シクロヘキシル（化合物78）
　クロロ炭酸シクロへキシルを用い、実施例74と同様にして、化合物78を得た。
ESI-MS m/z: 775 (M+H)+. (E) -3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -2- (3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide ) -4,5-Dihydrothieno [2,3-c] pyridine-6 (7H) -carboxylate cyclohexyl (Compound 78)
Compound 78 was obtained in the same manner as in Example 74, using cyclohexyl chlorocarbonate.
ESI-MS m / z: 775 (M + H) + .
(E)-3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-2-(3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド)-4,5-ジヒドロチエノ[2,3-c]ピリジン-6(7H)-カルボン酸(テトラヒドロ-2H-ピラン-4-イル)メチル（化合物79）
工程1：テトラヒドロピラン-4-メタノールを用い、Tetrahedron Letters, vol42, No38, p6645、2001に記載の方法に従い、4-ニトロフェニル(テトラヒドロ-2H-ピラン-4-イル)メチル　カーボネートを得た。
1H-NMR (270 MHz, CDCl3, δ): 1.26-1.52 (m, 2H), 1.74 (d, J = 12.7 Hz, 2H), 2.02-2.10 (m, 1H), 3.47 (t, J = 11.7 Hz, 2H), 4.04-4.08 (m, 2H), 4.17 (d, J = 6.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 8.29 (d, J = 8.8 Hz, 2H).
工程2：工程1で得られる4-ニトロフェニル(テトラヒドロ-2H-ピラン-4-イル)メチル　カーボネートを用い、実施例78と同様にして、化合物79を得た。
ESI-MS m/z: 791 (M+H)+. (E) -3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -2- (3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide ) -4,5-Dihydrothieno [2,3-c] pyridine-6 (7H) -carboxylic acid (tetrahydro-2H-pyran-4-yl) methyl (Compound 79)
Step 1: Using tetrahydropyran-4-methanol, 4-nitrophenyl (tetrahydro-2H-pyran-4-yl) methyl carbonate was obtained according to the method described in Tetrahedron Letters, vol42, No38, p6645, 2001.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.26-1.52 (m, 2H), 1.74 (d, J = 12.7 Hz, 2H), 2.02-2.10 (m, 1H), 3.47 (t, J = 11.7 Hz, 2H), 4.04-4.08 (m, 2H), 4.17 (d, J = 6.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 8.29 (d, J = 8.8 Hz, 2H) .
Step 2: Compound 79 was obtained in the same manner as in Example 78, using 4-nitrophenyl (tetrahydro-2H-pyran-4-yl) methyl carbonate obtained in Step 1.
ESI-MS m / z: 791 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-(4-ニトロベンジル)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((2- (ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド（化合物80）
　1-(ブロモメチル)-4-ニトロベンゼンを用い、実施例78と同様にして、化合物80を得た。
ESI-MS m/z: 784 (M+H)+.  (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6- (4-nitrobenzyl) -4,5,6,7-tetrahydrothieno [ 2,3-c] pyridin-2-yl) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide (Compound 80)
Compound 80 was obtained in the same manner as in Example 78, using 1- (bromomethyl) -4-nitrobenzene.
ESI-MS m / z: 784 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6- ((テトラヒドロ-2H-ピラン-4-イル)メチル)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド（化合物81）
　実施例77で得られる化合物77（0.460 g、0.709 mmol）を1,2-ジクロロエタン（5.00 mL）およびエタノール（5.00 mL）に溶解し、テトラヒドロ-2H-ピラン-4-カルバルデヒド（0.809 g、7.09 mmol）およびトリアセトキシ水素化ホウ素ナトリウム（0.901 g、4.25 mmol）を加え、室温で2時間撹拌した。混合物に飽和炭酸水素ナトリウム水溶液を加えてクロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／4%アンモニア含有メタノール＝4／1）で精製することにより、化合物81（0.167 g, 32%）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 0.94 (t, J = 17.8 Hz, 6H), 1.12-1.24 (m, 3H), 1.65 (d, J = 12.1 Hz, 2H), 2.17 (s, 3H), 2.39 (d, J = 7.0 Hz, 2H), 2.58 (s, 4H), 2.71 (s, 4H), 2.88 (s, 2H), 3.32 (t, J= 11.5 Hz, 4H), 3.58 (d, J = 8.1 Hz, 4H), 3.83 (d, J = 11.0 Hz, 2H), 7.46 (s, 2H), 7.74-7.96 (m, 4H), 8.10 (s, 1H), 8.43 (s, 1H).  ESI-MS m/z: 747 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6- ((tetrahydro-2H-pyran-4-yl) methyl) -4,5 , 6,7-Tetrahydrothieno [2,3-c] pyridin-2-yl) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide (Compound 81)
Compound 77 (0.460 g, 0.709 mmol) obtained in Example 77 was dissolved in 1,2-dichloroethane (5.00 mL) and ethanol (5.00 mL), and tetrahydro-2H-pyran-4-carbaldehyde (0.809 g, 7.09) was dissolved. mmol) and sodium triacetoxyborohydride (0.901 g, 4.25 mmol) were added and stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / 4% ammonia-containing methanol = 4/1) to give Compound 81 (0.167 g, 32%).
1 H-NMR (300 MHz, DMSO-d 6 , δ): 0.94 (t, J = 17.8 Hz, 6H), 1.12-1.24 (m, 3H), 1.65 (d, J = 12.1 Hz, 2H), 2.17 (s, 3H), 2.39 (d, J = 7.0 Hz, 2H), 2.58 (s, 4H), 2.71 (s, 4H), 2.88 (s, 2H), 3.32 (t, J = 11.5 Hz, 4H) , 3.58 (d, J = 8.1 Hz, 4H), 3.83 (d, J = 11.0 Hz, 2H), 7.46 (s, 2H), 7.74-7.96 (m, 4H), 8.10 (s, 1H), 8.43 ( s, 1H). ESI-MS m / z: 747 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-((テトラヒドロ-2H-チオピラン-4-イル)メチル)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド（化合物82）
　テトラヒドロチオピラン-4-カルバルデヒド用い、実施例81と同様にして、化合物82を得た。
ESI-MS m/z: 763 (M+H)+.  (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-((tetrahydro-2H-thiopyran-4-yl) methyl) -4,5 , 6,7-Tetrahydrothieno [2,3-c] pyridin-2-yl) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide (Compound 82)
Compound 82 was obtained in the same manner as in Example 81 using tetrahydrothiopyran-4-carbaldehyde.
ESI-MS m / z: 763 (M + H) + .  
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-(4-ニトロフェニルスルホニル)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド（化合物83）
　4-ニトロベンゼンスルホニルクロリドを用い、実施例78と同様にして、化合物83を得た。
ESI-MS m/z: 834 (M+H)+.  (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6- (4-nitrophenylsulfonyl) -4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide (Compound 83)
Compound 83 was obtained in the same manner as in Example 78, using 4-nitrobenzenesulfonyl chloride.
ESI-MS m / z: 834 (M + H) + .  
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-(4-メトキシフェニルスルホニル)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド（化合物84）
　4-メトキシベンゼンスルホニルクロリドを用い、実施例78と同様にして、化合物84を得た。
ESI-MS m/z: 819 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6- (4-methoxyphenylsulfonyl) -4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide (Compound 84)
Compound 84 was obtained in the same manner as in Example 78, using 4-methoxybenzenesulfonyl chloride.
ESI-MS m / z: 819 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-(テトラヒドロ-2H-ピラン-4-イルスルホニル)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド（化合物85）
　テトラヒドロピラン-4-スルホニルクロリドを用い、実施例78と同様にして、化合物85を得た。
ESI-MS m/z: 799 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6- (tetrahydro-2H-pyran-4-ylsulfonyl) -4,5,6 , 7-Tetrahydrothieno [2,3-c] pyridin-2-yl) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide (Compound 85)
Compound 85 was obtained in the same manner as in Example 78, using tetrahydropyran-4-sulfonyl chloride.
ESI-MS m / z: 799 (M + H) + .
(E)-N-(3-(2-((5,6-ジクロロピリジン-3-イル)メチレン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((4-ヒドロキシピペリジン-1-イル)メチル)ベンズアミド（化合物86）
工程1：4,4-ジメチルシクロヘキサノン（10.0 g, 79 mmol）をDMF（80 mL）に溶解し、シアノ酢酸tert-ブチル（11.3 mL）および硫黄(2.53 g, 79 mmol)を加えた。続いて、懸濁溶液（エチレンジアミン（2.64 mL）をDMF（10 mL）に溶解し、酢酸（4.53 mL）を加え、室温で30分間攪拌した溶液）をDMF（5 mL×6回）で洗いこみながら加え、室温で23時間攪拌した。混合物に室温で水を加え、酢酸エチルで抽出した。有機層を水および食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮することにより、2-アミノ-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（24.0 g, 定量的）を得た。
1H-NMR (270 MHz, CDCl3, δ): 0.99 (s, 6H), 1.47 (t, J = 6.4 Hz, 2H), 1.55 (s, 9H), 2.27 (s, 2H), 2.67 (t, J = 6.4 Hz, 2H), 5.86 (br s, 2H).
工程2：工程1で得られた2-アミノ-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（24.0 g, 85 mmol）をジロロメタン（130 mL）に溶解し、0℃にて3-(クロロメチル)ベンゾイルクロリド（12.38 mL, 87 mmol）およびピリジン（7.0 mL, 87 mmol）を加え、室温で30分間攪拌した。混合物に室温で水を加えてクロロホルムで抽出した。有機層を水および食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をヘキサンで洗浄することにより、2-(3-(クロロメチル)ベンゾイルアミノ)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（29.5 g, 86%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.02 (s, 6H), 1.54 (t, J = 6.4 Hz, 2H), 1.62 (s, 9H), 2.46 (s, 2H), 2.77 (t, J = 6.4 Hz, 2H), 4.67 (s, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 8.05 (s, 1H), 12.43 (br s, 1H).
工程3：工程2で得られた2-(3-(クロロメチル)ベンゾイルアミノ)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（10.0 g, 23 mmol）をジクロロメタン（50 mL）に溶解し、4-ヒドロキシピペリジン（6.98 g, 69 mmol）およびトリエチルアミン（9.6 mL, 69 mmol）を加え、室温で20時間攪拌した。混合物を濃縮し、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製することにより、2-(3-((4-ヒドロキシピペリジン-1-イル)メチル)ベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（10.0 g, 87%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.02 (s, 6H), 1.56 (t, J = 6.6 Hz, 2H), 1.60-1.65 (m, 2H), 1.62 (s, 9H), 1.90-1.93 (m, 2H), 2.18 (t, J = 12.0 Hz, 2H), 2.46 (s, 2H), 2.75-2.79 (m, 4H), 3.60 (s, 2H), 3.67-3.76 (m, 1H), 7.54-7.74 (m, 2H), 7.87 (d, J= 7.5 Hz, 1H), 8.00 (s, 1H), 12.39 (br s, 1H). 
工程4：工程3で得られた2-(3-((4-ヒドロキシピペリジン-1-イル)メチル)ベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（8.92 g, 18 mmol）をトリフルオロ酢酸（27.6 mL）に溶解し、トリフルオロ酢酸無水物（6.23 mL）を加え、室温で20時間攪拌した。混合物を濃縮し、0℃の飽和炭酸水素ナトリウム水溶液中へ滴下し中和した後、クロロホルムで抽出した。有機層を水および食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。得られた残渣をジクロロメタン-メタノール（25 mL－25 mL）に溶解し、ヒドラジン・一水和物（2.6 mL）を加え、室温で１時間攪拌した。混合物をクロロホルムで抽出した。有機層を水および食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮することにより、N-(3-(ヒドラジノカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((4-ヒドロキシピペリジン-1-イル)メチル)ベンズアミド（8.5 g, 定量的）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.03 (s, 6H), 1.60-1.65 (m, 4H), 1.88-1.90 (m, 2H), 2.20-2.30 (m, 2H), 2.50 (s, 2H), 2.71-2.77 (m, 4H), 3.61 (s, 2H), 3.68-3.75 (m, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 8.00 (s, 1H), 13.03 (br s, 1H).
工程5：工程4で得られたN-(3-(ヒドラジノカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((4-ヒドロキシピペリジン-1-イル)メチル)ベンズアミド（100 mg, 0.219 mmol）をクロロホルム（2 mL）に溶解し、5,6-ジクロロニコチンアルデヒド（77.0 mg, 0.438 mmol）を加え、50℃で3時間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝95／5）で精製することにより、化合物86（33.0 mg, 25%）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 1.41-1.48 (m, 2H), 1.53 (t, J = 6.4 Hz, 2H), 1.69-1.74 (m, 2H), 2.06-2.14 (m, 2H), 2.64-2.75 (m, 5H), 3.00-3.11 (m, 6H), 3.45-3.52 (m, 4H). 4.22-4.24 (m, 1H), 7.47-7.49 (m, 2H), 7.74-7.82 (m, 2H), 8.27-8.28 (m, 1H), 8.38 (s, 1H), 8.61-8.62 (m, 1H).  ESI-MS m/z: 614 (M+H)+. (E) -N- (3- (2-((5,6-Dichloropyridin-3-yl) methylene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] Thiophen-2-yl) -3-((4-hydroxypiperidin-1-yl) methyl) benzamide (Compound 86)
Step 1: 4,4-Dimethylcyclohexanone (10.0 g, 79 mmol) was dissolved in DMF (80 mL), and tert-butyl cyanoacetate (11.3 mL) and sulfur (2.53 g, 79 mmol) were added. Subsequently, the suspension solution (ethylenediamine (2.64 mL) dissolved in DMF (10 mL), acetic acid (4.53 mL) was added, and the mixture was stirred at room temperature for 30 minutes) was washed with DMF (5 mL × 6 times). And stirred at room temperature for 23 hours. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3- Tert-butyl carboxylate (24.0 g, quantitative) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 0.99 (s, 6H), 1.47 (t, J = 6.4 Hz, 2H), 1.55 (s, 9H), 2.27 (s, 2H), 2.67 (t , J = 6.4 Hz, 2H), 5.86 (br s, 2H).
Step 2: tert-butyl 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (24.0 g, 85 mmol) obtained in Step 1 is replaced with dichloromethane (130 mL), 3- (chloromethyl) benzoyl chloride (12.38 mL, 87 mmol) and pyridine (7.0 mL, 87 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water was added to the mixture at room temperature, and the mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue is washed with hexane to give tert-butyl 2- (3- (chloromethyl) benzoylamino) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (29.5 g, 86%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.02 (s, 6H), 1.54 (t, J = 6.4 Hz, 2H), 1.62 (s, 9H), 2.46 (s, 2H), 2.77 (t , J = 6.4 Hz, 2H), 4.67 (s, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H ), 8.05 (s, 1H), 12.43 (br s, 1H).
Step 3: tert-butyl 2- (3- (chloromethyl) benzoylamino) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in step 2 (10.0 g, 23 mmol) was dissolved in dichloromethane (50 mL), 4-hydroxypiperidine (6.98 g, 69 mmol) and triethylamine (9.6 mL, 69 mmol) were added, and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated and purified by silica gel column chromatography (chloroform / methanol) to give 2- (3-((4-hydroxypiperidin-1-yl) methyl) benzamide) -6,6-dimethyl-4,5 , 6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (10.0 g, 87%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.02 (s, 6H), 1.56 (t, J = 6.6 Hz, 2H), 1.60-1.65 (m, 2H), 1.62 (s, 9H), 1.90 -1.93 (m, 2H), 2.18 (t, J = 12.0 Hz, 2H), 2.46 (s, 2H), 2.75-2.79 (m, 4H), 3.60 (s, 2H), 3.67-3.76 (m, 1H ), 7.54-7.74 (m, 2H), 7.87 (d, J = 7.5 Hz, 1H), 8.00 (s, 1H), 12.39 (br s, 1H).
Step 4: 2- (3-((4-Hydroxypiperidin-1-yl) methyl) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene obtained in Step 3 Tert-Butyl-3-carboxylate (8.92 g, 18 mmol) was dissolved in trifluoroacetic acid (27.6 mL), trifluoroacetic anhydride (6.23 mL) was added, and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated, dropped into a saturated aqueous sodium hydrogen carbonate solution at 0 ° C. to neutralize, and extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was dissolved in dichloromethane-methanol (25 mL-25 mL), hydrazine monohydrate (2.6 mL) was added, and the mixture was stirred at room temperature for 1 hr. The mixture was extracted with chloroform. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give N- (3- (hydrazinocarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzoic acid. [b] Thiophen-2-yl) -3-((4-hydroxypiperidin-1-yl) methyl) benzamide (8.5 g, quantitative) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.03 (s, 6H), 1.60-1.65 (m, 4H), 1.88-1.90 (m, 2H), 2.20-2.30 (m, 2H), 2.50 ( s, 2H), 2.71-2.77 (m, 4H), 3.61 (s, 2H), 3.68-3.75 (m, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz , 1H), 7.88 (d, J = 7.6 Hz, 1H), 8.00 (s, 1H), 13.03 (br s, 1H).
Step 5: N- (3- (hydrazinocarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) -3-(( 4-Hydroxypiperidin-1-yl) methyl) benzamide (100 mg, 0.219 mmol) is dissolved in chloroform (2 mL), and 5,6-dichloronicotinaldehyde (77.0 mg, 0.438 mmol) is added. Stir for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 95/5) to give Compound 86 (33.0 mg, 25%).
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.41-1.48 (m, 2H), 1.53 (t, J = 6.4 Hz, 2H), 1.69-1.74 (m, 2H), 2.06-2.14 ( m, 2H), 2.64-2.75 (m, 5H), 3.00-3.11 (m, 6H), 3.45-3.52 (m, 4H). 4.22-4.24 (m, 1H), 7.47-7.49 (m, 2H), 7.74-7.82 (m, 2H), 8.27-8.28 (m, 1H), 8.38 (s, 1H), 8.61-8.62 (m, 1H). ESI-MS m / z: 614 (M + H) + .
(E)-N-(6,6-ジメチル-3-(2-((1-メチル-1H-インドール-5-イル)メチレン)ヒドラジンカルボニル)-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-((4-ヒドロキシピペリジン-1-イル)メチル)ベンズアミド（化合物87）
　1-メチル-1H-インドールカルバルデヒドを用い、実施例86と同様にして、化合物87を得た。
ESI-MS m/z: 598 (M+H)+. (E) -N- (6,6-Dimethyl-3- (2-((1-methyl-1H-indol-5-yl) methylene) hydrazinecarbonyl) -4,5,6,7-tetrahydrobenzo [b ] Thiophen-2-yl) -3-((4-hydroxypiperidin-1-yl) methyl) benzamide (Compound 87)
Compound 87 was obtained in the same manner as in Example 86, using 1-methyl-1H-indolecarbaldehyde.
ESI-MS m / z: 598 (M + H) + .
(E)-N-(3-(2-(ベンゾ[c][1,2,5]オキサジアゾール-5-イルメチレン)ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エトキシ)ベンズアミド（化合物88）
工程1：実施例86の工程1で得られる2-アミノ-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチルを用い、実施例1と同様にして、2-(3-ヒドロキシベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（17.8 g, 78%）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 0.97 (s, 6H), 1.51 (t, J = 6.2 Hz, 2H), 1.57 (s, 9H), 2.44 (s, 2H), 2.74 (t, J = 6.2 Hz, 2H), 7.13-7.16 (m, 1H), 7.30-7.33 (m, 1H), 7.40-7.45 (m, 1H), 7.53-7.55 (m, 1H), 12.04 (br s, 1H). 
工程2：工程１で得られた2-(3-ヒドロキシベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチルを用い、実施例8と同様にして、2-(3-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)ベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（7.20 g, 90%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.01 (s, 6H), 1.61 (s, 9H), 2.25 (t, J = 6.1 Hz, 2H), 2.46 (s, 2H), 2.77 (t, J = 6.1 Hz, 2H), 3.61-3.92 (m, 6H), 4.16-4.25 (m, 4H), 4.48 (t, J = 4.8 Hz, 2H), 7.12-7.15 (m, 1H), 7.39-7.45 (m, 1H), 7.53-7.56 (m, 2H). 
工程3：工程2で得られた2-(3-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)ベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（1.40 g, 2.62 mmol）をDMF（15 mL）に溶解し、トリエチルアミン（0.548 mL, 3.93 mmol）およびメタンスルホニルクロリド（0.307 mL, 3.93 mmol）を加え室温で終夜攪拌した。さらに100℃で2時間攪拌した後、混合物に水を加えて酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝1／1）で精製することにより、2-(3-(2-(2-(2-クロロエトキシ)エトキシ)エトキシ)ベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（0.520 mg, 36%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.01 (s, 6H), 1.54 (t, J = 6.4 Hz, 2H), 1.64 (s, 9H), 2.46 (s, 2H), 2.77 (t, J = 6.4 Hz, 2H), 3.26 (t, J = 7.0 Hz, 2H), 3.62-3.66 (m, 4H), 3.73-3.75 (m ,2H), 3.91 (t, J = 4.6 Hz, 2H), 4.21-4.24 (m, 2H), 7.12-7.16 (m, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.53-7.60 (m, 2H), 12.37 (br s, 1H).
工程4：工程3で得られた2-(3-(2-(2-(2-クロロエトキシ)エトキシ)エトキシ)ベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチルを用い、実施例10と同様にして、2-(3-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エトキシ)ベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（0.457 g, 82%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 0.99-1.04 (m, 12H), 1.54 (t, J = 6.6 Hz, 2H), 1.61 (s, 9H), 2.46 (s, 2H), 2.56 (q, J= 7.1 Hz, 4H), 2.66 (t, J= 6.6 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 6.4 Hz, 2H), 3.64-3.67 (m, 2H), 3.72-3.75 (m, 2H), 3.90 (t, J = 4.4 Hz, 2H), 4.22 (t, J = 4.4 Hz, 2H), 7.12-7.15 (m, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.53-7.59 (m, 2H), 12.37 (br s, 1H).
工程5：工程4で得られた2-(3-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エトキシ)ベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチルを用い、実施例86の工程4と同様にして、3-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エトキシ)-N-(3-(ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)ベンズアミド（59.0 mg, 64%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 0.97-1.05 (m, 12H), 1.63 (t, J = 6.4 Hz, 2H), 2.49 (s, 2H), 2.56 (q, J = 7.0 Hz, 4H), 2.66 (t, J = 6.4 Hz, 2H), 3.54-3.61 (m, 4H), 3.64 (m, 2H), 3.72-3.75 (m, 2H), 3.89 (t, J = 4.4 Hz, 2H), 4.22 (t, J = 4.4 Hz, 2H), 7.11-7.15 (m, 1H), 7.38-7.43 (m, 1H), 7.54-7.63 (m, 2H). 
工程6：2,1,3-ベンズオキサジアゾール-5-カルバルデヒドおよび工程5で得られた3-(2-(2-(2-(ジエチルアミノ)エトキシ)エトキシ)エトキシ)-N-(3-(ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)ベンズアミドを用い、実施例86の工程5と同様にして、化合物88（25.0 mg, 15%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.02 (t, J= 7.1 Hz, 6H), 1.09 (s, 6H), 1.71 (t, J= 6.0 Hz, 2H), 2.50 (s, 2H), 2.56 (q, J= 7.1 Hz, 4H), 2.67 (t, J = 6.6 Hz, 2H), 2.91 (t, J = 6.0 Hz, 2H), 3.58 (t, J = 6.6 Hz, 2H), 3.64-3.68 (m, 2H), 3.73-3.76 (m, 2H), 3.90 (t, J = 4.8 Hz, 2H), 4.22 (t, J = 4.8 Hz, 2H), 7.13-7.16 (m, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.61-7.63 (m, 2H), 7.87-7.90 (m, 2H), 8.26 (dd, J = 9.5, 1.5 Hz, 1H), 8.33 (s, 1H).  ESI-MS m/z: 677 (M+H)+. (E) -N- (3- (2- (Benzo [c] [1,2,5] oxadiazol-5-ylmethylene) hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7- Tetrahydrobenzo [b] thiophen-2-yl) -3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzamide (Compound 88)
Step 1: Example 1 using tert-butyl 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in Step 1 of Example 86 In the same way as tert-butyl 2- (3-hydroxybenzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (17.8 g, 78%) Obtained.
1 H-NMR (300 MHz, DMSO-d 6 , δ): 0.97 (s, 6H), 1.51 (t, J = 6.2 Hz, 2H), 1.57 (s, 9H), 2.44 (s, 2H), 2.74 (t, J = 6.2 Hz, 2H), 7.13-7.16 (m, 1H), 7.30-7.33 (m, 1H), 7.40-7.45 (m, 1H), 7.53-7.55 (m, 1H), 12.04 (br s, 1H).
Step 2: Performed using tert-butyl 2- (3-hydroxybenzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in Step 1 Similar to Example 8, 2- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] Obtained tert-butyl thiophene-3-carboxylate (7.20 g, 90%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.01 (s, 6H), 1.61 (s, 9H), 2.25 (t, J = 6.1 Hz, 2H), 2.46 (s, 2H), 2.77 (t , J = 6.1 Hz, 2H), 3.61-3.92 (m, 6H), 4.16-4.25 (m, 4H), 4.48 (t, J = 4.8 Hz, 2H), 7.12-7.15 (m, 1H), 7.39- 7.45 (m, 1H), 7.53-7.56 (m, 2H).
Step 3: 2- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] Dissolve tert-butyl thiophene-3-carboxylate (1.40 g, 2.62 mmol) in DMF (15 mL), add triethylamine (0.548 mL, 3.93 mmol) and methanesulfonyl chloride (0.307 mL, 3.93 mmol) at room temperature. And stirred overnight. After further stirring at 100 ° C. for 2 hours, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 2- (3- (2- (2- (2-chloroethoxy) ethoxy) ethoxy) benzamide) -6,6- Dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (0.520 mg, 36%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.01 (s, 6H), 1.54 (t, J = 6.4 Hz, 2H), 1.64 (s, 9H), 2.46 (s, 2H), 2.77 (t , J = 6.4 Hz, 2H), 3.26 (t, J = 7.0 Hz, 2H), 3.62-3.66 (m, 4H), 3.73-3.75 (m, 2H), 3.91 (t, J = 4.6 Hz, 2H) , 4.21-4.24 (m, 2H), 7.12-7.16 (m, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.53-7.60 (m, 2H), 12.37 (br s, 1H).
Step 4: 2- (3- (2- (2- (2-chloroethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] 2- (3- (2- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzamide) -6, as in Example 10, using tert-butyl thiophene-3-carboxylate 6-Dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (0.457 g, 82%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 0.99-1.04 (m, 12H), 1.54 (t, J = 6.6 Hz, 2H), 1.61 (s, 9H), 2.46 (s, 2H), 2.56 (q, J = 7.1 Hz, 4H), 2.66 (t, J = 6.6 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 6.4 Hz, 2H), 3.64-3.67 (m, 2H), 3.72-3.75 (m, 2H), 3.90 (t, J = 4.4 Hz, 2H), 4.22 (t, J = 4.4 Hz, 2H), 7.12-7.15 (m, 1H), 7.42 ( t, J = 7.9 Hz, 1H), 7.53-7.59 (m, 2H), 12.37 (br s, 1H).
Step 5: 2- (3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydro obtained in step 4 3- (2- (2- (2- (2- (Diethylamino) ethoxy) ethoxy) ethoxy) -N-) using tert-butyl benzo [b] thiophene-3-carboxylate as in Step 4 of Example 86 (3- (hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide (59.0 mg, 64%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 0.97-1.05 (m, 12H), 1.63 (t, J = 6.4 Hz, 2H), 2.49 (s, 2H), 2.56 (q, J = 7.0 Hz , 4H), 2.66 (t, J = 6.4 Hz, 2H), 3.54-3.61 (m, 4H), 3.64 (m, 2H), 3.72-3.75 (m, 2H), 3.89 (t, J = 4.4 Hz, 2H), 4.22 (t, J = 4.4 Hz, 2H), 7.11-7.15 (m, 1H), 7.38-7.43 (m, 1H), 7.54-7.63 (m, 2H).
Step 6: 2,1,3-Benzoxadiazole-5-carbaldehyde and 3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) -N- (3 obtained in Step 5 Compound 88 (25.0) was prepared in the same manner as in Step 5 of Example 86 using-(hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide. mg, 15%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.02 (t, J = 7.1 Hz, 6H), 1.09 (s, 6H), 1.71 (t, J = 6.0 Hz, 2H), 2.50 (s, 2H ), 2.56 (q, J = 7.1 Hz, 4H), 2.67 (t, J = 6.6 Hz, 2H), 2.91 (t, J = 6.0 Hz, 2H), 3.58 (t, J = 6.6 Hz, 2H), 3.64-3.68 (m, 2H), 3.73-3.76 (m, 2H), 3.90 (t, J = 4.8 Hz, 2H), 4.22 (t, J = 4.8 Hz, 2H), 7.13-7.16 (m, 1H) , 7.41 (t, J = 8.2 Hz, 1H), 7.61-7.63 (m, 2H), 7.87-7.90 (m, 2H), 8.26 (dd, J = 9.5, 1.5 Hz, 1H), 8.33 (s, 1H ESI-MS m / z: 677 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-メチル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-2-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)チアゾール-4-カルボキサミド（化合物89）
工程1：2-メチルチアゾ－ル-4-カルボン酸エチル（2.50 g, 14.6 mmol）を四塩化炭素（29.0 mL）に溶解し、2,2’-アゾビスイソブチロニトリル（AIBN）（24.0 mg, 0.146 mmol）およびN-ブロモスクシンイミド（2.60 g, 14.6 mmol）を加え、80℃で6時間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（クロロホルム／酢酸エチル＝9／1）で精製することにより、2-(ブロモメチル)チアゾール-4-カルボン酸エチル（1.44 g, 39%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.41 (t, J = 7.1 Hz, 3H), 4.44 (q, J = 7.1 Hz, 2H), 4.77 (s, 2H), 8.23 (s, 1H).
工程2：工程1で得られた2-(ブロモメチル)チアゾール-4-カルボン酸エチル（0.768 g, 3.07 mmol）をTHF（10.0 mL）に溶解し、トリエチルアミン（0.856 mL, 6.14 mmol）およびN,N-ジエチル-N’-メチルエタン-1,2-ジアミン（0.745 mL, 4.61 mmol）を加え、室温で30分間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（クロロホルム／メタノ－ル＝9／1）で精製することにより、2-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)チアゾール-4-カルボン酸エチル（0.817 g, 89%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.01 (t, J = 7.1 Hz, 6H), 1.41 (t, J = 7.1 Hz, 3H), 2.39 (s, 3H), 2.53 (q, J = 7.1 Hz, 4H), 2.62 (s, 4H), 3.94 (s, 2H), 4.42 (q, J= 7.1 Hz, 2H), 8.14 (s, 1H).
工程3：工程2で得られた2-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)チアゾール-4-カルボン酸エチル（0.817 g, 2.73 mmol）をTHF（１.00 mL）に溶解し、5.4 mol/Lの水酸化ナトリウム水溶液（1.00 mL, 5.40 mmol）を加え、50℃で1時間攪拌した。混合物に6 mol/L塩酸を加え、減圧下で濃縮した。残渣にクロロホルム／メタノ－ル＝10／1の混合溶媒を加え、ろ過した。得られたろ液を減圧下で濃縮することにより、2-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)チアゾール-4-カルボン酸（0.950 g, 定量的）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.39 (t, J = 7.1 Hz, 6H), 2.46 (s, 3H), 3.13-3.33 (m, 8H), 4.10 (s, 2H), 8.15 (s, 1H).
工程4：N-メチルピペリジン－４－オンを用い、参考例１と同様にして、(E)-2-アミノ-N’-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)-6-メチル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-3-カルボヒドラジドを得た。
1H-NMR (400 MHz，CDCl3, δ): 2.48 (s, 3H), 2.75 (t, J = 5.6 Hz, 2H), 2.87 (t, J = 5.6 Hz, 2H), 3.43 (s, 2H), 6.08 (br s, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 8.4, 1.8 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 8.17 (br s, 1H), 8.92 (br s, 1H). 
工程5：工程3で得られた2-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)チアゾール-4-カルボン酸（60 mg, 2.7 mmol）をジクロロメタン（1.0 mL）に溶解し、2,4,6-トリクロロベンゾイルクロリド（0.035 mL,0.22 mmol）、4-ジメチルアミノピリジン（27 mg, 0.22 mmol）および工程4で得られた(E)-2-アミノ-N’-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)-6-メチル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-3-カルボヒドラジド（46 mg, 0.11 mmol）を加え、室温で5時間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加えてクロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（クロロホルム／メタノ－ル＝9／1）で精製することにより、化合物89（34 mg, 23%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.02 (t, J = 7.1 Hz, 6H), 2.40 (s, 3H), 2.49 (s, 3H), 2.54 (q, J= 7.1 Hz, 4H), 2.63 (s, 4H), 2.73-2.78 (m, 2H), 2.94-3.00 (m, 2H), 3.57 (s, 2H), 3.94 (s, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.92 (dd, J = 8.4, 1.8 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 8.17 (s, 1H), 8.29 (s, 1H).  ESI-MS m/z: 670, 672 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-methyl-4,5,6,7-tetrahydrothieno [2,3-c ] Pyridin-2-yl) -2-(((2- (diethylamino) ethyl) (methyl) amino) methyl) thiazole-4-carboxamide (Compound 89)
Step 1: Dissolve ethyl 2-methylthiazol-4-carboxylate (2.50 g, 14.6 mmol) in carbon tetrachloride (29.0 mL) and add 2,2'-azobisisobutyronitrile (AIBN) (24.0 mg , 0.146 mmol) and N-bromosuccinimide (2.60 g, 14.6 mmol) were added, and the mixture was stirred at 80 ° C. for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 9/1) to give ethyl 2- (bromomethyl) thiazole-4-carboxylate (1.44 g, 39%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.41 (t, J = 7.1 Hz, 3H), 4.44 (q, J = 7.1 Hz, 2H), 4.77 (s, 2H), 8.23 (s, 1H ).
Step 2: Ethyl 2- (bromomethyl) thiazole-4-carboxylate (0.768 g, 3.07 mmol) obtained in Step 1 was dissolved in THF (10.0 mL), triethylamine (0.856 mL, 6.14 mmol) and N, N -Diethyl-N'-methylethane-1,2-diamine (0.745 mL, 4.61 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to give ethyl 2-(((2- (diethylamino) ethyl) (methyl) amino) methyl) thiazole-4-carboxylate ( 0.817 g, 89%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.01 (t, J = 7.1 Hz, 6H), 1.41 (t, J = 7.1 Hz, 3H), 2.39 (s, 3H), 2.53 (q, J = 7.1 Hz, 4H), 2.62 (s, 4H), 3.94 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 8.14 (s, 1H).
Step 3: Ethyl 2-(((2- (diethylamino) ethyl) (methyl) amino) methyl) thiazole-4-carboxylate (0.817 g, 2.73 mmol) obtained in Step 2 was added to THF (1.00 mL). 5.4 mol / L sodium hydroxide aqueous solution (1.00 mL, 5.40 mmol) was added, and the mixture was stirred at 50 ° C. for 1 hour. 6 mol / L hydrochloric acid was added to the mixture, and the mixture was concentrated under reduced pressure. A mixed solvent of chloroform / methanol = 10/1 was added to the residue and filtered. The obtained filtrate was concentrated under reduced pressure to obtain 2-(((2- (diethylamino) ethyl) (methyl) amino) methyl) thiazole-4-carboxylic acid (0.950 g, quantitative).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.39 (t, J = 7.1 Hz, 6H), 2.46 (s, 3H), 3.13-3.33 (m, 8H), 4.10 (s, 2H), 8.15 (s, 1H).
Step 4: Using (E) -2-amino-N ′-(4-chloro-3- (trifluoromethyl) benzylidene) -6-in the same manner as in Reference Example 1 using N-methylpiperidin-4-one Methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-3-carbohydrazide was obtained.
1 H-NMR (400 MHz, CDCl 3 , δ): 2.48 (s, 3H), 2.75 (t, J = 5.6 Hz, 2H), 2.87 (t, J = 5.6 Hz, 2H), 3.43 (s, 2H ), 6.08 (br s, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 8.4, 1.8 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 8.17 ( br s, 1H), 8.92 (br s, 1H).
Step 5: 2-((((2- (Diethylamino) ethyl) (methyl) amino) methyl) thiazole-4-carboxylic acid (60 mg, 2.7 mmol) obtained in Step 3 was dissolved in dichloromethane (1.0 mL). , 2,4,6-trichlorobenzoyl chloride (0.035 mL, 0.22 mmol), 4-dimethylaminopyridine (27 mg, 0.22 mmol) and (E) -2-amino-N ′-(4 -Chloro-3- (trifluoromethyl) benzylidene) -6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-3-carbohydrazide (46 mg, 0.11 mmol) was added, Stir at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to give Compound 89 (34 mg, 23%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.02 (t, J = 7.1 Hz, 6H), 2.40 (s, 3H), 2.49 (s, 3H), 2.54 (q, J = 7.1 Hz, 4H ), 2.63 (s, 4H), 2.73-2.78 (m, 2H), 2.94-3.00 (m, 2H), 3.57 (s, 2H), 3.94 (s, 2H), 7.54 (d, J = 8.4 Hz, ESI-MS m / z: 1H), 7.92 (dd, J = 8.4, 1.8 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 8.17 (s, 1H), 8.29 (s, 1H). 670, 672 (M + H) + .
(E)-N-(3-(2-(ベンゾ[c][1,2,5]オキサジアゾール-5-イルメチレン)ヒドラジンカルボニル)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド（化合物90）
工程1：N-シクロプロピルピペリジン-4-オンを用い、実施例86の工程1と同様にして、2-アミノ-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-b]ピリジン-3-カルボン酸tert-ブチル（13.8, 93%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 0.50-0.51 (m, 4H), 1.53 (s, 9H), 1.84-1.87 (m, 1H), 2.78-2.79 (m, 2H), 2.88-2.90 (m, 2H), 3.57-3.58 (m, 2H), 5.88 (s, 2H).
工程2：工程1で得られた2-アミノ-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-b]ピリジン-3-カルボン酸tert-ブチルを用い、実施例1と同様にして、2-(3-(クロロメチル)ベンズアミド)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-b]ピリジン-3-カルボン酸tert-ブチル（10.8 g, 89%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 0.54-0.56 (m, 4H), 1.60 (s, 9H), 1.83-1.92 (m, 1H), 2.89-2.95 (m, 4H), 3.75-3.77 (m, 2H), 4.67 (s, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.61-7.64 (m, 1H), 7.92-7.06 (m, 1H), 8.04-8.05 (m, 1H), 12.37 (br s, 1H).
工程3：工程2で得られた2-(3-(クロロメチル)ベンズアミド)-6-シクロプロピル-4,5,6,7-テトラヒドロチエノ[2,3-b]ピリジン-3-カルボン酸tert-ブチルを用い、実施例59と同様にして、6-シクロプロピル-2-(3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-3-カルボン酸tert-ブチル（5.86 g, 94%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 0.53-0.56 (m, 4H), 1.01 (t, J = 7.2 Hz, 6H), 1.59 (s, 9H), 1.63-1.74 (m, 2H), 1.84-1.90 (m, 1H), 2.20 (s, 3H), 2.39-2.55 (m, 8H), 2.89-2.95 (m, 4H), 3.57 (s, 2H), 3.75 (s, 2H), 7.47 (t, J= 7.6 Hz, 1H), 7.55-7.59 (m, 1H), 7.84-7.87 (m, 1H), 7.95-7.96 (m, 1H), 12.31 (br s, 1H).
工程4：工程3で得られた6-シクロプロピル-2-(3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-3-カルボン酸tert-ブチルを用い、実施例88の工程5と同様にして、N-(6-シクロプロピル-3-(ヒドラジンカルボニル)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((3-ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド（1.22 g, 81%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 0.50-0.60 (m, 4H), 1.06 (t, J = 6.8 Hz, 6H), 1.70-1.77 (m, 2H), 1.87-1.90 (m, 1H), 2.21 (s, 3H), 2.42 (t, J = 6.8 Hz, 2H), 2.54-2.64 (m, 6H), 2.83 (t, J = 5.9 Hz, 2H), 3.01 (t, J = 5.9 Hz, 2H), 3.61 (s, 2H), 3.79 (s, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.97 (s, 1H). 
工程5：2,1,3-ベンズオキサジアゾール-5-カルバルデヒドおよび工程4で得られたN-(6-シクロプロピル-3-(ヒドラジンカルボニル)-4,5,6,7-テトラヒドロチエノ[2,3-c]ピリジン-2-イル)-3-(((3-ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミドを用い、実施例86の工程5と同様にして、化合物90（40.4 mg, 44%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 0.56-0.60 (m, 4H), 1.01 (t, J = 7.2 Hz, 6H), 1.66-1.71 (m, 2H), 1.89-1.95 (m, 1H), 2.20 (s, 3H), 2.38-2.56 (m ,8H), 3.01-3.08 (m, 4H), 3.58 (s, 2H), 3.83 (s, 2H), 7.46 (t, J= 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.86-7.97 (m, 4H), 8.24 (dd, J = 9.4, 1.5 Hz, 1H), 8.30 (s, 1H).  ESI-MS m/z: 630 (M+H)+. (E) -N- (3- (2- (Benzo [c] [1,2,5] oxadiazol-5-ylmethylene) hydrazinecarbonyl) -6-cyclopropyl-4,5,6,7-tetrahydro Thieno [2,3-c] pyridin-2-yl) -3-(((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide (Compound 90)
Step 1: Using N-cyclopropylpiperidin-4-one in the same manner as in Step 1 of Example 86, 2-amino-6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3- b] tert-Butyl pyridine-3-carboxylate (13.8, 93%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 0.50-0.51 (m, 4H), 1.53 (s, 9H), 1.84-1.87 (m, 1H), 2.78-2.79 (m, 2H), 2.88- 2.90 (m, 2H), 3.57-3.58 (m, 2H), 5.88 (s, 2H).
Step 2: Example 1 using tert-butyl 2-amino-6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3-b] pyridine-3-carboxylate obtained in Step 1 In a similar manner to tert-butyl 2- (3- (chloromethyl) benzamido) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3-b] pyridine-3-carboxylate (10.8 g, 89%).
1 H-NMR (270 MHz, CDCl 3 , δ): 0.54-0.56 (m, 4H), 1.60 (s, 9H), 1.83-1.92 (m, 1H), 2.89-2.95 (m, 4H), 3.75- 3.77 (m, 2H), 4.67 (s, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.61-7.64 (m, 1H), 7.92-7.06 (m, 1H), 8.04-8.05 (m, 1H), 12.37 (br s, 1H).
Step 3: 2- (3- (Chloromethyl) benzamido) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3-b] pyridine-3-carboxylic acid tert obtained in Step 2 6-Cyclopropyl-2- (3-(((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide) -4,5,6,7 in the same manner as in Example 59. Tert-butyl (5.86 g, 94%) of 4-tetrahydrothieno [2,3-c] pyridine-3-carboxylate was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 0.53-0.56 (m, 4H), 1.01 (t, J = 7.2 Hz, 6H), 1.59 (s, 9H), 1.63-1.74 (m, 2H) , 1.84-1.90 (m, 1H), 2.20 (s, 3H), 2.39-2.55 (m, 8H), 2.89-2.95 (m, 4H), 3.57 (s, 2H), 3.75 (s, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.55-7.59 (m, 1H), 7.84-7.87 (m, 1H), 7.95-7.96 (m, 1H), 12.31 (br s, 1H).
Step 4: 6-Cyclopropyl-2- (3-((((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide) -4,5,6,7-tetrahydrothieno obtained in Step 3 [ N- (6-Cyclopropyl-3- (hydrazinecarbonyl) -4,5,6, using tert-butyl 2,3-c] pyridine-3-carboxylate as in Step 5 of Example 88 7-tetrahydrothieno [2,3-c] pyridin-2-yl) -3-(((3-diethylamino) propyl) (methyl) amino) methyl) benzamide (1.22 g, 81%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 0.50-0.60 (m, 4H), 1.06 (t, J = 6.8 Hz, 6H), 1.70-1.77 (m, 2H), 1.87-1.90 (m, 1H), 2.21 (s, 3H), 2.42 (t, J = 6.8 Hz, 2H), 2.54-2.64 (m, 6H), 2.83 (t, J = 5.9 Hz, 2H), 3.01 (t, J = 5.9 Hz, 2H), 3.61 (s, 2H), 3.79 (s, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.97 (s, 1H).
Step 5: 2,1,3-Benzoxadiazole-5-carbaldehyde and N- (6-cyclopropyl-3- (hydrazinecarbonyl) -4,5,6,7-tetrahydrothieno obtained in Step 4 Compound 90 ([2,3-c] pyridin-2-yl) -3-(((3-diethylamino) propyl) (methyl) amino) methyl) benzamide was prepared in the same manner as in Step 5 of Example 86. 40.4 mg, 44%).
1 H-NMR (270 MHz, CDCl 3 , δ): 0.56-0.60 (m, 4H), 1.01 (t, J = 7.2 Hz, 6H), 1.66-1.71 (m, 2H), 1.89-1.95 (m, 1H), 2.20 (s, 3H), 2.38-2.56 (m, 8H), 3.01-3.08 (m, 4H), 3.58 (s, 2H), 3.83 (s, 2H), 7.46 (t, J = 7.6 Hz , 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.86-7.97 (m, 4H), 8.24 (dd, J = 9.4, 1.5 Hz, 1H), 8.30 (s, 1H). ESI-MS m / z: 630 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-ヒドロキシ-6-メチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(クロロメチル)ベンズアミド（化合物91）
工程１：3-メチル-3-ヒドロキシ-シクロヘキサノンを用い、参考例１と同様にして、(E)-2-アミノ-N’-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)-6-ヒドロキシ-6-メチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボヒドラジン（983 mg, 57%）を得た。
1H-NMR (270 MHz, DMSO-d6, δ): 1.21 (s, 3H), 1.53-1.69 (m, 2H), 2.47 (s, 2H), 2.59-2.76 (m, 2H), 4.51 (s, 1H), 6.66 (s, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 8.10 (s, 1H), 8.30 (s, 1H), 10.79 (s, 1H).
工程2：工程1で得られた(E)-2-アミノ-N’-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)-6-ヒドロキシ-6-メチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボヒドラジンを用い、実施例1と同様にして、化合物91（0.177 g, 87%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.46 (s, 3H), 1.80-2.08 (m, 2H), 2.77-3.08 (m, 4H), 4.68 (s, 2H), 7.49-7.65 (m, 3H), 7.96-8.07 (m, 4H), 8.18 (s, 1H), 9.19 (s, 1H), 12.91 (s ,1H).  (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-hydroxy-6-methyl-4,5,6,7-tetrahydrobenzo [b ] Thiophen-2-yl) -3- (chloromethyl) benzamide (Compound 91)
Step 1: (E) -2-Amino-N ′-(4-chloro-3- (trifluoromethyl) benzylidene) -6 using 3-methyl-3-hydroxy-cyclohexanone in the same manner as in Reference Example 1. -Hydroxy-6-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carbohydrazine (983 mg, 57%) was obtained.
1 H-NMR (270 MHz, DMSO-d 6 , δ): 1.21 (s, 3H), 1.53-1.69 (m, 2H), 2.47 (s, 2H), 2.59-2.76 (m, 2H), 4.51 ( s, 1H), 6.66 (s, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 8.10 (s, 1H), 8.30 (s, 1H), 10.79 (s, 1H).
Step 2: (E) -2-amino-N ′-(4-chloro-3- (trifluoromethyl) benzylidene) -6-hydroxy-6-methyl-4,5,6,7 obtained in Step 1 Compound 91 (0.177 g, 87%) was obtained in the same manner as in Example 1 using -tetrahydrobenzo [b] thiophene-3-carbohydrazine.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.46 (s, 3H), 1.80-2.08 (m, 2H), 2.77-3.08 (m, 4H), 4.68 (s, 2H), 7.49-7.65 ( m, 3H), 7.96-8.07 (m, 4H), 8.18 (s, 1H), 9.19 (s, 1H), 12.91 (s, 1H).
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-ヒドロキシ-6-メチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド（化合物92）
　実施例91で得られた化合物91を用い、実施例59と同様にして、化合物92（194 mg, 94%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.03 (t, J= 7.1 Hz, 6H), 1.45 (s, 3H), 1.67-1.75 (m, 4H), 1.79-2.07 (m, 2H), 2.20 (s, 3H), 2.39-2.56 (m, 8H), 2.77-2.92 (m, 2H), 3.57 (s, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.56-7.59 (m, 2H), 7.90-7.97 (m, 3H), 8.04-8.05 (m, 1H), 8.21 (s, 1H).  ESI-MS m/z: 630, 632 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-hydroxy-6-methyl-4,5,6,7-tetrahydrobenzo [b ] Thiophen-2-yl) -3-(((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide (Compound 92)
Compound 92 (194 mg, 94%) was obtained in the same manner as in Example 59, using Compound 91 obtained in Example 91.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.03 (t, J = 7.1 Hz, 6H), 1.45 (s, 3H), 1.67-1.75 (m, 4H), 1.79-2.07 (m, 2H) , 2.20 (s, 3H), 2.39-2.56 (m, 8H), 2.77-2.92 (m, 2H), 3.57 (s, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.56-7.59 (m , 2H), 7.90-7.97 (m, 3H), 8.04-8.05 (m, 1H), 8.21 (s, 1H). ESI-MS m / z: 630, 632 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-6-クロロメチル-6-ヒドロキシメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド（化合物93）
工程1：US4985411に記載の方法で得た1,4-ジオキサスピロ[4.5]デカン-8-カルボン酸エチル（5.36 g, 25.0 mmol）をTHF（150 mL）に溶解し、-78℃にてリチウムジイソプロピルアミド（15.0 mL, 30.0 mmol）を加え、1時間撹拌した。混合物に-78℃にてクロロぎ酸エチル（3.6 mL, 27.5 mL）を加え、1時間撹拌した。混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝90／10）で精製することにより、4-ジオキサスピロ[4.5]デカン-8,8-ジカルボン酸ジエチル（6.94 g, 97%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.25 (t, J = 7.1 Hz, 6H), 1.66-1.71 (m, 4H), 2.16-2.21 (m, 4H), 3.94 (s, 4H), 4.19 (q, J = 7.1 Hz, 4H).
工程2：THF（30 mL）に水素化アルミニウムリチウム（0.725 g, 19.1 mmol）を懸濁させ、0℃にて工程1で得られた4-ジオキサスピロ[4.5]デカン-8,8-ジカルボン酸ジエチル（4.56 g, 15.9 mmol）を加えた。混合物を1時間攪拌した後、水素化アルミニウムリチウム（0.725 g, 19.1 mmol）を加え、室温にて1時間撹拌した。混合物に水（0.73 mL）、10 mol/L 水酸化ナトリウム水溶液（0.32 mL）、水（2.2 mL）および無水硫酸ナトリウムをこの順で加えて終夜撹拌した後、セライトを通してろ過し、ろ液を減圧下で濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝5／1）でリスラリーすることにより、1,4-ジオキサスピロ[4.5]デカン-8,8-ジイルジメタノール（2.46 g, 76%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.57 (m, 4H), 1.63 (m, 4H), 2.21 (t, J = 3.9 Hz, 2H), 3.66 (d, J = 3.9 Hz, 4H), 3.95 (s, 4H).
工程3：工程2で得られる1,4-ジオキサスピロ[4.5]デカン-8,8-ジイルジメタノール（3.17 g, 15.7 mmol）をTHF（150 mL）に溶解し、0℃にてn-ブチルリチウム（2.76mol/L THF溶液；6.81 mL, 18.8 mmol）を加えた。混合物を30分間攪拌した後、4-トルエンスルホニルクロリド（3.59 g, 18.8 mmol）のTHF溶液（30 mL）を加え、室温にて1時間撹拌した。混合物に0℃にてn-ブチルリチウム（2.76mol/L THF溶液；6.81 mL, 18.8 mmol）を加え、65℃にてさらに1時間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝80／20）で精製することにより、1,4,10-トリオキサスピロ[3.4.5]トリデカン（2.48 g, 86%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.58 (t, J = 6.2 Hz, 4H), 1.92 (t, J = 6.2 Hz, 4H), 3.93 (s, 4H), 4.41 (s, 4H).
工程4：工程3で得られた1,4,10-トリオキサスピロ[3.4.5]トリデカン（0.20 g, 1.09 mmol）をTHF（5 mL）に溶解し、室温にて10%塩酸（1 mL）を加え、終夜攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝70／30）で精製することにより、4-クロロメチル-4-(ヒドロキシメチル)シクロヘキサノン（0.14 g, 71%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.85 (t, J = 6.9 Hz, 4H), 2.37 (t, J = 6.9 Hz, 4H), 3.69 (s, 2H), 3.71 (s, 2H). 
工程5：工程4で得られる4-クロロメチル-4-(ヒドロキシメチル)シクロヘキサノンを用い、実施例86の工程1と同様にして、2-アミノ-6-(クロロメチル)-6-(ヒドロキシメチル)-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（238 mg, 94%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.54 (s, 9H), 1.72 (t, J= 6.6 Hz, 2H), 2.47 (s, 2H), 2.68-2.73 (m, 2H), 3.59-3.67 (m, 4H), 5.91 (s, 2H). 
工程6：工程5で得られる2-アミノ-6-(クロロメチル)-6-(ヒドロキシメチル)-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチルを用い、実施例86の工程2および工程3と同様にして、6-(クロロメチル)-2-(3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド)-6-(ヒドロキシメチル)-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（1.68 g, 88%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.01 (t, J = 7.1 Hz, 6H), 1.62 (s, 9H), 1.79 (t, J = 6.8 Hz, 2H), 2.24 (s, 3H), 2.50-2.57 (m, 6H), 2.61-2.66 (m, 4H), 2.82 (s, 2H), 3.60-3.63 (m, 6H), 7.48 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H), 12.37 (s, 1H). 
工程7：工程6で得られた6-(クロロメチル)-2-(3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド)-6-(ヒドロキシメチル)-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチルを用い、実施例86の工程4と同様にして、N-(6-(クロロメチル)-3-(ヒドラジンカルボニル)-6-(ヒドロキシメチル)-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミド（0.62 g, 65%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.01 (t, J = 7.1 Hz, 6H), 1.86-1.88 (m, 2H), 2.24 (s, 3H), 2.46-2.57 (m, 6H), 2.60-2.65 (m, 2H), 2.70 (d, J = 4.4 Hz, 2H), 2.77 (s, 2H), 3.62-3.72 (m, 6H), 4.12 (s, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.97 (s, 1H), 12.95 (s, 1H). 
工程8：工程7で得られるN-(6-(クロロメチル)-3-(ヒドラジンカルボニル)-6-(ヒドロキシメチル)-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)-3-(((2-(ジエチルアミノ)エチル)(メチル)アミノ)メチル)ベンズアミドを用い、実施例86の工程5と同様にして、化合物93（0.64 g, 76%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.02 (t, J = 7.1 Hz, 6H), 1.92 (t, J = 6.6 Hz, 2H), 2.24 (s, 3H), 2.51-2.64 (m, 8H), 2.71 (d, J = 3.3 Hz, 2H), 2.92 (s, 2H), 3.68 (q, J = 11.7 Hz, 6H), 7.46 (t, J= 7.6 Hz, 1H), 7.59 (t, J = 7.1 Hz, 2H), 7.92-7.96 (m, 3H), 8.04 (s, 1H), 8.23 (s, 1H).  ESI-MS m/z: 726 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6-chloromethyl-6-hydroxymethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide (Compound 93)
Step 1: Dissolve ethyl 1,4-dioxaspiro [4.5] decane-8-carboxylate (5.36 g, 25.0 mmol) obtained by the method described in US4985411 in THF (150 mL), and add lithium diisopropyl at -78 ° C. Amide (15.0 mL, 30.0 mmol) was added and stirred for 1 hour. Ethyl chloroformate (3.6 mL, 27.5 mL) was added to the mixture at −78 ° C., and the mixture was stirred for 1 hr. A saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 90/10) to obtain diethyl 4-dioxaspiro [4.5] decane-8,8-dicarboxylate (6.94 g, 97%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.25 (t, J = 7.1 Hz, 6H), 1.66-1.71 (m, 4H), 2.16-2.21 (m, 4H), 3.94 (s, 4H) , 4.19 (q, J = 7.1 Hz, 4H).
Step 2: Lithium aluminum hydride (0.725 g, 19.1 mmol) suspended in THF (30 mL) and diethyl 4-dioxaspiro [4.5] decane-8,8-dicarboxylate obtained in Step 1 at 0 ° C (4.56 g, 15.9 mmol) was added. The mixture was stirred for 1 hour, lithium aluminum hydride (0.725 g, 19.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (0.73 mL), 10 mol / L aqueous sodium hydroxide solution (0.32 mL), water (2.2 mL) and anhydrous sodium sulfate were added to the mixture in this order, and the mixture was stirred overnight, then filtered through celite, and the filtrate was depressurized. The residue was reslurried with silica gel column chromatography (hexane / ethyl acetate = 5/1) to give 1,4-dioxaspiro [4.5] decane-8,8-diyldimethanol (2.46 g, 76% )
1 H-NMR (270 MHz, CDCl 3 , δ): 1.57 (m, 4H), 1.63 (m, 4H), 2.21 (t, J = 3.9 Hz, 2H), 3.66 (d, J = 3.9 Hz, 4H ), 3.95 (s, 4H).
Step 3: 1,4-Dioxaspiro [4.5] decane-8,8-diyldimethanol (3.17 g, 15.7 mmol) obtained in Step 2 is dissolved in THF (150 mL) and n-butyllithium at 0 ° C. (2.76 mol / L THF solution; 6.81 mL, 18.8 mmol) was added. The mixture was stirred for 30 minutes, a THF solution (30 mL) of 4-toluenesulfonyl chloride (3.59 g, 18.8 mmol) was added, and the mixture was stirred at room temperature for 1 hour. N-Butyllithium (2.76 mol / L THF solution; 6.81 mL, 18.8 mmol) was added to the mixture at 0 ° C., and the mixture was further stirred at 65 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80/20) to obtain 1,4,10-trioxaspiro [3.4.5] tridecane (2.48 g, 86%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.58 (t, J = 6.2 Hz, 4H), 1.92 (t, J = 6.2 Hz, 4H), 3.93 (s, 4H), 4.41 (s, 4H ).
Step 4: Dissolve 1,4,10-trioxaspiro [3.4.5] tridecane (0.20 g, 1.09 mmol) obtained in Step 3 in THF (5 mL) and add 10% hydrochloric acid (1 mL) at room temperature. ) And stirred overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 70/30) to give 4-chloromethyl-4- (hydroxymethyl) cyclohexanone (0.14 g, 71%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.85 (t, J = 6.9 Hz, 4H), 2.37 (t, J = 6.9 Hz, 4H), 3.69 (s, 2H), 3.71 (s, 2H ).
Step 5: Using 4-chloromethyl-4- (hydroxymethyl) cyclohexanone obtained in Step 4, in the same manner as in Step 1 of Example 86, 2-amino-6- (chloromethyl) -6- (hydroxymethyl) ) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (238 mg, 94%) was obtained.
1 H-NMR (270 MHz, CDCl 3 , δ): 1.54 (s, 9H), 1.72 (t, J = 6.6 Hz, 2H), 2.47 (s, 2H), 2.68-2.73 (m, 2H), 3.59 -3.67 (m, 4H), 5.91 (s, 2H).
Step 6: Using tert-butyl 2-amino-6- (chloromethyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in Step 5 In the same manner as in Step 2 and Step 3 of Example 86, 6- (chloromethyl) -2- (3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide) -6- ( Hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (1.68 g, 88%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.01 (t, J = 7.1 Hz, 6H), 1.62 (s, 9H), 1.79 (t, J = 6.8 Hz, 2H), 2.24 (s, 3H ), 2.50-2.57 (m, 6H), 2.61-2.66 (m, 4H), 2.82 (s, 2H), 3.60-3.63 (m, 6H), 7.48 (t, J = 7.6 Hz, 1H), 7.57 ( d, J = 8.1 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H), 12.37 (s, 1H).
Step 7: 6- (Chloromethyl) -2- (3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide) -6- (hydroxymethyl) -4, obtained in Step 6 Using tert-butyl 5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate as in Step 4 of Example 86, N- (6- (chloromethyl) -3- (hydrazinecarbonyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide (0.62 g, 65%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.01 (t, J = 7.1 Hz, 6H), 1.86-1.88 (m, 2H), 2.24 (s, 3H), 2.46-2.57 (m, 6H) , 2.60-2.65 (m, 2H), 2.70 (d, J = 4.4 Hz, 2H), 2.77 (s, 2H), 3.62-3.72 (m, 6H), 4.12 (s, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.97 (s, 1H), 12.95 (s, 1H).
Step 8: N- (6- (chloromethyl) -3- (hydrazinecarbonyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl obtained in step 7 ) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide was used in the same manner as in Step 5 of Example 86 to give compound 93 (0.64 g, 76%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.02 (t, J = 7.1 Hz, 6H), 1.92 (t, J = 6.6 Hz, 2H), 2.24 (s, 3H), 2.51-2.64 (m , 8H), 2.71 (d, J = 3.3 Hz, 2H), 2.92 (s, 2H), 3.68 (q, J = 11.7 Hz, 6H), 7.46 (t, J = 7.6 Hz, 1H), 7.59 (t , J = 7.1 Hz, 2H), 7.92-7.96 (m, 3H), 8.04 (s, 1H), 8.23 (s, 1H). ESI-MS m / z: 726 (M + H) + .
(E)-N-(3-(2-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)ヒドラジンカルボニル)-5,7-ジヒドロ-4H-スピロ[ベンゾ[b]チオフェン-6,3’-オキセタン]-2-イル)-3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド（化合物94）
工程１：実施例93の工程3で得られる1,4,10-トリオキサスピロ[3.4.5]トリデカン（25g, 0.135 mol）をTHF（100 mL）に溶解し、0.2%塩酸（290 mL）を加え、室温にて終夜撹拌した。混合物を飽和炭酸水素ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝80／20）で精製することにより、2-オキサスピロ[3.5]ノナン-7-オン（17.1 g, 90%）を得た。
1H-NMR (400 MHz, CDCl3, δ):2.18 (t, J = 6.8 Hz, 4H), 2.33 (t, J = 6.8 Hz, 4H), 4.56 (s, 4H).
工程2：工程1で得られた2-オキサスピロ[3.5]ノナン-7-オンを用い、実施例86の工程1と同様にして、2-アミノ-5,7-ジヒドロ-4H-スピロ[ベンゾ[b]チオフェン-6,3’-オキセタン]-3-カルボン酸tert-ブチル（10.5 g, 58%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.55 (s, 9H), 2.01 (t, J= 6.3 Hz, 2H), 2.76 (t, J = 6.3 Hz, 2H), 2.82 (s, 2H), 4.44 (d, J= 5.9 Hz, 2H), 4.51 (d, J = 5.9 Hz, 2H), 5.90 (s, 2H).
工程3：工程2で得られた2-アミノ-5,7-ジヒドロ-4H-スピロ[ベンゾ[b]チオフェン-6,3’-オキセタン]-3-カルボン酸tert-ブチルを用い、実施例86の工程2と同様にして、2-(3-(クロロメチル)ベンズアミド)-5,7-ジヒドロ-4H-スピロ[ベンゾ[b]チオフェン-6,3’-オキセタン]-3-カルボン酸tert-ブチル（1.16 g, 76%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.62 (s, 9H), 2.08 (t, J= 6.4 Hz, 2H), 2.86 (t, J = 6.2 Hz, 2H), 3.02 (s, 2H), 4.48 (d, J= 6.0 Hz, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.68 (s, 2H), 7.54 (t, J= 7.6 Hz, 1H), 7.62-7.64 (m, 1H), 7.93 (dt, J = 7.8, 1.4 Hz, 1H), 8.04 (s, 1H), 12.41 (s, 1H).
工程4：工程3で得られた2-(3-(クロロメチル)ベンズアミド)-5,7-ジヒドロ-4H-スピロ[ベンゾ[b]チオフェン-6,3’-オキセタン]-3-カルボン酸tert-ブチルを用い、実施例86の工程3と同様にして、2-(3-(((2-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド)-5,7-ジヒドロ-4H-スピロ[ベンゾ[b]チオフェン-6,3’-オキセタン]-3-カルボン酸tert-ブチル（1.56 g, 77%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.11 (br s, 6H), 1.62 (s, 9H), 1.77 (br s, 4H), 2.08 (t, J = 6.3 Hz, 2H), 2.22 (s, 3H), 2.43 (t, J= 6.8 Hz, 2H), 2.66 (br s, 4H), 2.86 (t, J = 6.3 Hz, 2H), 3.01 (s, 2H), 3.58 (s, 2H), 4.47 (d, J = 5.9 Hz, 2H), 4.54 (d, J = 5.9 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H), 7.84 (d, J= 7.8 Hz, 1H), 7.96 (s, 1H), 12.36 (s, 1H).
工程5：工程4で得られた2-(3-(((2-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)ベンズアミド)-5,7-ジヒドロ-4H-スピロ[ベンゾ[b]チオフェン-6,3’-オキセタン]-3-カルボン酸tert-ブチルを用い、実施例86の工程4と同様にして、3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)-N-(3-(ヒドラジンカルボニル)-5,7-ジヒドロ-4H-スピロ[ベンゾ[b]チオフェン-6,3’-オキセタン]-2-イル)ベンズアミド（79 mg, 70%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.01 (t, J = 7.1 Hz, 6H), 1.67 (td, J = 16.4, 9.5 Hz, 2H), 2.18 (t, J = 6.0 Hz, 5H), 2.41 (t, J = 7.2 Hz, 2H), 2.46-2.56 (m, 6H), 2.82 (t, J = 6.0 Hz, 2H), 3.05 (s, 2H), 3.58 (s, 2H), 4.52 (dd, J = 13.7, 6.0 Hz, 4H), 7.47 (t, J = 7.5 Hz, 1H), 7.57 (d, J= 7.5 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.97 (s, 1H), 12.95 (s, 1H). 
工程6：工程5で得られる3-(((3-(ジエチルアミノ)プロピル)(メチル)アミノ)メチル)-N-(3-(ヒドラジンカルボニル)-5,7-ジヒドロ-4H-スピロ[ベンゾ[b]チオフェン-6,3’-オキセタン]-2-イル)ベンズアミドを用い、実施例86の工程5と同様にして、化合物94（70 mg, 65%）を得た。
1H-NMR (270 MHz, CDCl3, δ): 1.05 (t, J = 6.7 Hz, 6H), 1.69-1.71 (m, 2H), 2.21-2.23 (m, 5H), 2.42 (t, J = 7.1 Hz, 2H), 2.57 (br m, 6H), 2.95 (s, 2H), 3.09 (s, 2H), 3.57 (s, 2H), 4.55 (dd, J = 11.4, 5.7 Hz, 4H), 7.46 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 7.9 Hz, 2H), 7.96 (s, 1H), 8.04 (s, 1H), 8.25 (s, 1H).  ESI-MS m/z: 704 (M+H)+. (E) -N- (3- (2- (4-Chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3 ' -Oxetane] -2-yl) -3-(((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide (Compound 94)
Step 1: 1,4,10-trioxaspiro [3.4.5] tridecane (25 g, 0.135 mol) obtained in Step 3 of Example 93 was dissolved in THF (100 mL) and 0.2% hydrochloric acid (290 mL) And stirred at room temperature overnight. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80/20) to give 2-oxaspiro [3.5] nonan-7-one (17.1 g, 90%).
1 H-NMR (400 MHz, CDCl 3 , δ): 2.18 (t, J = 6.8 Hz, 4H), 2.33 (t, J = 6.8 Hz, 4H), 4.56 (s, 4H).
Step 2: Using 2-oxaspiro [3.5] nonan-7-one obtained in Step 1, in the same manner as in Step 1 of Example 86, 2-amino-5,7-dihydro-4H-spiro [benzo [benzo [ b] tert-butyl thiophene-6,3′-oxetane] -3-carboxylate (10.5 g, 58%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.55 (s, 9H), 2.01 (t, J = 6.3 Hz, 2H), 2.76 (t, J = 6.3 Hz, 2H), 2.82 (s, 2H ), 4.44 (d, J = 5.9 Hz, 2H), 4.51 (d, J = 5.9 Hz, 2H), 5.90 (s, 2H).
Step 3: Example 86 using tert-butyl 2-amino-5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3′-oxetane] -3-carboxylate obtained in Step 2 2- (3- (chloromethyl) benzamido) -5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3′-oxetane] -3-carboxylic acid tert- Butyl (1.16 g, 76%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.62 (s, 9H), 2.08 (t, J = 6.4 Hz, 2H), 2.86 (t, J = 6.2 Hz, 2H), 3.02 (s, 2H ), 4.48 (d, J = 6.0 Hz, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.68 (s, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.62-7.64 (m , 1H), 7.93 (dt, J = 7.8, 1.4 Hz, 1H), 8.04 (s, 1H), 12.41 (s, 1H).
Step 4: 2- (3- (Chloromethyl) benzamido) -5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3′-oxetane] -3-carboxylic acid tert obtained in Step 3 2- (3-(((2- (diethylamino) propyl) (methyl) amino) methyl) benzamido) -5,7-dihydro-4H-spiro in the same manner as Example 86, step 3 [Benzo [b] thiophene-6,3′-oxetane] -3-carboxylate tert-butyl (1.56 g, 77%) was obtained.
1 H-NMR (400 MHz, CDCl 3 , δ): 1.11 (br s, 6H), 1.62 (s, 9H), 1.77 (br s, 4H), 2.08 (t, J = 6.3 Hz, 2H), 2.22 (s, 3H), 2.43 (t, J = 6.8 Hz, 2H), 2.66 (br s, 4H), 2.86 (t, J = 6.3 Hz, 2H), 3.01 (s, 2H), 3.58 (s, 2H ), 4.47 (d, J = 5.9 Hz, 2H), 4.54 (d, J = 5.9 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.96 (s, 1H), 12.36 (s, 1H).
Step 5: 2- (3-(((2- (Diethylamino) propyl) (methyl) amino) methyl) benzamido) -5,7-dihydro-4H-spiro [benzo [b] thiophene- obtained in Step 4 3-((((3- (diethylamino) propyl) (methyl) amino) methyl) -N using tert-butyl 6,3′-oxetane] -3-carboxylate as in Step 4 of Example 86 -(3- (hydrazinecarbonyl) -5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3'-oxetane] -2-yl) benzamide (79 mg, 70%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.01 (t, J = 7.1 Hz, 6H), 1.67 (td, J = 16.4, 9.5 Hz, 2H), 2.18 (t, J = 6.0 Hz, 5H ), 2.41 (t, J = 7.2 Hz, 2H), 2.46-2.56 (m, 6H), 2.82 (t, J = 6.0 Hz, 2H), 3.05 (s, 2H), 3.58 (s, 2H), 4.52 (dd, J = 13.7, 6.0 Hz, 4H), 7.47 (t, J = 7.5 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.97 (s, 1H), 12.95 (s, 1H).
Step 6: 3-((((3- (Diethylamino) propyl) (methyl) amino) methyl) -N- (3- (hydrazinecarbonyl) -5,7-dihydro-4H-spiro [benzo [ b] Thiophene-6,3′-oxetane] -2-yl) benzamide was used in the same manner as in Step 5 of Example 86 to give compound 94 (70 mg, 65%).
1 H-NMR (270 MHz, CDCl 3 , δ): 1.05 (t, J = 6.7 Hz, 6H), 1.69-1.71 (m, 2H), 2.21-2.23 (m, 5H), 2.42 (t, J = 7.1 Hz, 2H), 2.57 (br m, 6H), 2.95 (s, 2H), 3.09 (s, 2H), 3.57 (s, 2H), 4.55 (dd, J = 11.4, 5.7 Hz, 4H), 7.46 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 7.9 Hz, 2H), 7.96 (s, 1H), 8.04 (s, 1H), 8.25 (s, 1H). ESI-MS m / z: 704 (M + H) + .
化合物95：3,6,9,12,15-ペンタオキサヘプタデカン-1,17-ジオール（6.09 mL, 31.6 mmol）をDMF（40 mL）に溶解し、水素化ナトリウム（1.26 g, 31.6 mmol）および実施例1で得られる化合物1（4.6 g, 7.90 mmol）を0℃で加え、室温で3時間撹拌した。混合物に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝4／1）で精製することにより化合物95（5.16 g,79%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 2.53 (s, 2H), 2.88 (s, 2H), 3.58-3.73 (m, 24H), 4.65 (s, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.59 (t, J = 8.2 Hz, 2H), 7.95-8.04 (m, 4H), 8.24 (s, 1H), 9.29 (s, 1H), 12.89 (s, 1H).  ESIMS m/z: 845 (M + 18)+. Compound 95: 3,6,9,12,15-pentaoxaheptadecane-1,17-diol (6.09 mL, 31.6 mmol) dissolved in DMF (40 mL) and sodium hydride (1.26 g, 31.6 mmol) And the compound 1 (4.6 g, 7.90 mmol) obtained in Example 1 was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 4/1) to give Compound 95 (5.16 g, 79%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 2.53 (s, 2H), 2.88 (s, 2H), 3.58-3.73 (m, 24H), 4.65 (s, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.59 (t, J = 8.2 Hz, 2H), 7.95-8.04 (m, 4H), 8.24 (s, 1H), 9.29 (s, 1H), 12.89 (s, 1H) .ESIMS m / z: 845 (M + 18) + .
化合物96：実施例95で得られる化合物95（1.96 g, 2.36 mmol）をジクロロメタン（12 mL）に溶解し、トリエチルアミン（0.66 mL, 4.73 mmol）およびメシルクロリド（0.277 mL, 3.55 mmol）を0℃で加え、室温で1時間撹拌した。混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘプタン／酢酸エチル＝1／9）で精製することにより化合物96（2.16 g,79%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 0.94 (s, 6H), 1.65 (s, 2H), 2.52 (s, 2H), 2.91 (s, 2H), 3.06 (s, 3H), 3.61-3.75 (m, 22H), 4.34-4.37 (m, 2H), 4.68 (s, 2H), 7.47-7.64 (m, 3H), 7.92-8.10 (m, 4H), 8.23 (s, 1H), 9.40 (s, 1H), 12.88 (s, 1H).  ESIMS m/z: 923 (M + 18)+. Compound 96: Compound 95 (1.96 g, 2.36 mmol) obtained in Example 95 was dissolved in dichloromethane (12 mL), and triethylamine (0.66 mL, 4.73 mmol) and mesyl chloride (0.277 mL, 3.55 mmol) were added at 0 ° C. The mixture was further stirred at room temperature for 1 hour. To the mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate = 1/9) to obtain Compound 96 (2.16 g, 79%).
1 H-NMR (300 MHz, CDCl 3 , δ): 0.94 (s, 6H), 1.65 (s, 2H), 2.52 (s, 2H), 2.91 (s, 2H), 3.06 (s, 3H), 3.61 -3.75 (m, 22H), 4.34-4.37 (m, 2H), 4.68 (s, 2H), 7.47-7.64 (m, 3H), 7.92-8.10 (m, 4H), 8.23 (s, 1H), 9.40 (s, 1H), 12.88 (s, 1H) .ESIMS m / z: 923 (M + 18) + .
化合物97：実施例96で得られる化合物96（0.20 g, 0.670 mmol）をDMA（0.50 mL）に溶解し、実施例46の工程1と同様にして得られるベンジル2-(2-メトキシエチルアミノ)アセテート（0.246g, 1.10 mmol）を加え、マイクロウェーブを用いて120℃で2時間撹拌した。混合物に1 mol/L塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝4／1）で精製することにより化合物97（0.231 g,定量的）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.04 (s, 6H), 1.65 (t, J = 5.9 Hz, 2H), 2.06 (s, 2H), 2.49 (s, 2H), 2.83-2.97 (m, 6H), 3.00 (s, 2H), 3.29 (s, 3H), 3.46 (q, J = 6.8 Hz, 2H), 3.50-3.69 (m, 20H), 4.64 (s, 2H), 5.13 (s, 2H), 7.31-7.35 (m, 5H), 7.47 (t, J = 7.8 Hz, 1H), 7.54-7.60 (m, 2H), 7.94 (d, J = 7.8 Hz, 2H), 7.99-8.03 (m, 2H), 8.27 (s, 1H), 9.50 (s, 1H), 12.86 (s, 1H).  ESIMS m/z: 1033 (M + H)+. Compound 97: Compound 96 (0.20 g, 0.670 mmol) obtained in Example 96 was dissolved in DMA (0.50 mL), and benzyl 2- (2-methoxyethylamino) obtained in the same manner as in Step 1 of Example 46 Acetate (0.246 g, 1.10 mmol) was added, and the mixture was stirred at 120 ° C. for 2 hours using a microwave. 1 mol / L hydrochloric acid was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 4/1) to give Compound 97 (0.231 g, quantitative).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.04 (s, 6H), 1.65 (t, J = 5.9 Hz, 2H), 2.06 (s, 2H), 2.49 (s, 2H), 2.83-2.97 (m, 6H), 3.00 (s, 2H), 3.29 (s, 3H), 3.46 (q, J = 6.8 Hz, 2H), 3.50-3.69 (m, 20H), 4.64 (s, 2H), 5.13 ( s, 2H), 7.31-7.35 (m, 5H), 7.47 (t, J = 7.8 Hz, 1H), 7.54-7.60 (m, 2H), 7.94 (d, J = 7.8 Hz, 2H), 7.99-8.03 (m, 2H), 8.27 (s, 1H), 9.50 (s, 1H), 12.86 (s, 1H) .ESIMS m / z: 1033 (M + H) + .
化合物98：実施例97で得られる化合物97（0.228 g, 0.221 mmol）をエタノール（2.00 mL）に溶解し、水酸化ナトリウム水溶液（0.884 mL, 0.884 mmol）を加え、室温で終夜撹拌した。混合物に2 mol/L塩酸を加え、クロロホルム／メタノール＝4／1で抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝4／1）で精製することにより化合物98（0.048 g,23%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.06 (s, 6H), 1.64 (brs, 2H), 2.53 (s, 2H), 2.89 (brs, 6H), 3.32 (brs, 5H), 3.49-3.67 (m, 24H), 4.63 (s, 2H), 7.44-7.58 (m, 3H), 7.96 (t, J = 7.3 Hz, 3H), 8.06 (s, 1H), 8.40 (s, 1H), 9.93 (s, 1H), 12.71 (s, 1H). ESIMS m/z: 943 (M + H)+.  Compound 98: Compound 97 (0.228 g, 0.221 mmol) obtained in Example 97 was dissolved in ethanol (2.00 mL), aqueous sodium hydroxide solution (0.884 mL, 0.884 mmol) was added, and the mixture was stirred at room temperature overnight. 2 mol / L hydrochloric acid was added to the mixture, and the mixture was extracted with chloroform / methanol = 4/1. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 4/1) to give Compound 98 (0.048 g, 23%).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.06 (s, 6H), 1.64 (brs, 2H), 2.53 (s, 2H), 2.89 (brs, 6H), 3.32 (brs, 5H), 3.49 -3.67 (m, 24H), 4.63 (s, 2H), 7.44-7.58 (m, 3H), 7.96 (t, J = 7.3 Hz, 3H), 8.06 (s, 1H), 8.40 (s, 1H), 9.93 (s, 1H), 12.71 (s, 1H) .ESIMS m / z: 943 (M + H) + .  
化合物99～104：対応するベンジル2-アミノアセテートを用い、実施例97および98と同様にして、化合物99～104を得た。
化合物99: ESIMS m/z: 943 (M + H)+.
化合物100: ESIMS m/z: 957 (M + H)+.
化合物101: ESIMS m/z: 971 (M + H)+.
化合物102: ESIMS m/z: 957 (M + H)+.
化合物103: ESIMS m/z: 939 (M + H)+.
化合物104: ESIMS m/z: 913 (M + H)+. Compounds 99 to 104: Compounds 99 to 104 were obtained in the same manner as in Examples 97 and 98 using the corresponding benzyl 2-aminoacetate.
Compound 99: ESIMS m / z: 943 (M + H) + .
Compound 100: ESIMS m / z: 957 (M + H) + .
Compound 101: ESIMS m / z: 971 (M + H) + .
Compound 102: ESIMS m / z: 957 (M + H) + .
Compound 103: ESIMS m / z: 939 (M + H) + .
Compound 104: ESIMS m / z: 913 (M + H) + .
化合物105：実施例3で得られる化合物3（7.00 g, 12.73 mmol）をDMF（50.0 mL）に溶解し、炭酸セシウム（8.29 g, 25.5 mmol）および17-ヒドロキシ-3,6,9,12,15-ペンタオキサヘプタデシル-4-メチルベンゼンスルホネート（11.11 g, 25.5 mmol）を加え、65℃で3時間撹拌した。混合物に蒸留水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣にメタノール（15 mL）を加え、スラリーすることにより化合物105（6.32 g,61%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.68 (t, J = 6.0 Hz, 2H), 2.53 (s, 2H), 2.87 (s, 2H), 3.58-3.75 (m, 20H), 3.88 (t, J = 4.8 Hz, 2H), 4.21 (t, J = 4.8 Hz, 2H), 7.13 (dd, J= 8.1, 1.8 Hz, 1H,), 7.39 (t, J = 8.1 Hz, 1H), 7.56-7.61 (m, 3H), 7.97 (d, J = 9.9 Hz, 1H), 8.04 (s, 1H), 8.23 (s, 1H), 9.24 (s, 1H), 12.87 (s, 1H).  ESIMS m/z: 814 (M + H)+. Compound 105: Compound 3 (7.00 g, 12.73 mmol) obtained in Example 3 was dissolved in DMF (50.0 mL), and cesium carbonate (8.29 g, 25.5 mmol) and 17-hydroxy-3,6,9,12, 15-Pentaoxaheptadecyl-4-methylbenzenesulfonate (11.11 g, 25.5 mmol) was added, and the mixture was stirred at 65 ° C. for 3 hours. Distilled water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methanol (15 mL) was added to the residue and slurryed to obtain Compound 105 (6.32 g, 61%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.68 (t, J = 6.0 Hz, 2H), 2.53 (s, 2H), 2.87 (s, 2H), 3.58-3.75 (m, 20H), 3.88 (t, J = 4.8 Hz, 2H), 4.21 (t, J = 4.8 Hz, 2H), 7.13 (dd, J = 8.1, 1.8 Hz, 1H,), 7.39 (t, J = 8.1 Hz, 1H), 7.56-7.61 (m, 3H), 7.97 (d, J = 9.9 Hz, 1H), 8.04 (s, 1H), 8.23 (s, 1H), 9.24 (s, 1H), 12.87 (s, 1H). ESIMS m / z: 814 (M + H) + .
　化合物106：実施例100で得られる化合物105（1.00 g, 1.22 mmol）を用い、実施例96と同様にして化合物106（0.804 g, 73%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.06 (s, 6H), 1.65-1.70 (m, 2H), 2.53 (s, 2H), 2.88 (s, 2H), 3.05 (s, 3H), 3.62-3.75 (m, 18H), 3.89 (t, J = 4.4 Hz, 2H), 4.21 (t, J = 4.9 Hz, 2H), 4.36 (dd, J= 5.4, 3.4 Hz, 2H), 7.13 (t, J = 4.9 Hz, 1H), 7.38-7.42 (m, 1H), 7.56-7.62 (m, 3H), 7.95-7.98 (m, 1H), 8.04 (s, 1H), 8.24 (s, 1H), 9.25 (s, 1H), 12.89 (s, 1H).  ESIMS m/z: 892 (M + H)+.   Compound 106: Compound 106 (0.804 g, 73%) was obtained in the same manner as in Example 96, using Compound 105 (1.00 g, 1.22 mmol) obtained in Example 100.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.06 (s, 6H), 1.65-1.70 (m, 2H), 2.53 (s, 2H), 2.88 (s, 2H), 3.05 (s, 3H) , 3.62-3.75 (m, 18H), 3.89 (t, J = 4.4 Hz, 2H), 4.21 (t, J = 4.9 Hz, 2H), 4.36 (dd, J = 5.4, 3.4 Hz, 2H), 7.13 ( t, J = 4.9 Hz, 1H), 7.38-7.42 (m, 1H), 7.56-7.62 (m, 3H), 7.95-7.98 (m, 1H), 8.04 (s, 1H), 8.24 (s, 1H) , 9.25 (s, 1H), 12.89 (s, 1H) .ESIMS m / z: 892 (M + H) + .   
化合物107：実施例101で得られる化合物106（0.410 g, 0.459 mmol）をアセトニトリル（7.50 mL）およびDMSO（5.00 mL）に溶解し、3-(ピリジン-3-イル)プロパン酸（3.47 g, 22.97 mmol）を加え、80℃で21時間撹拌した。混合物をろ過し、ろ液を減圧濃縮し、残渣をNHシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝4／1）で精製することにより化合物107（0.263 g, 60%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.03 (s, 6H), 1.57 (s, 2H), 2.44 (brs, 4H), 2.92 (brs, 4H), 3.43-3.69 (m, 16H), 3.82-3.84 (m, 4H), 4.14 (d, J = 4.9 Hz, 2H), 4.69 (s, 2H), 7.04-7.06 (m, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.46-7.56 (m, 3H), 7.71 (t, J = 6.8 Hz, 1H), 7.90 (s, 1H), 8.05-8.16 (m, 2H), 8.51-8.60 (m, 2H), 8.85 (s, 1H). ESIMS m/z: 947 (M + H)+. Compound 107: Compound 106 (0.410 g, 0.459 mmol) obtained in Example 101 was dissolved in acetonitrile (7.50 mL) and DMSO (5.00 mL), and 3- (pyridin-3-yl) propanoic acid (3.47 g, 22.97) was dissolved. mmol) and stirred at 80 ° C. for 21 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (chloroform / methanol = 4/1) to give Compound 107 (0.263 g, 60%).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.03 (s, 6H), 1.57 (s, 2H), 2.44 (brs, 4H), 2.92 (brs, 4H), 3.43-3.69 (m, 16H) , 3.82-3.84 (m, 4H), 4.14 (d, J = 4.9 Hz, 2H), 4.69 (s, 2H), 7.04-7.06 (m, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.46-7.56 (m, 3H), 7.71 (t, J = 6.8 Hz, 1H), 7.90 (s, 1H), 8.05-8.16 (m, 2H), 8.51-8.60 (m, 2H), 8.85 (s, ESIMS m / z: 947 (M + H) + .
化合物108～110：3-(ピリジン-3-イル)プロパン酸の代わりに対応するアミンを用い、実施例102と同様にして、化合物108～110を得た。
化合物108：ESIMS m/z: 919 (M + H)+.
化合物109：ESIMS m/z: 875 (M )+.
化合物110：ESIMS m/z: 897 (M )+. Compounds 108 to 110: Compounds 108 to 110 were obtained in the same manner as in Example 102, using the corresponding amine instead of 3- (pyridin-3-yl) propanoic acid.
Compound 108: ESIMS m / z: 919 (M + H) + .
Compound 109: ESIMS m / z: 875 (M) + .
Compound 110: ESIMS m / z: 897 (M) + .
化合物111：ピペリジン-4-カルボン酸エチル(3.194 g, 20.3 mmol)を用い、実施例13と同様にして、化合物111（1.45 g, 80%）を得た。
1H-NMR (400 MHz,CDCl3, δ): 1.07 (s, 6H), 1.22-1.28 (m, 3H), 1.65-1.93 (m, 6H), 2.06-3.08 (m, 11H), 3.43-3.57 (m, 2H), 3.65-3.79 (m, 8H), 3.87-3.95 (m, 3H),  4.09-4.17 (m, 2H), 4.20-4.27 (m, 2H), 7.11-7.15 (m, 1H), 7.39 (t, J = 8.3 Hz, 1H), 7.55-7.64 (m, 3H), 7.97 (t, J = 8.8 Hz, 1H), 8.04-8.05 (m, 1H), 8.24 (s, 1H), 9.27 (s, 1H), 12.88 (s, 1H).  Compound 111: Compound 111 (1.45 g, 80%) was obtained in the same manner as Example 13 using ethyl piperidine-4-carboxylate (3.194 g, 20.3 mmol).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.22-1.28 (m, 3H), 1.65-1.93 (m, 6H), 2.06-3.08 (m, 11H), 3.43- 3.57 (m, 2H), 3.65-3.79 (m, 8H), 3.87-3.95 (m, 3H), 4.09-4.17 (m, 2H), 4.20-4.27 (m, 2H), 7.11-7.15 (m, 1H ), 7.39 (t, J = 8.3 Hz, 1H), 7.55-7.64 (m, 3H), 7.97 (t, J = 8.8 Hz, 1H), 8.04-8.05 (m, 1H), 8.24 (s, 1H) , 9.27 (s, 1H), 12.88 (s, 1H).
化合物112：実施例104で得られる化合物111（0.749 g, 0.836 mmol）をエタノール（5.0 mL）に溶解し、4 mol/L水酸化ナトリウム水溶液（1.04 ml, 4.18 mmol）を加えて、室温で1時間攪拌した。混合物を1 mol/L塩酸で中和し、クロロホルム/メタノールの混合溶媒にて抽出し、有機層を濃縮することにより化合物112（0.685 g, 94%）を得た。
1H-NMR (400 MHz,DMSO-d6, δ): 1.02 (s, 6H), 1.36-1.79 (m, 6H), 2.18-2.90 (m, 9H), 3.30-3.38 (m, 2H), 3.50-3.61 (m, 10H), 3.72-3.78 (m, 3H), 4.15 (t, J = 4.2 Hz, 2H) 7.16-7.20 (m, 1H), 7.41-7.47 (m, 3H), 7.76 (t, J = 8.1 Hz, 1H), 7.95 (t, J = 8.1 Hz, 1H), 8.09 (s, 1H), 8.42 (s, 1H).  Compound 112: Compound 111 (0.749 g, 0.836 mmol) obtained in Example 104 was dissolved in ethanol (5.0 mL), and 4 mol / L aqueous sodium hydroxide solution (1.04 ml, 4.18 mmol) was added. Stir for hours. The mixture was neutralized with 1 mol / L hydrochloric acid, extracted with a mixed solvent of chloroform / methanol, and the organic layer was concentrated to obtain Compound 112 (0.685 g, 94%).
1 H-NMR (400 MHz, DMSO-d 6 , δ): 1.02 (s, 6H), 1.36-1.79 (m, 6H), 2.18-2.90 (m, 9H), 3.30-3.38 (m, 2H), 3.50-3.61 (m, 10H), 3.72-3.78 (m, 3H), 4.15 (t, J = 4.2 Hz, 2H) 7.16-7.20 (m, 1H), 7.41-7.47 (m, 3H), 7.76 (t , J = 8.1 Hz, 1H), 7.95 (t, J = 8.1 Hz, 1H), 8.09 (s, 1H), 8.42 (s, 1H).
化合物113：実施例105で得られる化合物112（0.450 g, 0.519 mmol）を用い、実施例16と同様にして、化合物113（0.230 g, 46%）を得た。
1H-NMR (300 MHz,CDCl3, δ): 1.07 (s, 6H), 1.46-2.21 (m, 9H), 2.27-2.55 (m, 4H), 2.78-3.16 (m, 4H), 3.31-3.40 (m, 1H), 3.49 (dd, J = 9.9, 3.7 Hz, 1H), 3.57-3.77 (m, 15H), 3.89 (t, J = 4.4 Hz, 2H), 3.92-4.00 (m, 1H), 4.22 (t, J = 4.4 Hz, 2H), 4.65 (br s, 3H), 7.12 (dd, J = 8.2, 2.0 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.54-7.63 (m, 3H), 7.95 (t, J = 7.7 Hz, 1H), 8.04 (s, 1H), 8.23 (s, 1H), 9.11-9.46 (m, 2H), 12.83 (s, 1H).  ESIMS m/z: 970, 972 (M + H)+. Compound 113: Compound 113 (0.230 g, 46%) was obtained in the same manner as in Example 16 using Compound 112 (0.450 g, 0.519 mmol) obtained in Example 105.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.46-2.21 (m, 9H), 2.27-2.55 (m, 4H), 2.78-3.16 (m, 4H), 3.31- 3.40 (m, 1H), 3.49 (dd, J = 9.9, 3.7 Hz, 1H), 3.57-3.77 (m, 15H), 3.89 (t, J = 4.4 Hz, 2H), 3.92-4.00 (m, 1H) , 4.22 (t, J = 4.4 Hz, 2H), 4.65 (br s, 3H), 7.12 (dd, J = 8.2, 2.0 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.54-7.63 (m, 3H), 7.95 (t, J = 7.7 Hz, 1H), 8.04 (s, 1H), 8.23 (s, 1H), 9.11-9.46 (m, 2H), 12.83 (s, 1H). ESIMS m / z: 970, 972 (M + H) + .
化合物114：実施例100で得られる化合物105（1.50 g, 1.84 mmol）を用いて、実施例12と同様にして、化合物114（0.800 g, 50%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.04 (s, 6H), 1.60-1.67 (m, 2H), 2.48 (s, 2H), 2.57-2.62 (m, 1H), 2.74-2.81 (m, 1H), 3.10-3.16 (m, 1H), 3.31-3.44 (m, 1H), 3.60-3.80 (m, 22H), 3.83-3.90 (m, 2H), 3.99-4.04 (m, 1H), 4.15-4.21 (m, 2H),  7.11 (t, J = 7.8 Hz, 1H), 7.52-7.61 (m, 3H), 7.90-8.03 (m, 3H), 8.29 (s, 1H), 9.57 (s, 1H), 12.76 (s, 1H). Compound 114: Compound 114 (0.800 g, 50%) was obtained in the same manner as in Example 12 using Compound 105 (1.50 g, 1.84 mmol) obtained in Example 100.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.04 (s, 6H), 1.60-1.67 (m, 2H), 2.48 (s, 2H), 2.57-2.62 (m, 1H), 2.74-2.81 ( m, 1H), 3.10-3.16 (m, 1H), 3.31-3.44 (m, 1H), 3.60-3.80 (m, 22H), 3.83-3.90 (m, 2H), 3.99-4.04 (m, 1H), 4.15-4.21 (m, 2H), 7.11 (t, J = 7.8 Hz, 1H), 7.52-7.61 (m, 3H), 7.90-8.03 (m, 3H), 8.29 (s, 1H), 9.57 (s, 1H), 12.76 (s, 1H).
化合物115：実施例107で得られる化合物114（0.25 g, 0.287 mmol）を用いて、実施例104と同様にして、化合物115（0.105 g, 36%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.06 (s, 6H), 1.22-1.28 (m, 3H), 1.67 (t, J = 6.0 Hz, 2H), 1.76-1.99 (m, 4H), 2.29-2.55 (m, 7H), 2.86-3.04 (m, 3H), 3.45-3.49 (m, 2H), 3.62-3.76 (m, 22H), 3.86-3.98 (m, 3H), 4.09-4.17 (m, 2H), 4.20 (t, J= 4.8 Hz, 2H), 7.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.39 (t, J = 8.2 Hz, 1H), 7.54-7.62 (m, 4H), 7.94-8.05 (m, 1H), 8.27 (s, 1H), 9.41 (s, 1H), 12.80 (s, 1H). Compound 115: Compound 115 (0.105 g, 36%) was obtained in the same manner as in Example 104, using Compound 114 (0.25 g, 0.287 mmol) obtained in Example 107.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.06 (s, 6H), 1.22-1.28 (m, 3H), 1.67 (t, J = 6.0 Hz, 2H), 1.76-1.99 (m, 4H) , 2.29-2.55 (m, 7H), 2.86-3.04 (m, 3H), 3.45-3.49 (m, 2H), 3.62-3.76 (m, 22H), 3.86-3.98 (m, 3H), 4.09-4.17 ( m, 2H), 4.20 (t, J = 4.8 Hz, 2H), 7.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.39 (t, J = 8.2 Hz, 1H), 7.54-7.62 (m, 4H ), 7.94-8.05 (m, 1H), 8.27 (s, 1H), 9.41 (s, 1H), 12.80 (s, 1H).
化合物116：実施例108で得られる化合物115（0.105 g, 0.102 mmol）を用いて、実施例105と同様にして、化合物116（0.090 g, 88%）を得た。
1H-NMR (300 MHz, CDCl3, δ):1.06(s, 6H), 1.65 (t, J = 5.8 Hz, 2H), 2.13-2.25 (m, 4H), 2.51 (s, 2H), 2.58-2.66 (m, 1H), 2.88-3.03 (m, 2H), 3.12-3.21 (m, 3H), 3.36-3.43 (m, 2H), 3.51-3.75 (m, 25H), 3.87 (t, J = 4.6 Hz, 2H), 4.19 (t, J = 4.8 Hz, 2H), 4.23-4.30 (m, 1H), 7.09-7.14 (m, 1H), 7.39 (t, J= 8.0 Hz, 1H), 7.53-7.60 (m, 3H), 7.93 (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 8.35 (s, 1H), 9.78 (s, 1H), 12.66 (s, 1H).  ESIMS m/z: 999, 1001 (M + H)+. Compound 116: Compound 116 (0.090 g, 88%) was obtained in the same manner as in Example 105, using Compound 115 (0.105 g, 0.102 mmol) obtained in Example 108.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.06 (s, 6H), 1.65 (t, J = 5.8 Hz, 2H), 2.13-2.25 (m, 4H), 2.51 (s, 2H), 2.58 -2.66 (m, 1H), 2.88-3.03 (m, 2H), 3.12-3.21 (m, 3H), 3.36-3.43 (m, 2H), 3.51-3.75 (m, 25H), 3.87 (t, J = 4.6 Hz, 2H), 4.19 (t, J = 4.8 Hz, 2H), 4.23-4.30 (m, 1H), 7.09-7.14 (m, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.53- 7.60 (m, 3H), 7.93 (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 8.35 (s, 1H), 9.78 (s, 1H), 12.66 (s, 1H). ESIMS m / z: 999, 1001 (M + H) + .
化合物117：実施例95で得られる化合物95を用いて、実施例12、104および105と同様にして、化合物117を得た。
ESIMS m/z: 1013 (M + H)+. Compound 117: Compound 117 was obtained in the same manner as in Examples 12, 104 and 105, using compound 95 obtained in Example 95.
ESIMS m / z: 1013 (M + H) + .
化合物118：実施例105で得られる化合物112（0.55 g, 0.634 mmol）および3-(2-(2-(2-アミノエトキシ)エトキシ)プロパン酸tert-ブチル（0.211 g, 0.761 mmol）を用いて、実施例16と同様にして、化合物118（0.678 g, 95%）を得た。
1H-NMR (300 MHz,CDCl3, δ): 1.06 (s, 6H), 1.43 (s, 9H), 1.67 (t, J = 5.9 Hz, 2H), 1.69-1.87 (m, 4H), 2.45-2.53 (m, 4H), 2.65-3.01 (m, 9H), 3.34-3.42 (m, 2H), 3.48-3.75 (m, 22H), 3.88 (t, J = 4.6 Hz, 2H), 4.02-4.08 (m, 1H), 4.22 (t, J = 4.6 Hz, 2H), 7.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.40 (t, J= 8.2 Hz, 1H), 7.54-7.63 (m, 3H), 7.95 (t, J = 8.2 Hz, 1H), 8.01 (s, 1H), 8.08 (s, 1H), 8.29 (s, 1H), 9.48 (s, 1H), 12.80 (s, 1H).  Compound 118: Using Compound 112 (0.55 g, 0.634 mmol) obtained in Example 105 and tert-butyl 3- (2- (2- (2-aminoethoxy) ethoxy) propanoate (0.211 g, 0.761 mmol) In the same manner as in Example 16, compound 118 (0.678 g, 95%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.06 (s, 6H), 1.43 (s, 9H), 1.67 (t, J = 5.9 Hz, 2H), 1.69-1.87 (m, 4H), 2.45 -2.53 (m, 4H), 2.65-3.01 (m, 9H), 3.34-3.42 (m, 2H), 3.48-3.75 (m, 22H), 3.88 (t, J = 4.6 Hz, 2H), 4.02-4.08 (m, 1H), 4.22 (t, J = 4.6 Hz, 2H), 7.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.54-7.63 (m, 3H), 7.95 (t, J = 8.2 Hz, 1H), 8.01 (s, 1H), 8.08 (s, 1H), 8.29 (s, 1H), 9.48 (s, 1H), 12.80 (s, 1H).
化合物119：実施例111で得られる化合物118（0.678 g, 0.602 mmol）を用いて、実施例15と同様にして、化合物119（0.510 g, 79%）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 1.04 (s, 6H), 1.41-1.69 (m, 6H), 2.27-2.52 (m, 5H), 2.44 (t, J = 6.4 Hz, 2H), 2.66-2.82 (m, 5H), 3.21 (q, J = 5.9 Hz, 2H),3.34-3.46 (m, 4H), 3.48-3.66 (m, 19H), 3.73-3.81 (m, 3H), 4.17 (t, J = 4.8 Hz, 2H), 7.16-7.23 (m, 1H), 7.42-7.48 (m, 3H), 7.70-7.80 (m, 1H), 7.97 (t, J = 8.4 Hz, 1H), 8.11 (s, 1H), 8.43 (s, 1H).  ESIMS m/z: 1070, 1072 (M + H)+. Compound 119: Compound 119 (0.510 g, 79%) was obtained in the same manner as Example 15 using Compound 118 (0.678 g, 0.602 mmol) obtained in Example 111.
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.04 (s, 6H), 1.41-1.69 (m, 6H), 2.27-2.52 (m, 5H), 2.44 (t, J = 6.4 Hz, 2H), 2.66-2.82 (m, 5H), 3.21 (q, J = 5.9 Hz, 2H), 3.34-3.46 (m, 4H), 3.48-3.66 (m, 19H), 3.73-3.81 (m, 3H) , 4.17 (t, J = 4.8 Hz, 2H), 7.16-7.23 (m, 1H), 7.42-7.48 (m, 3H), 7.70-7.80 (m, 1H), 7.97 (t, J = 8.4 Hz, 1H ), 8.11 (s, 1H), 8.43 (s, 1H) .ESIMS m / z: 1070, 1072 (M + H) + .
化合物120：3-(2-(2-(2-アミノエトキシ)エトキシ)エトキシ)プロパン酸tert-ブチル（0.939 g, 3.39 mmol）を用いて、実施例13と同様にして、化合物120（0.384 g, 56%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.04 (s, 6H), 1.42 (s, 9H), 1.64 (t, J = 6.0 Hz, 2H), 2.44-2.51 (m, 4H), 2.62-2.89 (m, 6H), 3.42-3.73 (m, 22H), 3.84-3.89 (m, 3H), 4.19 (t, J = 4.8 Hz, 2H), 7.08-7.12 (m, 1H), 7.37 (t, J = 8.2 Hz, 1H), 7.52-7.60 (m, 3H), 7.93 (t, J = 8.2 Hz, 1H), 8.01 (s, 1H), 8.26 (s, 1H).  Compound 120: Compound 120 (0.384 g) in the same manner as in Example 13 using tert-butyl 3- (2- (2- (2-aminoethoxy) ethoxy) ethoxy) propanoate (0.939 g, 3.39 mmol). , 56%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.04 (s, 6H), 1.42 (s, 9H), 1.64 (t, J = 6.0 Hz, 2H), 2.44-2.51 (m, 4H), 2.62 -2.89 (m, 6H), 3.42-3.73 (m, 22H), 3.84-3.89 (m, 3H), 4.19 (t, J = 4.8 Hz, 2H), 7.08-7.12 (m, 1H), 7.37 (t , J = 8.2 Hz, 1H), 7.52-7.60 (m, 3H), 7.93 (t, J = 8.2 Hz, 1H), 8.01 (s, 1H), 8.26 (s, 1H).
化合物121：実施例113で得られる化合物120（0.384 g, 0.378 mmol）を用いて、実施例25と同様にして、化合物121（0.389 g, 定量的）を得た。 Compound 121: Compound 121 (0.389 g, 化合物 quantitative) was obtained in the same manner as in Example 25, using Compound 120 (0.384 g, 0.378 mmol) obtained in Example 113.
化合物122：実施例114で得られる化合物121（0.380 g, 0.369 mmol）を用いて、実施例15と同様にして、化合物122（0.130 g, 36%）を得た。
1H-NMR (400 MHz, DMSO-d6, δ): 1.02 (s, 6H), 1.53 (t, J = 6.0 Hz, 2H), 2.27 (s, 3H), 2.30-2.51 (m, 4H), 2.59 (t, J = 6.0 Hz, 2H), 2.74-2.78 (m, 2H), 3.29-3.40 (m, 4H), 3.46-3.63 (m, 20H), 3.67-3.71 (m, 1H), 3.72-3.78 (m, 2H), 4.15 (t, J= 4.8 Hz, 2H), 7.16 (t, J = 7.8 Hz, 1H), 7.41-7.48 (m, 3H), 7.75 (t, J= 8.8 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 8.42 (s, 1H).  ESIMS m/z: 973, 975 (M + H)+. Compound 122: Compound 122 (0.130 g, 36%) was obtained in the same manner as Example 15 using Compound 121 (0.380 g, 0.369 mmol) obtained in Example 114.
1 H-NMR (400 MHz, DMSO-d 6 , δ): 1.02 (s, 6H), 1.53 (t, J = 6.0 Hz, 2H), 2.27 (s, 3H), 2.30-2.51 (m, 4H) , 2.59 (t, J = 6.0 Hz, 2H), 2.74-2.78 (m, 2H), 3.29-3.40 (m, 4H), 3.46-3.63 (m, 20H), 3.67-3.71 (m, 1H), 3.72 -3.78 (m, 2H), 4.15 (t, J = 4.8 Hz, 2H), 7.16 (t, J = 7.8 Hz, 1H), 7.41-7.48 (m, 3H), 7.75 (t, J = 8.8 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 8.42 (s, 1H) .ESIMS m / z: 973, 975 (M + H) + .
化合物123：3-(メチルアミノ)プロパン酸エチルを用いて、実施例108および109と同様にして、化合物123を得た。
ESIMS m/z: 973, 975 (M + H)+. Compound 123: Compound 123 was obtained in the same manner as in Examples 108 and 109 using ethyl 3- (methylamino) propanoate.
ESIMS m / z: 973, 975 (M + H) + .
化合物124：実施例8で得られる化合物8（0.500 g, 0.733 mmol）を用いて、実施例96と同様にして、化合物124（0.537 g, 75%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.69 (t, J = 6.2 Hz, 2H), 2.53 (s, 2H), 2.87 (t, J = 6.2 Hz, 2H), 3.06 (s, 3H), 3.68-3.80 (m, 6H), 3.86-3.90 (m, 2H), 4.18-4.23 (m, 2H), 4.36-4.40 (m, 2H), 7.10-7.15 (m, 1H), 7.41 (t, J= 8.0 Hz, 1H), 7.56-7.65 (m, 3H), 7.93-7.98 (m, 1H), 8.05 (d, J = 1.8 Hz, 1H), 8.22 (s, 1H), 9.24 (s, 1H), 12.90 (s, 1H). Compound 124: Compound 124 (0.537 g, 75%) was obtained in the same manner as in Example 96, using Compound 8 (0.500 g, 0.733 mmol) obtained in Example 8.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.69 (t, J = 6.2 Hz, 2H), 2.53 (s, 2H), 2.87 (t, J = 6.2 Hz, 2H ), 3.06 (s, 3H), 3.68-3.80 (m, 6H), 3.86-3.90 (m, 2H), 4.18-4.23 (m, 2H), 4.36-4.40 (m, 2H), 7.10-7.15 (m , 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.56-7.65 (m, 3H), 7.93-7.98 (m, 1H), 8.05 (d, J = 1.8 Hz, 1H), 8.22 (s, 1H), 9.24 (s, 1H), 12.90 (s, 1H).
化合物125：実施例117で得られる化合物124（1.70 g, 1.90 mmol）をDMF(10 mL）に溶解し、ピペリジン-4-カルボン酸エチル （2.93 ml, 19.0 mmol)を加えて100℃で2時間攪拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝10/1）で精製することにより化合物125（0.970 g, 62%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.23 (t, J = 7.0 Hz, 3H), 1.65-1.90 (m, 6H), 2.07 (td, J = 11.5, 2.6 Hz, 2H), 2.19-2.30 (m, 1H), 2.50-2.59 (m, 4H), 2.84-2.94 (m, 4H), 3.59-3.75 (m, 6H), 3.89 (t, J = 4.6 Hz, 2H), 4.11 (q, J = 7.0 Hz, 2H), 4.21 (t, J = 4.6 Hz, 2H), 7.13 (dd, J= 8.0, 2.0 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.55-7.63 (m, 3H), 7.94-7.98 (m, 1H), 8.03 (s, 1H), 8.24 (s, 1H), 9.27 (s, 1H), 12.89 (s, 1H). Compound 125: Compound 124 (1.70 g, 1.90 mmol) obtained in Example 117 was dissolved in DMF (10 mL), ethyl piperidine-4-carboxylate (2.93 ml, 19.0 mmol) was added, and the mixture was heated at 100 ° C. for 2 hours. Stir. Water was added to the mixture and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain Compound 125 (0.970 g, 62%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.23 (t, J = 7.0 Hz, 3H), 1.65-1.90 (m, 6H), 2.07 (td, J = 11.5, 2.6 Hz, 2H), 2.19-2.30 (m, 1H), 2.50-2.59 (m, 4H), 2.84-2.94 (m, 4H), 3.59-3.75 (m, 6H), 3.89 (t, J = 4.6 Hz , 2H), 4.11 (q, J = 7.0 Hz, 2H), 4.21 (t, J = 4.6 Hz, 2H), 7.13 (dd, J = 8.0, 2.0 Hz, 1H), 7.39 (t, J = 8.0 Hz , 1H), 7.55-7.63 (m, 3H), 7.94-7.98 (m, 1H), 8.03 (s, 1H), 8.24 (s, 1H), 9.27 (s, 1H), 12.89 (s, 1H).
化合物126：実施例118で得られる化合物125（0.970 g, 1.18 mmol）を用いて、実施例105と同様にして、化合物126（0.850 g, 91%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.67-1.70 (m, 2H), 1.92-2.54 (m, 6H), 2.74-3.21 (m, 6H), 3.40-3.75 (m, 8H), 3.81-3.87 (m, 2H), 3.93-3.99 (m, 2H), 4.17-4.23 (m, 2H), 7.10-7.14 (m, 1H), 7.37-7.44 (m, 1H), 7.52-7.62 (m, 3H), 7.90 (d, J = 8.0 Hz, 1H), 8.04-8.08 (m, 1H), 8.30 (s, 1H).  Compound 126: Compound 126 (0.850 g, 91%) was obtained in the same manner as in Example 105, using Compound 125 (0.970 g, 1.18 mmol) obtained in Example 118.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.67-1.70 (m, 2H), 1.92-2.54 (m, 6H), 2.74-3.21 (m, 6H), 3.40- 3.75 (m, 8H), 3.81-3.87 (m, 2H), 3.93-3.99 (m, 2H), 4.17-4.23 (m, 2H), 7.10-7.14 (m, 1H), 7.37-7.44 (m, 1H ), 7.52-7.62 (m, 3H), 7.90 (d, J = 8.0 Hz, 1H), 8.04-8.08 (m, 1H), 8.30 (s, 1H).
化合物127：実施例119で得られる化合物126（0.200 g, 0.252 mmol）を用いて、実施例111と同様にして、化合物127（0.190 g, 72%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.02 (s, 6H), 1.40 (s, 9H), 1.63 (t, J = 6.0 Hz, 2H), 1.86-1.94 (m, 4H), 2.33-2.49 (m, 5H), 2.75-2.89 (m, 4H), 3.07 (t, J= 4.4 Hz, 2H), 3.30-3.42 (m, 4H), 3.44-3.49 (m, 2H), 3.52-3.59 (m, 8H), 3.62-3.70 (m, 6H), 3.74 (t, J = 4.4 Hz, 2H), 3.83 (t, J = 4.4 Hz, 2H), 4.16 (t, J = 4.4 Hz, 2H), 6.61-6.66 (m, 1H), 7.07 (dd, J = 8.0, 2.2 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.49-7.60 (m, 3H), 7.88 (d, J= 8.0 Hz, 1H), 8.05 (d, J = 1.5 Hz, 1H), 8.26 (s, 1H), 9.47 (br s, 1H), 12.76 (br s, 1H). Compound 127: Compound 127 (0.190 g, 72%) was obtained in the same manner as in Example 111, using Compound 126 (0.200 g, 0.252 mmol) obtained in Example 119.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.02 (s, 6H), 1.40 (s, 9H), 1.63 (t, J = 6.0 Hz, 2H), 1.86-1.94 (m, 4H), 2.33 -2.49 (m, 5H), 2.75-2.89 (m, 4H), 3.07 (t, J = 4.4 Hz, 2H), 3.30-3.42 (m, 4H), 3.44-3.49 (m, 2H), 3.52-3.59 (m, 8H), 3.62-3.70 (m, 6H), 3.74 (t, J = 4.4 Hz, 2H), 3.83 (t, J = 4.4 Hz, 2H), 4.16 (t, J = 4.4 Hz, 2H) , 6.61-6.66 (m, 1H), 7.07 (dd, J = 8.0, 2.2 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.49-7.60 (m, 3H), 7.88 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 1.5 Hz, 1H), 8.26 (s, 1H), 9.47 (br s, 1H), 12.76 (br s, 1H).
化合物128：実施例120で得られる化合物127（0.170 g, 0.161 mmol）を用いて、実施例15と同様にして、化合物128（0.150 g, 93%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.66 (t, J = 5.9 Hz, 2H), 1.88-1.97 (m, 2H), 2.08-2.32 (m, 3H), 2.48-2.56 (m, 4H), 2.85-2.91 (m, 2H), 3.04-3.13 (m, 2H), 3.41-3.81 (m, 24H), 3.85 (t, J = 4.6 Hz, 2H), 4.23 (t, J = 4.6 Hz, 2H), 7.11-7.15 (m, 1H), 7.41 (t, J = 8.3 Hz, 1H), 7.55-7.63 (m, 3H), 7.95 (d, J = 8.3 Hz, 1H), 8.04 (s, 1H), 8.25 (s, 1H), 9.73 (br s, 1H), 12.71 (br s, 1H).  ESIMS m/z: 996, 998 (M + H)+. Compound 128: Compound 128 (0.150 g, 93%) was obtained in the same manner as in Example 15 using Compound 127 (0.170 g, 0.161 mmol) obtained in Example 120.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.66 (t, J = 5.9 Hz, 2H), 1.88-1.97 (m, 2H), 2.08-2.32 (m, 3H) , 2.48-2.56 (m, 4H), 2.85-2.91 (m, 2H), 3.04-3.13 (m, 2H), 3.41-3.81 (m, 24H), 3.85 (t, J = 4.6 Hz, 2H), 4.23 (t, J = 4.6 Hz, 2H), 7.11-7.15 (m, 1H), 7.41 (t, J = 8.3 Hz, 1H), 7.55-7.63 (m, 3H), 7.95 (d, J = 8.3 Hz, 1H), 8.04 (s, 1H), 8.25 (s, 1H), 9.73 (br s, 1H), 12.71 (br s, 1H) .ESIMS m / z: 996, 998 (M + H) + .
化合物129：実施例101で得られる化合物106（0.35 g, 0.298 mmol）を用いて、実施例118と同様にして、化合物129（0.130 g, 46%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.06 (s, 6H), 1.24 (t, J = 7.0 Hz, 3H), 1.62-1.91 (m, 6H), 2.07 (t, J = 11.5 Hz, 2H), 2.18-2.31 (m, 1H), 2.48-2.59 (m, 4H), 2.82-2.93 (m, 4H), 3.56-3.76 (m, 18H), 3.88 (t, J = 4.6 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 4.20 (t, J = 4.6 Hz, 2H), 7.12 (dd, J = 8.0, 2.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.54-7.62 (m, 3H), 7.94-7.97 (m, 1H), 8.01-8.04 (m, 1H), 8.25 (s, 1H), 9.29 (br s, 1H), 12.86 (br s, 1H). Compound 129: Compound 129 (0.130 g, 46%) was obtained in the same manner as in Example 118, using Compound 106 (0.35 g, 0.298 mmol) obtained in Example 101.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.06 (s, 6H), 1.24 (t, J = 7.0 Hz, 3H), 1.62-1.91 (m, 6H), 2.07 (t, J = 11.5 Hz , 2H), 2.18-2.31 (m, 1H), 2.48-2.59 (m, 4H), 2.82-2.93 (m, 4H), 3.56-3.76 (m, 18H), 3.88 (t, J = 4.6 Hz, 2H ), 4.12 (q, J = 7.0 Hz, 2H), 4.20 (t, J = 4.6 Hz, 2H), 7.12 (dd, J = 8.0, 2.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H) ), 7.54-7.62 (m, 3H), 7.94-7.97 (m, 1H), 8.01-8.04 (m, 1H), 8.25 (s, 1H), 9.29 (br s, 1H), 12.86 (br s, 1H ).
化合物130：実施例122で得られる化合物129（0.130 g, 0.136 mmol）を用いて、実施例105と同様にして、化合物130（0.120 g, 95%）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 1.02 (s, 6H), 1.47-1.61 (m, 2H), 1.70-1.79 (m, 2), 2.01-2.20 (m, 3H), 2.43-2.48 (m, 4H), 2.73-2.82 (m, 4H), 3.46-3.60 (m, 20H), 3.74 (t, J = 4.8 Hz, 2H), 4.15 (t, J = 4.8 Hz, 2H), 7.15 (d, J= 8.0 Hz, 1H), 7.38-7.50 (m, 3H), 7.74 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.95 (s, 1H), 8.09 (s, 1H), 8.42 (s, 1H).  ESIMS m/z: 925, 927 (M + H)+. Compound 130: Compound 130 (0.120 g, 95%) was obtained in the same manner as in Example 105, using Compound 129 (0.130 g, 0.136 mmol) obtained in Example 122.
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.02 (s, 6H), 1.47-1.61 (m, 2H), 1.70-1.79 (m, 2), 2.01-2.20 (m, 3H), 2.43-2.48 (m, 4H), 2.73-2.82 (m, 4H), 3.46-3.60 (m, 20H), 3.74 (t, J = 4.8 Hz, 2H), 4.15 (t, J = 4.8 Hz, 2H) , 7.15 (d, J = 8.0 Hz, 1H), 7.38-7.50 (m, 3H), 7.74 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.95 ( s, 1H), 8.09 (s, 1H), 8.42 (s, 1H) .ESIMS m / z: 925, 927 (M + H) + .
化合物131：3-(メチルアミノ)プロパン酸エチルを用いて、実施例122および123と同様にして、化合物131を得た。
ESIMS m/z: 899, 901 (M + H)+. Compound 131: Compound 131 was obtained in the same manner as in Examples 122 and 123 using ethyl 3- (methylamino) propanoate.
ESIMS m / z: 899, 901 (M + H) + .
化合物132
工程1：実施例14の工程1で得られる3-(2-(2-(2-トシロキシエトキシ)エトキシ)エトキシ)プロパン酸tert-ブチル（2.00g, 4.62 mmol）をトリフルオロ酢酸（5 mL）に溶解し、室温で1時間攪拌した。混合物を減圧下濃縮することで3-(2-(2-(2-トシロキシエトキシ)エトキシ)エトキシ)プロパン酸（1.74g, 定量的）を得た。
1H-NMR (270 MHz, CDCl3, δ): 2.45 (s, 3H), 2.64 (t, J = 6.1 Hz, 2H), 3.60-3.65 (m, 8H), 3.69 (t, J = 4.6 Hz, 2H),3.77 (t, J = 6.1 Hz, 2H), 4.17 (t, J = 3.6 HZ, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.80 (d, J = 7.9 Hz, 2H).
工程2：実施例36で得られる化合物36と工程1で得らる3-(2-(2-(2-トシロキシエトキシ)エトキシ)エトキシ)プロパン酸を用いて、実施例16と同様にして、化合物132（580mg, 60%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.08 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H), 2.54 (s, 2H), 2.64-2.76 (m, 2H), 2.88 (br s, 2H), 3.54-3.71 (m, 8H), 3.78-3.87 (m, 2H), 4.09-4.18 (m 2H), 4.65-4.69 (m, 2H), 7.30-7.34 (m, 2H), 7.43-7.61 (m, 3H), 7.75-7.81 (m, 2H), 7.89-7.98 (m, 2H), 8.05-8.07 (m, 1H), 8.24-8.30 (m, 1H), 9.28 (br s, 1H), 12.90-12.99 (m, 1H). Compound 132
Step 1: tert-Butyl 3- (2- (2- (2-tosyloxyethoxy) ethoxy) ethoxy) propanoate (2.00 g, 4.62 mmol) obtained in Step 1 of Example 14 was added to trifluoroacetic acid (5 mL). ) And stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain 3- (2- (2- (2-tosyloxyethoxy) ethoxy) ethoxy) propanoic acid (1.74 g, quantitative).
1 H-NMR (270 MHz, CDCl 3 , δ): 2.45 (s, 3H), 2.64 (t, J = 6.1 Hz, 2H), 3.60-3.65 (m, 8H), 3.69 (t, J = 4.6 Hz , 2H), 3.77 (t, J = 6.1 Hz, 2H), 4.17 (t, J = 3.6 HZ, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.80 (d, J = 7.9 Hz, 2H ).
Step 2: In the same manner as in Example 16, using Compound 36 obtained in Example 36 and 3- (2- (2- (2-tosyloxyethoxy) ethoxy) ethoxy) propanoic acid obtained in Step 1 Compound 132 (580 mg, 60%) was obtained.
1 H-NMR (300 MHz, CDCl 3, δ): 1.08 (s, 6H), 1.69 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H), 2.54 (s, 2H), 2.64-2.76 (m, 2H), 2.88 (br s, 2H), 3.54-3.71 (m, 8H), 3.78-3.87 (m, 2H), 4.09-4.18 (m 2H), 4.65-4.69 (m, 2H), 7.30 -7.34 (m, 2H), 7.43-7.61 (m, 3H), 7.75-7.81 (m, 2H), 7.89-7.98 (m, 2H), 8.05-8.07 (m, 1H), 8.24-8.30 (m, 1H), 9.28 (br s, 1H), 12.90-12.99 (m, 1H).
化合物133：実施例125で得られる化合物132および実施例46の工程1で得られる化合物を用いて、実施例97と同様にして、化合物133（296mg, 36%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.61-1.70 (m, 4H), 2.52 (s, 2H), 2.67-2.90 (m, 8H), 2.96-2.98 (m, 3H), 3.43-3.49 (m, 2H), 3.53-3.62 (m, 10H), 3.73-3.86 (m, 4H), 4.64-4.67 (m, 2H), 5.12-5.14 (m, 2H), 7.27-7.39 (m, 5H), 7.44-7.58 (m, 3H), 7.89-7.97 (m, 3H), 8.04-8.06 (m, 1H), 8.25-8.29 (m, 1H), 9.36 (s, 1H), 12.89 (br s, 1H). Compound 133: Compound 133 (296 mg, 36%) was obtained in the same manner as in Example 97, using Compound 132 obtained in Example 125 and the compound obtained in Step 1 of Example 46.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.61-1.70 (m, 4H), 2.52 (s, 2H), 2.67-2.90 (m, 8H), 2.96-2.98 ( m, 3H), 3.43-3.49 (m, 2H), 3.53-3.62 (m, 10H), 3.73-3.86 (m, 4H), 4.64-4.67 (m, 2H), 5.12-5.14 (m, 2H), 7.27-7.39 (m, 5H), 7.44-7.58 (m, 3H), 7.89-7.97 (m, 3H), 8.04-8.06 (m, 1H), 8.25-8.29 (m, 1H), 9.36 (s, 1H ), 12.89 (br s, 1H).
化合物134：実施例126で得られる化合物133を用いて、実施例18の工程2と同様にして、化合物134を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.05 (s, 6H), 1.62 (t, J = 6.8 Hz, 2H), 1.80 (br s, 2H), 2.50 (s, 2H), 2.66 (t, J = 6.2 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 2.89 (br s, 2H), 2.97-3.22 (m, 7H), 3.47-3.80 (m, 14H), 4.65 (s, 2H), 5.30 (s, 1H), 7.36-7.38 (m, 1H), 7.43-7.55 (m, 2H), 7.81-7.94 (m, 3H), 8.06 (s, 1H), 8.39-8.41 (m, 1H), 10.16 (br s, 1H), 12.64 (br s, 1H). ESIMS m/z: 896 (M+H)+. Compound 134: Compound 134 was obtained in the same manner as in Step 2 of Example 18 using Compound 133 obtained in Example 126.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.05 (s, 6H), 1.62 (t, J = 6.8 Hz, 2H), 1.80 (br s, 2H), 2.50 (s, 2H), 2.66 ( t, J = 6.2 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 2.89 (br s, 2H), 2.97-3.22 (m, 7H), 3.47-3.80 (m, 14H), 4.65 ( s, 2H), 5.30 (s, 1H), 7.36-7.38 (m, 1H), 7.43-7.55 (m, 2H), 7.81-7.94 (m, 3H), 8.06 (s, 1H), 8.39-8.41 ( m, 1H), 10.16 (br s, 1H), 12.64 (br s, 1H). ESIMS m / z: 896 (M + H) + .
化合物135～139：実施例126と同様にして、サルコシンtert-ブチルエステル、3-(メチルアミノ)プロパン酸エチルならびに実施例46の工程1と同様にして得られる3-(3-ヒドロキシプロピルアミノ)プロパン酸メチル、2-(2-(2-ヒドロキシエトキシ)エチルアミノ)酢酸ベンジルおよび2-(4-ヒドロキシブチルアミノ)酢酸ベンジルを用いて、化合物135～139を得た。
化合物135：ESIMS m/z: 908(M+H)+.
化合物136：ESIMS m/z: 894(M+H)+.
化合物137：ESIMS m/z: 924(M+H)+.
化合物138：ESIMS m/z: 1016(M+H)+.
化合物139：ESIMS m/z: 1000(M+H)+. Compounds 135 to 139: sarcosine tert-butyl ester, ethyl 3- (methylamino) propanoate as in Example 126 and 3- (3-hydroxypropylamino) obtained in the same manner as in Step 1 of Example 46 Compounds 135-139 were obtained using methyl propanoate, benzyl 2- (2- (2-hydroxyethoxy) ethylamino) acetate and benzyl 2- (4-hydroxybutylamino) acetate.
Compound 135: ESIMS m / z: 908 (M + H) + .
Compound 136: ESIMS m / z: 894 (M + H) + .
Compound 137: ESIMS m / z: 924 (M + H) + .
Compound 138: ESIMS m / z: 1016 (M + H) + .
Compound 139: ESIMS m / z: 1000 (M + H) + .
化合物140～144：化合物135、136、137、138および139を用いて、実施例15、実施例52または実施例127と同様にして、化合物140～144を得た。
化合物140：ESIMS m/z: 852 (M+H)+.
化合物141：ESIMS m/z: 866 (M+H)+.
化合物142：ESIMS m/z: 910 (M+H)+.
化合物143：ESIMS m/z: 926 (M+H)+.
化合物144：ESIMS m/z: 910 (M+H)+. Compounds 140 to 144: Compounds 140 to 144 were obtained in the same manner as in Example 15, Example 52, or Example 127 using Compounds 135, 136, 137, 138, and 139.
Compound 140: ESIMS m / z: 852 (M + H) + .
Compound 141: ESIMS m / z: 866 (M + H) + .
Compound 142: ESIMS m / z: 910 (M + H) + .
Compound 143: ESIMS m / z: 926 (M + H) + .
Compound 144: ESIMS m / z: 910 (M + H) + .
化合物145：3-アミノ-1-プロパノールを用い実施例36と同様にして得られる化合物を用いて、実施例127と同様にして、化合物140を得た。
ESIMS m/z: 940 (M+H)+. Compound 145: Compound 140 was obtained in the same manner as in Example 127, using 3-amino-1-propanol and the compound obtained in the same manner as in Example 36.
ESIMS m / z: 940 (M + H) + .
化合物146：3-アミノ-1,2-プロパンジオールを用い実施例36と同様にして得られる化合物を用いて、実施例127と同様にして、化合物146を得た。
ESIMS m/z: 956 (M+H)+. Compound 146: Compound 146 was obtained in the same manner as in Example 127, using a compound obtained in the same manner as in Example 36 using 3-amino-1,2-propanediol.
ESIMS m / z: 956 (M + H) + .
化合物147：2-アミノ-1,3-プロパンジオールを用い実施例36と同様にして得られる化合物を用いて、実施例127と同様にして、化合物147を得た。
ESIMS m/z：956 (M+H)+. Compound 147: Compound 147 was obtained in the same manner as in Example 127, using a compound obtained in the same manner as in Example 36 using 2-amino-1,3-propanediol.
ESIMS m / z: 956 (M + H) + .
化合物148：実施例36で得られる化合物36（280 mg, 0.485 mmol）をジクロロメタン（5 mL）に溶解し、氷冷下でピリジン（0.047 mL, 0.582 mmol）およびクロロアセチルクロリド（0.047 mL, 0.582 mmol）を加え室温で1時間攪拌した。混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下で留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン／酢酸エチル＝70／30）で精製することにより化合物148（186 mg, 59%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.08 (s, 6H), 1.55 (s, 3H), 1.70 (t, J = 6.2 Hz, 2H), 2.54 (s, 2H), 2.88 (t, J = 6.2 Hz, 2H), 3.08 (s, 2H), 4.71 (s, 2H), 7.48-7.60 (m, 3H), 7.89-8.07 (m, 4H), 8.24-8.30 (m 1H), 9.22 (br s, 1H), 13.00 (br s, 1H). Compound 148: Compound 36 (280 mg, 0.485 mmol) obtained in Example 36 was dissolved in dichloromethane (5 mL), and pyridine (0.047 mL, 0.582 mmol) and chloroacetyl chloride (0.047 mL, 0.582 mmol) were cooled with ice. ) And stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 70/30) to give Compound 148 (186 mg, 59%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.55 (s, 3H), 1.70 (t, J = 6.2 Hz, 2H), 2.54 (s, 2H), 2.88 (t , J = 6.2 Hz, 2H), 3.08 (s, 2H), 4.71 (s, 2H), 7.48-7.60 (m, 3H), 7.89-8.07 (m, 4H), 8.24-8.30 (m 1H), 9.22 (br s, 1H), 13.00 (br s, 1H).
化合物149
工程１：文献（Chemistry-A European Journal, 2003, 9, 2717-2725など）に記載の方法に従って合成した20-ヒドロキシ-3,6,9,12,15,18-ヘキサオキサイコサン-1-酸tert-ブチル（0.6 g, 1.513 mmol）をジクロロメタン（10 mL）に溶解させ、トリフルオロ酢酸（2.3 ml, 30 mmol）を加えて終夜撹拌した。混合物にトルエンを加えて溶媒を留去することにより粗20-ヒドロキシ-3,6,9,12,15,18-ヘキサオキサイコサン-1-酸（0.51 g, 99%）を得た。
1H-NMR (300MHz, CDCl3, δ): 3.68-3.70 (m, 18H), 3.76-3.80 (m, 4H), 4.18 (s, 2H), 4.50 (dd, J = 5.5, 4.0 Hz, 2H), 6.22 (s, 2H).
工程2：工程1で得られる粗20-ヒドロキシ-3,6,9,12,15,18-ヘキサオキサイコサン-1-酸（0.253 g, 0.744 mmol）をTHF（1 mL）およびDMF（0.1 mL）に溶解し、氷冷下、水素化ナトリウム（0.104 g, 2.60 mmol）を加えて10分間撹拌した。化合物143（0.243 g, 0.372 mmol）を加えて氷冷下で1時間撹拌した後、室温にて2時間撹拌した。混合物に飽和塩化アンモニウム水溶液と2 mol/L塩酸を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄後、濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝92／8）で精製することにより化合物149（0.043 g, 12%）を得た。
ESIMS m/z: 957(M+H)+. Compound 149
Step 1: 20-hydroxy-3,6,9,12,15,18-hexaoxaicosane-1-synthesized according to the method described in the literature (Chemistry-A European Journal, 2003, 9, 2717-2725, etc.) Tert-butyl acid (0.6 g, 1.513 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2.3 ml, 30 mmol) was added, and the mixture was stirred overnight. Toluene was added to the mixture and the solvent was distilled off to obtain crude 20-hydroxy-3,6,9,12,15,18-hexaoxaicosane-1-acid (0.51 g, 99%).
1 H-NMR (300MHz, CDCl 3 , δ): 3.68-3.70 (m, 18H), 3.76-3.80 (m, 4H), 4.18 (s, 2H), 4.50 (dd, J = 5.5, 4.0 Hz, 2H ), 6.22 (s, 2H).
Step 2: The crude 20-hydroxy-3,6,9,12,15,18-hexaoxaicosan-1-acid (0.253 g, 0.744 mmol) obtained in Step 1 was added to THF (1 mL) and DMF (0.1 In an ice bath, sodium hydride (0.104 g, 2.60 mmol) was added and stirred for 10 minutes. Compound 143 (0.243 g, 0.372 mmol) was added, and the mixture was stirred for 1 hour under ice-cooling, and then stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and 2 mol / L hydrochloric acid were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated to give a residue, which was purified by silica gel column chromatography (chloroform / methanol = 92/8) to give compound 149 (0.043 g, 12%).
ESIMS m / z: 957 (M + H) + .
化合物150：3-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)プロパン酸を用いて、実施例130と同様にして、化合物150を得た。
ESIMS m/z: 837(M-H)+.  Compound 150: Compound 150 was obtained in the same manner as in Example 130, using 3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) propanoic acid.
ESIMS m / z: 837 (MH) + .
化合物151：ヘキサエチレングリコール（0.242 g, 0.857 mmol）を用いて、実施例130と同様にして、化合物151（0.174 g, 79%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.08 (s, 6H), 1.70 (t, J = 6.2 Hz, 2H), 2.54 (s, 2H), 2.88 (t, J = 6.2 Hz, 2H), 2.93 (s, 1H), 2.97 (s, 2H), 3.53-3.75 (m, 25H), 4.30-4.32 (m, 2H), 4.68 (s, 2H), 7.43-7.51 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.90-7.97 (m, 3H), 8.05-8.06 (m, 1H), 8.28 (d, J = 12.8 Hz, 1H), 9.29 (s, 1H),  12.96 (s, 1H). Compound 151: Compound 151 (0.174 g, 79%) was obtained in the same manner as in Example 130 using hexaethylene glycol (0.242 g, 0.857 mmol).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.08 (s, 6H), 1.70 (t, J = 6.2 Hz, 2H), 2.54 (s, 2H), 2.88 (t, J = 6.2 Hz, 2H ), 2.93 (s, 1H), 2.97 (s, 2H), 3.53-3.75 (m, 25H), 4.30-4.32 (m, 2H), 4.68 (s, 2H), 7.43-7.51 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.90-7.97 (m, 3H), 8.05-8.06 (m, 1H), 8.28 (d, J = 12.8 Hz, 1H), 9.29 (s, 1H), 12.96 (s, 1H).
化合物152：実施例136で得られる化合物151（2.4 g, 2.67 mmol）を用いて、実施例96と同様にして、化合物152（1.67 g, 64%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.69 (t, J = 5.9 Hz, 2H), 2.54 (s, 2H), 2.89 (br s, 2H), 2.93-2.98 (m, 2H), 3.06-3.09 (m, 3H), 3.53-3.75 (m, 23H), 4.28-4.40 (m, 4H), 4.68 (s, 2H), 7.41-7.54 (m, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.88-8.12 (m, 4H), 8.25-8.30 (m, 1H), 9.32 (s, 1H), 12.97 (s, 1H). Compound 152: Compound 152 (1.67 g, 64%) was obtained in the same manner as in Example 96, using Compound 151 (2.4 g, 2.67 mmol) obtained in Example 136.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.69 (t, J = 5.9 Hz, 2H), 2.54 (s, 2H), 2.89 (br s, 2H), 2.93- 2.98 (m, 2H), 3.06-3.09 (m, 3H), 3.53-3.75 (m, 23H), 4.28-4.40 (m, 4H), 4.68 (s, 2H), 7.41-7.54 (m, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.88-8.12 (m, 4H), 8.25-8.30 (m, 1H), 9.32 (s, 1H), 12.97 (s, 1H).
化合物153：実施例137で得られる化合物152（0.550 g, 0.563 mmol）を用いて、実施例126と同様にして、化合物153（0.089 g, 14%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.07 (s, 6H), 1.61-1.70 (m, 4H), 2.53 (s, 2H), 2.80-2.98 (m, 9H), 3.47-3.77 (m, 27H), 4.25-4.36 (m, 2H), 4.67 (s, 2H), 5.14 (s, 2H), 7.32-7.37 (m, 5H),7.40-7.59 (m, 3H), 7.87-7.99 (m, 3H), 8.27-8.31 (m, 1H), 9.38 (s, 1H), 12.94 (s, 1H).  Compound 153: Compound 153 (0.089 g, 14%) was obtained in the same manner as in Example 126, using Compound 152 (0.550 g, 0.563 mmol) obtained in Example 137.
1 H-NMR (400 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.61-1.70 (m, 4H), 2.53 (s, 2H), 2.80-2.98 (m, 9H), 3.47-3.77 ( m, 27H), 4.25-4.36 (m, 2H), 4.67 (s, 2H), 5.14 (s, 2H), 7.32-7.37 (m, 5H), 7.40-7.59 (m, 3H), 7.87-7.99 ( m, 3H), 8.27-8.31 (m, 1H), 9.38 (s, 1H), 12.94 (s, 1H).
化合物154：実施例138で得られる化合物153（0.089 g, 0.081 mmol）を用いて、実施例47と同様にして、化合物154（0.065 g, 80%）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 1.03 (s, 6H), 1.54 (t, J = 6.2 Hz, 2H), 1.76-1.86 (m, 2H), 2.50 (s, 2H), 2.75 (t, J = 6.2 Hz, 2H), 2.89 (br s, 3H), 3.21-3.27 (m, 2H), 3.34 (t, J = 5.1 Hz, 2H), 3.47-3.61 (m, 23H), 3.76 (t, J= 5.1 Hz, 2H), 3.99 (s, 2H), 4.24 (s, 2H), 4.59 (s, 2H), 7.43-7.55 (m, 2H), 7.74-7.80 (m, 3H), 7.96 (t, J = 8.0 Hz, 1H), 8.10 (s, 1H), 8.45 (s, 1H), 11.24 (br s, 1H), 11.52 (br s, 1H).  ESIMS m/z: 1014, 1016 (M + H)+. Compound 154: Compound 154 (0.065 g, 80%) was obtained in the same manner as in Example 47, using Compound 153 (0.089 g, 0.081 mmol) obtained in Example 138.
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.03 (s, 6H), 1.54 (t, J = 6.2 Hz, 2H), 1.76-1.86 (m, 2H), 2.50 (s, 2H) , 2.75 (t, J = 6.2 Hz, 2H), 2.89 (br s, 3H), 3.21-3.27 (m, 2H), 3.34 (t, J = 5.1 Hz, 2H), 3.47-3.61 (m, 23H) , 3.76 (t, J = 5.1 Hz, 2H), 3.99 (s, 2H), 4.24 (s, 2H), 4.59 (s, 2H), 7.43-7.55 (m, 2H), 7.74-7.80 (m, 3H ), 7.96 (t, J = 8.0 Hz, 1H), 8.10 (s, 1H), 8.45 (s, 1H), 11.24 (br s, 1H), 11.52 (br s, 1H). ESIMS m / z: 1014 , 1016 (M + H) + .
化合物155：2-(4-ヒドロキシブチルアミノ)酢酸ベンジルを用いて、実施例138および139と同様にして、化合物155を得た。
ESIMS m/z: 1028, 1030 (M + H)+. Compound 155: Compound 155 was obtained in the same manner as in Examples 138 and 139 using benzyl 2- (4-hydroxybutylamino) acetate.
ESIMS m / z: 1028, 1030 (M + H) + .
化合物156：実施例95で得られる化合物95を用い実施例12と同様にして得られる化合物（530mg, 0.599mmol）をピリジン（6.0 mL）に溶解し、80℃で3時間攪拌した。混合物を濃縮し、残渣をアミノシリカゲルカラムクロマトグラフィ－（クロロホルム／メタノ－ル＝4／1）で精製することにより、化合物156（80.0 mg, 13%）を得た。
ESIMS m/z: 963 (M)+. Compound 156: Using the compound 95 obtained in Example 95, the compound (530 mg, 0.599 mmol) obtained in the same manner as in Example 12 was dissolved in pyridine (6.0 mL), and the mixture was stirred at 80 ° C. for 3 hr. The mixture was concentrated, and the residue was purified by amino silica gel column chromatography (chloroform / methanol = 4/1) to give Compound 156 (80.0 mg, 13%).
ESIMS m / z: 963 (M) + .
化合物157：実施例41で得られる化合物41（0.77 g, 0.972 mmol）をDMF（4.86 mL）に溶解し、炭酸セシウム（0.475 g, 1.458 mmol）および3-メルカプトプロパン-1-オール（0.100 mL, 1.166 mmol）を加え、90℃で2時間撹拌した。混合物に水を加え、析出した固体をろ過し、減圧乾燥することにより化合物157（0.638 g, 92%）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 1.04 (s, 6H), 1.52 (t, J = 6.2 Hz, 2H), 1.61-1.68 (m, 2H), 1.70-1.79 (m, 2H), 2.48-2.50 (m, 8H), 2.78 (d, J = 5.5 Hz, 2H), 3.44 (t, J = 6.2 Hz, 2H), 3.81 (d, J = 3.7 Hz, 2H), 7.45-7.49 (m, 2H), 7.74-7.80 (m, 2H), 7.89-7.97 (m, 2H), 8.11 (s, 1H), 8.43 (s, 1H).  ESIMS m/z: 712 (M + H)+. Compound 157: Compound 41 (0.77 g, 0.972 mmol) obtained in Example 41 was dissolved in DMF (4.86 mL), cesium carbonate (0.475 g, 1.458 mmol) and 3-mercaptopropan-1-ol (0.100 mL, 1.166 mmol) was added and the mixture was stirred at 90 ° C. for 2 hours. Water was added to the mixture, and the precipitated solid was filtered and dried under reduced pressure to obtain Compound 157 (0.638 g, 92%).
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.04 (s, 6H), 1.52 (t, J = 6.2 Hz, 2H), 1.61-1.68 (m, 2H), 1.70-1.79 (m, 2H), 2.48-2.50 (m, 8H), 2.78 (d, J = 5.5 Hz, 2H), 3.44 (t, J = 6.2 Hz, 2H), 3.81 (d, J = 3.7 Hz, 2H), 7.45- 7.49 (m, 2H), 7.74-7.80 (m, 2H), 7.89-7.97 (m, 2H), 8.11 (s, 1H), 8.43 (s, 1H). ESIMS m / z: 712 (M + H) + .
化合物158：実施例142で得られる化合物157（0.16 g, 0.225 mmol）をジクロロメタン（2.24 mL）に溶解し、トリエチルアミン（0.047 mL、0.337 mmol）およびメタンスルホニルクロリド（0.026 mL, 0.337 mmol）を加え、0℃で1.5時間撹拌した。混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去することにより化合物158（0.178 g, 定量的）を得た。
1H-NMR (300 MHz, CDCl3, δ):1.04 (s, 6H), 1.65 (t, J = 5.9 Hz, 2H), 1.76-1.86 (m, 2H), 1.95-1.99 (m, 2H), 2.42-2.62 (m, 8H), 2.88 (s, 2H), 3.00 (s, 3H), 3.76 (s, 2H), 4.30 (t, J= 6.0 Hz, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.89-8.08 (m, 4H), 8.25 (s, 1H), 9.44 (s, 1H), 12.88 (s, 1H). ESIMS m/z: 790 (M + H)+.   Compound 158: Compound 157 (0.16 g, 0.225 mmol) obtained in Example 142 was dissolved in dichloromethane (2.24 mL), triethylamine (0.047 mL, 0.337 mmol) and methanesulfonyl chloride (0.026 mL, 0.337 mmol) were added, Stir at 0 ° C. for 1.5 hours. To the mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 158 (0.178 g, quantitative).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.04 (s, 6H), 1.65 (t, J = 5.9 Hz, 2H), 1.76-1.86 (m, 2H), 1.95-1.99 (m, 2H) , 2.42-2.62 (m, 8H), 2.88 (s, 2H), 3.00 (s, 3H), 3.76 (s, 2H), 4.30 (t, J = 6.0 Hz, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.89-8.08 (m, 4H), 8.25 (s, 1H), 9.44 (s, 1H), 12.88 (s, 1H). ESIMS m / z: 790 (M + H) + .   
化合物159：実施例143で得られる化合物158（0.178 g, 0.225 mmol）をジクロロメタン（2.0 mL）に溶解し、m-クロロ過安息香酸（0.233 g, 1.013 mmol）を加え、室温で2時間撹拌した。混合物に飽和炭酸ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去することにより化合物159（0.197 g, 定量的）を得た。
ESIMS m/z: 854 (M + H)+. Compound 159: Compound 158 (0.178 g, 0.225 mmol) obtained in Example 143 was dissolved in dichloromethane (2.0 mL), m-chloroperbenzoic acid (0.233 g, 1.013 mmol) was added, and the mixture was stirred at room temperature for 2 hr. . A saturated aqueous sodium carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 159 (0.197 g, quantitative).
ESIMS m / z: 854 (M + H) + .
化合物160：実施例144で得られる化合物159（0.192 g, 0.225 mmol）をDMF（2.0 mL）に溶解し、ジエチルアミン（1.411 mL, 13.5 mmol）を加え、100℃で終夜撹拌した。混合物に飽和食塩水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝4／1）で精製することにより化合物160（0.076 g, 41%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.00-1.06 (m, 12H), 1.67 (s, 2H), 1.95-2.02 (m, 2H), 2.35-2.42 (m, 2H), 2.51 (s, 2H), 2.56-2.64 (m, 6H), 2.88 (s, 2H), 3.06-3.09 (m, 2H), 3.17-3.20 (m, 4H), 4.39 (s, 2H), 7.53-7.57 (m, 2H), 7.66 (d, J = 6.8 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 8.02-8.06 (m, 3H), 8.26 (s, 1H).  ESIMS m/z: 831 (M + H)+.   Compound 160: Compound 159 (0.192 g, 0.225 mmol) obtained in Example 144 was dissolved in DMF (2.0 mL), diethylamine (1.411 mL, 13.5 mmol) was added, and the mixture was stirred at 100 ° C. overnight. Saturated saline was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 4/1) to give Compound 160 (0.076 g, 41%).
1 H-NMR (400 MHz, CDCl 3 , δ): 1.00-1.06 (m, 12H), 1.67 (s, 2H), 1.95-2.02 (m, 2H), 2.35-2.42 (m, 2H), 2.51 ( s, 2H), 2.56-2.64 (m, 6H), 2.88 (s, 2H), 3.06-3.09 (m, 2H), 3.17-3.20 (m, 4H), 4.39 (s, 2H), 7.53-7.57 ( m, 2H), 7.66 (d, J = 6.8 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 8.02-8.06 (m, 3H), 8.26 (s, 1H). ESIMS m / z: 831 (M + H) + .   
化合物161：実施例1で得られる化合物１（254 mg, 0.436 mmol）をDMF（5 mL）に溶解し、炭酸セシウム（426 mg, 1.31 mmol）および1-メルカプト-3,6,9,12,15,18,21,24-オクタヘプタコサン-27酸(200 mg, 0.436 mmol)を加え50℃で7時間攪拌した。混合物にクエン酸（335 mg, 1.75 mmol）および水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィーにより精製することにより化合物161（328 mg, 75%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.68 (t, J = 5.8 Hz, 2H), 2.53 (s, 2H), 2.58-2.64 (m, 4H), 3.60-3.69 (m, 32H), 3.76 (t, J = 5.9 Hz, 2H), 3.92 (s, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.57 (d, J = 7.7 Hz, 2H), 7.91-8.05 (m, 4H), 8.25 (s, 1H), 9.36 (br s, 1H), 12.87 (br s, 1H).  ESIMS m/z: 1004 (M+H)+. Compound 161: Compound 1 (254 mg, 0.436 mmol) obtained in Example 1 was dissolved in DMF (5 mL), cesium carbonate (426 mg, 1.31 mmol) and 1-mercapto-3,6,9,12, 15,18,21,24-Octaheptacosane-27 acid (200 mg, 0.436 mmol) was added and stirred at 50 ° C. for 7 hours. Citric acid (335 mg, 1.75 mmol) and water were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography to give compound 161 (328 mg, 75%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.68 (t, J = 5.8 Hz, 2H), 2.53 (s, 2H), 2.58-2.64 (m, 4H), 3.60 -3.69 (m, 32H), 3.76 (t, J = 5.9 Hz, 2H), 3.92 (s, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.57 (d, J = 7.7 Hz, 2H) , 7.91-8.05 (m, 4H), 8.25 (s, 1H), 9.36 (br s, 1H), 12.87 (br s, 1H). ESIMS m / z: 1004 (M + H) + .
化合物162 
工程１：3-(2-(2-(2-(トシルオキシ)エトキシ)エトキシ)エトキシ)プロパン酸tert-ブチルを用いて、実施例45の工程1と同様にして、1-(14,14-ジメチル-12-オキソ-3,6,9,13-テトラオキサペンタデシル)-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸ベンジル（1.74 g, 81%）、および6-(14,14-ジメチル-12-オキソ-3,6,9,13-テトラオキサペンタデシルオキシ)ニコチン酸ベンジル（0.527 g, 25%）を得た。
工程2：工程1で得られる1-(14,14-ジメチル-12-オキソ-3,6,9,13-テトラオキサペンタデシル)-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸ベンジルを用いて、実施例45の工程4と同様にして1-(14,14-ジメチル-12-オキソ-3,6,9,13-テトラオキサペンタデシル)-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸（1.29 g, 91%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.44 (s, 9H), 2.52 (t, J = 6.4 Hz, 2H), 3.57-3.61 (m, 8H), 3.68-3.79 (m, 4H), 4.20 (t, J = 5.7 Hz, 2H), 6.56 (d, J = 9.5 Hz, 1H), 7.89 (dd, J = 9.5, 2.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H).
工程3：工程2で得られる1-(14,14-ジメチル-12-オキソ-3,6,9,13-テトラオキサペンタデシル)-6-オキソ-1,6-ジヒドロピリジン-3-カルボン酸を用いて、実施例6の工程3と同様にして化合物162（762 mg, 44%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.07 (s, 6H), 1.26 (t, J = 7.1 Hz, 2H), 1.58 (s, 9H), 1.65-1.72 (m, 2H), 2.44 (t, J = 6.6 Hz, 2H), 2.53 (s, 2H), 2.86 (m, 2H), 3.16-3.62 (m, 8H), 3.79 (t, J = 4.8 Hz, 2H), 4.22 (t, J = 4.8 Hz, 2H), 6.61 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.89-8.03 (m, 3H), 8.22 (s, 1H), 8.33 (s, 1H), 9.35 (s, 1H), 12.73 (br s, 1H). Compound 162
Step 1: 3- (2- (2- (2- (Tosyloxy) ethoxy) ethoxy) ethoxy) tert-butyl propanoate was used in the same manner as Step 1 of Example 45 to give 1- (14,14- Dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl) -6-oxo-1,6-dihydropyridine-3-carboxylate (1.74 g, 81%), and 6- (14,14 -Dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyloxy) nicotinic acid benzyl (0.527 g, 25%) was obtained.
Step 2: Benzyl 1- (14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 1 1- (14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl) -6-oxo-1,6-dihydropyridine in the same manner as in Step 4 of Example 45. -3-carboxylic acid (1.29 g, 91%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.44 (s, 9H), 2.52 (t, J = 6.4 Hz, 2H), 3.57-3.61 (m, 8H), 3.68-3.79 (m, 4H) , 4.20 (t, J = 5.7 Hz, 2H), 6.56 (d, J = 9.5 Hz, 1H), 7.89 (dd, J = 9.5, 2.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H) .
Step 3: 1- (14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl) -6-oxo-1,6-dihydropyridine-3-carboxylic acid obtained in Step 2 Was used to give compound 162 (762 mg, 44%) in the same manner as in Step 3 of Example 6.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.26 (t, J = 7.1 Hz, 2H), 1.58 (s, 9H), 1.65-1.72 (m, 2H), 2.44 (t, J = 6.6 Hz, 2H), 2.53 (s, 2H), 2.86 (m, 2H), 3.16-3.62 (m, 8H), 3.79 (t, J = 4.8 Hz, 2H), 4.22 (t, J = 4.8 Hz, 2H), 6.61 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.89-8.03 (m, 3H), 8.22 (s, 1H), 8.33 ( s, 1H), 9.35 (s, 1H), 12.73 (br s, 1H).
化合物163：実施例147で得られる化合物157を用いて、実施例15と同様にして、化合物163（431mg, 61%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 1.07 (s, 6H), 1.68 (t, J = 5.9 Hz, 2H), 2.52 (s, 2H), 2.60 (t, J = 5.9 Hz, 2H), 2.86 (br s, 2H), 3.57-3.60 (m, 8H), 3.76 (t, J = 5.9 Hz, 2H), 3.82 (t, J = 4.9 Hz, 2H), 4.30 (t, J = 4.9 Hz, 2H), 5.50 (br s, 1H), 6.70 (d, J = 9.8 Hz, 1H), 7.58 (d, J = 9.8 Hz, 1H), 7.95-8.00 (m, 3H), 8.07 (s, 1H), 8.18 (s, 1H), 8.42 (s, 1H), 9.35 (br s, 1H), 12.72 (br s, 1H). Compound 163: Compound 163 (431 mg, 61%) was obtained in the same manner as in Example 15 using Compound 157 obtained in Example 147.
1 H-NMR (400 MHz, CDCl 3 , δ): 1.07 (s, 6H), 1.68 (t, J = 5.9 Hz, 2H), 2.52 (s, 2H), 2.60 (t, J = 5.9 Hz, 2H ), 2.86 (br s, 2H), 3.57-3.60 (m, 8H), 3.76 (t, J = 5.9 Hz, 2H), 3.82 (t, J = 4.9 Hz, 2H), 4.30 (t, J = 4.9 Hz, 2H), 5.50 (br s, 1H), 6.70 (d, J = 9.8 Hz, 1H), 7.58 (d, J = 9.8 Hz, 1H), 7.95-8.00 (m, 3H), 8.07 (s, 1H), 8.18 (s, 1H), 8.42 (s, 1H), 9.35 (br s, 1H), 12.72 (br s, 1H).
化合物164：実施例148で得られる化合物158を用いて、実施例16と同様にして、化合物164（125mg, 55%）を得た。
ESIMS m/z: 858 (M+H)+. Compound 164: Compound 164 (125 mg, 55%) was obtained in the same manner as in Example 16 using Compound 158 obtained in Example 148.
ESIMS m / z: 858 (M + H) + .
化合物165：実施例147の工程１で得られる6-(14,14-ジメチル-12-オキソ-3,6,9,13-テトラオキサペンタデシルオキシ)ニコチン酸ベンジルを用いて、実施例147の工程2～3および実施例149と同様にして、化合物165を得た。
ESIMS m/z: 858 (M+H)+. Compound 165: Example 147 using benzyl 6- (14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyloxy) nicotinate obtained in Step 1 of Example 147 In the same manner as in Steps 2 to 3 and Example 149, compound 165 was obtained.
ESIMS m / z: 858 (M + H) + .
化合物166：実施例100で得られる化合物105（0.25 g, 0.31 mmol）をTHF（10 mL）に溶解し、1H-テトラゾール（0.043 g, 0.61 mmol）およびジ-tert-ブチルジエチルホスホロアミダイト（0.128 mL, 0.46 mmol）を加えて室温で12時間撹拌した。さらに1H-テトラゾール（0.034 g, 0.49 mmol）およびジ-tert-ブチルジエチルホスホロアミダイト（0.10 mL, 0.37 mmol）を加えた後、m-クロロ過安息香酸（0.16 g, 0.68 mmol）を加えて室温で10分間撹拌した。混合物に飽和チオ硫酸ナトリウム水溶液および飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝93／7）で精製することにより化合物166（0.30 g, 98%）を得た。
ESIMS m/z: 1004 (M-H)+. Compound 166: Compound 105 (0.25 g, 0.31 mmol) obtained in Example 100 was dissolved in THF (10 mL), and 1H-tetrazole (0.043 g, 0.61 mmol) and di-tert-butyldiethyl phosphoramidite (0.128 mL, 0.46 mmol) was added and stirred at room temperature for 12 hours. Add 1H-tetrazole (0.034 g, 0.49 mmol) and di-tert-butyldiethyl phosphoramidite (0.10 mL, 0.37 mmol), then add m-chloroperbenzoic acid (0.16 g, 0.68 mmol) at room temperature. For 10 minutes. Saturated aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 93/7) to obtain Compound 166 (0.30 g, 98%).
ESIMS m / z: 1004 (MH) + .
化合物167：実施例151で得られる化合物166（0.30 g, 5.2 mmol）をジクロロメタン（10 mL）に溶解し、トリフルオロ酢酸（1.1 mL, 14.9 mmol）を加え、室温で1時間攪拌した。混合物を濃縮した後、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝93／7）で精製することにより、化合物167（0.12 g, 45%）を得た。
ESIMS m/z: 894 (M+H)+. Compound 167: Compound 166 (0.30 g, 5.2 mmol) obtained in Example 151 was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1.1 mL, 14.9 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated and purified by silica gel column chromatography (chloroform / methanol = 93/7) to give compound 167 (0.12 g, 45%).
ESIMS m / z: 894 (M + H) + .
化合物168：文献（J. Org. Chem. 2004, 69, 639など）に従って得られた4-メチルベンゼンスルホン酸2-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)エチルを用いて、実施例8と同様にして、化合物168を得た。
ESIMS m/z: 726 (M+H)+. Compound 168: using 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate obtained according to the literature (J. Org. Chem. 2004, 69, 639 etc.) In the same manner as in Example 8, compound 168 was obtained.
ESIMS m / z: 726 (M + H) + .
化合物169：実施例153で得られる化合物168（0.513 g, 0.706 mmol）をDMF（1.5 ml）に溶解し、水酸化ナトリウム（0.085 g, 2.1 mmol）を氷冷下で加え、室温で10分間撹拌した。氷冷下、プロパルギルブロミド（0.115 ml, 1.060 mmol）を加え、1時間撹拌した。混合物に水および飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、シリカゲルカラムクロマトグラフィー（ヘプタン／酢酸エチル＝50／50）で精製することにより化合物169（0.23 g, 42%）を得た。
ESIMS m/z: 764 (M+H)+. Compound 169: Compound 168 (0.513 g, 0.706 mmol) obtained in Example 153 was dissolved in DMF (1.5 ml), sodium hydroxide (0.085 g, 2.1 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 10 minutes. did. Under ice cooling, propargyl bromide (0.115 ml, 1.060 mmol) was added and stirred for 1 hour. Water and saturated aqueous ammonium chloride solution were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (heptane / ethyl acetate = 50/50) to obtain Compound 169 (0.23 g, 42%).
ESIMS m / z: 764 (M + H) + .
化合物170：実施例154で得られる化合物169（0.136 g, 0.178 mmol）および5-アジドペンタン酸（0.025 g, 0.178 mmol）を1,4-ジオキサン（2.5 ml）と水（1 mL）に溶解し、アスコルビン酸ナトリウム（0.11 g, 0.53 mmol）および硫酸第二銅・五水和物（0.089 g, 0.36 mmol）を加え、室温で1時間撹拌した。混合物にアンモニア水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝94／6）で精製することにより化合物170（0.04 g, 25%）を得た。
ESIMS m/z: 907 (M+H)+. Compound 170: Compound 169 (0.136 g, 0.178 mmol) and 5-azidopentanoic acid (0.025 g, 0.178 mmol) obtained in Example 154 were dissolved in 1,4-dioxane (2.5 ml) and water (1 mL). , Sodium ascorbate (0.11 g, 0.53 mmol) and cupric sulfate pentahydrate (0.089 g, 0.36 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Aqueous ammonia was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 94/6) to give compound 170 ( 0.04 g, 25%).
ESIMS m / z: 907 (M + H) + .
化合物171, 172：対応するアジド化合物を用いて、実施例155と同様にして、化合物171および172を得た。
化合物171：ESIMS m/z: 987 (M + H)+.
化合物172：ESIMS m/z: 971 (M + H)+. Compounds 171 and 172: Compounds 171 and 172 were obtained in the same manner as in Example 155, using the corresponding azide compounds.
Compound 171: ESIMS m / z: 987 (M + H) + .
Compound 172: ESIMS m / z: 971 (M + H) + .
化合物173：4,4-ジフルオロシクロヘキサノンを用い参考例１、実施例2、3、8および96と同様にして得られる化合物とモルホリンを用いて、実施例10と同様にして、化合物173を得た。
ESIMS m/z: 759 (M + H)+.  Compound 173: Compound 173 was obtained in the same manner as in Example 10 by using 4,4-difluorocyclohexanone in the same manner as in Reference Example 1, Examples 2, 3, 8 and 96 and morpholine. .
ESIMS m / z: 759 (M + H) + .  
化合物174：テトラヒドロ-4H-ピラン-4-オンを用い参考例1、実施例２および3と同様にして得られる化合物を用いて、実施例17と同様にして化合物174を得た。
ESIMS m/z: 831 (M + H)+. Compound 174: Compound 174 was obtained in the same manner as in Example 17 using the compound obtained in the same manner as in Reference Example 1, Example 2 and 3 using tetrahydro-4H-pyran-4-one.
ESIMS m / z: 831 (M + H) + .
化合物175
工程１：2-(2-(2-メトキシエトキシ)エトキシ)エタノール（9.52 mL, 60.9 mmol）をピリジン（120 mL）に溶解し、4-メチルベンゼン-1-スルホニルクロリド（15.09 g, 79.0 mmol）を0℃で加え、室温で終夜撹拌した。混合物に1 mol/L塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去することで、2-(2-(2-メトキシエトキシ)エトキシ)エチル-4-メチルベンゼンスルホネート（0.804 g,73%）を得た。
ESIMS m/z: 319 (M + H)+.
工程2：3,5-ジヒドロキシ安息香酸メチル（0.35 g, 2.082 mmol）をDMF（10.0 mL）に溶解し、炭酸セシウム（2.035 g, 6.24 mmol）および工程１で得られる2-(2-(2-メトキシエトキシ)エトキシ)エチル-4-メチルベンゼンスルホネート（1.988 g, 6.24 mmol）を加え、100℃で２時間撹拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘプタン／酢酸エチル＝1／4）で精製することにより3,5-ビス(2-(2-(2-メトキシエトキシ)エトキシ)エトキシ)安息香酸メチル（0.85 g,89%）を得た。
1H-NMR (400 MHz, CDCl3, δ): 3.36 (s, 6H), 3.53-3.56 (m, 4H), 3.62-3.70 (m, 8H), 3.72-3.76 (m, 4H), 3.84-3.87 (m, 4H), 3.89 (s, 3H), 4.13-4.16 (m, 4H), 6.70 (t, J = 2.4 Hz, 1H), 7.19 (d, J= 2.2 Hz, 2H).  ESIMS m/z: 478 (M + 18)+.
工程3：工程2で得られる3,5-ビス(2-(2-(2-メトキシエトキシ)エトキシ)エトキシ)安息香酸メチル（0.85 g, 1.846 mmol）を6 mol/L塩酸（9.23 mL）に溶解し、100℃で終夜撹拌した。トルエンを用いて共沸することにより3,5-ビス(2-(2-(2-メトキシエトキシ)エトキシ)エトキシ)安息香酸（0.8 g, 97%）を得た。
ESIMS m/z: 464 (M + 18)+.
工程4：工程3で得られる3,5-ビス(2-(2-(2-メトキシエトキシ)エトキシ)エトキシ)安息香酸（0.433 g, 0.971 mmol）をジクロロメタン（4 mL）に溶解し、2,4,6-トリクロロベンゾイルクロリド（0.233 mL, 1.493 mmol）、トリエチルアミン（0.52 mL, 3.73 mmol）、4-ジメチルアミノピリジン（0.182 g, 1.493 mmol）および参考例1と同様にして合成した(E)-2-アミノ-N’-(4-クロロ-3-(トリフルオロメチル)ベンジリデン)-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボヒドラジド（0.3 g、0.747 mmol）を加え、室温で3時間撹拌した。混合物に飽和食塩水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝4／1）で精製することにより化合物175（0.16 g, 26%）を得た。
1H-NMR (300 MHz, DMSO-d6, δ): 1.78 (brs, 4H), 2.70 (brs, 4H), 3.23 (s, 6H), 3.41-3.45 (m, 4H), 3.51-3.58 (m, 12H), 3.72-3.75 (m, 4H), 4.11-4.15 (m, 4H), 6.74 (d, J = 2.2 Hz, 1H), 7.00 (d, J= 2.2 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 8.38 (s, 1H), 11.16 (s, 2H).  ESIMS m/z: 830 (M + H)+. Compound 175
Step 1: 2- (2- (2-methoxyethoxy) ethoxy) ethanol (9.52 mL, 60.9 mmol) was dissolved in pyridine (120 mL) and 4-methylbenzene-1-sulfonyl chloride (15.09 g, 79.0 mmol). Was added at 0 ° C. and stirred at room temperature overnight. 1 mol / L hydrochloric acid was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2- (2- (2-methoxyethoxy) ethoxy) ethyl-4-methylbenzenesulfonate (0.804 g, 73%).
ESIMS m / z: 319 (M + H) + .
Step 2: Methyl 3,5-dihydroxybenzoate (0.35 g, 2.082 mmol) was dissolved in DMF (10.0 mL) and cesium carbonate (2.035 g, 6.24 mmol) and 2- (2- (2 -Methoxyethoxy) ethoxy) ethyl-4-methylbenzenesulfonate (1.988 g, 6.24 mmol) was added and stirred at 100 ° C. for 2 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate = 1/4) to give methyl 3,5-bis (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) benzoate (0.85 g, 89 %).
1 H-NMR (400 MHz, CDCl 3 , δ): 3.36 (s, 6H), 3.53-3.56 (m, 4H), 3.62-3.70 (m, 8H), 3.72-3.76 (m, 4H), 3.84- 3.87 (m, 4H), 3.89 (s, 3H), 4.13-4.16 (m, 4H), 6.70 (t, J = 2.4 Hz, 1H), 7.19 (d, J = 2.2 Hz, 2H). ESIMS m / z: 478 (M + 18) + .
Step 3: Methyl 3,5-bis (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) benzoate (0.85 g, 1.846 mmol) obtained in Step 2 was added to 6 mol / L hydrochloric acid (9.23 mL). Dissolved and stirred at 100 ° C. overnight. By azeotroping with toluene, 3,5-bis (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) benzoic acid (0.8 g, 97%) was obtained.
ESIMS m / z: 464 (M + 18) + .
Step 4: Dissolve 3,5-bis (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) benzoic acid (0.433 g, 0.971 mmol) obtained in Step 3 in dichloromethane (4 mL), 4,6-trichlorobenzoyl chloride (0.233 mL, 1.493 mmol), triethylamine (0.52 mL, 3.73 mmol), 4-dimethylaminopyridine (0.182 g, 1.493 mmol) and synthesized in the same manner as Reference Example 1 (E)- Add 2-amino-N '-(4-chloro-3- (trifluoromethyl) benzylidene) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carbohydrazide (0.3 g, 0.747 mmol) And stirred at room temperature for 3 hours. Saturated saline was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 4/1) to give Compound 175 (0.16 g, 26%).
1 H-NMR (300 MHz, DMSO-d 6 , δ): 1.78 (brs, 4H), 2.70 (brs, 4H), 3.23 (s, 6H), 3.41-3.45 (m, 4H), 3.51-3.58 ( m, 12H), 3.72-3.75 (m, 4H), 4.11-4.15 (m, 4H), 6.74 (d, J = 2.2 Hz, 1H), 7.00 (d, J = 2.2 Hz, 2H), 7.73 (d , J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 8.38 (s, 1H), 11.16 (s, 2H) .ESIMS m / z: 830 (M + H) + .
化合物176, 化合物177
工程１：実施例86の工程1で得られる2-アミノ-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（25 g, 89.0 mmol）を用いて、実施例2および3と同様にして、2-(3-ヒドロキシベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（30.0 g, 83%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.01 (s, 6H), 1.52-1.56 (m, 2H), 1.62 (s, 9H), 2.46 (s, 2H), 2.77 (t, J = 6.0 Hz, 2H), 7.07 (t, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.60 (s, 1H).
工程2：工程1で得られる2-(3-ヒドロキシベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（20.0 g, 49.8 mmol）を用いて、実施例8と同様にして、2-(3-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)ベンズアミド)- 6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（15.6 g, 59%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.01 (s, 6H), 1.54 (t, J = 6.4 Hz, 2H), 1.61 (s, 9H), 2.40 (t, J = 6.4 Hz, 1H), 2.46 (s, 2H), 2.77 (t, J = 6.4 Hz, 2H), 3.62 (t, J = 4.6 Hz, 2H), 3.68-3.77 (m, 6H), 3.90 (t, J = 4.6 Hz, 2H), 4.23 (t, J = 4.6 Hz, 2H), 7.14 (dd, J = 8.0, 1.8 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 12.36 (s, 1H). 
工程3：工程2で得られる2-(3-(2-(2-(2-ヒドロキシエトキシ)エトキシ)エトキシ)ベンズアミド)- 6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（5.00 g, 9.37 mmol）を用いて、実施例12と同様にして、2-(3-(2-(2-(2-(2-オキシラン-2-イルメトキシ)エトキシ)エトキシ)エトキシ)ベンズアミド)- 6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（3.25 g, 59%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.01 (s, 6H), 1.54 (t, J = 6.4 Hz, 2H), 1.61 (s, 9H), 2.46 (s, 2H), 2.60 (dd, J = 4.9, 2.7 Hz, 1H), 2.75-2.80 (m, 3H), 3.13-3.17 (m, 1H), 3.43 (t, J = 11.7, 5.9 Hz, 1H), 3.63-3.81 (m, 9H), 3.90 (t, J= 4.8 Hz, 2H), 4.21 (t, J = 4.8 Hz, 2H), 7.13 (dd, J = 8.0, 2.2 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 2.2 Hz, 1H), 12.36 (s, 1H). 
工程4：工程3で得られる2-(3-(2-(2-(2-(2-オキシラン-2-イルメトキシ)エトキシ)エトキシ)エトキシ)ベンズアミド)- 6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（3.16 g, 5.36 mmol）を用いて、実施例13と同様にして、2-(3-(13-エチル-11-ヒドロキシ-3,6,9-トリオキサ-13-アザペンタデシロキシ)ベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（3.20 g, 90%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.01 (s, 6H), 1.01 (t, J = 7.0 Hz, 6H), 1.54 (t, J = 6.4 Hz, 2H), 1.61 (s, 9H), 2.38-2.67 (m, 8H), 2.77 (d, J = 6.4 Hz, 2H), 3.45-3.84 (m, 12H), 3.89 (t, J = 4.8 Hz, 2H), 4.22 (t, J= 4.8 Hz, 2H), 7.14 (dd, J = 8.0, 2.4 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 2.4 Hz, 1H), 12.36 (s, 1H). 
工程5：工程4で得られる2-(3-(13-エチル-11-ヒドロキシ-3,6,9-トリオキサ-13-アザペンタデシロキシ)ベンズアミド)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-3-カルボン酸tert-ブチル（2.00 g, 3.02 mmol）を用いて、実施例86の工程4と同様にして、3-(13-エチル-11-ヒドロキシ-3,6,9-トリオキサ-13-アザザペンタデシロキシ)-N-(3-(ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)ベンズアミド（1.50 g, 80%）を得た。
1H-NMR (300 MHz, CDCl3, δ): 1.02 (s, 6H), 1.09 (t, J = 7.0 Hz, 6H), 1.61 (t, J = 6.2 Hz, 2H), 2.48 (s, 2H), 2.52-2.81 (m, 8H), 3.50 (d, J = 5.1 Hz, 2H), 3.61-3.76 (m, 9H), 3.85-3.97 (m, 3H), 4.21 (t, J = 4.6 Hz, 2H), 4.59 (br s, 2H), 7.12 (dd, J = 8.4, 2.6 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 13.02 (br s, 1H).
工程6：工程5で得られる3-(13-エチル-11-ヒドロキシ-3,6,9-トリオキサ-13-アザザペンタデシロキシ)-N-(3-(ヒドラジンカルボニル)-6,6-ジメチル-4,5,6,7-テトラヒドロベンゾ[b]チオフェン-2-イル)ベンズアミド（0.100 g, 0.161mmol）およびEP2080761に記載の方法で合成した4,5-ジクロロチアゾール-2-カルボアルデヒド（0.040g, 0.220 mmol）を用いて、実施例86の工程5と同様にして、化合物176（E体）（19 mg, 15%）および化合物177（Z体）（53 mg, 42%）を得た。
化合物176
1H-NMR (300 MHz, CDCl3, δ): 1.06 (s, 6H), 1.06 (t, J = 7.0 Hz, 6H), 1.68 (t, J = 6.0 Hz, 2H), 2.49-2.78 (m, 6H), 2.52 (s, 2H), 2.84 (t, J = 6.0 Hz, 2H), 3.49 (d, J = 5.1 Hz, 2H), 3.63-3.76 (m, 8H), 3.83-3.92 (m, 3H), 4.22 (t, J = 4.8 Hz, 2H), 7.14 (dd, J = 8.1, 2.8 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.56-7.60 (m, 2H), 8.61 (s, 1H).  ESIMS m/z: 784, 786 (M + H)+.
化合物177
1H-NMR (300 MHz, CDCl3, δ): 1.03 (t, J = 7.0 Hz, 6H), 1.09 (s, 6H), 1.72 (t, J = 6.0 Hz, 2H), 2.43-2.70 (m, 8H), 3.05 (t, J = 6.0 Hz, 2H), 3.45-3.54 (m, 2H), 3.65-3.76 (m, 9H), 3.81-3.91 (m, 3H), 4.21 (t, J = 4.8 Hz, 2H), 7.12 (dd, J = 8.2, 2.6 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.62-7.66 (m, 2H), 12.82 (s, 1H), 13.18 (s, 1H).  ESIMS m/z: 784, 786 (M + H)+. Compound 176, Compound 177
Step 1: tert-butyl 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in Step 1 of Example 86 (25 g, 89.0 mmol) 2- (3-hydroxybenzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylic acid tert -Butyl (30.0 g, 83%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.01 (s, 6H), 1.52-1.56 (m, 2H), 1.62 (s, 9H), 2.46 (s, 2H), 2.77 (t, J = 6.0 Hz, 2H), 7.07 (t, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.60 (s, 1H).
Step 2: tert-butyl 2- (3-hydroxybenzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in Step 1 (20.0 g, 49.8 2- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamido) -6,6-dimethyl-4,5,6, in the same manner as in Example 8. 7-Tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (15.6 g, 59%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.01 (s, 6H), 1.54 (t, J = 6.4 Hz, 2H), 1.61 (s, 9H), 2.40 (t, J = 6.4 Hz, 1H ), 2.46 (s, 2H), 2.77 (t, J = 6.4 Hz, 2H), 3.62 (t, J = 4.6 Hz, 2H), 3.68-3.77 (m, 6H), 3.90 (t, J = 4.6 Hz , 2H), 4.23 (t, J = 4.6 Hz, 2H), 7.14 (dd, J = 8.0, 1.8 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz , 1H), 7.60 (s, 1H), 12.36 (s, 1H).
Step 3: 2- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b ] 2- (3- (2- (2- (2- (2-oxirane-2-)-2- (3- (2- (2- (2-oxirane-2-) oxirane-2-tert-butyl] thiophene-3-carboxylate (5.00 g, 9.37 mmol) in the same manner as in Example 12. Irmethoxy) ethoxy) ethoxy) ethoxy) benzamido) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (3.25 g, 59%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.01 (s, 6H), 1.54 (t, J = 6.4 Hz, 2H), 1.61 (s, 9H), 2.46 (s, 2H), 2.60 (dd , J = 4.9, 2.7 Hz, 1H), 2.75-2.80 (m, 3H), 3.13-3.17 (m, 1H), 3.43 (t, J = 11.7, 5.9 Hz, 1H), 3.63-3.81 (m, 9H ), 3.90 (t, J = 4.8 Hz, 2H), 4.21 (t, J = 4.8 Hz, 2H), 7.13 (dd, J = 8.0, 2.2 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H ), 7.54 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 2.2 Hz, 1H), 12.36 (s, 1H).
Step 4: 2- (3- (2- (2- (2- (2-oxiran-2-ylmethoxy) ethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5, obtained in Step 3 2- (3- (13-Ethyl-11-hydroxy) as in Example 13 using tert-butyl 6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (3.16 g, 5.36 mmol) -3,6,9-trioxa-13-azapentadecyloxy) benzamide) tert-butyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (3.20 g , 90%).
1 H-NMR (300 MHz, CDCl 3 , δ): 1.01 (s, 6H), 1.01 (t, J = 7.0 Hz, 6H), 1.54 (t, J = 6.4 Hz, 2H), 1.61 (s, 9H ), 2.38-2.67 (m, 8H), 2.77 (d, J = 6.4 Hz, 2H), 3.45-3.84 (m, 12H), 3.89 (t, J = 4.8 Hz, 2H), 4.22 (t, J = 4.8 Hz, 2H), 7.14 (dd, J = 8.0, 2.4 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 2.4 Hz, 1H), 12.36 (s, 1H).
Step 5: 2- (3- (13-Ethyl-11-hydroxy-3,6,9-trioxa-13-azapentadecyloxy) benzamide) -6,6-dimethyl-4,5, obtained in Step 4 3- (13-Ethyl-11-hydroxy) as in Step 4 of Example 86 using tert-butyl 6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (2.00 g, 3.02 mmol) -3,6,9-trioxa-13-azazapentadecyloxy) -N- (3- (hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-2 -Yl) benzamide (1.50 g, 80%) was obtained.
1 H-NMR (300 MHz, CDCl 3 , δ): 1.02 (s, 6H), 1.09 (t, J = 7.0 Hz, 6H), 1.61 (t, J = 6.2 Hz, 2H), 2.48 (s, 2H ), 2.52-2.81 (m, 8H), 3.50 (d, J = 5.1 Hz, 2H), 3.61-3.76 (m, 9H), 3.85-3.97 (m, 3H), 4.21 (t, J = 4.6 Hz, 2H), 4.59 (br s, 2H), 7.12 (dd, J = 8.4, 2.6 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 13.02 (br s, 1H).
Step 6: 3- (13-Ethyl-11-hydroxy-3,6,9-trioxa-13-azazapentadecyloxy) -N- (3- (hydrazinecarbonyl) -6,6- Dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide (0.100 g, 0.161 mmol) and 4,5-dichlorothiazole-2-carbaldehyde synthesized by the method described in EP2080761 ( 0.040 g, 0.220 mmol), and in the same manner as in Step 5 of Example 86, compound 176 (E form) (19 mg, 15%) and compound 177 (Z form) (53 mg, 42%) were obtained. It was.
Compound 176
1 H-NMR (300 MHz, CDCl 3 , δ): 1.06 (s, 6H), 1.06 (t, J = 7.0 Hz, 6H), 1.68 (t, J = 6.0 Hz, 2H), 2.49-2.78 (m , 6H), 2.52 (s, 2H), 2.84 (t, J = 6.0 Hz, 2H), 3.49 (d, J = 5.1 Hz, 2H), 3.63-3.76 (m, 8H), 3.83-3.92 (m, 3H), 4.22 (t, J = 4.8 Hz, 2H), 7.14 (dd, J = 8.1, 2.8 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.56-7.60 (m, 2H), 8.61 (s, 1H). ESIMS m / z: 784, 786 (M + H) + .
Compound 177
1 H-NMR (300 MHz, CDCl 3 , δ): 1.03 (t, J = 7.0 Hz, 6H), 1.09 (s, 6H), 1.72 (t, J = 6.0 Hz, 2H), 2.43-2.70 (m , 8H), 3.05 (t, J = 6.0 Hz, 2H), 3.45-3.54 (m, 2H), 3.65-3.76 (m, 9H), 3.81-3.91 (m, 3H), 4.21 (t, J = 4.8 Hz, 2H), 7.12 (dd, J = 8.2, 2.6 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.62-7.66 (m, 2H), 12.82 (s , 1H), 13.18 (s, 1H) .ESIMS m / z: 784, 786 (M + H) + .
化合物178：2-クロロ-6-(トリフルオロメチル)イソニコチンアルデヒドを用いて、実施例155と同様にして、化合物178を得た。
ESIMS m/z: 812, 814 (M + H)+. Compound 178: Compound 178 was obtained in the same manner as in Example 155, using 2-chloro-6- (trifluoromethyl) isonicotinaldehyde.
ESIMS m / z: 812, 814 (M + H) + .
錠剤(化合物26)
　常法により、次の組成からなる錠剤を調製する。化合物26、40g、乳糖286.8gおよび馬鈴薯澱粉60gを混合し、これにヒドロキシプロピルセルロースの10%水溶液120gを加える。得られた混合物を常法により練合し、造粒して乾燥させた後、整粒し打錠用顆粒とする。これにステアリン酸マグネシウム1.2gを加えて混合し、径8mmの杵をもった打錠機(菊水社製RT-15型)で打錠を行って、錠剤(1錠あたり活性成分20mgを含有する)を得る。 Tablet (Compound 26)
A tablet having the following composition is prepared by a conventional method. Compound 26, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 10% aqueous solution of hydroxypropylcellulose 120 g is added thereto. The obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this was added 1.2 g of magnesium stearate, mixed, and tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) with a 8 mm diameter punch, and tablets (containing 20 mg of active ingredient per tablet) )
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
　本発明により、腸管におけるNaPi2bを阻害し、血中への吸収性が低下した、血清のリン濃度が影響する疾患（例えば、高リン血症など）の治療および／または予防剤として有用な縮環チオフェン誘導体またはその薬学的に許容される塩などを提供することができる。 INDUSTRIAL APPLICABILITY According to the present invention, a condensed ring useful as a therapeutic and / or prophylactic agent for a disease that inhibits NaPi2b in the intestinal tract and has decreased absorbability into blood and is affected by serum phosphorus concentration (for example, hyperphosphatemia). A thiophene derivative or a pharmaceutically acceptable salt thereof can be provided.

Claims (17)

  1. 　下記式（I）
    Figure JPOXMLDOC01-appb-C000001
     ＜式中、R1およびR2は、一方は水素原子を表し、他方は置換基を有していてもよいアリールまたは置換基を有していてもよい芳香族複素環基を表し、
    Lは、フェニル、芳香族複素環基または脂肪族複素環基を表すが、該フェニル、該芳香族複素環基および該脂肪族複素環基はそれぞれ1～2個の下記式（II）
    -(CH2)h-A-B-Y-D-C  (II)
    ｛式中、hは0～3の整数を表し、
    Cは、水素原子、ハロゲン、ヒドロキシ、ニトロ、アミノ、シアノ、カルボキシ、カルバモイル、置換基を有していてもよい低級アルキル、置換基を有していてもよいシクロアルキル、置換基を有していてもよいアリール、置換基を有していてもよい脂肪族複素環基、置換基を有していてもよい芳香族複素環基、置換基を有していてもよいアラルキル、置換基を有していてもよい低級アルカノイル、置換基を有していてもよいシクロアルキルカルボニル、置換基を有していてもよいアロイル、置換基を有していてもよい脂肪族複素環カルボニル、置換基を有していてもよい芳香族複素環カルボニル、置換基を有していてもよい低級アルコキシカルボニル、置換基を有していてもよいシクロアルキルオキシカルボニル、置換基を有していてもよいアリールオキシカルボニル、置換基を有していてもよい脂肪族複素環オキシカルボニル、置換基を有していてもよい芳香族複素環オキシカルボニル、置換基を有していてもよい低級アルキルカルバモイル、置換基を有していてもよいジ低級アルキルカルバモイル、置換基を有していてもよいアリールカルバモイル、置換基を有していてもよい低級アルコキシ、置換基を有していてもよいシクロアルキルオキシ、置換基を有していてもよいアリールオキシ、置換基を有していてもよい脂肪族複素環オキシ、置換基を有していてもよい芳香族複素環オキシ、置換基を有していてもよい低級アルカノイルオキシ、置換基を有していてもよいシクロアルキルカルボニルオキシ、置換基を有していてもよいアロイルオキシ、置換基を有していてもよい脂肪族複素環カルボニルオキシ、置換基を有していてもよい芳香族複素環カルボニルオキシ、置換基を有していてもよい低級アルキルスルホニルオキシ、置換基を有していてもよいアリールスルホニルオキシ、置換基を有していてもよい低級アルキルチオ、置換基を有していてもよいアリールチオ、置換基を有していてもよい脂肪族複素環チオ、置換基を有していてもよい芳香族複素環チオ、置換基を有していてもよい低級アルキルスルホニル、置換基を有していてもよいアリールスルホニル、－NR3R4（式中、R3およびR4は、同一または異なって、水素原子、置換基を有していてもよい低級アルキル、置換基を有していてもよいシクロアルキル、置換基を有していてもよいアリール、置換基を有していてもよい脂肪族複素環基、置換基を有していてもよい芳香族複素環基、置換基を有していてもよい低級アルカノイル、置換基を有していてもよいシクロアルキルカルボニル、置換基を有していてもよいアロイル、置換基を有していてもよい脂肪族複素環カルボニル、置換基を有していてもよい芳香族複素環カルボニル、置換基を有していてもよい低級アルコキシカルボニル、置換基を有していてもよいシクロアルキルオキシカルボニル、置換基を有していてもよいアリールオキシカルボニル、置換基を有していてもよい低級アルキルスルホニル、置換基を有していてもよいアリールスルホニル、または置換基を有していてもよい芳香族複素環スルホニルを表すか、またはR3とR4が隣接する窒素原子と一緒になって置換基を有していてもよい含窒素複素環基を形成する）、－NRARBRC＋XA－［式中、RA、RBおよびRCは、同一または異なって、低級アルキル、シクロアルキルまたはアラルキルを表し、XAは、塩素原子、臭素原子、ヨウ素原子、またはRDASO3（式中、RDAはメチル、エチル、トリフルオロメチル、フェニルまたはトリルを表す）を表す］、下記式（A）
    Figure JPOXMLDOC01-appb-C000002
     ［式中、REは、水素原子；ハロゲン；カルボキシ；カルボキシレート；低級アルコキシカルボニル；またはヒドロキシ、低級アルコキシ、カルボキシまたはカルボキシレートで置換されていてもよい低級アルキルを表し、XBは、塩素原子、臭素原子、ヨウ素原子、またはRDBSO3（式中、RDBは、前記RDAと同義である）を表す（但しREがカルボキシレートまたはカルボキシレートが置換した低級アルキルの場合、XB-は欠損している）］で表される基、または－OPO(ORE)2（式中、REは、水素原子または低級アルキルを表す）を表し、
    Dは、(1) 結合、または(2) 少なくとも1つ以上のCH2基が－O－、－S－、－SO2－および－NR5－（式中、R5は、水素原子、低級アルキル、シクロアルキル、低級アルカノイルまたは低級アルコキシカルボニルを表す）から選ばれる基で置換されていてもよい直鎖C3-30アルキレンを表し、
    Yは、(1) 結合、(2) －O－、(3) －S－、(4) －SO2－、(5) －NR6－（式中、R6は、－DY-CY（式中、DYおよびCYはそれぞれ前記DおよびCと同義である）を表す）、(6) 脂肪族複素環ジイル、(7) 芳香族複素環ジイル、(8) －Het-CONR7－（式中、Hetは芳香族複素環ジイルまたは脂肪族複素環ジイルを表し、R7は水素原子または低級アルキルを表す）または(9)－CH2CH(OH)CH2NR8－（式中、R8は水素原子または低級アルキルを表す）を表し、
    Bは、(1) 結合、または(2) 少なくとも1つ以上のCH2基が－O－、－S－、－SO2－、および－NR9－（式中、R9は、水素原子、低級アルキル、シクロアルキル、低級アルカノイルまたは低級アルコキシカルボニルを表す）から選ばれる基で置換されていてもよい直鎖C3-30アルキレンを表し、
    Aは、(1) 結合、(2) －O－、(3) －S－、(4) －SO2－、(5) －NR10－（式中、R10は、－BA1-YA1-DA1-CA1（式中、BA1、YA1、DA1およびCA1はそれぞれ前記B、Y、DおよびCと同義である）を表す）、(6) －CONR11－（式中、R11は、－BA2-YA2-DA2-CA2（式中、BA2、YA2、DA2およびCA2はそれぞれ前記B、Y、DおよびCと同義である）を表す）、(7) －NR12CO－（式中、R12は、－BA3-YA3-DA3-CA3（式中、BA3、YA3、DA3およびCA3はそれぞれ前記B、Y、DおよびCと同義である）を表す）、(8) －SO2NR13－（式中、R13は水素原子または置換基を有していてもよい低級アルキルを表す）、(9) 下記式(a1)で表される基
    Figure JPOXMLDOC01-appb-C000003
     （式中、s1およびs2は、同一または異なって0～2の整数を表し、Qは酸素原子、硫黄原子またはメチレンを表す）または(10) 下記式(a2)で表される基
    Figure JPOXMLDOC01-appb-C000004
     （式中、s3およびs4は、同一または異なって0～2の整数を表し、Yaは結合または－SO2－を表す）を表す］を表す｝
    で表される置換基を有しており、さらに該フェニル、該芳香族複素環基および該脂肪族複素環基はさらに置換基を有していてもよく、
    nは、1または2を表し、mは、1または2を表し、
    Zは、－CR14R15－｛式中、R14およびR15は、同一または異なって、水素原子、ハロゲン、カルボキシ、置換基を有していてもよい低級アルキル、置換基を有していてもよい低級アルコキシカルボニル、置換基を有していてもよい低級アルキルカルバモイル、置換基を有していてもよいジ低級アルキルカルバモイルまたは置換基を有していてもよい脂肪族複素環カルボニルを表すか［但し、Bおよび／またはDが、少なくとも1つ以上のCH2基が－O－、－S－および－NR5－（式中、R5は前記と同義である）または－NR9－（式中、R9は前記と同義である）から選ばれる基で置換されていてもよい直鎖C3-30アルキレンであり、該アルキレン中の炭素原子数の総和が７以下であるとき、あるいはBおよびDが共に結合であるとき、R14およびR15は同時に水素原子になることはない］、またはR14とR15が隣接する炭素原子と一緒になってシクロアルカン、オキセタン、オキソランまたはオキサンを形成する｝、
    －NR16－（式中、R16は、水素原子、置換基を有していてもよい低級アルキル、置換基を有していてもよいシクロアルキル、置換基を有していてもよいアラルキル、置換基を有していてもよい低級アルカノイル、置換基を有していてもよいアロイル、置換基を有していてもよい脂肪族複素環カルボニル、置換基を有していてもよい芳香族複素環カルボニル、置換基を有していてもよい低級アルコキシカルボニル、置換基を有していてもよいアリールオキシカルボニル、置換基を有していてもよい低級アルキルスルホニル、置換基を有していてもよいアリールスルホニル、置換基を有していてもよい脂肪族複素環スルホニルまたは置換基を有していてもよい芳香族複素環スルホニルを表す）、
    －O－、－S－または－SO2－を表す＞
    で表される化合物またはその薬学的に許容される塩。     Formula (I) below
    Figure JPOXMLDOC01-appb-C000001
     <In the formula, one of R 1 and R 2 represents a hydrogen atom, and the other represents an aryl which may have a substituent or an aromatic heterocyclic group which may have a substituent,
    L represents phenyl, an aromatic heterocyclic group or an aliphatic heterocyclic group, and each of the phenyl, the aromatic heterocyclic group and the aliphatic heterocyclic group is represented by the following formula (II):
    -(CH 2 ) h -ABYDC (II)
    {In the formula, h represents an integer of 0 to 3,
    C is a hydrogen atom, halogen, hydroxy, nitro, amino, cyano, carboxy, carbamoyl, optionally substituted lower alkyl, optionally substituted cycloalkyl, or optionally substituted. Aryl which may have a substituent, an aliphatic heterocyclic group which may have a substituent, an aromatic heterocyclic group which may have a substituent, an aralkyl which may have a substituent, and a substituent. Lower alkanoyl which may be substituted, cycloalkylcarbonyl which may have substituent, aroyl which may have substituent, aliphatic heterocyclic carbonyl which may have substituent, substituent Aromatic heterocyclic carbonyl which may have, lower alkoxycarbonyl which may have a substituent, cycloalkyloxycarbonyl which may have a substituent, optionally having a substituent Aryloxycarbonyl, optionally substituted aliphatic heterocyclic oxycarbonyl, optionally substituted aromatic heterocyclic oxycarbonyl, optionally substituted lower alkylcarbamoyl, substituted Di-lower alkylcarbamoyl which may have a group, arylcarbamoyl which may have a substituent, lower alkoxy which may have a substituent, cycloalkyloxy which may have a substituent, Aryloxy optionally having substituent, aliphatic heterocyclic oxy optionally having substituent, aromatic heterocyclic oxy optionally having substituent, optionally having substituent Good lower alkanoyloxy, optionally substituted cycloalkylcarbonyloxy, optionally substituted aroyloxy, optionally substituted fat Aromatic heterocyclic carbonyloxy, optionally substituted aromatic heterocyclic carbonyloxy, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, substituted Lower alkylthio optionally having a group, arylthio optionally having a substituent, an aliphatic heterocyclic thio optionally having a substituent, an aromatic heterocyclic ring optionally having a substituent Thio, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, —NR 3 R 4 (wherein R 3 and R 4 are the same or different and represent a hydrogen atom , Lower alkyl optionally having substituents, cycloalkyl optionally having substituents, aryl optionally having substituents, aliphatic heterocyclic groups optionally having substituents Have a substituent Aromatic heterocyclic group which may have, lower alkanoyl which may have substituent, cycloalkylcarbonyl which may have substituent, aroyl which may have substituent, and substituent Aliphatic heterocyclic carbonyl which may have, aromatic heterocyclic carbonyl which may have a substituent, lower alkoxycarbonyl which may have a substituent, cycloalkyloxy which may have a substituent Carbonyl, aryloxycarbonyl optionally having substituent, lower alkylsulfonyl optionally having substituent, arylsulfonyl optionally having substituent, or optionally having substituent Represents an aromatic heterocyclic sulfonyl, or R 3 and R 4 together with the adjacent nitrogen atom form an optionally substituted nitrogen-containing heterocyclic group), —NR A R B R C + X A— [wherein R A , R B and R C are the same or different and each represents lower alkyl, cycloalkyl or aralkyl, and X A represents a chlorine atom, a bromine atom, an iodine atom, or R DA SO 3 (Wherein R DA represents methyl, ethyl, trifluoromethyl, phenyl or tolyl)], the following formula (A)
    Figure JPOXMLDOC01-appb-C000002
     [Wherein R E represents a hydrogen atom; halogen; carboxy; carboxylate; lower alkoxycarbonyl; or lower alkyl optionally substituted with hydroxy, lower alkoxy, carboxy or carboxylate, and X B represents a chlorine atom] , Bromine atom, iodine atom, or R DB SO 3 (wherein R DB has the same meaning as R DA ) (wherein R E is carboxylate or lower alkyl substituted with carboxylate, X B - is a group represented by deficiency have to) or -OPO (oR E) 2 (wherein, R E, represents represents) a hydrogen atom or a lower alkyl,
    D is (1) a bond, or (2) at least one CH 2 group is —O—, —S—, —SO 2 — and —NR 5 — (wherein R 5 is a hydrogen atom, lower Represents a linear C 3-30 alkylene optionally substituted with a group selected from alkyl, cycloalkyl, lower alkanoyl or lower alkoxycarbonyl),
    Y is (1) a bond, (2) -O-, (3) -S-, (4) -SO 2- , (5) -NR 6- (wherein R 6 is -D Y -C Y (wherein D Y and C Y are as defined above for D and C), (6) aliphatic heterocyclic diyl, (7) aromatic heterocyclic diyl, (8) -Het-CONR 7 — (wherein Het represents an aromatic heterocyclic diyl or an aliphatic heterocyclic diyl, and R 7 represents a hydrogen atom or lower alkyl) or (9) —CH 2 CH (OH) CH 2 NR 8 — ( Wherein R 8 represents a hydrogen atom or lower alkyl)
    B is (1) a bond, or (2) at least one CH 2 group is —O—, —S—, —SO 2 —, and —NR 9 — (wherein R 9 is a hydrogen atom, Represents a straight-chain C 3-30 alkylene optionally substituted with a group selected from: lower alkyl, cycloalkyl, lower alkanoyl or lower alkoxycarbonyl;
    A is (1) a bond, (2) -O-, (3) -S-, (4) -SO 2- , (5) -NR 10- (wherein R 10 is -B A1 -Y A1 -D A1 -C A1 (wherein B A1 , Y A1 , D A1 and C A1 are as defined above for B, Y, D and C, respectively), (6) —CONR 11 — (formula Wherein R 11 represents -B A2 -Y A2 -D A2 -C A2 (wherein B A2 , Y A2 , D A2 and C A2 are as defined above for B, Y, D and C, respectively). ), (7) —NR 12 CO— (wherein R 12 is —B A3 —Y A3 —D A3 —C A3 (wherein B A3 , Y A3 , D A3 and C A3 are the aforementioned B, (Same as Y, D and C)), (8) —SO 2 NR 13 — (wherein R 13 represents a hydrogen atom or optionally substituted lower alkyl), (9 ) Group represented by the following formula (a1)
    Figure JPOXMLDOC01-appb-C000003
     (Wherein s1 and s2 are the same or different and each represents an integer of 0 to 2, Q represents an oxygen atom, a sulfur atom or methylene) or (10) a group represented by the following formula (a2)
    Figure JPOXMLDOC01-appb-C000004
     (Wherein s3 and s4 are the same or different and each represents an integer of 0 to 2, and Y a represents a bond or —SO 2 —)]
    The phenyl, the aromatic heterocyclic group and the aliphatic heterocyclic group may further have a substituent,
    n represents 1 or 2, m represents 1 or 2,
    Z is —CR 14 R 15 — {wherein R 14 and R 15 are the same or different and each has a hydrogen atom, halogen, carboxy, optionally substituted lower alkyl, or substituent. Lower alkylcarbonyl which may be substituted, lower alkylcarbamoyl which may have a substituent, dilower alkylcarbamoyl which may have a substituent or aliphatic heterocyclic carbonyl which may have a substituent carded [However, B and / or D is at least one or more CH 2 groups -O -, - S- and -NR 5 - (wherein, R 5 is as defined above) or -NR 9 - (Wherein R 9 is as defined above) is a linear C 3-30 alkylene optionally substituted with a group selected from the above, and the total number of carbon atoms in the alkylene is 7 or less, Alternatively, when B and D are both bonds, R 14 and R 15 are simultaneously hydrogen atoms. Or R 14 and R 15 together with adjacent carbon atoms form a cycloalkane, oxetane, oxolane or oxane},
    —NR 16 — (wherein R 16 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, Lower alkanoyl optionally having substituent, aroyl optionally having substituent, aliphatic heterocyclic carbonyl optionally having substituent, aromatic heterocyclic optionally having substituent Ring carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted A good arylsulfonyl, an optionally substituted aliphatic heterocyclic sulfonyl or an optionally substituted aromatic heterocyclic sulfonyl),
    Represents —O—, —S— or —SO 2 —>
    Or a pharmaceutically acceptable salt thereof.
  2. 　R1が水素原子であり、R2が置換基を有していてもよいアリールである請求項1記載の化合物またはその薬学的に許容される塩。 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is a hydrogen atom, and R 2 is an aryl which may have a substituent.
  3. 　Lが1個の式（II）で表される基で置換されたフェニルまたは芳香族複素環基である請求項1または2記載の化合物またはその薬学的に許容される塩。 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is a phenyl or aromatic heterocyclic group substituted with one group represented by formula (II).
  4. 　Lが表す芳香族複素環基がピリジルまたはチアゾリルである請求項1～3のいずれかに記載の化合物またはその薬学的に許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the aromatic heterocyclic group represented by L is pyridyl or thiazolyl.
  5. 　Lが下記式（La）～（Ld）のいずれかで表される基である請求項1～3のいずれかに記載の化合物またはその薬学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000005
     （式中、h、A、B、Y、DおよびCは、それぞれ前記と同義である）     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L is a group represented by any of the following formulas (La) to (Ld).
    Figure JPOXMLDOC01-appb-C000005
     (Wherein h, A, B, Y, D and C are as defined above)
  6. 　Zが－CR14R15－（式中、R14およびR15は、それぞれ前記と同義である）である請求項1～5のいずれかに記載の化合物またはその薬学的に許容される塩。 6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein Z is —CR 14 R 15 — (wherein R 14 and R 15 are as defined above, respectively).
  7. 　Zが－NR16－（式中、R16は、前記と同義である）である請求項1～5のいずれかに記載の化合物またはその薬学的に許容される塩。 6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein Z is —NR 16 — (wherein R 16 is as defined above).
  8. 　Bが、(1) －(CH2CH2Wa)qa-(CH2)ra－（式中、Waは－O－、－S－、－SO2－、または－NR9－（式中、R9は前記と同義である）を表し、qaは1～8の整数を表し、raは0～3の整数を表す）、(2) －(CH2CH2CH2Waa)ua-(CH2)va－（式中、Waaは－O－、－S－、－SO2－、または－NR9－（式中、R9は前記と同義である）を表し、uaは1～6の整数を表し、vaは0～6の整数を表す）、または(3) －(CH2)ta－（式中、ta は1～30の整数を表す）である請求項1～7のいずれかに記載の化合物またはその薬学的に許容される塩。 B is, (1) - (CH 2 CH 2 W a) qa - (CH 2) ra - ( wherein, W a is -O -, - S -, - SO 2 -, or -NR 9 - (wherein Wherein R 9 is as defined above, qa represents an integer of 1 to 8, and ra represents an integer of 0 to 3), (2) — (CH 2 CH 2 CH 2 W aa ) ua — (CH 2 ) va — (wherein W aa is —O—, —S—, —SO 2 —, or —NR 9 — (wherein R 9 is as defined above), and ua is 1 to 6 and va represents an integer of 0 to 6), or (3) — (CH 2 ) ta — (wherein ta represents an integer of 1 to 30) 8. The compound according to any one of 7 or a pharmaceutically acceptable salt thereof.
  9. 　Dが、(1) －(CH2CH2Wb)qb-(CH2)rb－（式中、Wbは－O－、－S－、－SO2－、または－NR5－（式中、R5は前記と同義である）を表し、qbは1～8の整数を表し、rbは0～3の整数を表す）、(2) －(CH2CH2CH2Wbb)ub-(CH2)vb－（式中、Wbbは－O－、－S－、－SO2－、または－NR5－（式中、R5は前記と同義である）を表し、ubは1～6の整数を表し、vbは0～6の整数を表す）、または(3) －(CH2)tb－（式中、tb は1～30の整数を表す）である請求項1～8のいずれかに記載の化合物またはその薬学的に許容される塩。 D is (1)-(CH 2 CH 2 W b ) qb- (CH 2 ) rb- (where W b is -O-, -S-, -SO 2- , or -NR 5- (formula Wherein R 5 is as defined above, qb represents an integer of 1 to 8 and rb represents an integer of 0 to 3), (2)-(CH 2 CH 2 CH 2 W bb ) ub — (CH 2 ) vb — (wherein W bb represents —O—, —S—, —SO 2 —, or —NR 5 — (wherein R 5 is as defined above), and ub represents 1 to 6 and vb represents an integer of 0 to 6), or (3) — (CH 2 ) tb — (wherein tb represents an integer of 1 to 30) 9. The compound according to any one of 8 or a pharmaceutically acceptable salt thereof.
  10. 　請求項1～9のいずれかに記載の化合物またはその薬学的に許容される塩を含有する血中へのリンの取り込み阻害剤。 An inhibitor of phosphorus uptake into blood containing the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
  11. 　請求項1～9のいずれかに記載の化合物またはその薬学的に許容される塩を含有する高リン血症の治療および／または予防剤。 A therapeutic and / or prophylactic agent for hyperphosphatemia comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
  12. 　請求項１～9のいずれかに記載の化合物またはその薬学的に許容される塩の有効量を投与する工程を含む血中へのリンの取り込み阻害方法。 A method for inhibiting uptake of phosphorus into blood, comprising a step of administering an effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
  13. 　請求項１～9のいずれかに記載の化合物またはその薬学的に許容される塩の有効量を投与する工程を含む高リン血症の治療および／または予防方法。 A method for treating and / or preventing hyperphosphatemia, comprising a step of administering an effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
  14. 　血中へのリンの取り込み阻害に使用するための請求項１～9のいずれかに記載の化合物またはその薬学的に許容される塩。 10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use in inhibiting phosphorus uptake into blood.
  15. 　高リン血症の治療および／または予防に使用するための請求項１～9のいずれかに記載の化合物またはその薬学的に許容される塩。 10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of hyperphosphatemia.
  16. 　血中へのリンの取り込み阻害剤の製造のための請求項１～9のいずれかに記載の化合物またはその薬学的に許容される塩の使用。 Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the manufacture of an inhibitor of phosphorus uptake into blood.
  17. 　高リン血症の治療および／または予防剤の製造のための請求項１～9のいずれかに記載の化合物またはその薬学的に許容される塩の使用。
     
          Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for hyperphosphatemia.

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