WO2018151240A1 - 3,6,7,8-TETRAHYDROCYCLOPENTA[e]INDOLE COMPOUND - Google Patents

3,6,7,8-TETRAHYDROCYCLOPENTA[e]INDOLE COMPOUND Download PDF

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WO2018151240A1
WO2018151240A1 PCT/JP2018/005361 JP2018005361W WO2018151240A1 WO 2018151240 A1 WO2018151240 A1 WO 2018151240A1 JP 2018005361 W JP2018005361 W JP 2018005361W WO 2018151240 A1 WO2018151240 A1 WO 2018151240A1
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group
compound
tetrahydrocyclopenta
indol
nmr
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Japanese (ja)
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藤井　邦彦
理恵子 高野
幸伸 沼田
優真 梅崎
アガルワル アディティ
正憲 泉
中村　弘明
昌生 吉田
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第一三共株式会社
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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    • A61K31/433—Thidiazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the present invention relates to a 3,6,7,8-tetrahydrocyclopenta [e] indole compound or a pharmaceutically acceptable salt thereof, and further to an acid-sensitive ion channel inhibitor containing the compound.
  • An acid-sensitive ion channel is a cation channel activated by extracellular protons.
  • ASIC1, ASIC2, ASIC3, and ASIC4 are subtypes of ASIC1, ASIC2, ASIC3, and ASIC4 in ASIC, and each subtype functions by forming a homo or hetero trimer. Since ASIC1 and ASIC3 are expressed in sensory nerves, it is considered to be involved in pain perception in pathological conditions where tissue pH decreases such as inflammation, ischemia and cancer.
  • ASIC is widely distributed in addition to sensory nerves, and its involvement in various pathological conditions has been suggested.
  • ASIC1 polymorphism is associated with panic disorder (Neuromolecular Med. 2016, 18 (1), 91-98)
  • ASIC2 and ASIC3 expression is increased in the bladder of patients with interstitial cystitis (J Urology, 2011, 186, 1509-1516), and increased expression of ASIC1 in human breast cancer (Oncogene, 2015, 1-10) have been reported.
  • inhibitors of ASIC1 and ASIC3 exhibit analgesia, neuroprotection, cartilage protection, suppression of vasodilation, and insulin resistance improvement (Toxicon., 2013, 75, 187- 204). Therefore, ASIC is considered an important molecule for the development and maintenance of various pathological conditions.
  • Amiloride is widely used as a low molecular weight inhibitor for ASIC. However, amiloride also inhibits epithelial sodium channel (ENaC: Epithelial Na + channel) at the same time, so its specificity is not sufficient.
  • EaC Epithelial Na + channel
  • various peptide inhibitors such as mambalgin-1 which is an ASIC1 specific inhibitor and APETx2 which is an ASIC3 specific inhibitor have been reported (Toxicon., 2013, 75, 187-204).
  • A-317567 Pain, 2005, 117 (1-2), 88-96
  • NS383 CNS383
  • Amiloride may inhibit experimental acid-induced pain in humans (J. Clin. Invest., 2002, 110 (8), 1185-1190) and may be neuroprotective against multiple sclerosis It has been reported (Brain, 2013, 136, 106-15). Furthermore, PPC-5650, an ASIC inhibitor, has been reported to suppress pain in human esophagus (Basic Clin. Pharmacol. Toxicol., 2015, 116 (2), 140-5). These reports suggest that ASIC inhibitors may have therapeutic effects on various pathologies including pain in humans. Under these circumstances, attempts have been made to create novel ASIC inhibitors (see Patent Documents 1 to 10, Non-Patent Documents 1 and 2).
  • ASIC inhibitors exhibit oral absorption. Being able to orally administer ASIC inhibitors leads to improved patient convenience and improved usability. Furthermore, it is unclear whether conventional ASIC inhibitors have selective inhibitory properties.
  • the selective side effects of ASIC can reduce the side effects caused by non-selective inhibition, can ensure safety, and the safety can be ensured for the main medicinal effects. It is also possible to increase the dose and achieve a higher therapeutic effect.
  • the present invention aims to obtain a selective ASIC inhibitor that can be administered orally. Thereby, an excellent therapeutic effect can be achieved.
  • the present inventors have found that the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has ASIC inhibitory properties with excellent selectivity and has oral absorbability. Completed the invention.
  • R represents a hydrogen atom or a halogen atom
  • Structure shown in represents an aromatic group represented by R 1 or R 2 is substituted, R 1 and R 2, the following group: Hydrogen atom, C1-C6-alkyl group, C1-C6-alkoxy group, hydroxy C1-C6-alkyl group, dihydroxy C2-C6-alkyl group, halogeno C1-C6-alkyl group, C3-C6-cycloalkyl (hydroxy)
  • the aromatic group is a group selected from a 5- or 6-membered aromatic heterocyclic group and a hydrocarbon-based aromatic group having a heteroatom 1 to 3 selected from a nitrogen atom and a sulfur atom [1] Or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are the following groups: A group independently selected from a hydrogen atom, a C1-C6-alkyl group, a C1-C6-alkoxy group, a hydroxy C1-C6-alkyl group, a dihydroxy C2-C6-alkyl group, a C1-C6-alkylsulfonyl group and a halogen atom
  • a group independently selected from a hydrogen atom, a C1-C6-alkyl group, a C1-C6-alkoxy group, a hydroxy C1-C6-alkyl group, a dihydroxy C2-C6-alkyl group, a C1-C6-alkylsulfonyl group and a halogen atom The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are the following groups: Hydrogen atom, methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxy Ethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2 -Dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclo Independently selected from propyl-1-hydroxyethyl group, methylsulfonyl group, cyano group, acetyl group, 1,
  • R 1 and R 2 are the following groups: Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group, [1] to [4], which is a group independently selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group Or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 is a hydrogen atom, and the other is the following group: Methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl Group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1 1-hydroxyethyl group, methylsulfonyl group, cyano group, acetyl group, methyl
  • R 1 and R 2 is a hydrogen atom, and the other is the following group: Methyl group, fluorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxy Ethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl group, 1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1-hydroxyethyl Any one of [1] to [4], which is a group selected from a group, a methyls
  • R 1 and R 2 are hydrogen atom, and the other is the following group: Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group,
  • the compound according to any one of [1] to [4], which is a group selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group Its pharmaceutically acceptable salt.
  • R 1 and R 2 are a hydrogen atom, and the other is the following group: A group selected from a hydrogen atom, a methyl group, a fluorine atom, a methoxy group, a hydroxymethyl group, a (1R) -1-hydroxyethyl group, a (1R) -1,2-dihydroxyethyl group, and a methylsulfonyl group [1] To [4] or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are One is a hydroxymethyl group and the other is a methylsulfonyl group, a methoxy group, a cyano group, or a fluorine atom, or The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein one is a 1,2-dihydroxyethyl group and the other is a fluorine atom or a chlorine atom.
  • R 1 and R 2 are One is a hydroxymethyl group and the other is a methylsulfonyl group or a methoxy group, or The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein one is a 1,2-dihydroxyethyl group and the other is a fluorine atom.
  • R 1 and R 2 are One is a hydroxymethyl group and the other is a methylsulfonyl group or a methoxy group, or The compound according to any one of [1] to [4], wherein one is a (1R) -1,2-dihydroxyethyl group and the other is a fluorine atom, or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (I) is represented by the following group:
  • a compound of formula (I) is represented by the following group:
  • the compound represented by the formula (I) is: (1R) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol, (1S) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol, (6R) -2- [5- (methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine, (6R) -2- (5-methyl-1,3,4-thiadiazol-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine, (6R) -2- (5-methyl-1,3,4-thiadia
  • the compound represented by the formula (I) is: (1R) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol, (1S) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol, (6R) -2- [5- (methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine, (6R) -2- (5-methyl-1,3,4-thiadiazol-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine, (6R) -2- (1-methyl-1H-pyra
  • a pharmaceutical composition comprising the compound according to any one of [1] to [24] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • An acid-sensitive ion channel (ASIC) inhibitor comprising the compound according to any one of [1] to [24] or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent selective acid-sensitive ion channel (ASIC) inhibitory action and can be administered orally, and thus is acid-sensitive. It is useful for the treatment and / or prevention of various pathological conditions involving ion channels.
  • ASIC acid-sensitive ion channel
  • the blood concentration transition (unit: nanomolar) when the compound of Example 25 of the present invention was orally administered to mice is shown.
  • the rhombus shows the change at the dose of 3 mg / kg, and the square shows the change at the dose of 10 mg / kg.
  • the horizontal axis indicates time.
  • the present invention relates to a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof. That is, 3,6,7,8-tetrahydrocyclopenta [e] indole is a mother nucleus, R 1 and R 2 are substituted at the 2- position, an amino group at the 6-position, and the 7-position Is a compound having a structure having a substituent R.
  • a part of the aromatic group represented by is a hydrocarbon-based aromatic group or a 5-membered or 6-membered aromatic having a hetero atom of 1 to 3 selected from a nitrogen atom and a sulfur atom It is a group selected from heterocyclic groups.
  • R 1 and R 2 on this aromatic group are the following groups: A hydrogen atom, a C1-C6-alkyl group (“C1-C6-” means 1 to 6 carbon atoms), a C1-C6-alkoxy group, a hydroxy C1-C6-alkyl group, a dihydroxy C2- C6-alkyl group, halogeno C1-C6-alkyl group, C3-C6-cycloalkyl (hydroxy) C1-C6-alkyl group, C1-C6-alkylsulfonyl group, (N-hydroxyimino) C1-C6-alkyl group, It is a group independently selected from a halogen atom, a cyano group and a C2-C6-acyl group.
  • the substituent R at the 7-position is a hydrogen atom or a halogen atom.
  • the substitution R may be a hydrogen atom or a halogen atom. That is, it may be a hydrogen atom, a fluorine atom, a chloro atom, a bromo atom, or an iodo atom. Among these, a hydrogen atom or a fluorine atom is preferable, and a hydrogen atom is more preferable.
  • the compound represented by the formula (I) has an amino group at the 6-position and a substituent R at the 7-position.
  • amino group coordination is alpha:
  • the substituent R at the 7-position is a halogen atom, it is 6,7-gem-disubstituted.
  • the amino group at the 6-position and the halogen atom at the 7-position exist in either a cis configuration or a trans configuration.
  • the ASIC inhibitor of the present invention may be any configuration, but more preferably is a cis configuration (the following formula).
  • the structure represented by is considered to be a preferable structure.
  • the A moiety is a hydrocarbon-based aromatic group or a 5-membered or 6-membered aromatic heterocyclic group having a heteroatom 1-3 selected from a nitrogen atom and a sulfur atom.
  • the hydrocarbon aromatic group include a phenyl group
  • the heterocyclic aromatic group include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a pyrimidyl group, or a pyrazinyl group.
  • phenyl group pyrazol-4-yl group, thiazol-2-yl group, thiazol-5-yl group, thiadiazol-2-yl group, pyridin-2-yl group, and pyridin-4-yl.
  • phenyl group pyrazol-4-yl group, thiazol-2-yl group, thiazol-5-yl group, thiadiazol-2-yl group, pyridin-2-yl group, and pyridin-4-yl.
  • pyrimidin-2-yl group pyrimidin-4-yl group
  • pyrazin-2-yl group pyrazin-2-yl group.
  • a phenyl group, a pyrazol-4-yl group, a thiazol-2-yl group, a thiadiazol-2-yl group, a pyridin-2-yl group, a pyrimidin-4-yl group, or a pyrazin-2-yl group It is.
  • R 1 and R 2 which are substituents on the aromatic group can be independently the following substituents.
  • R 1 or R 2 is a C 1 -C 6 -alkyl group, preferably it may be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a sec-butyl group, and more Preferably, it is a methyl group or an ethyl group.
  • R 1 or R 2 is a C 1 -C 6 -alkoxy group, preferably a methoxy group, an ethoxy group, a propoxy group, a 2-methylethoxy group, a butoxy group, a 1-methylpropoxy group, or a 2-methylpropoxy group More preferably, it is a methoxy group or an ethoxy group.
  • R 1 or R 2 is a hydroxy C 1 -C 6 -alkyl group
  • the position of the hydroxy group is not particularly limited, but is more preferably the carbon atom bonded to the aromatic group, that is, the benzyl position. preferable.
  • hydroxy C 1 -C 6 -alkyl groups are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy -1-methylethyl group, 2-hydroxy-1-methylethyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1-hydroxy-1-methylpropyl group 1-hydroxy-2-methylpropyl group, 2-hydroxy-1-methylpropyl group, 3-hydroxy-1-methylpropyl group, 2-hydroxy-2-methylpropyl group, or 3-hydroxy-2-methylpropyl group It is a group.
  • R 1 or R 2 is a dihydroxy C 2 -C 6 -alkyl group
  • the position of the two hydroxy groups is not particularly limited, but one having a 1,2-diol structure is more preferable, and ( Those which are 1R) -hydroxy are preferred.
  • Dihydroxy C 2 -C 6 -alkyl groups are preferably 1,2-dihydroxyethyl group, 1,2-dihydroxypropyl group, 1,3-dihydroxypropyl group, 2,3-dihydroxypropyl group, 1,2-dihydroxy Butyl group, 1,3-dihydroxybutyl group, 1,4-dihydroxybutyl group, 2,3-dihydroxybutyl group, 2,4-dihydroxybutyl group, 3,4-dihydroxybutyl group, 1,2-dihydroxy-1 -Methylpropyl group, 1,2-dihydroxy-2-methylpropyl group, 1,3-dihydroxy-1-methylpropyl group, 1,3-dihydroxy-2-methylpropyl group, 2,3-dihydroxy-1-methyl A propyl group or a 2,3-dihydroxy-2-methylpropyl group can be mentioned.
  • more preferable examples include 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl group, or (1R) -1,2-dihydroxyethyl group. More preferred is a dihydroxyalkyl group containing (1R) -hydroxy, and a (1R) -1,2-dihydroxyethyl group is preferred.
  • R 1 or R 2 is a halogeno C 1 -C 6 -alkyl group
  • the number of substituted halogens may be between 1 and per substitution.
  • the substitution position is more preferably the carbon atom at the terminal of the alkyl group, but there is no particular limitation.
  • the halogeno C 1 -C 6 -alkyl group is preferably a fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, perfluoroethyl group, chloromethyl. And a 2-chloroethyl group.
  • a fluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, or a 2,2,2-trifluoroethyl group is more preferable, and a trifluoromethyl group is more preferable.
  • R 1 or R 2 is a structure in which a C3-C6-cycloalkyl (hydroxy) C1-C6-alkyl group is further substituted with a hydroxy group-substituted alkyl group and a C3-C6 cycloalkyl group.
  • cyclopropylhydroxymethyl group, cyclopropylhydroxyethyl group, cyclobutylhydroxymethyl group, cyclobutylhydroxyethyl group, cyclopentylhydroxymethyl group, cyclopentylhydroxyethyl group, cyclohexylhydroxymethyl group, or cyclohexylhydroxyethyl group Can be mentioned.
  • a 2-cyclopropyl-1-hydroxyethyl group, a (1R) -2-cyclopropyl-1-hydroxyethyl group, or a (1S) -2-cyclopropyl-1-hydroxyethyl group is preferred.
  • R 1 or R 2 is a C 1 -C 6 -alkylsulfonyl group
  • a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, or a 2-methylethylsulfonyl group can be exemplified.
  • a methylsulfonyl group is more preferable.
  • R 1 or R 2 is a halogen atom
  • examples thereof include a fluorine atom, a chloro atom, a bromo atom, and an iodo atom, preferably a fluorine atom or a chloro atom, and more preferably a fluorine atom.
  • R 1 or R 2 is a hydroxyimino C 1 -C 6 -alkyl group
  • the position of the hydroxyimino group is not particularly limited, but is more preferably a carbon atom that becomes the benzyl position (particularly, the number of carbon atoms is 2).
  • a 1- (hydroxyimino) C 1 -C 6 -alkyl group is more preferred.
  • the hydroxyimino C 1 -C 6 -alkyl group is preferably a hydroxyiminomethyl group, 1-hydroxyiminoethyl group, 2-hydroxyiminoethyl group, 1-hydroxyiminopropyl group, 2-hydroxyiminopropyl group, or 3- Examples thereof include a hydroxyiminocypropyl group, more preferably a hydroxyiminomethyl group or a 1-hydroxyiminoethyl group, and still more preferably a 1-hydroxyiminoethyl group.
  • R 1 or R 2 is a C 2 -C 6 -alkylcarbonyl group (acyl group), preferably a methylcarbonyl group (acetyl group), ethylcarbonyl group, propylcarbonyl group, 2-methylethylcarbonyl group, butylcarbonyl Group, 1-methylpropylcarbonyl group, or 2-methylpropylcarbonyl group, and more preferably an acetyl group.
  • acyl group preferably a methylcarbonyl group (acetyl group), ethylcarbonyl group, propylcarbonyl group, 2-methylethylcarbonyl group, butylcarbonyl Group, 1-methylpropylcarbonyl group, or 2-methylpropylcarbonyl group, and more preferably an acetyl group.
  • R 1 and R 2 include the following groups: Hydrogen atom, methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxy Ethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2 -Dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclo Independently selected from propyl-1-hydroxyethyl, methylsulfonyl, cyano, acetyl, 1,1-dimethoxy
  • R 1 and R 2 are the following groups: Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group, Examples thereof include a group selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group.
  • R 1 and R 2 are the following groups: And a group selected from a hydrogen atom, a methyl group, a fluorine atom, a methoxy group, a hydroxymethyl group, a (1R) -1-hydroxyethyl group, a (1R) -1,2-dihydroxyethyl group, and a methylsulfonyl group. .
  • R 1 and R 2 when one of R 1 and R 2 is a hydrogen atom, the other is in the following group: Methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl Group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1 It is preferably selected from -hydroxyethyl group, methylsulfonyl group
  • the other is the following group: Methyl group, fluorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxy Ethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl group, 1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1-hydroxyethyl A group selected from a group, a methylsulfonyl group, a cyano group, an acetyl group, a 1- (N) atom
  • the other is the following group: Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group, This is a case selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group.
  • the other is the following group: This is a case selected from a hydrogen atom, a methyl group, a fluorine atom, a methoxy group, a hydroxymethyl group, a (1R) -1-hydroxyethyl group, a (1R) -1,2-dihydroxyethyl group, and a methylsulfonyl group.
  • R 1 and R 2 One is a hydroxymethyl group and the other is a methylsulfonyl group, a methoxy group, a cyano group, or a fluorine atom, or It is preferable that one is a 1,2-dihydroxyethyl group and the other is a fluorine atom or a chlorine atom.
  • One is a 1,2-dihydroxyethyl group, more preferably, One is a (1R) -1,2-dihydroxyethyl group and the other is a fluorine atom or a chlorine atom.
  • R 1 and R 2 One is a hydroxymethyl group and the other is a methylsulfonyl group or a methoxy group, or More preferably, one is a 1,2-dihydroxyethyl group and the other is a fluorine atom.
  • One is a 1,2-dihydroxyethyl group, more preferably, One is a (1R) -1,2-dihydroxyethyl group and the other is a fluorine atom.
  • the compound represented by the formula (I) of the present invention can be produced according to Method A to Method G described below.
  • the solvent used in the reaction in each step of the following methods A to G is not particularly limited as long as it does not inhibit the reaction, does not adversely affect the reaction, and dissolves the starting materials to some extent.
  • reaction temperature varies depending on the solvent, starting material, reagent, etc.
  • reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.
  • each target compound is usually collected from the reaction mixture according to a method employed in the technical field. For example, after adjusting the liquidity of the reaction mixture as appropriate and removing insoluble matter by filtration, mixing with water and an organic solvent that is not miscible with water, such as ethyl acetate, and mixing by shaking. The organic layer containing the target compound is separated, and the extract is washed with water, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtered to remove the desiccant, and then distilled off the solvent in the filtrate. Can do.
  • the obtained target compound may be obtained by a method usually employed in the technical field, such as recrystallization, reprecipitation, chromatography [for example, silica gel, alumina, magnesium-silica gel type florisil, SO3H-silica (Fuji Silysia Chemical Ltd.).
  • a suitable combination of photographic methods (preferably high performance liquid chromatography) Of] such eluting with a suitable eluent, usually separated by combining the methods which are customary for separation and purification of organic compounds as appropriate, can be purified.
  • Production method A is a method for producing tetrahydrocyclopentaindole (IX), which can be used as a synthetic intermediate when the compound represented by formula (I) is produced.
  • This step is a step of producing the compound represented by the formula (III) by reducing the olefin using a known organic chemical technique with respect to the compound represented by the formula (II).
  • the compound represented by formula (II) is used as a solvent (for example, alcohols, specifically ethanol, methanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.). And may be carried out by catalytic hydrogenation in the presence of a transition metal catalyst (such as palladium). This reaction is usually performed in a hydrogen atmosphere, but ammonium formate, formic acid, or the like may be used as a hydrogen donor.
  • a solvent for example, alcohols, specifically ethanol, methanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • a transition metal catalyst such as palladium
  • the compound represented by the formula (II) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.
  • This step is a step of producing the compound represented by the formula (IV) by hydrolyzing the ester of the compound represented by the formula (III) using a known organic chemical technique.
  • the compound represented by the formula (III) is present in the presence of a base (for example, alkyl metal hydroxides, specifically lithium hydroxide) in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxy). Ethane, etc .; alcohols, specifically methanol, ethanol, etc. may be used as the organic solvent, and water may be mentioned as the solvent, but the organic solvent is preferably miscible with water, These are preferably used as mixed solvents).
  • a base for example, alkyl metal hydroxides, specifically lithium hydroxide
  • a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxy.
  • Ethane, etc .; alcohols, specifically methanol, ethanol, etc. may be used as the organic solvent, and water may be mentioned as the solvent, but the organic solvent is preferably miscible with water, These are preferably used as mixed solvents).
  • the carboxylic acid compound represented by the formula (IV) is converted into an acid chloride (oxalyl chloride, thionyl chloride) in a solvent (for example, halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.). Etc.) and a small amount of N, N-dimethylformamide may be added.
  • a solvent for example, halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • Etc. halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • Etc. halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • Etc. halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • the compound represented by the formula (V) is carried out in a solvent (for example, a halogenated hydrocarbon, specifically 1,2-dichloroethane) by adding a Lewis acid (for example, aluminum chloride).
  • a solvent for example, a halogenated hydrocarbon, specifically 1,2-dichloroethane
  • a Lewis acid for example, aluminum chloride.
  • the compound represented by formula (VI) is used as a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; alcohols, specifically methanol, ethanol, etc.).
  • a reducing agent for example, metal borohydride compounds, specifically sodium borohydride, etc. is added.
  • This step is a step of producing the compound represented by the formula (VIII) by subjecting the compound represented by the formula (VII) to Mitsunobu reaction using a known organic chemical technique.
  • the compound represented by formula (VII) is used as a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; alcohols, specifically methanol, ethanol, etc.). In this case, N-Boc-o-nitrobenzenesulfonamide, triphenylphosphine and diethyl azodicarboxylate are added.
  • This step is a step of producing a compound represented by the formula (IX) by hydrolyzing o-nitrobenzenesulfonamide using a known organic chemical method for the compound represented by the formula (VIII). It is.
  • Production method B is a method for producing fluorotetrahydrocyclopentaindole (XII), which can be used as a synthetic intermediate when the compound represented by formula (I) is produced.
  • This step is a step of producing a compound represented by the formula (X) by subjecting the compound represented by the formula (VI) to a fluorination reaction using a known organic chemical technique.
  • the compound represented by the formula (VI) is converted into 1-fluoro-4-hydroxy-1,4-diazoniabicyclo [2,2, in a solvent (for example, alcohols, specifically methanol, ethanol, etc.). 2] Add octanebis (tetrafluoroborate) and so on. (Process B-II)
  • This step is a step of producing the compound represented by the formula (XI) by subjecting the compound represented by the formula (X) to an oximation reaction using a known organic chemical technique.
  • a compound represented by formula (X) is used as a solvent (for example, alcohols, specifically ethanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; water, these are used as a mixed solvent. In this case, sodium acetate and O-methylhydroxyamine hydrochloride are added.
  • This reaction is a step of producing a compound represented by the formula (XII) by reducing the oxime to the compound represented by the formula (XI) using a known organic chemical technique and then Boc protecting it. is there.
  • a compound represented by the formula (XI) in a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • borane-ether complexes specifically borane-tetrahydrofuran complexes, etc.
  • an alkali metal hydroxide aqueous solution for example, sodium hydroxide aqueous solution as a base, ethyl acetate and di-t-butyl dicarbonate as a solvent are added.
  • Production method C produces aryltetrahydrocyclopentaindole (XV), which can be used as a synthetic intermediate when producing the compound represented by formula (I), via bromotetrahydrocyclopentaindole (XIV). Is the method.
  • This step is a step of producing the compound represented by the formula (XIV) by brominating the compound represented by the formula (XIII) using a known organic chemical technique.
  • a compound represented by the formula (XIII) in a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • a lithium metal strong base for example, lithium diisopropylamide, and 1,2-dibromo Carry out with the addition of -1,1,2,2-tetrachloroethane.
  • C-II process This step is a step of producing a compound represented by the formula (XV) by subjecting the compound represented by the formula (XIV) to Suzuki coupling using a known organic chemical technique.
  • a compound represented by the formula (XIV) in a solvent for example, ethers, specifically 1,4-dioxane; water, or a mixed solvent thereof
  • a solvent for example, ethers, specifically 1,4-dioxane; water, or a mixed solvent thereof
  • a palladium catalyst, arylboronic acid or arylboronic acid Carry out with the addition of the ester.
  • a microwave reactor may be used.
  • Production Method D produces aryltetrahydrocyclopentaindole (XV), which can be used as a synthetic intermediate when producing the compound represented by formula (I), via tributylstannanyltetrahydrocyclopentaindole (XVI). It is a method to do.
  • This step is a step of producing a compound represented by the formula (XVI) by subjecting the compound represented by the formula (XIII) to tributylstannylation using a known organic chemical technique.
  • lithium diisopropylamide and tributyltin iodide are added as a lithium metal strong base in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.) to a compound represented by the formula (XIII).
  • a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • This step is a step of producing a compound represented by the formula (XV) by subjecting a compound represented by the formula (XVI) to Stille coupling using a known organic chemical technique.
  • a compound represented by the formula (XVI) in a solvent for example, amides, specifically, N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.
  • a solvent for example, amides, specifically, N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.
  • tetrakis triphenylphosphine
  • a microwave reactor may be used.
  • Stille coupling the method described in Angewandte Chemie, International Edition, 25, 6, 1986, 508-524; Tetrahedron Letters, 35, 19, 1994, 3195-3196; Synthesis, 1986, 7, 564-565, etc. It can be performed according to.
  • This step is a step for producing a compound represented by the formula (XVII) by subjecting the compound represented by the formula (XIII) to alkyloxycarbonylation using a known organic chemical technique.
  • This step is a step of producing the compound represented by the formula (XVIII) by hydrolyzing the compound represented by the formula (XVII) using a known organic chemical technique. This is carried out in the same manner as in step A-II of method A.
  • a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • This step is a step for producing a compound represented by the formula (XIX) by subjecting the compound represented by the formula (XVIII) to a condensation reaction using a known organic chemical technique.
  • a compound represented by the formula (XVIII) is mixed with O- (7-azabenzotriazole-1-form in a solvent (for example, amides, specifically N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.).
  • a solvent for example, amides, specifically N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.
  • This step is a step of producing the compound represented by the formula (XX) by cyclizing the compound represented by the formula (XIX) using a known organic chemical technique.
  • Production method E is a method for producing aminotetrahydrocyclopentaindole (XXI), which can be used as a synthesis intermediate when synthesizing a compound represented by formula (I), from a compound represented by formula (XV). .
  • This step is a step of producing a compound represented by the formula (XXI) by de-Bocating the compound represented by the formula (XV) using a known organic chemical technique.
  • the compound represented by the formula (XV) in a solvent for example, ethers, specifically 1,4-dioxane, 1,2-dimethoxyethane; halogenated hydrocarbons, dichloromethane, etc.
  • Hydrogen Dioxane solution
  • the reaction conditions are not limited to these conditions, and can be carried out, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and P. G. Wuts.
  • Production method F is another method for producing a synthetic intermediate represented by the formula (XXVIII).
  • This step is a step of producing the compound represented by the formula (XXIII) by fluorinating the compound represented by the formula (XXII) using a known organic chemical technique. Performed in the same manner as the BI process of Method B.
  • This step is a step of producing the compound represented by the formula (XXIV) by reducing the compound represented by the formula (XXIII) using a known organic chemical technique. Performed in the same manner as the AV process of Method A.
  • This step is a step of producing a compound represented by the formula (XXV) by brominating the compound represented by the formula (XXIV) using a known organic chemical technique. Performed in the same manner as the CI process in Method C.
  • This step is a step of producing a compound represented by the formula (XXVI) by subjecting the compound represented by the formula (XXV) to Suzuki coupling using a known organic chemical technique. This is carried out in the same manner as the C-II step of Method C.
  • This step is a step of producing a compound represented by the formula (XXVII) by subjecting the compound represented by the formula (XXVI) to a Mitsunobu reaction using a known organic chemical technique.
  • a compound represented by the formula (XXVI) is dissolved in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.), diphenylphosphorylamide, 1,8-diazabicyclo [5.4.0] undec-7 -Carry out with the addition of en.
  • a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • diphenylphosphorylamide 1,8-diazabicyclo [5.4.0] undec-7 -Carry out with the addition of en.
  • F-VI process This step is a step of producing a compound represented by the formula (XXVIII) by subjecting the compound represented by the formula (XXVII) to a reduction reaction using a known organic chemical technique.
  • Production method G is a method for producing a compound represented by formula (I) from a compound represented by formula (XXI).
  • This step is a step of producing the compound represented by the formula (I) by dearylsulfonylating the compound represented by the formula (XXI) using a known organic chemical method.
  • a compound represented by the formula (XXI) in a solvent for example, alcohols, specifically methanol, ethanol, n-propanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • a solvent for example, alcohols, specifically methanol, ethanol, n-propanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • cesium carbonate is added as a base.
  • the compound represented by the formula (I) of the present invention can be a pharmaceutically acceptable salt if desired.
  • a pharmaceutically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicament.
  • the compound represented by the formula (I) of the present invention has a basic moiety, and can be converted into a salt by treating with an acid.
  • Salts based on basic substituents and basic heteroaryl groups include hydrohalides such as hydrofluorates, hydrochlorides, hydrobromides and hydroiodides; hydrochlorides, nitrates, peroxides
  • Inorganic acid salts such as chlorate, sulfate and phosphate; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; benzene sulfonate and p-toluene sulfonate
  • Aryl sulfonates such as: acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate and maleate, etc .
  • glycine salt, lysine Examples include salts, arginine salts, ornithine salts, amino acid salts such as glutamate and aspartate. Among these, preferred are in
  • the compound represented by the formula (I) or a salt thereof When the compound represented by the formula (I) or a salt thereof is left in the atmosphere or recrystallized, it may absorb moisture and attach adsorbed water to form a hydrate. Such hydrates are also included in the salts of the present invention.
  • the compound represented by the formula (I) or a salt thereof may absorb a certain solvent and become a solvate, and such a solvate is also included in the salt of the present invention.
  • the compound represented by the formula (I) Since the compound represented by the formula (I) has an asymmetric carbon atom in its molecule, an optical isomer exists. These isomers and mixtures of these isomers are all represented by a single formula, ie, formula (I). Therefore, the compound represented by the formula (I) includes all of a single optical isomer and a mixture of optical isomers in an arbitrary ratio within the scope of the present invention.
  • optical isomers as described above can be obtained by using an optically active raw material compound, or by synthesizing the compound according to the present invention using an asymmetric synthesis or asymmetric induction method.
  • the synthesized compound according to the present invention can be obtained by isolation using a normal optical resolution method or a separation method using an optically active carrier.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound can be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the compound represented by the formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate thereof not only has an excellent inhibitory action on acid-sensitive ion channels, but also has an inhibitory action on acid. It is an excellent compound that exhibits excellent selectivity for sensitive ion channels.
  • Such acid-sensitive ion channel inhibitors include ischemic heart disease, heart failure, peripheral arterial disease, arrhythmia, hypertension, hypotension, rheumatoid arthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative Colitis, dermatitis including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with cancer , Osteoarthritis, interstitial cystitis, reflux esophagitis, irritable bowel syndrome, cough, gustatory injury, hearing loss, visual impairment in diabetic retinopathy and glaucoma, colorectal cancer, ovarian epithelial cancer, breast cancer, stomach Associated with diseases or disorders such as tumorigenesis, hyperventilation syndrome, asthma, insulin resistant diabetes, multiple sclerosis, generalized anxiety disorder, panic disorder, cerebral infarction, Parkinson
  • the compound of the present invention is expected to have an acid-sensitive ion channel inhibitory action even when administered orally, it is possible to easily use an excellent acid-sensitive ion channel inhibitory action. QOL can be improved.
  • the compound of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate thereof can be administered in various forms.
  • the administration form is, for example, oral administration such as tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), or injections (intravenous, intramuscular, subcutaneous, or intraperitoneal administration). And parenteral administration such as drops, suppositories (rectal administration) and the like.
  • These various preparations can be usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. with respect to the main drug.
  • An auxiliary agent can be appropriately selected and added, and can be formulated according to a commonly practiced method.
  • excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as esters, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegrators such as sucrose, stearin, cocoa butter and hydrogenated oil; quaternary ammonium salts and lauryl sulfate Absorption promoters such as sodium; humectants such as glycerin and star
  • the tablet which gave the normal coating for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.
  • excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin and talc; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; laminaran, Disintegrants such as agar can be used.
  • a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, and semi-synthetic glyceride.
  • solutions, emulsions or suspensions When used as an injection, it can be used as a solution, emulsion, or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood.
  • the solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent.
  • the preparation may contain a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. May be included.
  • the above-mentioned preparation can contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as necessary, and can further contain other pharmaceuticals.
  • the amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight in the total composition.
  • the amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animals, particularly humans), but in the case of oral administration, the upper limit is 1000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg (preferably 1 mg, more preferably 5 mg) is preferably administered to adults 1 to 6 times daily depending on symptoms.
  • Example 1 [3- (6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl) -5-methoxy-phenyl] methanol [Step 1] Ethyl 3- ⁇ 1-[(4-methylphenyl) sulfonyl] -1H-indol-4-yl ⁇ propanoate
  • Lithium hydroxide monohydrate (17.8 g, 425 mmol) was added to a mixture of the compound (63.1 g) obtained in Step 1 above in tetrahydrofuran (300 mL), ethanol (100 mL), and water (200 mL) at room temperature. Stir. The reaction mixture was cooled to 0 ° C., 3N hydrochloric acid (150 mL) was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Oxalyl chloride (17.1 mL) was added dropwise to a solution of the compound (57.1 g) obtained in Step 2 above in dichloromethane (300 mL). After completion of dropping, the mixture was stirred at room temperature for 2 hours, N, N-dimethylformamide (3 drops) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain the title compound (60.2 g) as a black oily substance.
  • the compound (2.2 g) obtained in the above step 7 was dissolved in tetrahydrofuran (100 mL).
  • the reaction mixture was cooled to ⁇ 78 ° C., lithium diisopropylamide (9.9 mL) was added under a nitrogen atmosphere, and the mixture was stirred for 30 min.
  • a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (5.0 g) in tetrahydrofuran (30 mL) was added in one portion, and the mixture was stirred at -78 ° C. for 2 hours.
  • a saturated aqueous ammonium solution was poured into the reaction solution, and the organic layer was extracted with ethyl acetate.
  • Example 2 [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-methoxy-phenyl] methanol [Step 1] tert-Butyl N-[(6R) -2- [3- (hydroxymethyl) -5-methoxy-phenyl] -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [ e] Indol-6-yl] carbamate; tert-butyl N-[(6S) -2- [3- (hydroxymethyl) -5-methoxy-phenyl] -3- (p-tolylsulfonyl) -7,8- Dihydro-6H-cyclopenta [e] indol-6-yl] carbamate
  • IPA isopropyl alcohol
  • Step 3 [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-methoxy-phenyl] methanol
  • Example 1 Compound (300 mg) obtained in Step 8 and methyl 3-cyano-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (256 mg) was used to give the title compound (260 mg) as a white solid in the same manner as in Example 1, Step 9.
  • Example 4 2- [4- (Methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl ⁇ 3-[(4-methylphenyl) sulfonyl] -2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6- Il ⁇ Carbamate
  • Example 1 Step 8 Using the compound (150 mg) obtained in Example 1 Step 8 and (4-methylsulfonylphenyl) boronic acid (89 mg), the title compound (150 mg) was obtained as a white solid by the same method as Example 1 Step 9. .
  • Example 5 [3-[(6R) -6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-fluoro-phenyl] ethane-1,2- Diol [Step 1] Ethyl 3- ⁇ 6-[(tert-butoxycarbonyl) amino] -3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-2- Il ⁇ -5-fluorobenzoate
  • Example 1 Compound obtained in Step 8 (350 mg), water (2.7 mL) and 3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) The title compound (360 mg) was obtained as a yellow solid in the same manner as in Example 1, Step 9 using methyl benzoate (233 mg).
  • Step 2 The compound obtained in Step 2 (192 mg) was dissolved in dichloromethane (30 mL), and desmartin periodinane (295 mg) and sodium bicarbonate (87 mg) were added at 0 ° C. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (190 mg) as a white solid.
  • Methyltriphenylphosphonium bromide 160 mg was dissolved in tetrahydrofuran (30 mL), n-butyllithium (1.6 mol / l in hexane, 0.30 mL, 0.4848 mmol) was added at room temperature, and the mixture was stirred for 1 hour.
  • n-butyllithium 1.6 mol / l in hexane, 0.30 mL, 0.4848 mmol
  • To the reaction solution was added a tetrahydrofuran solution (5 mL) of the compound (190 mg) obtained in Step 3 above, and the mixture was stirred at room temperature for 12 hours.
  • the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (190 mg) as a white solid.
  • Step 4 The compound obtained in Step 4 (190 mg) was dissolved in 1,4-dioxane (30 mL) and water (1 mL), and osmium tetroxide (2.5 wt.% Tert-butanol solution, 0.070 mL), 4-methylmorpholine. N-oxide (61 mg) was added, and the mixture was stirred at room temperature for 4 hours. Water was poured into the reaction solution, and the organic layer was extracted with ethyl acetate and washed with brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure.
  • Example 6 [5-[(6S) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -2-methylsulfonyl-phenyl] methanol [Step 1] Methyl 5- ⁇ (6R) -6-[(tert-butoxycarbonyl) amino] -3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] Indol-2-yl ⁇ -2- (methylsulfonyl) benzoate
  • Example 10 Compound (770 mg) obtained by the method of Example 10 steps 1 to 5 and 2-methylsulfonyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) The title compound (1.0 g) was obtained as a white solid in the same manner as in Example 1, Step 9 using methyl benzoate (0.67 g).
  • Example 10 Compound (2.5 g) obtained by the method of Example 10 steps 1 to 5 and 2- (3-chloro-5-vinyl-phenyl) -4,4,5,5-tetramethyl-1,3,2 The title compound (250 mg) was obtained as a white solid in the same manner as in Example 1, Step 9 using -dioxaborolane (1.00 g).
  • the compound (130 mg) obtained in the above step 1 was dissolved in tert-butyl alcohol (10 mL), AD-mix beta (1.0 g) was added, water (2 mL) was added, and the mixture was stirred at room temperature for 6 hours.
  • the reaction solution was poured into an aqueous sodium sulfite solution, and the organic matter was extracted with ethyl acetate. After washing with brine, it was dried over sodium sulfate and the solvent was distilled off.
  • the obtained residue was purified by diol silica gel chromatography [hexane / ethyl acetate] to give the title compound (80 mg) as a white solid.
  • Example 8 2- (6-Methoxypyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-Butyl N- [2- (2-methoxypyrimidin-5-yl) -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-6-yl] Carbamate
  • Example 1 Using the compound obtained in Step 8 (250 mg) and 6-ethoxypyrazine-2-boronic acid pinacol ester (148 mg) in the same manner as Example 1 Step 9, the title compound (87 mg) was converted to a yellow solid. Obtained.
  • Optical resolution of the compound (67.3 g) obtained in the above Step 3 was performed using column chromatography (Daicel Chiralcel OJ-H, methanol 100%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl N-[(6S) -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] Indol-6-yl] carbamate (14.6 g, optical purity> 98% ee) was obtained as a white solid.
  • Example 11 Using the compound (267 g) obtained in Step 3 of Example 11, the title compound (154 g; containing about 15% of (6R) -isomer) was obtained as a white solid by the same procedure as in Step 10 of Example 10. .
  • Step 2 tert-Butyl [(2-nitrophenyl) sulfonyl] [(6R) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
  • Optical resolution of the compound (383 g) obtained in Step 3 above was performed using column chromatography (Daicel Chiralcel OJ-H, methanol 100%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl N-[(6S) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] Indol-6-yl] carbamate (46.9 g, optical purity> 98% ee) was obtained as a white solid.
  • Example 16 (6R) -2- (3-Methylpyridin-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- (3-methylpyridin-4-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
  • Example 14 Using the compound (200 mg) obtained in Step 1 and 3-picoline-4-boronic acid (83.6 mg) in the same manner as in Example 1, Step 9, the title compound (117 mg) was obtained as a pale yellow oil. Obtained.
  • 1 H-NMR (CDCl 3 ) ⁇ ppm: 8.51 (1H, s), 8.48-8.46 (1H, m), 8.19-8.15 (1H, m), 7.51-7.44 (3H, m), 7.37-7.30 (3H, m), 7.06-6.99 (1H, m), 6.46 (1H, s), 5.31-5.22 (1H, m), 4.78-4.72 (1H, m), 3.09-3.00 (1H, m), 2.94-2.83 ( 1H, m), 2.70-2.60 (1H, m), 2.22 (3H, d, J 19.5Hz), 1.92-1.82 (1H, m), 1.48 (9H, s).
  • Example 13 Using the compound obtained in Step 5 of Step (240 mg) and (6-chloropyrazin-2-yl) methanol (98.9 mg) in the same manner as in Step 11 of Example 11, the title compound (190 mg) was obtained as a white solid. Got as.
  • Example 13 Using the compound (240m) obtained in Step 5 and 2-chloro-6-methylpyrazine (88.0 mg), the title compound (170 mg) was obtained as a white solid in the same manner as in Step 11 of Example 11. .
  • Example 13 Using the compound (250 mg) obtained in Step 5 and 2-chloro-3-methylpyrazine (91.6 mg), the title compound (190 mg) was obtained as a white solid in the same manner as in Example 11, Step 8. .
  • Example 20 [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] methanol [Step 1] tert-butyl N-[(6R) -3- (benzenesulfonyl) -2- [3- (hydroxymethyl) pyrazin-2-yl] -7,8-dihydro-6H-cyclopenta [e] indole -6-yl] carbamate
  • Example 21 (6R) -2- (3-Fluoropyridin-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- (3-fluoropyridin-4-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
  • Example 14 Using the compound (200 mg) obtained in Step 1 and 3-fluoro-4-pyridineboronic acid pinacol ester (136 mg), the title compound (154 mg) was prepared as a pale yellow oil in the same manner as in Example 1, Step 9. Obtained as material.
  • Example 22 (6R) -2- (2-Methylpyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- (2-methylpyrimidin-5-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
  • Example 14 Using the compound (200 mg) obtained in Step 1 and 2-methylpyrimidine-5-boronic acid (84.2 mg), the title compound (194 mg) was obtained as a pale yellow oily substance in the same manner as in Example 1, Step 9.
  • the title compound (194 mg) was obtained as a pale yellow oily substance in the same manner as in Example 1, Step 9.
  • Example 23 [5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] ethanone [Step 1] tert-Butyl [(6R) -2- (5-acetylpyrazin-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
  • Example 13 Using the compound (7.0 g) obtained in Step 5 and 1- (5-chloropyrazin-2-yl) ethanone (1.7 g), the title compound (5.3 g) was prepared in the same manner as in Example 11, Step 8. ) Was obtained as a white solid.
  • Example 25 (1R) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol [Step 1] tert-Butyl [(6R) -2- ⁇ 5-[(1R) -1-hydroxyethyl] pyrazin-2-yl ⁇ -3- (phenylsulfonyl) -3,6,7,8-tetrahydro Cyclopenta [e] indol-6-yl] carbamate
  • Example 23 Compound (5.80 g) obtained in Step 1 and chloro [(1R, 2R) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium (II) (350 mg) was used to give the title compound (4.98 g) as a white solid in the same manner as in Step 10 of Example 10.
  • Example 26 ⁇ 4-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyrimidin-2-yl ⁇ methanol [Step 1] ⁇ 4-[(6R) -6-[(tert-butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl ] -6-Methoxypyrimidin-2-yl ⁇ methyl acetate
  • Example 13 Using the compound obtained in Step 5 (400 mg) and (4-chloro-6-methoxy-pyrimidin-2-yl) methyl acetate (247 mg) in the same manner as in Example 11, Step 8, the title compound ( 230 mg) was obtained as a yellow oil.
  • Example 28 (1R) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ propane-1 -All [Step 1] tert-Butyl [(6R) -2- ⁇ 5- [methoxy (methyl) carbamoyl] pyrazin-2-yl ⁇ -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [ e] Indol-6-yl] carbamate
  • Example 13 Using the compound synthesized in Step 5 (1.11 g) and 5-chloro-N-methoxy-N-methylpyrazine-2-carboxamide (319 mg) in the same manner as Example 11 Step 8, the title compound (910 mg ) was obtained as a white solid.
  • the compound (1.0 g) obtained in the above step 1 was dissolved in tetrahydrofuran (30 mL), and an ethylmagnesium bromide tetrahydrofuran solution (1.0 M, 1.53 mL) was added dropwise at 0 ° C. in a nitrogen atmosphere. After stirring at room temperature for 30 minutes, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing with brine, it was dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (149 mg) as a white solid.
  • Triethylamine (0.0945 mL) and formic acid (0.0442 mL) were stirred and chloro [(1R, 2R) -N- (2 ', 6'-dimethylbenzylsulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium ( II) (8.8 mg) and a dichloromethane solution (3 mL) of the compound obtained in Step 2 above (149 mg) were added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (118 mg) as a white solid.
  • Example 29 (6R) -2- ⁇ 5-[(1Z) -N-hydroxyethaneimidoyl] pyrazin-2-yl ⁇ -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- ⁇ 5-[(1Z) -N-hydroxyethaneimidoyl] pyrazin-2-yl ⁇ -3- (phenylsulfonyl) -3,6,7,8 -Tetrahydrocyclopenta [e] indol-6-yl] carbamate
  • Example 23 The compound (50 mg) obtained in Step 1 was dissolved in methanol (5 mL), hydroxylamine hydrochloride (9.8 mg) and sodium acetate (12 mg) were added, and the mixture was stirred at 80 ° C. for 1 hr. Water was poured into the reaction solution, and the organic matter was extracted with ethyl acetate. After washing with brine, it was dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (28 mg) as a white solid.
  • Example 30 (6R) -2- ⁇ 5-[(Z)-(Hydroxyimino) methyl] pyrazin-2-yl ⁇ -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] Methyl 5-[(6R) -6-[(tert-butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl Pyrazine-2-carboxylate
  • Example 13 Using the compound synthesized in Step 5 (1.15 g) and methyl 5-bromopyrazine-2-carboxylate (711 mg), the title compound (890 mg) was obtained as a white solid in the same manner as in Step 11 of Example 11. It was.
  • Example 31 2- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol [Step 1] tert-Butyl [(6R) -2- (5-ethenylpyrazin-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl ] Carbamate
  • Triethylamine (2 mL) and a 10% carbon palladium catalyst (0.300 g) were added to a solution of the compound obtained in Step 4 (500 mg) in tetrahydrofuran (10 mL) and methanol (10 mL), and the mixture was stirred for 30 minutes in a hydrogen atmosphere. After completion of the reaction, the solution from which the palladium catalyst had been removed by Celite filtration was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to obtain the title compound (410 mg) as a white solid. .
  • Example 32 (6R) -2- [5- (S-methylsulfonimidoyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- [5- (methylsulfinyl) pyridin-2-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-yl] carbamate
  • Example 33 2- [5- (2-Methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole- 6-amine [Step 1] Methyl 6-[(tert-butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-2-carboxylate
  • Example 13 Using the compound obtained in Step 5 (300 mg) and 2-bromo-N-methoxy-N-methyl-thiazole-5-carboxamide (215 mg) in the same manner as Example 11 Step 8, the title compound ( 210 mg) was obtained as a white solid.
  • Example 36 (6R) -2- (1-Methyl-1H-pyrazol-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-Butyl [(6R) -2- (1-methyl-1H-pyrazol-4-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-yl] carbamate
  • Example 14 Compound obtained in Step 1 (200 mg) and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -1H pyrazole (127 mg) was used to give the title compound (171 mg) as a pale-yellow oil in the same manner as in Example 1, Step 9.
  • Example 37 (6R) -2- (1,3-thiazol-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -3- (phenylsulfonyl) -2- (1,3-thiazol-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6 -Il] Carbamate
  • Example 13 Using the compound (200 mg) obtained in Step 5 and 5-bromothiazole (93.5 mg), the title compound (141 mg) was obtained as a crude product in the same manner as in Example 11, Step 8.
  • Step 2 (6R) -3- (Phenylsulfonyl) -2- (1,3-thiazol-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
  • Example 38 (1S) -1- ⁇ 2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazol-5- Il ⁇ ethanol [Step 1] tert-butyl N-[(6R) -3- (benzenesulfonyl) -2- [5-[(1S) -1-hydroxyethyl] thiazol-2-yl] -7,8-dihydro-6H -Cyclopenta [e] indol-6-yl] carbamate
  • Example 39 (1R) -1- ⁇ 2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazol-5- Il ⁇ ethanol [Step 1] tert-Butyl [(6R) -2- ⁇ 5-[(1R) -1-hydroxyethyl] -1,3-thiazol-2-yl ⁇ -3- (phenylsulfonyl) -3,6, 7,8-Tetrahydrocyclopenta [e] indol-6-yl] carbamate
  • Example 35 Compound (230 mg) obtained in Step 2 and chloro [(1R, 2R) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium (II) (13.3 mg) was used to give the title compound (200 mg) as a white solid in the same manner as in Step 1 of Example 10.
  • Example 40 (6R) -2- (5-Methyl-1,3,4-thiadiazol-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- (5-methyl-1,3,4-thiadiazol-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] Indol-6-yl] carbamate
  • Example 13 Using the compound obtained in Step 5 of Step (3.00 g) and 2-bromo-5-methyl-1,3,4-thiadiazole (1.15 g) in the same manner as in Step 11 of Example 11, the title compound (1.12 g) was obtained as a pale yellow solid.
  • Example 14 Using the compound obtained in Step 1 of Step 1 (250 mg) and N-methyl-1H-pyridone-2-one-5-boronic acid pinacol ester (239 mg) in the same manner as in Step 1 of Example 1, the title compound (160 mg) was obtained as a colorless oil.
  • Example 42 (6R * , 7S * )-7-Fluoro-2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] 7-Fluoro-3-[(4-methylphenyl) sulfonyl] -7,8-dihydrocyclopenta [e] indole-6 (3H) -one
  • Example 1 1-fluoro-4-hydroxy-1,4-diazoniabicyclo [2,2,2] octanebis (tetrafluoroborate) (1.09 g) in a methanol (30.7 mL) solution of the compound obtained in Step 4 And stirred at 80 ° C. for 5 hours. The reaction was stopped by adding water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (280 mg) as a white solid.
  • Example 42 Using the compound (600 mg) obtained in Step 3 and (2-methoxymyrimidin-5-yl) boronic acid (283 mg), the title compound (450 mg) was prepared in the same manner as in Example 1, Step 9. Obtained as a white solid.
  • Step 7 tert-butyl [(6S, 7R) -7-fluoro-2- [2- (hydroxymethyl) -6-methoxypyridin-4-yl] -3- (phenylsulfonyl) -3,6,7 , 8-tetrahydrocyclopenta [e] indol-6-yl] carbamate; tert-butyl [(6R, 7S) -7-fluoro-2- [2- (hydroxymethyl) -6-methoxypyridin-4-yl] -3- (Phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
  • Example 45 ⁇ 4-[(6R, 7S) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyridin-2-yl ⁇ methanol [Step 1] ⁇ 4-[(6R, 7S) -6-amino-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl]- 6-Methoxypyridin-2-yl ⁇ methanol
  • Example 46 ⁇ 5-[(6R * , 7S * )-6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ methanol [Step 1] tert-Butyl [(6R * , 7S * )-7-fluoro-3- (phenylsulfonyl) -2- (tributylstannanyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-yl] carbamate
  • Example 44 Using the compound (1.10 g) obtained in Step 3 of Example 44 and the procedure of Example 11 Step 7, the title compound (1.20 g) was obtained as a colorless oil.
  • Example 48 (1S) -1- ⁇ 5-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazine-2 -Il ⁇ ethanol [Step 1] tert-Butyl [(6S, 7R) -7-fluoro-2- ⁇ 5-[(1S) -1-hydroxyethyl] pyrazin-2-yl ⁇ -3- (phenylsulfonyl) -3,6 , 7,8-Tetrahydrocyclopenta [e] indol-6-yl] carbamate
  • Example 47 Compound (250 mg) obtained in Step 3 and chloro [(1S, 2S) -N- (2 ', 6'-dimethylbenzenesulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium (II ) (0.0150 g) to give the title compound (245 mg) as a crude product by the same procedure as in Example 28, step 3.
  • [Step 2] (1S) -1- ⁇ 5-[(6S, 7R) -6-amino-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -2-yl] pyrazin-2-yl ⁇ ethanol
  • Example 50 ⁇ 4-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyrimidin-2-yl ⁇ methanol [Step 1] ⁇ 4-[(6S, 7R) -6-[(tert-butoxycarbonyl) amino] -7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e ] Indol-2-yl] -6-methoxypyrimidin-2-yl ⁇ methyl acetate
  • Example 2 The compound of Example 25 (5 g), lactose (90 g), corn starch (34 g), crystalline cellulose (20 g) and magnesium stearate (1 g) were mixed in a blender and then tableted to form a tablet. can get.
  • Evaluation Example 1 In vitro evaluation method of ASIC Human ASIC3-expressing cells were purchased from Millipore (catalog number: CYL3055).
  • the stable expression cell lines of Human ASIC1a, human ASIC2a, and mouse ⁇ ⁇ ASIC1a are V5-His-ASICs-vector prepared using GeneSwitch System Complate kit (Invitrogen), and GeneSwitch-2000 Transfection Reagent (Invitrogen). A gene was introduced into CHO Cells (Invitrogen). The vector preparation method and gene introduction method were in accordance with the manual attached to each kit.
  • Mouse ASIC3-expressing cells were transfected into HEK293A cells (Invitrogen) using Lipofectamine 2000 Transfection Reagent (Invitrogen) according to the method attached to the kit to produce a stable expression cell line.
  • Table 1 shows the relationship between gene names and host cells.
  • Human ASIC1a-expressing cells were treated with 1 nM Mifepristone (Sigma-Aldrich) for 18 hours to induce expression, and then used for measurement.
  • Human ASIC2a-expressing cells and Mouse ASIC1a-expressing cells were treated with 10 nM Mifepristone (Sigma-Aldrich) for 18 hours to induce expression and then used for measurement.
  • the ASIC inhibitory activity was evaluated by contacting the cells with the compound and measuring the peak change of the acid-induced current using the whole cell automatic patch clamp method (Patchliner, Nanion Technologies GmBH). The holding potential was -60 mV.
  • the composition of the inner liquid and the outer liquid is described below.
  • Internal solution (mM) 50 CsCl, 60 CsF, 10 NaCl, 20 EGTA, and 10 HEPES, pH 7.2.
  • Acid-stimulated external solution 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, and 10 HEPES, pH 6.4 (ASIC1a, 3 function measurement), or 10 MES, pH 4.0 (ASIC2a function measurement) .
  • the reference value of the acid-induced current was defined by the current peak generated when the non-standard solution was replaced with an acid-stimulated solution containing 0.1% DMSO.
  • the ASIC current inhibition rate of the compound was defined by the change in the current peak when substituting the acid-stimulated external solution containing the compound with respect to the reference value. The inhibition rate at each concentration was plotted, and the IC 50 value was calculated from the concentration response curve fitted using the Hill equation.
  • Table 2 shows the inhibitory action of each compound of the present invention on human ASIC3.
  • Evaluation Example 2 ENac In Vitro Evaluation Method CHOK1 cells functionally co-expressing Human ENaC ⁇ , Human ENaC ⁇ , and Human ENaC ⁇ using Lipofectamine TM LTX Reagent (Invitrogen) according to the manual attached to the kit (DS pharma biochemical) was prepared and used for testing.
  • the introduced genes are shown in Table 3.
  • the measurement principle is based on the method of Krumm et al. (Bioorg. Med. Chem., 2012, 20, 3979-3984).
  • the ENaC inhibitory activity was evaluated by contacting the cells with the compound and measuring the peak change in current using the whole cell automatic patch clamp method (Syncropatch384PE, Nanion Technologies GmBH). The holding potential was -60 mV.
  • the composition of the inner liquid and the outer liquid is described below.
  • Nonstandard solution 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, 100 amiloride and 10 HEPES, pH 7.4.
  • External solution for evaluation mM: 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, and 10 HEPES, pH 7.4.
  • ENaC current was defined by the current peak generated when the non-standard solution was replaced with an evaluation solution containing 0.1% DMSO.
  • ENaC current inhibition rate of the compound was defined by the change in current peak when the compound was replaced with an evaluation liquid containing the compound with respect to the reference value. The inhibition rate at each concentration was plotted, and the IC 50 value was calculated from the concentration response curve fitted using the Hill equation.
  • Evaluation Example 3 Confirmation of Oral Absorption
  • the 3,6,7,8-tetrahydrocyclopenta [e] indole compound of the present invention, a salt thereof, or a hydrate thereof is an excellent oral acid-sensitive ion channel inhibitor and useful as a medicine.
  • SEQ ID NO: 1 Base sequence of human ENaC ⁇ subunit
  • SEQ ID NO: 2 Base sequence of human ENaC ⁇ subunit
  • SEQ ID NO: 3 Base sequence of human ENaC ⁇ subunit

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Abstract

The present invention addresses the problem of providing an orally deliverable acid-sensing ion channel inhibitor. The present invention solves said problem through the means of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof: (wherein R is a hydrogen atom or a halogen atom; and, in formula (II), R1 and R2 are substituted aromatic groups, and R1 and R2 each independently represent groups selected from the group consisting of hydrogen atoms, an alkyl group, an alkoxy group, a hydroxyalkyl group, a dihydroxyalkyl group, a halogenoalkyl group, a cycloalkyl(hydroxy) C1 to C6 alkyl group, an alkylsulfonyl group, an (N-hydroxyimino)alkyl group, a halogen atom, a cyano group, and an acyl group).

Description

３，６，７，８－テトラヒドロシクロペンタ［ｅ］インドール化合物3,6,7,8-tetrahydrocyclopenta [e] indole compound
　本発明は、3,6,7,8-テトラヒドロシクロペンタ[e]インドール化合物又はその薬学的に許容される塩に関し、さらに該化合物を含有する酸感受性イオンチャネル阻害剤に関する。 The present invention relates to a 3,6,7,8-tetrahydrocyclopenta [e] indole compound or a pharmaceutically acceptable salt thereof, and further to an acid-sensitive ion channel inhibitor containing the compound.
　酸感受性イオンチャネル（ASIC：acid-sensing ion channel）は、細胞外プロトンにより活性化される陽イオンチャネルである。ASICには、ASIC1、ASIC2、ASIC3及びASIC4のサブタイプが存在し、それぞれのサブタイプが、ホモ又はヘテロ3量体を形成して機能する。ASIC1及びASIC3は知覚神経に発現することから、炎症、虚血及び癌などの組織pHが低下する病態における、疼痛知覚に関与すると考えられている。 An acid-sensitive ion channel (ASIC) is a cation channel activated by extracellular protons. There are subtypes of ASIC1, ASIC2, ASIC3, and ASIC4 in ASIC, and each subtype functions by forming a homo or hetero trimer. Since ASIC1 and ASIC3 are expressed in sensory nerves, it is considered to be involved in pain perception in pathological conditions where tissue pH decreases such as inflammation, ischemia and cancer.
　ASICは、知覚神経以外にも広く分布し、種々の病態への関与が示唆されている。例えば、ASIC1の遺伝子多型がパニック障害と関連すること（Neuromolecular Med. 2016, 18(1), 91-98）、間質性膀胱炎患者の膀胱でASIC2及びASIC3の発現が上昇すること（J. Urology, 2011, 186, 1509-1516）、及びヒト乳癌でASIC1の発現が増加すること（Oncogene, 2015, 1-10）が報告されている。さらに動物実験レベルでは、ASIC1及びASIC3の阻害剤が、鎮痛、神経保護、軟骨保護、血管拡張の抑制、インスリン抵抗性改善作用を示すことが報告されている（Toxicon., 2013, 75, 187-204）。したがって、ASICは様々な病態の発症及び維持に重要な分子と考えられる。 ASIC is widely distributed in addition to sensory nerves, and its involvement in various pathological conditions has been suggested. For example, ASIC1 polymorphism is associated with panic disorder (Neuromolecular Med. 2016, 18 (1), 91-98), and ASIC2 and ASIC3 expression is increased in the bladder of patients with interstitial cystitis (J Urology, 2011, 186, 1509-1516), and increased expression of ASIC1 in human breast cancer (Oncogene, 2015, 1-10) have been reported. Furthermore, at the level of animal experiments, it has been reported that inhibitors of ASIC1 and ASIC3 exhibit analgesia, neuroprotection, cartilage protection, suppression of vasodilation, and insulin resistance improvement (Toxicon., 2013, 75, 187- 204). Therefore, ASIC is considered an important molecule for the development and maintenance of various pathological conditions.
　ASICの低分子阻害剤として、アミロライドが広く用いられる。しかしながらアミロライドは、上皮型ナトリウムチャネル（ENaC：Epithelial Na+ channel）も同時に阻害するため、特異性は十分ではない。近年、ASIC1特異的阻害剤であるmambalgin-1やASIC3特異的阻害剤であるAPETx2を初めとする種々のペプチド阻害剤が報告されている（Toxicon., 2013, 75, 187-204）。さらに低分子ASIC阻害剤としてA-317567（Pain, 2005, 117(1-2), 88-96）やNS383（CNS Neurosci. Ther., 2016, 22(2), 135-145）が報告された。しかしながら、アミロライド以外のASIC阻害剤の薬効評価は非経口投与で行われているため、経口吸収性を示すかは不明である。すなわち、ASICを選択的に阻害し、かつ経口吸収可能性が明示された化合物の報告は存在しない。 Amiloride is widely used as a low molecular weight inhibitor for ASIC. However, amiloride also inhibits epithelial sodium channel (ENaC: Epithelial Na + channel) at the same time, so its specificity is not sufficient. In recent years, various peptide inhibitors such as mambalgin-1 which is an ASIC1 specific inhibitor and APETx2 which is an ASIC3 specific inhibitor have been reported (Toxicon., 2013, 75, 187-204). Furthermore, A-317567 (Pain, 2005, 117 (1-2), 88-96) and NS383 (CNS Neurosci. Ther., 2016, 22 (2), 135-145) were reported as small molecule ASIC inhibitors. . However, since pharmacological evaluation of ASIC inhibitors other than amiloride is performed by parenteral administration, it is unclear whether or not it exhibits oral absorbability. In other words, there are no reports of compounds that selectively inhibit ASIC and have been shown to be orally absorbable.
　ヒトにおいて、アミロライドが実験的な酸誘発疼痛を抑制すること（J. Clin. Invest., 2002, 110(8), 1185-1190）及び多発性硬化症に対して神経保護作用を示す可能性のあることが報告されている（Brain, 2013, 136, 106-15）。さらに、ASIC阻害剤であるPPC-5650が、ヒトの食道の痛みを抑制することが報告された（Basic Clin. Pharmacol. Toxicol., 2015, 116(2), 140-5）。これらの報告から、ASIC阻害剤が、ヒトにおいて、疼痛を初めとする種々の病態に対して治療効果を示す可能性が示唆される。このような背景の下に新規ASIC阻害剤の創出が試みられている（特許文献１～１０、非特許文献１、２参照）。 Amiloride may inhibit experimental acid-induced pain in humans (J. Clin. Invest., 2002, 110 (8), 1185-1190) and may be neuroprotective against multiple sclerosis It has been reported (Brain, 2013, 136, 106-15). Furthermore, PPC-5650, an ASIC inhibitor, has been reported to suppress pain in human esophagus (Basic Clin. Pharmacol. Toxicol., 2015, 116 (2), 140-5). These reports suggest that ASIC inhibitors may have therapeutic effects on various pathologies including pain in humans. Under these circumstances, attempts have been made to create novel ASIC inhibitors (see Patent Documents 1 to 10, Non-Patent Documents 1 and 2).
　本発明に係る三環性のテトラヒドロシクロペンタ[e]インドール構造を有する化合物が、ASIC阻害阻害作用を示すことは全く明らかではなかった。 It was not clear at all that the compound having a tricyclic tetrahydrocyclopenta [e] indole structure according to the present invention exhibited an ASIC inhibition inhibitory action.
国際公開第2006/063466号International Publication No. 2006/063466 国際公開第2007/134434号International Publication No. 2007/134434 国際公開第2011/023812号International Publication No. 2011/023812 国際公開第2007/042816号International Publication No. 2007/042816 国際公開第2008/071944号International Publication No. 2008/071944 国際公開第2010/034796号International Publication No. 2010/034796 国際公開第2012/022793号International Publication No.2012 / 022793 国際公開第2010/132016号International Publication No. 2010/132016 国際公開第2011/077313号International Publication No. 2011/077313 国際公開第2011/131975号International Publication No. 2011/131975
　公知のASIC阻害剤については、経口吸収性を示すかは不明である。ASIC阻害剤が経口投与可能であることによって患者の利便性の向上につながり、有用性が向上する。さらに従来のASIC阻害薬は選択的な阻害特性を有しているか否かについても不明であった。ASIC阻害が選択的であることによって非選択的な阻害によってもたらされる副作用を軽減することができ、安全性を担保することが可能であり、さらに安全性が担保されることで主薬効のための投与量を増量することも可能となり、より高い治療効果を達成することも可能である。 It is unclear whether known ASIC inhibitors exhibit oral absorption. Being able to orally administer ASIC inhibitors leads to improved patient convenience and improved usability. Furthermore, it is unclear whether conventional ASIC inhibitors have selective inhibitory properties. The selective side effects of ASIC can reduce the side effects caused by non-selective inhibition, can ensure safety, and the safety can be ensured for the main medicinal effects. It is also possible to increase the dose and achieve a higher therapeutic effect.
　すなわち、本願発明は経口投与可能で選択的なASIC阻害薬を獲得することを目的とするものである。これによって優れた治療効果を達成することができる。 That is, the present invention aims to obtain a selective ASIC inhibitor that can be administered orally. Thereby, an excellent therapeutic effect can be achieved.
　本願発明者らは、式（I）で示される化合物又はその薬学的に許容される塩が、選択性に優れたASIC阻害特性を有し、かつ経口吸収性を備えていることを見い出して本発明を完成させた。 The present inventors have found that the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has ASIC inhibitory properties with excellent selectivity and has oral absorbability. Completed the invention.
　すなわち本願発明は、
［１］　式（I）で示される化合物又はその薬学的に許容される塩： That is, the present invention
[1] A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
（式中、Rは、水素原子又はハロゲン原子を示し、次式： (In the formula, R represents a hydrogen atom or a halogen atom, and the following formula:
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
で示される構造は、R1及びR2が置換した芳香族基を示し、R1及びR2は、次の群：
水素原子、C1-C6-アルキル基、C1-C6-アルコキシ基、ヒドロキシC1-C6-アルキル基、ジヒドロキシC2-C6-アルキル基、ハロゲノC1-C6-アルキル基、C3-C6-シクロアルキル(ヒドロキシ)C1-C6-アルキル基、C1-C6-アルキルスルホニル基、(N-ヒドロキシイミノ)C1-C6-アルキル基、ハロゲン原子、シアノ基及びC2-C6-アシル基
から独立して選ばれる基を示す。）
に関する。 Structure shown in represents an aromatic group represented by R 1 or R 2 is substituted, R 1 and R 2, the following group:
Hydrogen atom, C1-C6-alkyl group, C1-C6-alkoxy group, hydroxy C1-C6-alkyl group, dihydroxy C2-C6-alkyl group, halogeno C1-C6-alkyl group, C3-C6-cycloalkyl (hydroxy) A group independently selected from a C1-C6-alkyl group, a C1-C6-alkylsulfonyl group, a (N-hydroxyimino) C1-C6-alkyl group, a halogen atom, a cyano group, and a C2-C6-acyl group. )
About.
　さらに本発明は、以下の各々に関する。
［２］　芳香族基が、窒素原子及び硫黄原子から選ばれる複素原子1～3を有する5又は6員環の芳香族複素環基及び炭化水素系芳香族基から選ばれる基である［１］に記載の化合物又はその薬学的に許容される塩。
［３］　芳香族基が、フェニル基、ピロリル基、ピラゾリル基、イミダゾリル基、チアゾリル基、チアジアゾリル基、ピリジル基、ピリダジニル基、ピリミジル基、又はピラジニル基である［１］に記載の化合物又はその薬学的に許容される塩。
［４］　芳香族基が、フェニル基、ピラゾリル基、チアゾリル基、チアジアゾリル基、ピリジル基、ピリミジル基、又はピラジニル基である［１］から［３］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［５］　R1及びR2が、次の群：
水素原子、C1-C6-アルキル基、C1-C6-アルコキシ基、ヒドロキシC1-C6-アルキル基、ジヒドロキシC2-C6-アルキル基、C1-C6-アルキルスルホニル基及びハロゲン原子
から独立して選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［６］　R1及びR2が、次の群：
水素原子、メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、2-シクロプロピル-1-ヒドロキシエチル基、(1R)-2-シクロプロピル-1-ヒドロキシエチル基、(1S)-2-シクロプロピル-1-ヒドロキシエチル基、メチルスルホニル基、シアノ基、アセチル基、1,1-ジメトキシエチル基、1-(N-ヒドロキシイミノ)エチル基及び(N-ヒドロキシイミノ)メチル基
から独立して選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［７］　R1及びR2が、次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から独立して選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［８］　R1及びR2の一方が水素原子であって、他方が次の群：
メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、2-シクロプロピル-1-ヒドロキシエチル基、(1R)-2-シクロプロピル-1-ヒドロキシエチル基、(1S)-2-シクロプロピル-1-ヒドロキシエチル基、メチルスルホニル基、シアノ基、アセチル基、1,1-ジメトキシエチル基、1-(N-ヒドロキシイミノ)エチル基及び(N-ヒドロキシイミノ)メチル基
から選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［９］　R1及びR2の一方が水素原子であって、他方が次の群：
メチル基、フッ素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、2-シクロプロピル-1-ヒドロキシエチル基、(1R)-2-シクロプロピル-1-ヒドロキシエチル基、(1S)-2-シクロプロピル-1-ヒドロキシエチル基、メチルスルホニル基、シアノ基、アセチル基、1-(N-ヒドロキシイミノ)エチル基及び(N-ヒドロキシイミノ)メチル基
から選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１０］　R1及びR2の一方が水素原子であって、他方が次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１１］　R1及びR2の一方が水素原子であって、他方が次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、(1R)-1-ヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１２］　R1及びR2が、
一方がヒドロキシメチル基であって、他方がメチルスルホニル基、メトキシ基、シアノ基、又はフッ素原子であるか、或は、
一方が1,2-ジヒドロキシエチル基であって、他方がフッ素原子又は塩素原子である
［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１３］　R1及びR2が、
一方がヒドロキシメチル基であって、他方がメチルスルホニル基又はメトキシ基であるか、或は、
一方が1,2-ジヒドロキシエチル基であって、他方がフッ素原子である
［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１４］　R1及びR2が、
一方がヒドロキシメチル基であって、他方がメチルスルホニル基又はメトキシ基であるか、或は、
一方が(1R)-1,2-ジヒドロキシエチル基であって、他方がフッ素原子である
［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１５］　式（I）で示される化合物が、次の群： Furthermore, this invention relates to each of the following.
[2] The aromatic group is a group selected from a 5- or 6-membered aromatic heterocyclic group and a hydrocarbon-based aromatic group having a heteroatom 1 to 3 selected from a nitrogen atom and a sulfur atom [1] Or a pharmaceutically acceptable salt thereof.
[3] The compound according to [1] or a pharmacy thereof, wherein the aromatic group is a phenyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidyl group, or a pyrazinyl group. Acceptable salt.
[4] The compound according to any one of [1] to [3] or the pharmacy thereof, wherein the aromatic group is a phenyl group, a pyrazolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a pyrimidyl group, or a pyrazinyl group. Acceptable salt.
[5] R 1 and R 2 are the following groups:
A group independently selected from a hydrogen atom, a C1-C6-alkyl group, a C1-C6-alkoxy group, a hydroxy C1-C6-alkyl group, a dihydroxy C2-C6-alkyl group, a C1-C6-alkylsulfonyl group and a halogen atom The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
[6] R 1 and R 2 are the following groups:
Hydrogen atom, methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxy Ethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2 -Dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclo Independently selected from propyl-1-hydroxyethyl group, methylsulfonyl group, cyano group, acetyl group, 1,1-dimethoxyethyl group, 1- (N-hydroxyimino) ethyl group and (N-hydroxyimino) methyl group The group according to any one of [1] to [4], Compound, or a pharmaceutically acceptable salt thereof.
[7] R 1 and R 2 are the following groups:
Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group, [1] to [4], which is a group independently selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group Or a pharmaceutically acceptable salt thereof.
[8] One of R 1 and R 2 is a hydrogen atom, and the other is the following group:
Methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl Group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1 1-hydroxyethyl group, methylsulfonyl group, cyano group, acetyl group, 1,1-dimethoxyethyl group, 1- (N-hydroxyimino) ethyl group and (N-hydroxyimino) methyl group To [4] or a pharmacy thereof Acceptable salt to.
[9] One of R 1 and R 2 is a hydrogen atom, and the other is the following group:
Methyl group, fluorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxy Ethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl group, 1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1-hydroxyethyl Any one of [1] to [4], which is a group selected from a group, a methylsulfonyl group, a cyano group, an acetyl group, a 1- (N-hydroxyimino) ethyl group and a (N-hydroxyimino) methyl group The described compound or a pharmaceutically acceptable salt thereof.
[10] One of R 1 and R 2 is a hydrogen atom, and the other is the following group:
Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group, The compound according to any one of [1] to [4], which is a group selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group Its pharmaceutically acceptable salt.
[11] One of R 1 and R 2 is a hydrogen atom, and the other is the following group:
A group selected from a hydrogen atom, a methyl group, a fluorine atom, a methoxy group, a hydroxymethyl group, a (1R) -1-hydroxyethyl group, a (1R) -1,2-dihydroxyethyl group, and a methylsulfonyl group [1] To [4] or a pharmaceutically acceptable salt thereof.
[12] R 1 and R 2 are
One is a hydroxymethyl group and the other is a methylsulfonyl group, a methoxy group, a cyano group, or a fluorine atom, or
The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein one is a 1,2-dihydroxyethyl group and the other is a fluorine atom or a chlorine atom.
[13] R 1 and R 2 are
One is a hydroxymethyl group and the other is a methylsulfonyl group or a methoxy group, or
The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein one is a 1,2-dihydroxyethyl group and the other is a fluorine atom.
[14] R 1 and R 2 are
One is a hydroxymethyl group and the other is a methylsulfonyl group or a methoxy group, or
The compound according to any one of [1] to [4], wherein one is a (1R) -1,2-dihydroxyethyl group and the other is a fluorine atom, or a pharmaceutically acceptable salt thereof.
[15] The compound represented by the formula (I) is represented by the following group:
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
（式中、A部分、R、R1及びR2は先の定義に等しい。）
のいずれかである［１］から［１４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１６］　式（I）で示される化合物が、次式 (Wherein the A moiety, R, R 1 and R 2 are equivalent to the previous definition.)
Or the pharmaceutically acceptable salt thereof according to any one of [1] to [14].
[16] The compound represented by the formula (I) is represented by the following formula:
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
で示される化合物である［１］から［１４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１７］　Rが、水素原子又はフッ素原子である［１］から［１６］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１８］　Rが、水素原子である［１］から［１６］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１９］　式（I）で示される化合物が、次の群： [1] to [14], or a pharmaceutically acceptable salt thereof.
[17] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [16], wherein R is a hydrogen atom or a fluorine atom.
[18] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [16], wherein R is a hydrogen atom.
[19] A compound of formula (I) is represented by the following group:
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
のいずれかの化合物である［１］から［１４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［２０］　式（I）で示される化合物が、次式： The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [14], which is any compound of
[20] The compound represented by the formula (I) is represented by the following formula:
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
で示される化合物である［１］から［１４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［２１］　Rが、フッ素原子である［１］から［１６］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［２２］　式（I）で示される化合物が、次の群： [1] to [14], or a pharmaceutically acceptable salt thereof.
[21] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [16], wherein R is a fluorine atom.
[22] The compound represented by the formula (I) is represented by the following group:
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
のいずれかの化合物である［２１］に記載の化合物又はその薬学的に許容される塩。
［２３］　式（I）で示される化合物が、
(1R)-1-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール、
(1S)-1-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール、
(6R)-2-[5-(メチルスルホニル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
(6R)-2-(5-メチル-1,3,4-チアジアゾール-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
(6R)-2-(1-メチル-1H-ピラゾール-4-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
(6S)-2-[5-(メチルスルホニル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
(1S)-1-{2-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1,3-チアゾール-5-イル}エタノール、
[3-(6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル)-5-メトキシ－フェニル]メタノール、
2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
1-[3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-5-フルオロ-フェニル]エタン-1,2-ジオール、
[5-[(6S)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-2-メチルスルホニル-フェニル]メタノール、
(6R)-2-(6-メトキシピリミジン-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
(6R)-2-(2-メチルピリミジン-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
{4-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリミジン-2-イル}メタノール、
2-(6-エトキシピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
2-(5-メトキシピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
[5-(6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル)ピラジン-2-イル]メタノール、
(6R)-2-(ピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
[6-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル]メタノール、
(6R)-2-(6-メチルピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
(1R)-1-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}プロパン-1-オール、
2-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール、
(6R)-2-{5-[(1Z)-N-ヒドロキシエタンイミドイル]ピラジン-2-イル}-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
(6R)-2-{5-[(Z)-(ヒドロキシイミノ)メチル]ピラジン-2-イル}-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
1-[5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル]エタノン、
(6R)-2-(3-メチルピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、又は
[3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル]メタノール
である［１］に記載の化合物又はその薬学的に許容される塩。
［２４］　式（I）で示される化合物が、
(1R)-1-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール、
(1S)-1-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール、
(6R)-2-[5-(メチルスルホニル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
(6R)-2-(5-メチル-1,3,4-チアジアゾール-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
(6R)-2-(1-メチル-1H-ピラゾール-4-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
(6S)-2-[5-(メチルスルホニル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
(1S)-1-{2-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1,3-チアゾール-5-イル}エタノール、
[3-(6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル)-5-メトキシ－フェニル]メタノール、
2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン、
1-[3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-5-フルオロ-フェニル]エタン-1,2-ジオール、
[5-[(6S)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-2-メチルスルホニル-フェニル]メタノール、又は
(6R)-2-(6-メトキシピリミジン-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
である［１］に記載の化合物又はその薬学的に許容される塩。
［２５］　［１］から［２４］のいずれかに記載の化合物又はその薬学的に許容される塩と、薬学的に許容し得る担体とを含有する医薬組成物。
［２６］　虚血性心疾患、心不全、末梢動脈疾患、不整脈、高血圧症、低血圧症、慢性関節リウマチ、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、癌に伴う疼痛、変形性関節症、間質性膀胱炎、逆流性食道炎、過敏性腸症候群、咳、味覚傷害、難聴、糖尿病網膜症や緑内障における視機能障害、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、過換気症候群、喘息、インスリン抵抗性糖尿病、多発性硬化症、全般性不安障害、パニック障害、脳梗塞、パーキンソン病、ハンチントン病、又はアルツハイマー病からなる群から選択される疾患又は症状を治療及び／又は予防するための［２３］に記載の医薬組成物。
［２７］　［１］から［２４］のいずれかに記載の化合物又はその薬学的に許容される塩を含有する酸感受性イオンチャネル（ASIC）阻害剤。
［２８］　［１］から［２４］のいずれかに記載の化合物又はその薬学的に許容される塩を投与することを特徴とする酸感受性イオンチャネル（ASIC）が介在する疾病を治療及び／又は予防する方法。
［２９］　酸感受性イオンチャネル（ASIC）が介在する疾病を治療及び／又は予防するための［１］から［２４］のいずれかに記載の化合物又はその薬学的に許容される塩の使用。 Or a pharmaceutically acceptable salt thereof. [21]
[23] The compound represented by the formula (I) is:
(1R) -1- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} ethanol,
(1S) -1- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} ethanol,
(6R) -2- [5- (methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
(6R) -2- (5-methyl-1,3,4-thiadiazol-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
(6R) -2- (1-methyl-1H-pyrazol-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
(6S) -2- [5- (methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
(1S) -1- {2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazol-5-yl} ethanol ,
[3- (6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl) -5-methoxy-phenyl] methanol,
2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
1- [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-fluoro-phenyl] ethane-1,2-diol,
[5-[(6S) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -2-methylsulfonyl-phenyl] methanol,
(6R) -2- (6-methoxypyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
(6R) -2- (2-methylpyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
{4-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyrimidin-2-yl} methanol,
2- (6-ethoxypyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
2- (5-methoxypyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
[5- (6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl) pyrazin-2-yl] methanol,
(6R) -2- (pyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
[6-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] methanol,
(6R) -2- (6-methylpyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
(1R) -1- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} propan-1-ol,
2- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} ethanol,
(6R) -2- {5-[(1Z) -N-hydroxyethaneimidoyl] pyrazin-2-yl} -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
(6R) -2- {5-[(Z)-(hydroxyimino) methyl] pyrazin-2-yl} -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
1- [5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] ethanone,
(6R) -2- (3-methylpyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine, or
[3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] methanol according to [1] or a compound thereof A pharmaceutically acceptable salt.
[24] The compound represented by the formula (I) is:
(1R) -1- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} ethanol,
(1S) -1- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} ethanol,
(6R) -2- [5- (methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
(6R) -2- (5-methyl-1,3,4-thiadiazol-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
(6R) -2- (1-methyl-1H-pyrazol-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
(6S) -2- [5- (methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
(1S) -1- {2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazol-5-yl} ethanol ,
[3- (6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl) -5-methoxy-phenyl] methanol,
2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine,
1- [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-fluoro-phenyl] ethane-1,2-diol,
[5-[(6S) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -2-methylsulfonyl-phenyl] methanol, or
(6R) -2- (6-Methoxypyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine or a pharmaceutically acceptable compound thereof Acceptable salt.
[25] A pharmaceutical composition comprising the compound according to any one of [1] to [24] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[26] Ischemic heart disease, heart failure, peripheral arterial disease, arrhythmia, hypertension, hypotension, rheumatoid arthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis , Eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with cancer, osteoarthritis, stroma Cystitis, reflux esophagitis, irritable bowel syndrome, cough, taste injury, hearing loss, visual dysfunction in diabetic retinopathy and glaucoma, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, hyperventilation syndrome, Treat and / or prevent a disease or condition selected from the group consisting of asthma, insulin-resistant diabetes, multiple sclerosis, generalized anxiety disorder, panic disorder, cerebral infarction, Parkinson's disease, Huntington's disease, or Alzheimer's disease The pharmaceutical composition according to [23].
[27] An acid-sensitive ion channel (ASIC) inhibitor comprising the compound according to any one of [1] to [24] or a pharmaceutically acceptable salt thereof.
[28] Treating and / or treating a disease mediated by an acid-sensitive ion channel (ASIC), which comprises administering the compound according to any one of [1] to [24] or a pharmaceutically acceptable salt thereof. How to prevent.
[29] Use of the compound according to any one of [1] to [24] or a pharmaceutically acceptable salt thereof for treating and / or preventing a disease mediated by an acid-sensitive ion channel (ASIC).
　本発明の式（I）で示される化合物又はその薬学的に許容される塩は、優れた選択性の酸感受性イオンチャネル（ASIC）阻害作用を有し、かつ経口投与可能であり、したがって酸感受性イオンチャネルが関与する種々の病態の治療及び／又は予防に有用である。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent selective acid-sensitive ion channel (ASIC) inhibitory action and can be administered orally, and thus is acid-sensitive. It is useful for the treatment and / or prevention of various pathological conditions involving ion channels.
本発明の実施例２５の化合物をマウスに経口投与した時の血中濃度推移（単位：ナノモル）を示す。菱形は3mg/kgの用量、四角は10mg/kgの用量での推移を示す。横軸は時間を示す。The blood concentration transition (unit: nanomolar) when the compound of Example 25 of the present invention was orally administered to mice is shown. The rhombus shows the change at the dose of 3 mg / kg, and the square shows the change at the dose of 10 mg / kg. The horizontal axis indicates time.
　以下、本発明を実施するための好適な形態について以下に説明する。なお、以下に説明する実施形態は、本発明の代表的な実施形態の一例を示したものであり、これによって本発明の範囲が狭く解釈されることはない。 Hereinafter, preferred embodiments for carrying out the present invention will be described below. In addition, embodiment described below shows an example of typical embodiment of this invention, and, thereby, the range of this invention is not interpreted narrowly.
　本発明は、式（I）で示される化合物、その薬学的に許容される塩、又はそれらの水和物に関するものである。すなわち、3,6,7,8-テトラヒドロシクロペンタ[e]インドールを母核とし、その2位にR1及びR2が置換した芳香族基を有し、6位にアミノ基、そして7位に置換基Rを有する構造の化合物である。 The present invention relates to a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof. That is, 3,6,7,8-tetrahydrocyclopenta [e] indole is a mother nucleus, R 1 and R 2 are substituted at the 2- position, an amino group at the 6-position, and the 7-position Is a compound having a structure having a substituent R.
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　ここで、次式 Where
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
で示される芳香族基のうちのA部分は、炭化水素系芳香族基であるか、或は窒素原子及び硫黄原子から選ばれる複素原子1～3を有する5員環又は6員環の芳香族複素環基から選ばれる基である。この芳香族基上にあるR1及びR2は、次の群：
水素原子、C1-C6-アルキル基（「C1-C6-」は、炭素数が1～6であることを示す。）、C1-C6-アルコキシ基、ヒドロキシC1-C6-アルキル基、ジヒドロキシC2-C6-アルキル基、ハロゲノC1-C6-アルキル基、C3-C6-シクロアルキル(ヒドロキシ)C1-C6-アルキル基、C1-C6-アルキルスルホニル基、(N-ヒドロキシイミノ)C1-C6-アルキル基、ハロゲン原子、シアノ基及びC2-C6-アシル基
から独立して選ばれる基である。 A part of the aromatic group represented by is a hydrocarbon-based aromatic group or a 5-membered or 6-membered aromatic having a hetero atom of 1 to 3 selected from a nitrogen atom and a sulfur atom It is a group selected from heterocyclic groups. R 1 and R 2 on this aromatic group are the following groups:
A hydrogen atom, a C1-C6-alkyl group (“C1-C6-” means 1 to 6 carbon atoms), a C1-C6-alkoxy group, a hydroxy C1-C6-alkyl group, a dihydroxy C2- C6-alkyl group, halogeno C1-C6-alkyl group, C3-C6-cycloalkyl (hydroxy) C1-C6-alkyl group, C1-C6-alkylsulfonyl group, (N-hydroxyimino) C1-C6-alkyl group, It is a group independently selected from a halogen atom, a cyano group and a C2-C6-acyl group.
　そして、7位の置換基Rは、水素原子又はハロゲン原子である。 The substituent R at the 7-position is a hydrogen atom or a halogen atom.
　以下に本発明化合物の構造について説明する。 The structure of the compound of the present invention will be described below.
　置換Rとしては、水素原子又はハロゲン原子であればよい。すなわち、水素原子、フッ素原子、クロロ原子、ブロモ原子、又はヨード原子であればよい。これらのうちでは、水素原子又はフッ素原子が好ましく、より好ましくは水素原子である。 The substitution R may be a hydrogen atom or a halogen atom. That is, it may be a hydrogen atom, a fluorine atom, a chloro atom, a bromo atom, or an iodo atom. Among these, a hydrogen atom or a fluorine atom is preferable, and a hydrogen atom is more preferable.
　式（I）で示される化合物は、6位にアミノ基そして7位に置換基Rを有する。 The compound represented by the formula (I) has an amino group at the 6-position and a substituent R at the 7-position.
　置換基Rが水素原子であるときは、 When the substituent R is a hydrogen atom,
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
のいずれかの態様となる。これらのうちではアミノ基の配位がアルファである次式： It becomes either aspect. Of these, the amino group coordination is alpha:
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
の構造がより好ましいと考えられた。なおこの配置は、分子内フリーデルクラフツ反応で得られる本発明化合物の製造中間体のカルボニル基を、文献（J. Am. Chem. Soc. 1995, 117, 7562）記載の方法で不斉還元し、得られたヒドロキシ体の配置を同文献の記載に従って決定し、該ヒドロキシ化合物から誘導された配置として決定した。 This structure was considered to be more preferable. In this arrangement, the carbonyl group of the production intermediate of the compound of the present invention obtained by intramolecular Friedel-Crafts reaction is asymmetrically reduced by the method described in the literature (J. Am. Chem. Soc. 1995, 117, 7562). The configuration of the obtained hydroxy form was determined according to the description in the same document, and the configuration derived from the hydroxy compound was determined.
　7位の置換基Rがハロゲン原子であるときは、6,7-gem-ジ置換となる。6位のアミノ基と7位のハロゲン原子とはシス配置又はトランス配置のいずれかで存在する。本発明のASIC阻害薬としては、いずれ配置であってもよいが、より好ましくはシス配置である（次式）。 When the substituent R at the 7-position is a halogen atom, it is 6,7-gem-disubstituted. The amino group at the 6-position and the halogen atom at the 7-position exist in either a cis configuration or a trans configuration. The ASIC inhibitor of the present invention may be any configuration, but more preferably is a cis configuration (the following formula).
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　なおRが水素原子である化合物における特性を考慮すると、これらのうちではアミノ基の配位がアルファである次式： In consideration of the properties of compounds in which R is a hydrogen atom, among these, the amino group coordination is alpha:
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
で示される構造が好ましい構造と考えられる。 The structure represented by is considered to be a preferable structure.
　芳香族基として次式： The following formula as an aromatic group:
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
で示される置換基におけるA部分は、炭化水素系芳香族基であるか、窒素原子及び硫黄原子から選ばれる複素原子1～3を有する、5員環又は6員環の芳香族複素環基である。炭化水素系芳香族基として、フェニル基を挙げることができ、複素環芳香族基として、ピロリル基、イミダゾリル基、ピラゾリル基、チアゾリル基、チアジアゾリル基、ピリジル基、ピリミジル基、又はピラジニル基を挙げることができる。 In the substituent represented by A, the A moiety is a hydrocarbon-based aromatic group or a 5-membered or 6-membered aromatic heterocyclic group having a heteroatom 1-3 selected from a nitrogen atom and a sulfur atom. is there. Examples of the hydrocarbon aromatic group include a phenyl group, and examples of the heterocyclic aromatic group include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a pyrimidyl group, or a pyrazinyl group. Can do.
　芳香族基におけるA部分として具体的には、フェニル基、ピロリル-2-イル基、ピロリル-3-イル基、ピラゾール-3-イル基、ピラゾール-4-イル基、イミダゾール-2-イル基、イミダゾール-4-イル基、チアゾール-2-イル基、チアゾール-5-イル基、チアジアゾール-2-イル基、ピリジン-2-イル基、ピリジン-3-イル基、ピリジン-4-イル基、ピリミジン-2-イル基、ピリミジン-4-イル基及びピラジン-2-イル基を挙げることができる。 Specifically, as the A moiety in the aromatic group, phenyl group, pyrrolyl-2-yl group, pyrrolyl-3-yl group, pyrazol-3-yl group, pyrazol-4-yl group, imidazol-2-yl group, Imidazol-4-yl group, thiazol-2-yl group, thiazol-5-yl group, thiadiazol-2-yl group, pyridin-2-yl group, pyridin-3-yl group, pyridin-4-yl group, pyrimidine Mention may be made of -2-yl, pyrimidin-4-yl and pyrazin-2-yl groups.
　これらのうちより好ましくは、フェニル基、ピラゾール-4-イル基、チアゾール-2-イル基、チアゾール-5-イル基、チアジアゾール-2-イル基、ピリジン-2-イル基、ピリジン-4-イル基、ピリミジン-2-イル基、ピリミジン-4-イル基、又はピラジン-2-イル基である。 Of these, more preferred are phenyl group, pyrazol-4-yl group, thiazol-2-yl group, thiazol-5-yl group, thiadiazol-2-yl group, pyridin-2-yl group, and pyridin-4-yl. Group, pyrimidin-2-yl group, pyrimidin-4-yl group, or pyrazin-2-yl group.
　そしてさらに好ましくは、フェニル基、ピラゾール-4-イル基、チアゾール-2-イル基、チアジアゾール-2-イル基、ピリジン-2-イル基、ピリミジン-4-イル基、又はピラジン-2-イル基である。 More preferably, a phenyl group, a pyrazol-4-yl group, a thiazol-2-yl group, a thiadiazol-2-yl group, a pyridin-2-yl group, a pyrimidin-4-yl group, or a pyrazin-2-yl group It is.
　芳香族基上の置換基であるR1及びR2は、各々独立に、以下の置換基となることができる。 R 1 and R 2 which are substituents on the aromatic group can be independently the following substituents.
　R1又はR2がC1-C6-アルキル基であるとき、好ましくは、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、又はsec-ブチル基であればよく、より好ましくは、メチル基又はエチル基である。 When R 1 or R 2 is a C 1 -C 6 -alkyl group, preferably it may be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a sec-butyl group, and more Preferably, it is a methyl group or an ethyl group.
　R1又はR2がC1-C6-アルコキシ基であるとき、好ましくはメトキシ基、エトキシ基、プロポキシ基、2-メチルエトキシ基、ブトキシ基、1-メチルプロポキシ基、又は2-メチルプロポキシ基であればよく、より好ましくは、メトキシ基又はエトキシ基である。 When R 1 or R 2 is a C 1 -C 6 -alkoxy group, preferably a methoxy group, an ethoxy group, a propoxy group, a 2-methylethoxy group, a butoxy group, a 1-methylpropoxy group, or a 2-methylpropoxy group More preferably, it is a methoxy group or an ethoxy group.
　R1又はR2がヒドロキシC1-C6-アルキル基であるとき、ヒドロキシ基の位置は特に制限はないが、芳香族基に結合した炭素原子、すなわちベンジル位に相当、にあることがより好ましい。ヒドロキシC1-C6-アルキル基として好ましくは、ヒドロキシメチル基、1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、2-ヒドロキプロピル基、3-ヒドロキプロピル基、1-ヒドロキシ-1-メチルエチル基、2-ヒドロキシ-1-メチルエチル基、1-ヒドロキシブチル基、2-ヒドロキシブチル基、3-ヒドロキシブチル基、4-ヒドロキシブチル基、1-ヒドロキシ-1-メチルプロピル基、1-ヒドロキシ-2-メチルプロピル基、2-ヒドロキシ-1-メチルプロピル基、3-ヒドロキシ-1-メチルプロピル基、2-ヒドロキシ-2-メチルプロピル基、又は3-ヒドロキシ-2-メチルプロピル基である。これらのうちより好ましくは、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基であり、さらに好ましくは、(1R)のヒドロキシアルキル基であり、(1R)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシプロピル基が好ましく、そして(1R)-1-ヒドロキシエチル基が好ましい。 When R 1 or R 2 is a hydroxy C 1 -C 6 -alkyl group, the position of the hydroxy group is not particularly limited, but is more preferably the carbon atom bonded to the aromatic group, that is, the benzyl position. preferable. Preferred as hydroxy C 1 -C 6 -alkyl groups are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy -1-methylethyl group, 2-hydroxy-1-methylethyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1-hydroxy-1-methylpropyl group 1-hydroxy-2-methylpropyl group, 2-hydroxy-1-methylpropyl group, 3-hydroxy-1-methylpropyl group, 2-hydroxy-2-methylpropyl group, or 3-hydroxy-2-methylpropyl group It is a group. Of these, more preferably, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1 -Hydroxypropyl group, (1S) -1-hydroxypropyl group, more preferably (1R) hydroxyalkyl group, (1R) -1-hydroxyethyl group, (1R) -1-hydroxypropyl group And (1R) -1-hydroxyethyl groups are preferred.
　R1又はR2がジヒドロキシC2-C6-アルキル基であるとき、2個のヒドロキシ基の位置としては特に制限はないが、1,2-ジオール構造であるものがより好ましく、さらには(1R)-ヒドロキシであるものが好ましい。ジヒドロキシC2-C6-アルキル基として好ましくは、1,2-ジヒドロキシエチル基、1,2-ジヒドロキシプロピル基、1,3-ジヒドロキシプロピル基、2,3-ジヒドロキシプロピル基、1,2-ジヒドロキシブチル基、1,3-ジヒドロキシブチル基、1,4-ジヒドロキシブチル基、2,3-ジヒドロキシブチル基、2,4-ジヒドロキシブチル基、3,4-ジヒドロキシブチル基、1,2-ジヒドロキシ-1-メチルプロピル基、1,2-ジヒドロキシ-2-メチルプロピル基、1,3-ジヒドロキシ-1-メチルプロピル基、1,3-ジヒドロキシ-2-メチルプロピル基、2,3-ジヒドロキシ-1-メチルプロピル基、又は2,3-ジヒドロキシ-2-メチルプロピル基を挙げることができる。これらのうちでより好ましくは、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、又は(1R)-1,2-ジヒドロキシエチル基を挙げることができる。さらに好ましくは、(1R)-ヒドロキシを含むジヒドロキシアルキル基であり、(1R)-1,2-ジヒドロキシエチル基が好ましい。 When R 1 or R 2 is a dihydroxy C 2 -C 6 -alkyl group, the position of the two hydroxy groups is not particularly limited, but one having a 1,2-diol structure is more preferable, and ( Those which are 1R) -hydroxy are preferred. Dihydroxy C 2 -C 6 -alkyl groups are preferably 1,2-dihydroxyethyl group, 1,2-dihydroxypropyl group, 1,3-dihydroxypropyl group, 2,3-dihydroxypropyl group, 1,2-dihydroxy Butyl group, 1,3-dihydroxybutyl group, 1,4-dihydroxybutyl group, 2,3-dihydroxybutyl group, 2,4-dihydroxybutyl group, 3,4-dihydroxybutyl group, 1,2-dihydroxy-1 -Methylpropyl group, 1,2-dihydroxy-2-methylpropyl group, 1,3-dihydroxy-1-methylpropyl group, 1,3-dihydroxy-2-methylpropyl group, 2,3-dihydroxy-1-methyl A propyl group or a 2,3-dihydroxy-2-methylpropyl group can be mentioned. Among these, more preferable examples include 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl group, or (1R) -1,2-dihydroxyethyl group. More preferred is a dihydroxyalkyl group containing (1R) -hydroxy, and a (1R) -1,2-dihydroxyethyl group is preferred.
　R1又はR2がハロゲノC1-C6-アルキル基であるとき、置換するハロゲンの数は1からパー置換までの間で置換するものでよい。置換の位置は、アルキル基の末端の炭素原子であるものがより好ましいが、特に制限はない。ハロゲノC1-C6-アルキル基として好ましくは、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、2-フルオロエチル基、2,2,2-トリフルオロエチル基、パーフルオロエチル基、クロロメチル基、又は2-クロロエチル基を挙げることができる。これらのうちでより好ましくは、フルオロメチル基、トリフルオロメチル基、2-フルオロエチル基、又は2,2,2-トリフルオロエチル基であり、さらに好ましくはトリフルオロメチル基である。 When R 1 or R 2 is a halogeno C 1 -C 6 -alkyl group, the number of substituted halogens may be between 1 and per substitution. The substitution position is more preferably the carbon atom at the terminal of the alkyl group, but there is no particular limitation. The halogeno C 1 -C 6 -alkyl group is preferably a fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, perfluoroethyl group, chloromethyl. And a 2-chloroethyl group. Of these, a fluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, or a 2,2,2-trifluoroethyl group is more preferable, and a trifluoromethyl group is more preferable.
　R1又はR2は、C3-C6-シクロアルキル(ヒドロキシ)C1-C6-アルキル基として、ヒドロキシ基の置換したアルキル基に、炭素数3から6のシクロアルキル基がさらに置換した構造であってもよく、好ましくはシクロプロピルヒドロキシメチル基、シクロプロピルヒドロキシエチル基、シクロブチルヒドロキシメチル基、シクロブチルヒドロキシエチル基、シクロペンチルヒドロキシメチル基、シクロペンチルヒドロキシエチル基、シクロヘキシルヒドロキシメチル基、又はシクロヘキシルヒドロキシエチル基を挙げることができる。これらのうちでは、2-シクロプロピル-1-ヒドロキシエチル基、(1R)-2-シクロプロピル-1-ヒドロキシエチル基、又は(1S)-2-シクロプロピル-1-ヒドロキシエチル基を好ましいものとしてあげることができる。より好ましくは、(1R)のシクロアルキル(ヒドロキシ)アルキル基である(1R)-2-シクロプロピル-1-ヒドロキシエチル基である。 R 1 or R 2 is a structure in which a C3-C6-cycloalkyl (hydroxy) C1-C6-alkyl group is further substituted with a hydroxy group-substituted alkyl group and a C3-C6 cycloalkyl group. Preferably, cyclopropylhydroxymethyl group, cyclopropylhydroxyethyl group, cyclobutylhydroxymethyl group, cyclobutylhydroxyethyl group, cyclopentylhydroxymethyl group, cyclopentylhydroxyethyl group, cyclohexylhydroxymethyl group, or cyclohexylhydroxyethyl group Can be mentioned. Of these, a 2-cyclopropyl-1-hydroxyethyl group, a (1R) -2-cyclopropyl-1-hydroxyethyl group, or a (1S) -2-cyclopropyl-1-hydroxyethyl group is preferred. I can give you. More preferred is a (1R) -2-cyclopropyl-1-hydroxyethyl group that is a cycloalkyl (hydroxy) alkyl group of (1R).
　R1又はR2がC1-C6-アルキルスルホニル基であるとき、メチルスルホニル基、エチルスルホニル基、プロピルスルホニル基、又は2-メチルエチルスルホニル基を挙げることができる。このうちでより好ましくは、メチルスルホニル基である。 When R 1 or R 2 is a C 1 -C 6 -alkylsulfonyl group, a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, or a 2-methylethylsulfonyl group can be exemplified. Of these, a methylsulfonyl group is more preferable.
　R1又はR2がハロゲン原子であるとき、フッ素原子、クロロ原子、ブロモ原子、又はヨード原子を挙げることができるが、好ましくはフッ素原子又はクロロ原子であり、より好ましくはフッ素原子である。 When R 1 or R 2 is a halogen atom, examples thereof include a fluorine atom, a chloro atom, a bromo atom, and an iodo atom, preferably a fluorine atom or a chloro atom, and more preferably a fluorine atom.
　R1又はR2がヒドロキシイミノC1-C6-アルキル基であるとき、ヒドロキシイミノ基の位置は特に制限はないが、ベンジル位となる炭素原子にあることがより好ましく（特に炭素数が2以上のアルキル基の場合）、1-(ヒドロキシイミノ)C1-C6-アルキル基がより好ましい。ヒドロキシイミノC1-C6-アルキル基として好ましくは、ヒドロキシイミノメチル基、1-ヒドロキシイミノエチル基、2-ヒドロキシイミノエチル基、1-ヒドロキシイミノプロピル基、2-ヒドロキシイミノプロピル基、又は3-ヒドロキイミノシプロピル基を挙げることができるが、より好ましくはヒドロキシイミノメチル基又は1-ヒドロキシイミノエチル基であり、さらに好ましくは1-ヒドロキシイミノエチル基である。 When R 1 or R 2 is a hydroxyimino C 1 -C 6 -alkyl group, the position of the hydroxyimino group is not particularly limited, but is more preferably a carbon atom that becomes the benzyl position (particularly, the number of carbon atoms is 2). In the case of the above alkyl groups), a 1- (hydroxyimino) C 1 -C 6 -alkyl group is more preferred. The hydroxyimino C 1 -C 6 -alkyl group is preferably a hydroxyiminomethyl group, 1-hydroxyiminoethyl group, 2-hydroxyiminoethyl group, 1-hydroxyiminopropyl group, 2-hydroxyiminopropyl group, or 3- Examples thereof include a hydroxyiminocypropyl group, more preferably a hydroxyiminomethyl group or a 1-hydroxyiminoethyl group, and still more preferably a 1-hydroxyiminoethyl group.
　R1又はR2がC2-C6-アルキルカルボニル基（アシル基）であるとき、好ましくはメチルカルボニル基（アセチル基）、エチルカルボニル基、プロピルカルボニル基、2-メチルエチルカルボニル基、ブチルカルボニル基、1-メチルプロピルカルボニル基、又は2-メチルプロピルカルボニル基を挙げることができ、より好ましくはアセチル基である。 When R 1 or R 2 is a C 2 -C 6 -alkylcarbonyl group (acyl group), preferably a methylcarbonyl group (acetyl group), ethylcarbonyl group, propylcarbonyl group, 2-methylethylcarbonyl group, butylcarbonyl Group, 1-methylpropylcarbonyl group, or 2-methylpropylcarbonyl group, and more preferably an acetyl group.
　R1及びR2としては、次の群：
水素原子、メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、2-シクロプロピル-1-ヒドロキシエチル基、(1R)-2-シクロプロピル-1-ヒドロキシエチル基、(1S)-2-シクロプロピル-1-ヒドロキシエチル基、メチルスルホニル基、シアノ基、アセチル基、1,1-ジメトキシエチル基、1-(N-ヒドロキシイミノ)エチル基及び(N-ヒドロキシイミノ)メチル基
から独立に選ばれる基であればよい。 R 1 and R 2 include the following groups:
Hydrogen atom, methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxy Ethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2 -Dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclo Independently selected from propyl-1-hydroxyethyl, methylsulfonyl, cyano, acetyl, 1,1-dimethoxyethyl, 1- (N-hydroxyimino) ethyl and (N-hydroxyimino) methyl Any group may be used.
　このうち好ましくは、R1及びR2として、次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる基を挙げることができる。 Of these, preferably, R 1 and R 2 are the following groups:
Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group, Examples thereof include a group selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group.
　さらに好ましくは、R1及びR2として、次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、(1R)-1-ヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる基を挙げることができる。 More preferably, R 1 and R 2 are the following groups:
And a group selected from a hydrogen atom, a methyl group, a fluorine atom, a methoxy group, a hydroxymethyl group, a (1R) -1-hydroxyethyl group, a (1R) -1,2-dihydroxyethyl group, and a methylsulfonyl group. .
　また、R1及びR2の一方が水素原子であるときに、他方は次の群：
メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、2-シクロプロピル-1-ヒドロキシエチル基、(1R)-2-シクロプロピル-1-ヒドロキシエチル基、(1S)-2-シクロプロピル-1-ヒドロキシエチル基、メチルスルホニル基、シアノ基、アセチル基、1,1-ジメトキシエチル基、1-(N-ヒドロキシイミノ)エチル基及び(N-ヒドロキシイミノ)メチル基
から選ばれることが好ましい。 Also, when one of R 1 and R 2 is a hydrogen atom, the other is in the following group:
Methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl Group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1 It is preferably selected from -hydroxyethyl group, methylsulfonyl group, cyano group, acetyl group, 1,1-dimethoxyethyl group, 1- (N-hydroxyimino) ethyl group and (N-hydroxyimino) methyl group.
　さらに好ましくは、他方が次の群：
メチル基、フッ素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、2-シクロプロピル-1-ヒドロキシエチル基、(1R)-2-シクロプロピル-1-ヒドロキシエチル基、(1S)-2-シクロプロピル-1-ヒドロキシエチル基、メチルスルホニル基、シアノ基、アセチル基、1-(N-ヒドロキシイミノ)エチル基及び(N-ヒドロキシイミノ)メチル基
から選ばれる場合である。 More preferably, the other is the following group:
Methyl group, fluorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxy Ethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl group, 1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1-hydroxyethyl A group selected from a group, a methylsulfonyl group, a cyano group, an acetyl group, a 1- (N-hydroxyimino) ethyl group, and a (N-hydroxyimino) methyl group.
　より好ましくは、他方が次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる場合である。 More preferably, the other is the following group:
Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group, This is a case selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group.
　さらに好ましくは、他方が次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、(1R)-1-ヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる場合である。 More preferably, the other is the following group:
This is a case selected from a hydrogen atom, a methyl group, a fluorine atom, a methoxy group, a hydroxymethyl group, a (1R) -1-hydroxyethyl group, a (1R) -1,2-dihydroxyethyl group, and a methylsulfonyl group.
　さらに、R1及びR2において、
一方がヒドロキシメチル基であって、他方がメチルスルホニル基、メトキシ基、シアノ基、又はフッ素原子であるか、或は、
一方が1,2-ジヒドロキシエチル基であって、他方がフッ素原子又は塩素原子である
場合が好ましい。 Further, in R 1 and R 2 ,
One is a hydroxymethyl group and the other is a methylsulfonyl group, a methoxy group, a cyano group, or a fluorine atom, or
It is preferable that one is a 1,2-dihydroxyethyl group and the other is a fluorine atom or a chlorine atom.
　一方が1,2-ジヒドロキシエチル基の場合、さらに好ましくは、
一方が、(1R)-1,2-ジヒドロキシエチル基であって、他方がフッ素原子又は塩素原子である場合である。 When one is a 1,2-dihydroxyethyl group, more preferably,
One is a (1R) -1,2-dihydroxyethyl group and the other is a fluorine atom or a chlorine atom.
　そして、R1及びR2において、
一方がヒドロキシメチル基であって、他方がメチルスルホニル基又はメトキシ基であるか、或は、
一方が1,2-ジヒドロキシエチル基であって、他方がフッ素原子である
場合がさらに好ましい。 And in R 1 and R 2
One is a hydroxymethyl group and the other is a methylsulfonyl group or a methoxy group, or
More preferably, one is a 1,2-dihydroxyethyl group and the other is a fluorine atom.
　一方が1,2-ジヒドロキシエチル基の場合、さらに好ましくは、
一方が、(1R)-1,2-ジヒドロキシエチル基であって、他方がフッ素原子である場合である。 When one is a 1,2-dihydroxyethyl group, more preferably,
One is a (1R) -1,2-dihydroxyethyl group and the other is a fluorine atom.
　次式： The following formula:
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
で示される本発明化合物の置換基として好ましいものを次の群に示す： Preferred examples of the substituent of the compound of the present invention represented by the following are shown in the following group:
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　これらのうち、より好ましくは次の群： Of these, more preferably the following groups:
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
から選ばれる基である。 Is a group selected from
　そしてさらに好ましくは次の群： And more preferably the following groups:
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
から選ばれる基である。 Is a group selected from
　これらのうちでさらに好ましくは次の群： Of these, more preferably the following groups:
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
から選ばれる基である。 Is a group selected from
　本発明の式（I）で表される化合物は、以下に記載するA法乃至G法に従って製造することができる。 The compound represented by the formula (I) of the present invention can be produced according to Method A to Method G described below.
　下記A法乃至G法の各工程の反応において使用される溶媒は、反応を阻害せず、反応に悪影響を及ぼさず、出発原料をある程度溶解するものであれば特に限定はない。 The solvent used in the reaction in each step of the following methods A to G is not particularly limited as long as it does not inhibit the reaction, does not adversely affect the reaction, and dissolves the starting materials to some extent.
　下記A法乃至G法の各工程の反応において、反応温度は、溶媒、出発原料、試薬等により異なり、反応時間は、溶媒、出発原料、試薬、反応温度等により異なる。 In the reaction of each step of Method A to Method G below, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.
　下記A法乃至G法の各工程の反応において、反応終了後、各目的化合物は、通常当該技術分野において採用される方法に従って、反応混合物から採取される。例えば、反応混合物の液性を適宜調整し、不溶物が存在する場合には濾過により除去した後、水と、酢酸エチル等水と混和しない有機溶媒を加えて振盪する等して混和させた後、目的化合物を含む有機層を分離し、抽出液を水等で洗浄後、無水硫酸マグネシウム、無水硫酸ナトリウム等で乾燥し、乾燥剤をろ過後、ろ液の溶剤を留去することによって得ることができる。得られた目的化合物は必要に応じ、通常当該技術分野において採用される方法、例えば再結晶、再沈殿、クロマトグラフィー［例えば、シリカゲル、アルミナ、マグネシウム－シリカゲル系のフロリジル、SO3H-シリカ（富士シリシア化学株式会社）のような担体を用いた吸着カラムクロマトグラフィー法；セファデックスLH-20（GEヘルスケア・ジャパン株式会社）、アンバーライトXAD-11（ローム・アンド・ハース・ジャパン株式会社）、ダイヤイオンHP-20（三菱化学株式会社）等の担体を用いた分配カラムクロマトグラフィー等の合成吸着剤を使用する方法；イオン交換クロマトを使用する方法；シリカゲル若しくはアルキル化シリカゲルによる順相・逆相カラムクロマトグラフィー法（好適には、高速液体クロマトグラフィー）を適宜組合せ、適切な溶離剤で溶出する］等の、通常、有機化合物の分離精製に慣用されている方法を適宜組合せることによって分離、精製することができる。目的化合物が溶媒に難溶性である場合には、得られた固体の粗生成物を溶媒で洗浄することによって精製することができる。また、製造中間体となる各工程の目的化合物は精製することなくそのまま次の工程の反応に使用することもできる。
（製造法A）
　製造法Aは式（I）で表される化合物を製造する際に合成中間体として用いることのできるテトラヒドロシクロペンタインドール（IX）を製造する方法である。 In the reaction of each step of the following method A to method G, after completion of the reaction, each target compound is usually collected from the reaction mixture according to a method employed in the technical field. For example, after adjusting the liquidity of the reaction mixture as appropriate and removing insoluble matter by filtration, mixing with water and an organic solvent that is not miscible with water, such as ethyl acetate, and mixing by shaking. The organic layer containing the target compound is separated, and the extract is washed with water, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtered to remove the desiccant, and then distilled off the solvent in the filtrate. Can do. If necessary, the obtained target compound may be obtained by a method usually employed in the technical field, such as recrystallization, reprecipitation, chromatography [for example, silica gel, alumina, magnesium-silica gel type florisil, SO3H-silica (Fuji Silysia Chemical Ltd.). Adsorption column chromatography using a carrier such as Co., Ltd .; Sephadex LH-20 (GE Healthcare Japan Co., Ltd.), Amberlite XAD-11 (Rohm and Haas Japan Co., Ltd.), Diaion Method using a synthetic adsorbent such as partition column chromatography using a carrier such as HP-20 (Mitsubishi Chemical Corporation); Method using ion exchange chromatography; Normal phase / reverse phase column chromatography using silica gel or alkylated silica gel A suitable combination of photographic methods (preferably high performance liquid chromatography) Of] such eluting with a suitable eluent, usually separated by combining the methods which are customary for separation and purification of organic compounds as appropriate, can be purified. When the target compound is sparingly soluble in a solvent, the obtained solid crude product can be purified by washing with a solvent. Moreover, the target compound of each process used as a manufacturing intermediate can also be used for reaction of the following process as it is, without refine | purifying.
(Production method A)
Production method A is a method for producing tetrahydrocyclopentaindole (IX), which can be used as a synthetic intermediate when the compound represented by formula (I) is produced.
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
(A-I工程)
　本工程は、式（II）で表される化合物に対して公知の有機化学的手法を用いてオレフィンを還元させることにより、式（III）で表される化合物を製造する工程である。 (AI process)
This step is a step of producing the compound represented by the formula (III) by reducing the olefin using a known organic chemical technique with respect to the compound represented by the formula (II).
　式（II）で表される化合物を溶媒（例えば、アルコール類、具体的にはエタノール、メタノール等；エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等、これらは混合溶媒として使用してもよい。）中、遷移金属触媒（パラジウム等）存在下、接触水素化させることによって実施すればよい。本反応は、通常水素雰囲気下で行うが、水素供与体としてギ酸アンモニウム、ギ酸等を用いてもよい。 The compound represented by formula (II) is used as a solvent (for example, alcohols, specifically ethanol, methanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.). And may be carried out by catalytic hydrogenation in the presence of a transition metal catalyst (such as palladium). This reaction is usually performed in a hydrogen atmosphere, but ammonium formate, formic acid, or the like may be used as a hydrogen donor.
　式（II）で表される化合物は、公知化合物であるか、或いは公知化合物を出発原料として公知の方法又はそれに類似した方法に従って容易に製造される。
(A-II工程)
　本工程は、式（III）で表される化合物に対して公知の有機化学的手法を用いてエステルを加水分解させることにより、式（IV）で表される化合物を製造する工程である。 The compound represented by the formula (II) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.
(Process A-II)
This step is a step of producing the compound represented by the formula (IV) by hydrolyzing the ester of the compound represented by the formula (III) using a known organic chemical technique.
　式（III）で表される化合物を塩基（例えば、水酸化アルキル金属類、具体的には水酸化リチウム等）存在下、溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等；アルコール類、具体的には、メタノール、エタノール等を有機溶媒として使用すればよい。さらに溶媒として水を挙げることができるが、有機溶媒としては水と混和するものであることが好ましく、これらは混合溶媒として使用することが好ましい。）中で実施する。
(A-III工程)
　本工程は、式（IV）で表される化合物に対して公知の有機化学的手法を用いて、式（V）で表されるカルボン酸クロライドを製造する工程である。 The compound represented by the formula (III) is present in the presence of a base (for example, alkyl metal hydroxides, specifically lithium hydroxide) in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxy). Ethane, etc .; alcohols, specifically methanol, ethanol, etc. may be used as the organic solvent, and water may be mentioned as the solvent, but the organic solvent is preferably miscible with water, These are preferably used as mixed solvents).
(Process A-III)
This step is a step for producing the carboxylic acid chloride represented by the formula (V) by using a known organic chemical method for the compound represented by the formula (IV).
　式（IV）で表されるカルボン酸化合物を、溶媒（例えば、ハロゲン化炭化水素類、具体的にはジクロロメタン、クロロホルム、1,2-ジクロロエタン等。）中、酸塩化物（塩化オキサリル、チオニルクロリド等）及び少量のN,N-ジメチルホルムアミドを加えて実施すればよい。
(A-IV工程)
　本工程は、式（V）で表される化合物に対して公知の有機化学的手法を用いてフリーデルクラフツ分子内環化反応させることにより、式（VI）で表される化合物を製造する工程である。式（V）で表される化合物を、溶媒（例えば、ハロゲン化炭化水素類、具体的には1,2-ジクロロエタン等）中、ルイス酸（例えば、塩化アルミニウム等）を加えて実施する。
(A-V工程)
　本工程は、式（VI）で表されるケトン化合物に対して公知の有機化学的手法を用いて当該ケトンを還元させることにより、式（VII）で表される化合物を製造する工程である。 The carboxylic acid compound represented by the formula (IV) is converted into an acid chloride (oxalyl chloride, thionyl chloride) in a solvent (for example, halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.). Etc.) and a small amount of N, N-dimethylformamide may be added.
(A-IV process)
This step is a step of producing a compound represented by the formula (VI) by subjecting the compound represented by the formula (V) to a Friedel-Crafts intramolecular cyclization reaction using a known organic chemical technique. It is. The compound represented by the formula (V) is carried out in a solvent (for example, a halogenated hydrocarbon, specifically 1,2-dichloroethane) by adding a Lewis acid (for example, aluminum chloride).
(AV process)
This step is a step of producing a compound represented by the formula (VII) by reducing the ketone with respect to the ketone compound represented by the formula (VI) using a known organic chemical technique.
　式（VI）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等；アルコール類、具体的にはメタノール、エタノール等。これらは混合溶媒として使用してもよい。）中、還元剤（例えば、金属水素化ホウ素化合物類、具体的には水素化ホウ素ナトリウム等）を加えて実施する。 The compound represented by formula (VI) is used as a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; alcohols, specifically methanol, ethanol, etc.). In this case, a reducing agent (for example, metal borohydride compounds, specifically sodium borohydride, etc.) is added.
　また、この還元は、文献（J. Am. Chem. Soc. 1995, 117, 7562）記載の方法で不斉還元することによって、本発明の6位のアミノ基の立体異性体を誘導することができる。
(A-VI工程)
　本工程は、式（VII）で表される化合物に対して公知の有機化学的手法を用いて光延反応させることにより、式（VIII）で表される化合物を製造する工程である。 In addition, this reduction can induce the stereoisomer of the amino group at the 6-position of the present invention by asymmetric reduction by the method described in the literature (J. Am. Chem. Soc. 1995, 117, 7562). it can.
(A-VI process)
This step is a step of producing the compound represented by the formula (VIII) by subjecting the compound represented by the formula (VII) to Mitsunobu reaction using a known organic chemical technique.
　式（VII）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等；アルコール類、具体的にはメタノール、エタノール等。これらは混合物として使用してもよい。）中、N-Boc-o-ニトロベンゼンスルホンアミド、トリフェニルホスフィン、アゾジカルボン酸ジエチルを加えて実施する。
(A-VII工程)
　本工程は、式（VIII）で表される化合物に対して公知の有機化学的手法を用いてo-ニトロベンゼンスルホンアミドを加水分解させることにより、式（IX）で表される化合物を製造する工程である。 The compound represented by formula (VII) is used as a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; alcohols, specifically methanol, ethanol, etc.). In this case, N-Boc-o-nitrobenzenesulfonamide, triphenylphosphine and diethyl azodicarboxylate are added.
(Process A-VII)
This step is a step of producing a compound represented by the formula (IX) by hydrolyzing o-nitrobenzenesulfonamide using a known organic chemical method for the compound represented by the formula (VIII). It is.
　式（VIII）で表される化合物を、溶媒（例えば、アミド類、具体的にはN,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルアセトアミド等）中、チオグリコール酸及び塩基として水酸化アルカリ金属類、例えば水酸化リチウム1水和物、を加えて実施する。
（製造法B）
　製造法Bは式（I）で表される化合物を製造する際に合成中間体として用いることのできるフルオロテトラヒドロシクロペンタインドール（XII）を製造する方法である。 Alkali metal hydroxide as a thioglycolic acid and base in a solvent (for example, amides, specifically N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.) For example, lithium hydroxide monohydrate.
(Production method B)
Production method B is a method for producing fluorotetrahydrocyclopentaindole (XII), which can be used as a synthetic intermediate when the compound represented by formula (I) is produced.
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
(B-I工程)
　本工程は、式（VI）で表される化合物に対して公知の有機化学的手法を用いてフッ素化反応することにより、式（X）で表される化合物を製造する工程である。 (BI process)
This step is a step of producing a compound represented by the formula (X) by subjecting the compound represented by the formula (VI) to a fluorination reaction using a known organic chemical technique.
　式（VI）で表される化合物を、溶媒（例えば、アルコール類、具体的にはメタノール、エタノール等。）中、1-フルオロ-4-ヒドロキシ-1,4-ジアゾニアビシクロ[2,2,2]オクタンビス(テトラフルオロボレート)等を加えて実施する。
(B-II工程)
　本工程は、式（X）で表される化合物に対して公知の有機化学的手法を用いてオキシム化反応させることにより、式（XI）で表される化合物を製造する工程である。 The compound represented by the formula (VI) is converted into 1-fluoro-4-hydroxy-1,4-diazoniabicyclo [2,2, in a solvent (for example, alcohols, specifically methanol, ethanol, etc.). 2] Add octanebis (tetrafluoroborate) and so on.
(Process B-II)
This step is a step of producing the compound represented by the formula (XI) by subjecting the compound represented by the formula (X) to an oximation reaction using a known organic chemical technique.
　式（X）で表される化合物を、溶媒（例えば、アルコール類、具体的にはエタノール等；エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等；水、これらは混合溶媒として使用してもよい。）中、酢酸ナトリウム、O-メチルヒドロキシアミン塩酸塩を加えて実施する。
(B-III工程)
　本反応は、式（XI）で表される化合物に対して公知の有機化学的手法を用いてオキシムを還元した後Boc保護することにより、式（XII）で表される化合物を製造する工程である。 A compound represented by formula (X) is used as a solvent (for example, alcohols, specifically ethanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; water, these are used as a mixed solvent. In this case, sodium acetate and O-methylhydroxyamine hydrochloride are added.
(Process B-III)
This reaction is a step of producing a compound represented by the formula (XII) by reducing the oxime to the compound represented by the formula (XI) using a known organic chemical technique and then Boc protecting it. is there.
　式（XI）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等）中、例えば、ボラン－エーテル錯体類、具体的にはボラン－テトラヒドロフラン錯体等を加えて還元後、塩基として水酸化アルカリ金属水溶液、例えば水酸化ナトリウム水溶液、溶媒として酢酸エチルそしてジ-t-ブチルジカルボネートを加えて実施する。
（製造法C）
　製造法Cは、式（I）で表される化合物を製造する際に合成中間体として用いることのできるアリールテトラヒドロシクロペンタインドール（XV）をブロモテトラヒドロシクロペンタインドール（XIV）を経由して製造する方法である。 A compound represented by the formula (XI) in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.), for example, borane-ether complexes, specifically borane-tetrahydrofuran complexes, etc. After the reduction, an alkali metal hydroxide aqueous solution, for example, sodium hydroxide aqueous solution as a base, ethyl acetate and di-t-butyl dicarbonate as a solvent are added.
(Production method C)
Production method C produces aryltetrahydrocyclopentaindole (XV), which can be used as a synthetic intermediate when producing the compound represented by formula (I), via bromotetrahydrocyclopentaindole (XIV). Is the method.
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
(C-I工程)
　本工程は、式（XIII）で表される化合物に対して公知の有機化学的手法を用いてブロモ化させることにより、式（XIV）で表される化合物を製造する工程である。 (CI process)
This step is a step of producing the compound represented by the formula (XIV) by brominating the compound represented by the formula (XIII) using a known organic chemical technique.
　式（XIII）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等）中、リチウム金属強塩基として、例えばリチウムジイソプロピルアミド、そして1,2-ジブロモ-1,1,2,2-テトラクロロエタンを加えて実施する。
(C-II工程)
　本工程は、式（XIV）で表される化合物に対して公知の有機化学的手法を用いて鈴木カップリングさせることにより、式（XV）で表される化合物を製造する工程である。 A compound represented by the formula (XIII) in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.) as a lithium metal strong base, for example, lithium diisopropylamide, and 1,2-dibromo Carry out with the addition of -1,1,2,2-tetrachloroethane.
(C-II process)
This step is a step of producing a compound represented by the formula (XV) by subjecting the compound represented by the formula (XIV) to Suzuki coupling using a known organic chemical technique.
　式（XIV）で表される化合物を溶媒（例えば、エーテル類、具体的には1,4-ジオキサン；水、或はこれらの混合溶媒）中、パラジウム触媒存在下、アリールボロン酸又はアリールボロン酸エステルを加えて実施する。マイクロウェーブ反応装置を用いてもよい。鈴木カップリンングの例として、Journal of Organic Chemistry, 68, 20, 2003, 7733-7741；Journal of Organic Chemistry, 70, 6, 2005, 2191-2194；Journal of Organic Chemistry, 68, 24, 2003, 9412-9415；Bioorganic Medicinal Chemistry, 18, 2, 2010, 707-718；Tetrahedron, 66, 49, 2010, 9552-9559；Synthetic Communications, 30, 19, 2000, 3501-3510；Chemistry A European Journal, 12, 19, 2006, 5142-5148等に記載の方法に準じて行うことができる。
（製造法D）(1)
　製造法Dは式（I）で表される化合物を製造する際に合成中間体として用いることのできるアリールテトラヒドロシクロペンタインドール（XV）をトリブチルスタナニルテトラヒドロシクロペンタインドール（XVI）を経由して製造する方法である。 A compound represented by the formula (XIV) in a solvent (for example, ethers, specifically 1,4-dioxane; water, or a mixed solvent thereof) in the presence of a palladium catalyst, arylboronic acid or arylboronic acid Carry out with the addition of the ester. A microwave reactor may be used. Examples of the Suzuki coupling loop ring, Journal of Organic Chemistry, 68, 20, 2003, 7733 - 7741; Journal of Organic Chemistry, 70, 6, 2005, 2191 - 2194; Journal of Organic Chemistry, 68, 24, 2003, 9412 -9415; Bioorganic Medicinal Chemistry, 18, 2, 2010, 707-718; Tetrahedron, 66, 49, 2010, 9552-9559; Synthetic Communications, 30, 19, 2000, 3501 - 3510; Chemistry A European Journal, 12, 19 , 2006, 5142-5148 and the like.
(Production Method D) (1)
Production Method D produces aryltetrahydrocyclopentaindole (XV), which can be used as a synthetic intermediate when producing the compound represented by formula (I), via tributylstannanyltetrahydrocyclopentaindole (XVI). It is a method to do.
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
(D-I工程)
　本工程は、式（XIII）で表される化合物に対して公知の有機化学的手法を用いてトリブチルスタニル化させることにより、式（XVI）で表される化合物を製造する工程である。 (DI process)
This step is a step of producing a compound represented by the formula (XVI) by subjecting the compound represented by the formula (XIII) to tributylstannylation using a known organic chemical technique.
　式（XIII）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等）中、リチウム金属強塩基として、例えばリチウムジイソプロピルアミド、そしてヨウ化トリブチルスズを加えて実施する。
(D-II工程)
　本工程は、式（XVI）で表される化合物に対して公知の有機化学的手法を用いてStilleカップリングさせることにより、式（XV）で表される化合物を製造する工程である。 For example, lithium diisopropylamide and tributyltin iodide are added as a lithium metal strong base in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.) to a compound represented by the formula (XIII). To implement.
(D-II process)
This step is a step of producing a compound represented by the formula (XV) by subjecting a compound represented by the formula (XVI) to Stille coupling using a known organic chemical technique.
　式（XVI）で表される化合物を溶媒（例えば、アミド類、具体的にはN,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルアセトアミド等）中、テトラキス(トリフェニルホスフィン)パラジウム、ヨウ化銅(I)、アリールハライドを加えて実施する。マイクロウェーブ反応装置を用いてもよい。Stilleカップリングの例として、Angewandte Chemie, International Edition, 25, 6, 1986, 508-524；Tetrahedron Letters, 35, 19, 1994, 3195-3196；Synthesis, 1986 , 7, 564-565等に記載の方法に準じて行うことができる。
（製造法D）(2)
　さらに、製造法Dは式（I）で表される化合物を合成する際に合成中間体として用いることのできるオキサゾール置換テトラヒドロシクロペンタインドール（XX）を、カルボン酸中間体（XVIII）を経由して合成する方法である。 A compound represented by the formula (XVI) in a solvent (for example, amides, specifically, N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.), tetrakis (triphenylphosphine) palladium, copper iodide (I) Carry out with addition of aryl halide. A microwave reactor may be used. As an example of Stille coupling, the method described in Angewandte Chemie, International Edition, 25, 6, 1986, 508-524; Tetrahedron Letters, 35, 19, 1994, 3195-3196; Synthesis, 1986, 7, 564-565, etc. It can be performed according to.
(Production Method D) (2)
Further, in the production method D, an oxazole-substituted tetrahydrocyclopentaindole (XX), which can be used as a synthesis intermediate when synthesizing the compound represented by the formula (I), is obtained via a carboxylic acid intermediate (XVIII). It is a method of synthesis.
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
(D-III工程)
　本工程は、式（XIII）で表される化合物に対して公知の有機化学的手法を用いてアルキルオキシカルボニル化させることにより、式（XVII）で表される化合物を製造する工程である。 (D-III process)
This step is a step for producing a compound represented by the formula (XVII) by subjecting the compound represented by the formula (XIII) to alkyloxycarbonylation using a known organic chemical technique.
　式（XIII）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等）中、リチウム金属強塩基として、例えばリチウムジイソプロピルアミド、そしてクロロギ酸エチルを用いて実施する。
(D-IV工程)
　本工程は、式（XVII）で表される化合物に対して公知の有機化学的手法を用いて加水分解させることにより、式（XVIII）で表される化合物を製造する工程である。A法のA-II工程と同様に行われる。
(D-V工程)
　本工程は、式（XVIII）で表される化合物に対して公知の有機化学的手法を用いて縮合反応させることにより、式（XIX）で表される化合物を製造する工程である。 Using a compound represented by the formula (XIII) in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.) as a lithium metal strong base, for example, lithium diisopropylamide and ethyl chloroformate To implement.
(D-IV process)
This step is a step of producing the compound represented by the formula (XVIII) by hydrolyzing the compound represented by the formula (XVII) using a known organic chemical technique. This is carried out in the same manner as in step A-II of method A.
(DV process)
This step is a step for producing a compound represented by the formula (XIX) by subjecting the compound represented by the formula (XVIII) to a condensation reaction using a known organic chemical technique.
　式（XVIII）で表される化合物を溶媒（例えば、アミド類、具体的にはN,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルアセトアミド等）中、O-(7-アザ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ホスファート存在下、そしてトリアルキルアミン類、例えばN,N-ジイソプロピルエチルアミンを用いて、ベンゾイルヒドラジンを反応させて実施する。
(D-VI工程)
　本工程は、式（XIX）で表される化合物に対して公知の有機化学的手法を用いて環化させることにより、式（XX）で表される化合物を製造する工程である。 A compound represented by the formula (XVIII) is mixed with O- (7-azabenzotriazole-1-form in a solvent (for example, amides, specifically N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.). Yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate and reaction with benzoylhydrazine using trialkylamines such as N, N-diisopropylethylamine.
(D-VI process)
This step is a step of producing the compound represented by the formula (XX) by cyclizing the compound represented by the formula (XIX) using a known organic chemical technique.
　式（XIX）で表される化合物を溶媒（アセトニトリル等）中、トリフェニルホスフィン、そしてトリアルキルアミン類、例えばN,N-ジイソプロピルエチルアミン、さらにヘキサクロロエタンを用いて実施する。
（製造法E）
　製造法Eは式（I）で表される化合物を合成する際に合成中間体として用いることのできるアミノテトラヒドロシクロペンタインドール（XXI）を式（XV）で表される化合物から製造する方法である。 The compound represented by the formula (XIX) is carried out in a solvent (such as acetonitrile) using triphenylphosphine and trialkylamines such as N, N-diisopropylethylamine and hexachloroethane.
(Production method E)
Production method E is a method for producing aminotetrahydrocyclopentaindole (XXI), which can be used as a synthesis intermediate when synthesizing a compound represented by formula (I), from a compound represented by formula (XV). .
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
(E-I工程)
　本工程は、式（XV）で表される化合物に対して公知の有機化学的手法を用いて脱Boc化することにより、式（XXI）で表される化合物を製造する工程である。 (EI process)
This step is a step of producing a compound represented by the formula (XXI) by de-Bocating the compound represented by the formula (XV) using a known organic chemical technique.
　式（XV）で表される化合物を溶媒（例えば、エーテル類、具体的には1,4-ジオキサン、1,2-ジメトキシエタン；ハロゲン化炭化水素類、ジクロロメタン等）中、4規定塩酸（塩化水素）ジオキサン溶液を加えて実施する。反応条件は本条件に限らず、例えば、T.W. Greene及びP. G. Wuts著、「Protective Groups in Organic Synthesis（第３版、1999年）」に記載の方法に準じて行うことができる。
（製造法F）
　製造法Fは式（XXVIII）で表される合成中間体を製造する別方法である。 The compound represented by the formula (XV) in a solvent (for example, ethers, specifically 1,4-dioxane, 1,2-dimethoxyethane; halogenated hydrocarbons, dichloromethane, etc.) Hydrogen) Dioxane solution is added. The reaction conditions are not limited to these conditions, and can be carried out, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and P. G. Wuts.
(Production method F)
Production method F is another method for producing a synthetic intermediate represented by the formula (XXVIII).
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
(F-I工程)
　本工程は、式（XXII）で表される化合物に対して公知の有機化学的手法を用いてフッ素化させることにより、式（XXIII）で表される化合物を製造する工程である。B法のB-I工程と同様に行われる。
(F-II工程)
　本工程は、式（XXIII）で表される化合物に対して公知の有機化学的手法を用いて還元させることにより、式（XXIV）で表される化合物を製造する工程である。A法のA-V工程と同様に行われる。
(F-III工程)
　本工程は、式（XXIV）で表される化合物に対して公知の有機化学的手法を用いてブロモ化させることにより、式（XXV）で表される化合物を製造する工程である。C法のC-I工程と同様に行われる。
(F-IV工程)
　本工程は、式（XXV）で表される化合物に対して公知の有機化学的手法を用いて鈴木カップリングさせることにより、式（XXVI）で表される化合物を製造する工程である。C法のC-II工程と同様に行われる。
(F-V工程)
　本工程は、式（XXVI）で表される化合物に対して公知の有機化学的手法を用いて光延反応させることにより、式(XXVII)で表される化合物を製造する工程である。 (FI process)
This step is a step of producing the compound represented by the formula (XXIII) by fluorinating the compound represented by the formula (XXII) using a known organic chemical technique. Performed in the same manner as the BI process of Method B.
(F-II process)
This step is a step of producing the compound represented by the formula (XXIV) by reducing the compound represented by the formula (XXIII) using a known organic chemical technique. Performed in the same manner as the AV process of Method A.
(F-III process)
This step is a step of producing a compound represented by the formula (XXV) by brominating the compound represented by the formula (XXIV) using a known organic chemical technique. Performed in the same manner as the CI process in Method C.
(F-IV process)
This step is a step of producing a compound represented by the formula (XXVI) by subjecting the compound represented by the formula (XXV) to Suzuki coupling using a known organic chemical technique. This is carried out in the same manner as the C-II step of Method C.
(FV process)
This step is a step of producing a compound represented by the formula (XXVII) by subjecting the compound represented by the formula (XXVI) to a Mitsunobu reaction using a known organic chemical technique.
　式（XXVI）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等）中、ジフェニルホスホリルアミド、1,8-ジアザビシクロ[5.4.0]ウンデセ-7-エンを加えて実施する。
(F-VI工程)
　本工程は、式（XXVII）で表される化合物に対して公知の有機化学的手法を用いて還元反応させることにより、式（XXVIII）で表される化合物を製造する工程である。 A compound represented by the formula (XXVI) is dissolved in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.), diphenylphosphorylamide, 1,8-diazabicyclo [5.4.0] undec-7 -Carry out with the addition of en.
(F-VI process)
This step is a step of producing a compound represented by the formula (XXVIII) by subjecting the compound represented by the formula (XXVII) to a reduction reaction using a known organic chemical technique.
　式（XXVII）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等；水、或はこれらを混合溶媒として使用してもよい。）中、トリフェニルホスフィンを加えて実施する。
（製造法G）
　製造法Gは式（I）で表される化合物を式（XXI）で表される化合物から製造する方法である。 The compound represented by the formula (XXVII) is dissolved in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; water or a mixture thereof may be used). Carry out with the addition of phenylphosphine.
(Production method G)
Production method G is a method for producing a compound represented by formula (I) from a compound represented by formula (XXI).
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
(G-I工程)
　本工程は、式（XXI）で表される化合物に対して公知の有機化学的手法を用いて脱アリールスルホニル化することにより、式（I）で表される化合物を製造する工程である。 (GI process)
This step is a step of producing the compound represented by the formula (I) by dearylsulfonylating the compound represented by the formula (XXI) using a known organic chemical method.
　式（XXI）で表される化合物を溶媒（例えば、アルコール類、具体的には、メタノール、エタノール、n-プロパノール等；エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等）中、塩基として例えば炭酸セシウムを加えて実施する。 A compound represented by the formula (XXI) in a solvent (for example, alcohols, specifically methanol, ethanol, n-propanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.), For example, cesium carbonate is added as a base.
　本発明の式（I）で表される化合物は、所望により医薬的に許容される塩とすることができる。医薬的に許容される塩とは、著しい毒性を有さず、医薬として使用され得る塩をいう。本発明の式（I）で表される化合物は、塩基性部分を有しており、酸と処理することにより塩にすることができる。 The compound represented by the formula (I) of the present invention can be a pharmaceutically acceptable salt if desired. A pharmaceutically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicament. The compound represented by the formula (I) of the present invention has a basic moiety, and can be converted into a salt by treating with an acid.
　塩基性置換基及び塩基性ヘテロアリール基に基づく塩としては、フッ化水素酸塩、塩酸塩、臭化水素酸塩及びヨウ化水素酸塩等のハロゲン化水素酸塩；塩酸塩、硝酸塩、過塩素酸塩、硫酸塩及びリン酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩及びエタンスルホン酸塩等の低級アルカンスルホン酸塩；ベンゼンスルホン酸塩及びp-トルエンスルホン酸塩等のアリールスルホン酸塩；酢酸塩、リンゴ酸塩、フマル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、シュウ酸塩及びマレイン酸塩等の有機酸塩；グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩及びアスパラギン酸塩等のアミノ酸塩等がある。これらのうちで好ましくは、無機酸塩又はアリールスルホン酸塩であり、より好ましくは、塩酸塩、ベンゼンスルホン酸塩、又はp-トルエンスルホン酸塩である。 Salts based on basic substituents and basic heteroaryl groups include hydrohalides such as hydrofluorates, hydrochlorides, hydrobromides and hydroiodides; hydrochlorides, nitrates, peroxides Inorganic acid salts such as chlorate, sulfate and phosphate; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; benzene sulfonate and p-toluene sulfonate Aryl sulfonates such as: acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate and maleate, etc .; glycine salt, lysine Examples include salts, arginine salts, ornithine salts, amino acid salts such as glutamate and aspartate. Among these, preferred are inorganic acid salts or aryl sulfonates, and more preferred are hydrochlorides, benzene sulfonates, or p-toluene sulfonates.
　式（I）で表される化合物又はその塩は、大気中に放置したり、又は再晶析を行ったりすることにより、水分を吸収して吸着水が付き、水和物となる場合があり、そのような水和物も本発明の塩に包含される。 When the compound represented by the formula (I) or a salt thereof is left in the atmosphere or recrystallized, it may absorb moisture and attach adsorbed water to form a hydrate. Such hydrates are also included in the salts of the present invention.
　式（I）で表される化合物又はその塩は、ある種の溶媒を吸収し、溶媒和物となる場合があり、そのような溶媒和物も本発明の塩に包含される。 The compound represented by the formula (I) or a salt thereof may absorb a certain solvent and become a solvate, and such a solvate is also included in the salt of the present invention.
　式（I）で表される化合物は、その分子内に不斉炭素原子を有するので、光学異性体が存在する。これらの異性体及びこれらの異性体の混合物がすべて単一の式、すなわち式（I）で表されている。したがって、式（I）で表される化合物は単一の光学異性体及び光学異性体の任意の割合の混合物も全て本発明の範囲に包含される。 Since the compound represented by the formula (I) has an asymmetric carbon atom in its molecule, an optical isomer exists. These isomers and mixtures of these isomers are all represented by a single formula, ie, formula (I). Therefore, the compound represented by the formula (I) includes all of a single optical isomer and a mixture of optical isomers in an arbitrary ratio within the scope of the present invention.
　上記のような光学異性体は、光学活性な原料化合物を用いるか、又は不斉合成もしくは不斉誘導の手法を用いて本発明に係る化合物を合成することで得ることができる。この他、合成した本発明に係る化合物を通常の光学分割法又は光学活性担体を利用した分離法等を用いて単離することにより得ることができる。 The optical isomers as described above can be obtained by using an optically active raw material compound, or by synthesizing the compound according to the present invention using an asymmetric synthesis or asymmetric induction method. In addition, the synthesized compound according to the present invention can be obtained by isolation using a normal optical resolution method or a separation method using an optically active carrier.
　本発明の化合物は、当該化合物を構成する原子の1以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素（2H）、トリチウム（3H）、ヨウ素－125（125I）、又は炭素－14（14C）等を挙げることができる。また、前記化合物は、例えば、トリチウム（3H）、ヨウ素－125（125I）、又は炭素－14（14C）等の放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like. In addition, the compound can be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
　本発明の式（I）で示される化合物、その薬学的に許容される塩、又はそれらの水和物は、酸感受性イオンチャネルに対して優れた阻害作用を有するのみでなく、阻害作用が酸感受性イオンチャネルに対して優れた選択性を示す優れた化合物である。このような酸感受性イオンチャネル阻害剤として、虚血性心疾患、心不全、末梢動脈疾患、不整脈、高血圧症、低血圧症、慢性関節リウマチ、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、癌に伴う疼痛、変形性関節症、間質性膀胱炎、逆流性食道炎、過敏性腸症候群、咳、味覚傷害、難聴、糖尿病網膜症や緑内障における視機能障害、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、過換気症候群、喘息、インスリン抵抗性糖尿病、多発性硬化症、全般性不安障害、パニック障害、脳梗塞、パーキンソン病、ハンチントン病、又はアルツハイマー病等の疾患又は疾患に伴う症状に対して優れた治療効果及び／又は予防効果を期待することができる。なお、疼痛の緩和のための鎮痛薬としても優れた治療効果及び／又は予防効果を期待することができる。 The compound represented by the formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate thereof not only has an excellent inhibitory action on acid-sensitive ion channels, but also has an inhibitory action on acid. It is an excellent compound that exhibits excellent selectivity for sensitive ion channels. Such acid-sensitive ion channel inhibitors include ischemic heart disease, heart failure, peripheral arterial disease, arrhythmia, hypertension, hypotension, rheumatoid arthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative Colitis, dermatitis including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with cancer , Osteoarthritis, interstitial cystitis, reflux esophagitis, irritable bowel syndrome, cough, gustatory injury, hearing loss, visual impairment in diabetic retinopathy and glaucoma, colorectal cancer, ovarian epithelial cancer, breast cancer, stomach Associated with diseases or disorders such as tumorigenesis, hyperventilation syndrome, asthma, insulin resistant diabetes, multiple sclerosis, generalized anxiety disorder, panic disorder, cerebral infarction, Parkinson's disease, Huntington's disease, or Alzheimer's disease Excellent therapeutic and / or prophylactic effect against Jo can be expected. An excellent therapeutic effect and / or prophylactic effect can also be expected as an analgesic for pain relief.
　さらに本発明化合物は、経口投与的に投与されることによっても酸感受性イオンチャネル阻害作用が期待されることから、優れた酸感受性イオンチャネル阻害作用を簡便に利用することが可能であり、患者のQOLの向上が可能となる。 Furthermore, since the compound of the present invention is expected to have an acid-sensitive ion channel inhibitory action even when administered orally, it is possible to easily use an excellent acid-sensitive ion channel inhibitory action. QOL can be improved.
　本発明の化合物、その薬学的に許容される塩、又はそれらの水和物は、種々の形態で投与することができる。その投与形態としては、例えば、錠剤、カプセル剤、顆粒剤、乳剤、丸剤、散剤、シロップ剤（液剤）等による経口投与、あるいは注射剤（静脈内、筋肉内、皮下、又は腹腔内投与）、点滴剤、坐剤（直腸投与）等による非経口投与を挙げることができる。これらの各種製剤は、主薬に対して賦形剤、結合剤、崩壊剤、滑沢剤、矯味矯臭剤、溶解補助剤、懸濁剤、コーティング剤等の医薬の製剤技術分野において通常使用し得る補助剤を適宜選択・添加して通常実施される方法に従って製剤化することができる。 The compound of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate thereof can be administered in various forms. The administration form is, for example, oral administration such as tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), or injections (intravenous, intramuscular, subcutaneous, or intraperitoneal administration). And parenteral administration such as drops, suppositories (rectal administration) and the like. These various preparations can be usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. with respect to the main drug. An auxiliary agent can be appropriately selected and added, and can be formulated according to a commonly practiced method.
　錠剤として使用する場合、担体として、例えば、乳糖、白糖、塩化ナトリウム、グルコース、尿素、デンプン、炭酸カルシウム、カオリン、結晶セルロース及びケイ酸等の賦形剤；水、エタノール、プロパノール、単シロップ、グルコース液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム及びポリビニルピロリドン等の結合剤；乾燥デンプン、アルギン酸ナトリウム、寒天末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、デンプン及び乳糖等の崩壊剤；白糖、ステアリン、カカオバター及び水素添加油等の崩壊抑制剤；第四級アンモニウム塩類及びラウリル硫酸ナトリウム等の吸収促進剤；グリセリン及びデンプン等の保湿剤；デンプン、乳糖、カオリン、ベントナイト及びコロイド状ケイ酸等の吸着剤；精製タルク、ステアリン酸塩、硼酸末及びポリエチレングリコール等の潤沢剤等を使用することができる。また、必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被錠及びフィルムコーティング錠あるいは二重錠、多層錠とすることができる。 When used as a tablet, as a carrier, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as esters, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegrators such as sucrose, stearin, cocoa butter and hydrogenated oil; quaternary ammonium salts and lauryl sulfate Absorption promoters such as sodium; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; and lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol Can be used. Moreover, it can be set as the tablet which gave the normal coating as needed, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.
　丸剤として使用する場合、担体として、例えば、グルコース、乳糖、カカオバター、デンプン、硬化植物油、カオリン及びタルク等の賦形剤；アラビアゴム末、トラガント末、ゼラチン及びエタノール等の結合剤；ラミナラン、寒天等の崩壊剤等を使用することができる。 When used as pills, as carriers, for example, excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin and talc; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; laminaran, Disintegrants such as agar can be used.
　坐剤として使用する場合、担体としてこの分野で従来公知のものを広く使用でき、例えばポリエチレングリコール、カカオバター、高級アルコール、高級アルコールのエステル類、ゼラチン及び半合成グリセリド等を挙げることができる。 When used as a suppository, a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, and semi-synthetic glyceride.
　注射剤として使用する場合、液剤、乳剤、又は懸濁剤として使用することができる。これらの液剤、乳剤、又は懸濁剤は、殺菌され、血液と等張であることが好ましい。これら液剤、乳剤、又は懸濁剤の製造に用いる溶媒は、医療用の希釈剤として使用できるものであれば特に限定はなく、例えば、水、エタノール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール及びポリオキシエチレンソルビタン脂肪酸エステル類等を挙げることができる。なお、この場合、等張性の溶液を調製するのに充分な量の食塩、グルコース、又はグリセリンを製剤中に含んでいてもよく、また通常の溶解補助剤、緩衝剤及び無痛化剤等を含んでいてもよい。 When used as an injection, it can be used as a solution, emulsion, or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood. The solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylation Examples thereof include isostearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In this case, the preparation may contain a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. May be included.
　また、上記の製剤には、必要に応じて、着色剤、保存剤、香料、風味剤及び甘味剤等を含めることもでき、更に、他の医薬品を含めることもできる。 In addition, the above-mentioned preparation can contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as necessary, and can further contain other pharmaceuticals.
　上記製剤に含まれる有効成分化合物の量は、特に限定されず広範囲に適宜選択されるが、通常、全組成物中0.5から70重量%、好ましくは1から30重量％含む。 The amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight in the total composition.
　その使用量は患者（温血動物、特に人間）の症状、年齢等により異なるが、経口投与の場合には、1日あたり、上限として1000mg（好ましくは100mg）であり、下限として0.1mg（好ましくは1mg、さらに好ましくは5mg）を成人に対して、1日当り1から6回症状に応じて投与することが望ましい。 The amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animals, particularly humans), but in the case of oral administration, the upper limit is 1000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg (preferably 1 mg, more preferably 5 mg) is preferably administered to adults 1 to 6 times daily depending on symptoms.
　以下に示す例によって本発明を具体的に説明するが、本発明はこれらに限定されるものではない。また、これらはいかなる意味においても限定的に解釈されるものではない。
実施例１　[3-(6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル)-5-メトキシ－フェニル]メタノール
[工程１]　エチル 3-{1-[(4-メチルフェニル)スルホニル]-1H-インドール-4-イル}プロパノエート The present invention will be specifically described with reference to the following examples, but the present invention is not limited thereto. Moreover, these are not limitedly interpreted in any sense.
Example 1 [3- (6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl) -5-methoxy-phenyl] methanol
[Step 1] Ethyl 3- {1-[(4-methylphenyl) sulfonyl] -1H-indol-4-yl} propanoate
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　エチル (2E)-3-{1-[(4-メチルフェニル)スルホニル]-1H-インドール-4-イル}プロプ-2-エノレート（66.5g）のテトラヒドロフラン（300mL）及びエタノール（100mL）溶液へ、窒素雰囲気下、10%パラジウム炭素触媒(M)Wet（3.0g，2.8mmol）を加え、水素雰囲気下、室温で4時間攪拌した。窒素置換後、さらに10% Pd-C（1.0g）を加え、水素雰囲気下、3時間攪拌した反応混合物にクロロホルムを加え、パラジウム－炭素を濾別してクロロホルムで洗浄した。減圧下にて溶媒を留去して得られた残留物を、シリカゲルカラムクロマトグラフィー［クロロホルム］にて精製し、得られた固体を洗浄［溶媒：n-ヘキサン／エーテル］することにより標題化合物（63.1g）を淡黄白色固体として得た。
1H-NMR(CDCl3)δppm:7.83-7.80(1H,m),7.75-7.71(2H,m),7.55-7.53(1H,m),7.23-7.17(3H,m),7.03-7.00(1H,m),6.69-6.67(1H,m),4.06(2H,q,J=7.0Hz),3.09(2H,t,J=7.8Hz),2.61(2H,t,J=7.8Hz),2.30(3H,s),1.15(3H,t,J=7.0Hz).
[工程２]　3-{1-[(4-メチルフェニル)スルホニル]-1H-インドール-4-イル}プロパノイックアシッド To a solution of ethyl (2E) -3- {1-[(4-methylphenyl) sulfonyl] -1H-indol-4-yl} prop-2-enolate (66.5 g) in tetrahydrofuran (300 mL) and ethanol (100 mL), Under a nitrogen atmosphere, 10% palladium carbon catalyst (M) Wet (3.0 g, 2.8 mmol) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After purging with nitrogen, 10% Pd-C (1.0 g) was further added, chloroform was added to the reaction mixture stirred for 3 hours under a hydrogen atmosphere, palladium-carbon was filtered off and washed with chloroform. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [chloroform], and the resulting solid was washed [solvent: n-hexane / ether] to give the title compound ( 63.1 g) was obtained as a pale yellowish white solid.
1 H-NMR (CDCl 3 ) δppm: 7.83-7.80 (1H, m), 7.75-7.71 (2H, m), 7.55-7.53 (1H, m), 7.23-7.17 (3H, m), 7.03-7.00 ( 1H, m), 6.69-6.67 (1H, m), 4.06 (2H, q, J = 7.0Hz), 3.09 (2H, t, J = 7.8Hz), 2.61 (2H, t, J = 7.8Hz), 2.30 (3H, s), 1.15 (3H, t, J = 7.0Hz).
[Step 2] 3- {1-[(4-Methylphenyl) sulfonyl] -1H-indol-4-yl} propanoic acid
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
　上記工程１で得られた化合物（63.1g）のテトラヒドロフラン（300mL）、エタノール（100mL）、水（200mL）の混合液へ、水酸化リチウム1水和物（17.8g，425mmol）を加え、室温で攪拌した。反応混合物を0℃に冷却し、反応混合物に3規定塩酸（150mL）を加え、反応混合物を酢酸エチルで抽出した。抽出液を、水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた固体を洗浄［ヘキサン／エーテル］することにより標題化合物（57.1g）を淡橙白色固体として得た。
1H-NMR(CDCl3)δppm:7.84-7.80(1H,m),7.75-7.72(2H,m),7.56-7.54(1H,m),7.20-7.18(3H,m),7.04-7.01(1H,m),6.69-6.67(1H,m),3.11(2H,t,J=7.8Hz),2.70-2.65(2H,m),2.30(3H,s).
[工程３]　3-{1-[(4-メチルフェニル)スルホニル]-1H-インドール-4-イル}プロパノイルクロリド Lithium hydroxide monohydrate (17.8 g, 425 mmol) was added to a mixture of the compound (63.1 g) obtained in Step 1 above in tetrahydrofuran (300 mL), ethanol (100 mL), and water (200 mL) at room temperature. Stir. The reaction mixture was cooled to 0 ° C., 3N hydrochloric acid (150 mL) was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solid obtained by distilling off the solvent under reduced pressure was washed [hexane / ether] to give the title compound (57.1 g) as a pale orange white solid.
1 H-NMR (CDCl 3 ) δppm: 7.84-7.80 (1H, m), 7.75-7.72 (2H, m), 7.56-7.54 (1H, m), 7.20-7.18 (3H, m), 7.04-7.01 ( 1H, m), 6.69-6.67 (1H, m), 3.11 (2H, t, J = 7.8Hz), 2.70-2.65 (2H, m), 2.30 (3H, s).
[Step 3] 3- {1-[(4-Methylphenyl) sulfonyl] -1H-indol-4-yl} propanoyl chloride
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　上記工程２で得られた化合物（57.1g）のジクロロメタン（300mL）溶液へ、オキサリルクロリド（17.1mL）を滴下した。滴下終了後室温で2時間攪拌し、N,N-ジメチルホルムアミド（3 drops）を加え、室温で18時間攪拌した。反応終了後、減圧下にて溶媒を留去して、標題化合物（60.2g）を黒色油状物質として得た。
1H-NMR(CDCl3)δppm:7.87-7.83(1H,m),7.76-7.72(2H,m),7.59-7.57(1H,m),7.23-7.19(3H,m),7.02-6.99(1H,m),6.66-6.64(1H,m),3.22-3.13(4H,m),2.31(3H,s).
[工程４]　3-[(4-メチルフェニル)スルホニル]-7,8-ジヒドロシクロペンタ[e]インドール-6(3H)-オン Oxalyl chloride (17.1 mL) was added dropwise to a solution of the compound (57.1 g) obtained in Step 2 above in dichloromethane (300 mL). After completion of dropping, the mixture was stirred at room temperature for 2 hours, N, N-dimethylformamide (3 drops) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain the title compound (60.2 g) as a black oily substance.
1 H-NMR (CDCl 3 ) δ ppm: 7.87-7.83 (1H, m), 7.76-7.72 (2H, m), 7.59-7.57 (1H, m), 7.23-7.19 (3H, m), 7.02-6.99 ( 1H, m), 6.66-6.64 (1H, m), 3.22-3.13 (4H, m), 2.31 (3H, s).
[Step 4] 3-[(4-Methylphenyl) sulfonyl] -7,8-dihydrocyclopenta [e] indole-6 (3H) -one
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　上記工程３で得られた化合物（60.2g）の1,2-ジクロロエタン（500mL）溶液へ、塩化アルミニウム（24.4g）を少量ずつ加え、室温で100分間攪拌した。反応混合物を0℃に冷却し、反応混合物を水に注ぎ、反応混合物をクロロホルムで抽出した。抽出液を、飽和重曹水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残留物を、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］にて精製することにより標題化合物（40.3g）を淡橙白色固体として得た。
1H-NMR(CDCl3)δppm:7.99-7.95(1H,m),7.78-7.74(2H,m),7.69-7.64(2H,m),7.24-7.20(2H,m),6.78-6.75(1H,m),3.22-3.18(2H,m),2.73-2.69(2H,m),2.32(3H,s).
[工程５]　3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-オール Aluminum chloride (24.4 g) was added little by little to a solution of the compound obtained in Step 3 (60.2 g) in 1,2-dichloroethane (500 mL), and the mixture was stirred at room temperature for 100 minutes. The reaction mixture was cooled to 0 ° C., the reaction mixture was poured into water, and the reaction mixture was extracted with chloroform. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography [chloroform / methanol] to obtain the title compound (40.3 g) as a pale orange white solid.
1 H-NMR (CDCl 3 ) δ ppm: 7.99-7.95 (1H, m), 7.78-7.74 (2H, m), 7.69-7.64 (2H, m), 7.24-7.20 (2H, m), 6.78-6.75 ( 1H, m), 3.22-3.18 (2H, m), 2.73-2.69 (2H, m), 2.32 (3H, s).
[Step 5] 3-[(4-Methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-ol
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　上記工程４で得られた化合物（9.02g）のテトラヒドロフラン（90mL）、メタノール（90mL）混合液へ、0℃で水素化ホウ素ナトリウム（2.62g）を加え、室温で攪拌した。反応混合物を0℃に冷却し、反応混合物に飽和塩化アンモニウム水溶液を加え、反応混合物を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。シリカゲルを用いて濾過（酢酸エチル洗浄）した後、減圧下にて溶媒を留去することにより標題化合物（9.26g）を白色泡状物質として得た。
1H-NMR(CDCl3)δppm:7.95-7.91(1H,m),7.81-7.77(2H,m),7.65-7.63(1H,m),7.41-7.38(1H,m),7.27-7.22(2H,m),6.66-6.63(1H,m),5.40-5.32(1H,m),3.26-3.17(1H,m),2.99-2.91(1H,m),2.64-2.55(1H,m),2.37(3H,s),2.12-2.02(1H,m).
[工程６]　tert-ブチル {3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル}[(2-ニトロフェニル)スルホニル]カルバメート Sodium borohydride (2.62 g) was added to a mixed solution of the compound (9.02 g) obtained in Step 4 above in tetrahydrofuran (90 mL) and methanol (90 mL) at 0 ° C., and the mixture was stirred at room temperature. The reaction mixture was cooled to 0 ° C., saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration using silica gel (washing with ethyl acetate), the solvent was distilled off under reduced pressure to obtain the title compound (9.26 g) as a white foam.
1 H-NMR (CDCl 3 ) δ ppm: 7.95-7.91 (1H, m), 7.81-7.77 (2H, m), 7.65-7.63 (1H, m), 7.41-7.38 (1H, m), 7.27-7.22 ( 2H, m), 6.66-6.63 (1H, m), 5.40-5.32 (1H, m), 3.26-3.17 (1H, m), 2.99-2.91 (1H, m), 2.64-2.55 (1H, m), 2.37 (3H, s), 2.12-2.02 (1H, m).
[Step 6] tert-butyl {3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl} [(2-nitrophenyl) sulfonyl] carbamate
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　上記工程５で得られた化合物（9.26g）のテトラヒドロフラン（200mL）溶液へ、0℃でN-BOC-o-ニトロベンゼンスルホンアミド（10.3g）、トリフェニルホスフィン（8.53g）、アゾジカルボン酸ジエチル（40% in Toluene，ca.2.2mol/L；15mL）を加え、室温で攪拌した。反応混合物にシリカゲル（90mL）とエーテル（200mL）を加え、濾過後（エーテル洗浄）、減圧下にて溶媒を留去して得られた残留物をテトラヒドロフランを用いて溶かし、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］にて精製し、標題化合物（23.1g）を白色固体として得た。この固体は精製せずそのまま工程７で用いた。
[工程７]　tert-ブチル {3-[(4-メチルフェニル)スルホニル]-2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル}カルバメート To a solution of the compound (9.26 g) obtained in Step 5 above in tetrahydrofuran (200 mL) at 0 ° C., N-BOC-o-nitrobenzenesulfonamide (10.3 g), triphenylphosphine (8.53 g), diethyl azodicarboxylate ( 40% in Toluene, ca.2.2 mol / L; 15 mL) was added and stirred at room temperature. Silica gel (90 mL) and ether (200 mL) were added to the reaction mixture, and after filtration (washing with ether), the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran, followed by silica gel column chromatography [hexane / Ethyl acetate] to give the title compound (23.1 g) as a white solid. This solid was used directly in step 7 without purification.
[Step 7] tert-butyl {3-[(4-methylphenyl) sulfonyl] -2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6- Il} Carbamate
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　上記工程６で得られた化合物（23.1g）のN,N-ジメチルホルムアミド（150mL）溶液へ、チオグリコール酸（5.25mL）、水酸化リチウム1水和物（6.34g）を0℃で加え、室温で1時間半攪拌した。反応混合物を0℃に冷却し、反応混合物に水を加え、反応混合物を酢酸エチルで抽出した。抽出液を、水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残留物を、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］にて精製し、得られた固体を洗浄［ヘキサン／エーテル］することにより標題化合物（8.16g）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.91-7.87(1H,m),7.81-7.77(2H,m),7.64-7.61(1H,m),7.31-7.24(3H,m),6.64-6.62(1H,m),5.32-5.22(1H,m),4.79-4.70(1H,m),3.17-3.07(1H,m),2.98-2.90(1H,m),2.72-2.62(1H,m),2.37(3H,s),1.95-1.85(1H,m),1.52(9H,s).
[工程８]　tert-ブチル {2-ブロモ-3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル}カルバメート To a solution of the compound obtained in Step 6 (23.1 g) in N, N-dimethylformamide (150 mL), thioglycolic acid (5.25 mL) and lithium hydroxide monohydrate (6.34 g) are added at 0 ° C., Stir at room temperature for 1.5 hours. The reaction mixture was cooled to 0 ° C., water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [hexane / ethyl acetate], and the resulting solid was washed [hexane / ether] to give the title compound (8.16 g) was obtained as a white solid.
1 H-NMR (CDCl 3 ) δppm: 7.91-7.87 (1H, m), 7.81-7.77 (2H, m), 7.64-7.61 (1H, m), 7.31-7.24 (3H, m), 6.64-6.62 ( 1H, m), 5.32-5.22 (1H, m), 4.79-4.70 (1H, m), 3.17-3.07 (1H, m), 2.98-2.90 (1H, m), 2.72-2.62 (1H, m), 2.37 (3H, s), 1.95-1.85 (1H, m), 1.52 (9H, s).
[Step 8] tert-butyl {2-bromo-3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl} carbamate
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
　上記工程７で得られた化合物（2.2g）をテトラヒドロフラン（100mL）に溶解した。反応液を-78℃に冷却し、窒素雰囲気下、リチウムジイソプロピルアミド（9.9mL）を加えて30分攪拌した。1,2-ジブロモ-1,1,2,2-テトラクロロエタン（5.0g）のテトラヒドロフラン（30mL）溶液を一度に加え、-78℃で2時間攪拌した。反応溶液に飽和アンモニウム水溶液を注ぎ、有機層を酢酸エチルで抽出した。食塩水で洗浄後、硫酸ナトリウムで洗浄した。溶媒を留去し、残留物をカラムクロマトグラフィー［ヘキサン／酢酸エチル］で精製し、標題化合物（1.45g）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.17-8.13(1H,m),7.80-7.76(2H,m),7.31-7.21(10H,m),6.68-6.67(1H,m),4.79-4.72(1H,m),3.07-2.97(1H,m),2.89-2.81(1H,m),2.70-2.61(1H,m),2.36(3H,s),1.92-1.84(1H,m),1.57(9H,s).
[工程９]　メチル 3-[6-(tert-ブトキシカルボニルアミノ)-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-2-イル]-5-メトキシ-ベンゾエート The compound (2.2 g) obtained in the above step 7 was dissolved in tetrahydrofuran (100 mL). The reaction mixture was cooled to −78 ° C., lithium diisopropylamide (9.9 mL) was added under a nitrogen atmosphere, and the mixture was stirred for 30 min. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (5.0 g) in tetrahydrofuran (30 mL) was added in one portion, and the mixture was stirred at -78 ° C. for 2 hours. A saturated aqueous ammonium solution was poured into the reaction solution, and the organic layer was extracted with ethyl acetate. After washing with brine, it was washed with sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography [hexane / ethyl acetate] to give the title compound (1.45 g) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 8.17-8.13 (1H, m), 7.80-7.76 (2H, m), 7.31-7.21 (10H, m), 6.68-6.67 (1H, m), 4.79-4.72 ( 1H, m), 3.07-2.97 (1H, m), 2.89-2.81 (1H, m), 2.70-2.61 (1H, m), 2.36 (3H, s), 1.92-1.84 (1H, m), 1.57 ( 9H, s).
[Step 9] Methyl 3- [6- (tert-butoxycarbonylamino) -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-2-yl] -5-methoxy- Benzoate
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　上記工程８で得られた化合物（400mg）及びメチル 3-メトキシ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾエート（301mg）のジオキサン（15.8mL）及び水（3.17mL）溶液に炭酸カリウム（328mg）、Pd(dppf)Cl2（0.172g）を加え、100℃で2時間攪拌した。反応液を直接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］で精製することにより標題化合物（467mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:8.16(1H,d,J=8.6Hz),7.75-7.72(1H,m),7.64-7.61(1H,m),7.34-7.16(4H,m),7.07(1H,d,J=7.8Hz),6.55(1H,d,J=0.8Hz),5.32-5.20(1H,m),4.82-4.70(1H,m),3.95(3H,s),3.91(3H,s),3.09-2.96(1H,m),2.92-2.80(1H,m),2.70-2.58(1H,m),2.30(3H,s),1.93-1.80(1H,m),1.51(9H,s).
[工程１０]　tert-ブチル N-[2-[3-(ヒドロキシメチル)-5-メトキシ-フェニル]-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート The compound obtained in Step 8 above (400 mg) and methyl 3-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (301 mg) in dioxane ( 15.8 mL) and water (3.17 mL) were added with potassium carbonate (328 mg) and Pd (dppf) Cl 2 (0.172 g), and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was directly purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (467 mg) as a colorless oil.
1 H-NMR (CDCl 3 ) δppm: 8.16 (1H, d, J = 8.6Hz), 7.75-7.72 (1H, m), 7.64-7.61 (1H, m), 7.34-7.16 (4H, m), 7.07 (1H, d, J = 7.8Hz), 6.55 (1H, d, J = 0.8Hz), 5.32-5.20 (1H, m), 4.82-4.70 (1H, m), 3.95 (3H, s), 3.91 ( 3H, s), 3.09-2.96 (1H, m), 2.92-2.80 (1H, m), 2.70-2.58 (1H, m), 2.30 (3H, s), 1.93-1.80 (1H, m), 1.51 ( 9H, s).
[Step 10] tert-Butyl N- [2- [3- (hydroxymethyl) -5-methoxy-phenyl] -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indole- 6-yl] carbamate
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　上記工程９で得られた化合物（467mg）のテトラヒドロフラン（15.8mL）溶液にリチウムボロハイドライド（172mg）及びメタノール（3.16mL）を加え、室温で1時間攪拌した。水を加えて反応を停止した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物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］で精製することにより標題化合物（310mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.15(1H,d,J=8.6Hz),7.34-7.27(3H,m),7.09-6.94(5H,m),6.51(1H,s),5.30-5.18(1H,m),4.81-4.66(3H,m),3.87(3H,s),3.07-2.97(1H,m),2.91-2.80(1H,m),2.70-2.57(1H,m),2.30(3H,s),1.90-1.80(1H,m),1.50(9H,s).
[工程１１]　[3-[6-アミノ-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]-5-メトキシ-フェニル]メタノール Lithium borohydride (172 mg) and methanol (3.16 mL) were added to a tetrahydrofuran (15.8 mL) solution of the compound (467 mg) obtained in Step 9 above, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by adding water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (310 mg) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 8.15 (1H, d, J = 8.6Hz), 7.34-7.27 (3H, m), 7.09-6.94 (5H, m), 6.51 (1H, s), 5.30-5.18 (1H, m), 4.81-4.66 (3H, m), 3.87 (3H, s), 3.07-2.97 (1H, m), 2.91-2.80 (1H, m), 2.70-2.57 (1H, m), 2.30 (3H, s), 1.90-1.80 (1H, m), 1.50 (9H, s).
[Step 11] [3- [6-Amino-3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-6-yl] -5-methoxy-phenyl] methanol
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　上記工程１０で得られた化合物（200mg）のテトラヒドロフラン（4mL）溶液にca. 4mol/L 塩化水素／1,4-ジオキサン（4mL）を加え、室温で3時間攪拌した。1規定水酸化ナトリウム水溶液を加えて中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物をアミノシリカゲルカラムクロマトグラフィー［ジクロロメタン／メタノール］で精製することにより標題化合物（130mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.16(1H,d,J=8.6Hz),7.35-7.28(3H,m),7.20-6.90(5H,m),6.51(1H,s),4.73(2H,s),4.45(1H,dd,J=7.0,7.0Hz),3.86(3H,s),3.07-2.96(1H,m),2.88-2.76(1H,m),2.62-2.51(1H,m),2.29(3H,s),1.81-1.56(1H,m).
[工程１２]　[3-(6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル)-5-メトキシ-フェニル]メタノール Ca. 4 mol / L hydrogen chloride / 1,4-dioxane (4 mL) was added to a tetrahydrofuran (4 mL) solution of the compound (200 mg) obtained in Step 10 above, and the mixture was stirred at room temperature for 3 hours. The mixture was neutralized with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography [dichloromethane / methanol] to give the title compound (130 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 8.16 (1H, d, J = 8.6Hz), 7.35-7.28 (3H, m), 7.20-6.90 (5H, m), 6.51 (1H, s), 4.73 (2H , s), 4.45 (1H, dd, J = 7.0,7.0Hz), 3.86 (3H, s), 3.07-2.96 (1H, m), 2.88-2.76 (1H, m), 2.62-2.51 (1H, m ), 2.29 (3H, s), 1.81-1.56 (1H, m).
[Step 12] [3- (6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl) -5-methoxy-phenyl] methanol
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　上記工程１１で得られた化合物（130mg）のテトラヒドロフラン（5.62mL）及びメタノール（5.62mL）溶液に炭酸セシウム（458mg）を加え、70℃で5時間攪拌した。反応液を減圧留去した後、得られた残留物をアミノシリカゲルカラムクロマトグラフィー［ジクロロメタン／メタノール］で精製することにより標題化合物（50mg）を黄色固体として得た。
1H-NMR(MeOH-d4)δppm:7.41(1H,s),7.34-7.28(2H,m),7.19(1H,d,J=8.2Hz),6.91(1H,s),6.79(1H,s),4.68(2H,s),4.50(1H,dd,J=6.6,6.6Hz),3.91(3H,s),3.35-3.20(1H,m),3.08-2.96(1H,m),2.67-2.56(1H,m),1.95-1.85(1H,m).
実施例２　[3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-5-メトキシ-フェニル]メタノール
[工程１]　tert-ブチル N-[(6R)-2-[3-(ヒドロキシメチル)-5-メトキシ-フェニル]-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート；tert-ブチル N-[(6S)-2-[3-(ヒドロキシメチル)-5-メトキシ-フェニル]-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Cesium carbonate (458 mg) was added to a solution of the compound (130 mg) obtained in Step 11 above in tetrahydrofuran (5.62 mL) and methanol (5.62 mL), and the mixture was stirred at 70 ° C. for 5 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography [dichloromethane / methanol] to give the title compound (50 mg) as a yellow solid.
1 H-NMR (MeOH-d4) δ ppm: 7.41 (1H, s), 7.34-7.28 (2H, m), 7.19 (1H, d, J = 8.2 Hz), 6.91 (1H, s), 6.79 (1H, s), 4.68 (2H, s), 4.50 (1H, dd, J = 6.6, 6.6Hz), 3.91 (3H, s), 3.35-3.20 (1H, m), 3.08-2.96 (1H, m), 2.67 -2.56 (1H, m), 1.95-1.85 (1H, m).
Example 2 [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-methoxy-phenyl] methanol
[Step 1] tert-Butyl N-[(6R) -2- [3- (hydroxymethyl) -5-methoxy-phenyl] -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [ e] Indol-6-yl] carbamate; tert-butyl N-[(6S) -2- [3- (hydroxymethyl) -5-methoxy-phenyl] -3- (p-tolylsulfonyl) -7,8- Dihydro-6H-cyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　実施例１工程１０で得られた化合物（240mg）の光学分割をカラムクロマトグラフィー（株式会社ダイセル キラルフラッシュIC、ヘキサン／イソプロピルアルコール（IPA）＝50%→100%）を用いて行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル N-[(6R)-2-[3-(ヒドロキシメチル)-5-メトキシ-フェニル]-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート（0.115g，光学純度>98%ee）を無色油状物質として得た。また、後から溶出する第二ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル N-[(6S)-2-[3-(ヒドロキシメチル)-5-メトキシ-フェニル]-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート（0.110g，光学純度>98%ee）を無色油状物質として得た。
分析条件：キラルカラムIC、Hexane/IPA = 30/70、流速1.0mL/min、吸収波長254nm
1st peak（R体）；保持時間（rt）= 6.1min, >98%ee
2nd peak（S体）；保持時間（rt）= 20.4min, >98%ee
[工程２]　[3-[(6R)-6-アミノ-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-2-イル]-5-メトキシ-フェニル]メタノール Example 1 Optical resolution of the compound (240 mg) obtained in Step 10 was performed using column chromatography (Daicel Chiral Flash IC, hexane / isopropyl alcohol (IPA) = 50% → 100%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl N-[(6R) -2- [3- (hydroxymethyl) -5-methoxy-phenyl] -3 -(p-Tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-6-yl] carbamate (0.115 g, optical purity> 98% ee) was obtained as a colorless oil. Further, after collecting the second peak eluting later, the solvent was distilled off under reduced pressure, and tert-butyl N-[(6S) -2- [3- (hydroxymethyl) -5-methoxy-phenyl] -3- (p-Tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-6-yl] carbamate (0.110 g, optical purity> 98% ee) was obtained as a colorless oil.
Analysis conditions: Chiral column IC, Hexane / IPA = 30/70, flow rate 1.0 mL / min, absorption wavelength 254 nm
1st peak (R body); retention time (rt) = 6.1 min,> 98% ee
2nd peak (S body); retention time (rt) = 20.4min,> 98% ee
[Step 2] [3-[(6R) -6-amino-3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-2-yl] -5-methoxy-phenyl] methanol
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　上記工程１で第一ピークとして得られた化合物（120mg）を用いて実施例１工程１１と同様の手法により標題化合物（80mg）を白色固体として得た。この固体は精製せずそのまま工程３で用いた。
[工程３]　[3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-5-メトキシ-フェニル]メタノール Using the compound (120 mg) obtained as the first peak in Step 1 above, the title compound (80 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1. This solid was used directly in step 3 without purification.
[Step 3] [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-methoxy-phenyl] methanol
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
　上記工程２で得られた化合物（80mg）を用いて実施例１工程１２と同様の手法により標題化合物（25mg）を白色固体として得た。
1H-NMR(MeOH-d4)δppm:7.41(1H,s),7.34-7.28(2H,m),7.19(1H,d,J=8.2Hz),6.91(1H,s),6.80(1H,d,J=0.8Hz),4.68(2H,s),4.51(1H,dd,J=6.6,6.6Hz),3.91(3H,s),3.35-3.20(1H,m),3.08-2.96(1H,m),2.67-2.56(1H,m),1.95-1.85(1H,m).
実施例３　3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-5-(ヒドロキシメチル)ベンゾニトリル
[工程１]　メチル 3-[6-(tert-ブトキシカルボニルアミノ)-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-2-イル]-5-シアノ-ベンゾエート Using the compound (80 mg) obtained in the above Step 2, the title compound (25 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δ ppm: 7.41 (1H, s), 7.34-7.28 (2H, m), 7.19 (1H, d, J = 8.2 Hz), 6.91 (1H, s), 6.80 (1H, d, J = 0.8Hz), 4.68 (2H, s), 4.51 (1H, dd, J = 6.6,6.6Hz), 3.91 (3H, s), 3.35-3.20 (1H, m), 3.08-2.96 (1H , m), 2.67-2.56 (1H, m), 1.95-1.85 (1H, m).
Example 3 3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5- (hydroxymethyl) benzonitrile
[Step 1] Methyl 3- [6- (tert-butoxycarbonylamino) -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-2-yl] -5-cyano- Benzoate
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　実施例１工程８で得られた化合物（300mg）及びメチル 3-シアノ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾエート（256mg）を用いて実施例１工程９と同様の手法により標題化合物（260mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.43-8.40(1H,m),8.38(1H,m),8.16(1H,d,J=8.6Hz),7.96(1H,m),7.36(1H,d,J=8.6Hz),7.30-7.23(2H,m),7.10(1H,d,J=8.2Hz),6.63(1H,s),5.34-5.30(1H,m),4.85(1H,m),4.00(3H,s),3.10-2.99(1H,m),2.93-2.80(1H,m),2.71-2.60(1H,m),2.32(3H,s),1.95-1.80(1H,m),1.51(9H,s).
[工程２]　tert-ブチル N-[2-[3-シアノ-5-(ヒドロキシメチル)フェニル]-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Example 1 Compound (300 mg) obtained in Step 8 and methyl 3-cyano-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (256 mg) Was used to give the title compound (260 mg) as a white solid in the same manner as in Example 1, Step 9.
1 H-NMR (CDCl 3 ) δppm: 8.43-8.40 (1H, m), 8.38 (1H, m), 8.16 (1H, d, J = 8.6Hz), 7.96 (1H, m), 7.36 (1H, d , J = 8.6Hz), 7.30-7.23 (2H, m), 7.10 (1H, d, J = 8.2Hz), 6.63 (1H, s), 5.34-5.30 (1H, m), 4.85 (1H, m) , 4.00 (3H, s), 3.10-2.99 (1H, m), 2.93-2.80 (1H, m), 2.71-2.60 (1H, m), 2.32 (3H, s), 1.95-1.80 (1H, m) , 1.51 (9H, s).
[Step 2] tert-Butyl N- [2- [3-Cyano-5- (hydroxymethyl) phenyl] -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indole-6 -Il] Carbamate
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　上記工程１で得られた化合物（230mg）を用いて実施例１工程１０と同様の手法により標題化合物（180mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.15(1H,d,J=8.6Hz),7.83-7.79(1H,m),7.76-7.73(1H,m),7.63-7.60(1H,m),7.34(1H,md,J=8.6Hz),7.31-7.23(2H,m),7.10(1H,d,J=7.8Hz),6.57(1H,d,J=0.8Hz),5.33(1H,m),4.83(2H,d,J=5.9Hz),4.80-4.70(1H,m),3.09-2.94(1H,m),2.94-2.80(1H,m),2.70-2.58(1H,m),2.32(3H,s),1.95-1.80(1H,m),1.51(9H,s).
 [工程３]　tert-ブチル N-[(6R)-2-[3-シアノ-5-(ヒドロキシメチル)フェニル]-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート；tert-ブチル N-[(6S)-2-[3-シアノ-5-(ヒドロキシメチル)フェニル]-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Using the compound (230 mg) obtained in the above Step 1, the title compound (180 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.15 (1H, d, J = 8.6Hz), 7.83-7.79 (1H, m), 7.76-7.73 (1H, m), 7.63-7.60 (1H, m), 7.34 (1H, md, J = 8.6Hz), 7.31-7.23 (2H, m), 7.10 (1H, d, J = 7.8Hz), 6.57 (1H, d, J = 0.8Hz), 5.33 (1H, m) , 4.83 (2H, d, J = 5.9Hz), 4.80-4.70 (1H, m), 3.09-2.94 (1H, m), 2.94-2.80 (1H, m), 2.70-2.58 (1H, m), 2.32 (3H, s), 1.95-1.80 (1H, m), 1.51 (9H, s).
[Step 3] tert-Butyl N-[(6R) -2- [3-cyano-5- (hydroxymethyl) phenyl] -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e ] Indol-6-yl] carbamate; tert-butyl N-[(6S) -2- [3-cyano-5- (hydroxymethyl) phenyl] -3- (p-tolylsulfonyl) -7,8-dihydro- 6H-cyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　上記工程２で得られた化合物（180mg）の光学分割をカラムクロマトグラフィー（株式会社ダイセル キラルフラッシュIC、ヘキサン／イソプロピルアルコール＝50%→100%）を用いて行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル N-[(6R)-2-[3-シアノ-5-(ヒドロキシメチル)フェニル]-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート（0.082g，光学純度＞98%ee）を無色油状物質として得た。また、後から溶出する第二ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル N-[(6S)-2-[3-シアノ-5-(ヒドロキシメチル)フェニル]-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート（0.075g，光学純度＞98%ee）を無色油状物質として得た。
分析条件：キラルカラムIC、Hexane/IPA = 30/70、流速1.0 mL/min、吸収波長254nm
1st peak（R体）；保持時間（rt）= 6.4min, >98%ee
2nd peak（S体）；保持時間（rt）= 13.9min, >98%ee
[工程４]　3-[(6R)-6-アミノ-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-2-イル]-5-(ヒドロキシメチル)ベンゾニトリル Optical resolution of the compound (180 mg) obtained in the above Step 2 was performed using column chromatography (Daicel Chiral Flash IC, hexane / isopropyl alcohol = 50% → 100%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl N-[(6R) -2- [3-cyano-5- (hydroxymethyl) phenyl] -3- (p-Tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-6-yl] carbamate (0.082 g, optical purity> 98% ee) was obtained as a colorless oil. Further, after collecting the second peak eluting later, the solvent was distilled off under reduced pressure, and tert-butyl N-[(6S) -2- [3-cyano-5- (hydroxymethyl) phenyl]- 3- (p-Tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-6-yl] carbamate (0.075 g, optical purity> 98% ee) was obtained as a colorless oil.
Analysis conditions: Chiral column IC, Hexane / IPA = 30/70, flow rate 1.0 mL / min, absorption wavelength 254 nm
1st peak (R body); retention time (rt) = 6.4min,> 98% ee
2nd peak (S body); retention time (rt) = 13.9min,> 98% ee
[Step 4] 3-[(6R) -6-amino-3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-2-yl] -5- (hydroxymethyl) benzo Nitrile
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　上記工程３で第一ピークとして得られた化合物（85mg）を用いて実施例１工程１１と同様の手法により標題化合物（45mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.15(1H,d,J=8.6Hz),7.80(1H,s),7.72(1H,s),7.64(1H,s),7.35(1H,d,J=8.6Hz),7.29-7.23(2H,m),7.09(1H,d,J=8.2Hz),6.57(1H,s),4.80(2H,s),4.46(1H,dd,J=7.2,7.2Hz),3.09-2.99(1H,m),2.90-2.78(1H,m),2.64-2.53(1H,m),2.31(3H,s),1.88-1.70(1H,m).
[工程５]　3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-5-(ヒドロキシメチル)ベンゾニトリル The title compound (45 mg) was obtained as a white solid in the same manner as in Example 1, Step 11 using the compound (85 mg) obtained as the first peak in Step 3 above.
1 H-NMR (CDCl 3 ) δ ppm: 8.15 (1H, d, J = 8.6 Hz), 7.80 (1 H, s), 7.72 (1 H, s), 7.64 (1 H, s), 7.35 (1 H, d, J = 8.6Hz), 7.29-7.23 (2H, m), 7.09 (1H, d, J = 8.2Hz), 6.57 (1H, s), 4.80 (2H, s), 4.46 (1H, dd, J = 7.2, 7.2Hz), 3.09-2.99 (1H, m), 2.90-2.78 (1H, m), 2.64-2.53 (1H, m), 2.31 (3H, s), 1.88-1.70 (1H, m).
[Step 5] 3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5- (hydroxymethyl) benzonitrile
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　上記工程４で得られた化合物（40mg）を用いて実施例１工程１２と同様の手法により標題化合物（17.8mg）を黄色固体として得た。
1H-NMR(MeOH-d4)δppm:8.10(1H,s),8.07(1H,s),7.64(1H,s),7.34(1H,d,J=8.2Hz),7.25(1H,d,J=8.2Hz),6.95(1H,s),4.75(2H,s),4.54(1H,dd,J=6.7,6.7Hz),3.36-3.20(1H,m),3.10-3.00(1H,m),2.70-2.57(1H,m),2.00-1.90(1H,m).
実施例４　2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル {3-[(4-メチルフェニル)スルホニル]-2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル}カルバメート Using the compound (40 mg) obtained in the above Step 4, the title compound (17.8 mg) was obtained as a yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δ ppm: 8.10 (1H, s), 8.07 (1H, s), 7.64 (1H, s), 7.34 (1H, d, J = 8.2 Hz), 7.25 (1H, d, J = 8.2Hz), 6.95 (1H, s), 4.75 (2H, s), 4.54 (1H, dd, J = 6.7,6.7Hz), 3.36-3.20 (1H, m), 3.10-3.00 (1H, m ), 2.70-2.57 (1H, m), 2.00-1.90 (1H, m).
Example 4 2- [4- (Methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-butyl {3-[(4-methylphenyl) sulfonyl] -2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6- Il} Carbamate
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　実施例１工程８で得られた化合物（150mg）及び(4-メチルスルホニルフェニル)ボロン酸（89mg）を用いて実施例１工程９と同様の手法により標題化合物（150mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.18-8.14(1H,m),8.02-7.99(2H,m),7.77-7.73(2H,m),7.36-7.27(6H,m),7.11-7.07(2H,m),6.61(1H,s),5.32-5.22(1H,m),4.82-4.72(1H,m),3.16(3H,s),3.12-3.00(1H,m),2.93-2.81(1H,m),2.64(1H,s),2.31(3H,s).1.93-1.83(1H,m),1.51(9H,s).
[工程２]　3-[(4-メチルフェニル)スルホニル]-2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (150 mg) obtained in Example 1 Step 8 and (4-methylsulfonylphenyl) boronic acid (89 mg), the title compound (150 mg) was obtained as a white solid by the same method as Example 1 Step 9. .
1 H-NMR (CDCl 3 ) δ ppm: 8.18-8.14 (1H, m), 8.02-7.99 (2H, m), 7.77-7.73 (2H, m), 7.36-7.27 (6H, m), 7.11-7.07 ( 2H, m), 6.61 (1H, s), 5.32-5.22 (1H, m), 4.82-4.72 (1H, m), 3.16 (3H, s), 3.12-3.00 (1H, m), 2.93-2.81 ( 1H, m), 2.64 (1H, s), 2.31 (3H, s) .1.93-1.83 (1H, m), 1.51 (9H, s).
[Step 2] 3-[(4-Methylphenyl) sulfonyl] -2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　上記工程１で得られた化合物（355mg）を用いて実施例１工程１１と同様の手法により標題化合物（251mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.16-8.14(1H,m),8.00-7.96(2H,m),7.75-7.71(2H,m),7.36-7.32(1H,m),7.28-7.24(2H,m),7.08-7.03(2H,m),6.59(1H,s),4.48-4.41(1H,m),3.13(3H,s),3.07-2.98(1H,m),2.86-2.78(1H,m),2.60-2.52(1H,m),2.28(3H,s),1.80-1.69(1H,m).
[工程３]　2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (355 mg) obtained in the above Step 1, the title compound (251 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.16-8.14 (1H, m), 8.00-7.96 (2H, m), 7.75-7.71 (2H, m), 7.36-7.32 (1H, m), 7.28-7.24 ( 2H, m), 7.08-7.03 (2H, m), 6.59 (1H, s), 4.48-4.41 (1H, m), 3.13 (3H, s), 3.07-2.98 (1H, m), 2.86-2.78 ( 1H, m), 2.60-2.52 (1H, m), 2.28 (3H, s), 1.80-1.69 (1H, m).
[Step 3] 2- [4- (Methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　上記工程２で得られた化合物（250mg）を用いて実施例１工程１２と同様の手法により標題化合物（92mg）を黄色固体として得た。
1H-NMR(CD3OD)δppm:8.05-7.95(4H,m),7.33-7.28(1H,m),7.25-7.21(1H,m),6.99(1H,s),4.49-4.43(1H,m),3.30-3.20(1H,m),3.15(3H,s),3.03-2.95(1H,m),2.63-2.55(1H,m),1.93-1.82(1H,m).
実施例５　1-[3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-5-フルオロ-フェニル]エタン-1,2-ジオール
[工程１]　エチル 3-{6-[(tert-ブトキシカルボニル)アミノ]-3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル}-5-フルオロベンゾエート Using the compound (250 mg) obtained in the above Step 2, the title compound (92 mg) was obtained as a yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CD 3 OD) δ ppm: 8.05-7.95 (4H, m), 7.33-7.28 (1H, m), 7.25-7.21 (1H, m), 6.99 (1H, s), 4.49-4.43 (1H , m), 3.30-3.20 (1H, m), 3.15 (3H, s), 3.03-2.95 (1H, m), 2.63-2.55 (1H, m), 1.93-1.82 (1H, m).
Example 5 1- [3-[(6R) -6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-fluoro-phenyl] ethane-1,2- Diol
[Step 1] Ethyl 3- {6-[(tert-butoxycarbonyl) amino] -3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-2- Il} -5-fluorobenzoate
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　実施例１工程８で得られた化合物（350mg）、水（2.7mL）及び3-フルオロ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸メチル（233mg）を用いて実施例１工程９と同様の手法により標題化合物（360mg）を黄色固体として得た。
1H-NMR(CDCl3)δppm:8.19(1H,d,J=8.6Hz),7.99(1H,t,J=1.4Hz),7.82(1H,dd,J=5.9,4.3Hz),7.50-7.47(1H,m),7.37(1H,d,J=8.6Hz),7.32(2H,d,J=8.2Hz),7.11(2H,d,J=8.2Hz),6.61(1H,s),5.33-5.26(1H,m),4.82(1H,d,J=7.4Hz),4.00(3H,s),3.09-3.03(1H,m),2.93-2.85(1H,m),2.67-2.60(1H,m),2.33(3H,s),1.92-1.87(1H,m),1.53(9H,s).
[工程２]　tert-ブチル N-[(6R)-2-[3-フルオロ-5-(ヒドロキシメチル)フェニル]-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Example 1 Compound obtained in Step 8 (350 mg), water (2.7 mL) and 3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) The title compound (360 mg) was obtained as a yellow solid in the same manner as in Example 1, Step 9 using methyl benzoate (233 mg).
1 H-NMR (CDCl 3 ) δppm: 8.19 (1H, d, J = 8.6Hz), 7.99 (1H, t, J = 1.4Hz), 7.82 (1H, dd, J = 5.9,4.3Hz), 7.50- 7.47 (1H, m), 7.37 (1H, d, J = 8.6Hz), 7.32 (2H, d, J = 8.2Hz), 7.11 (2H, d, J = 8.2Hz), 6.61 (1H, s), 5.33-5.26 (1H, m), 4.82 (1H, d, J = 7.4Hz), 4.00 (3H, s), 3.09-3.03 (1H, m), 2.93-2.85 (1H, m), 2.67-2.60 ( 1H, m), 2.33 (3H, s), 1.92-1.87 (1H, m), 1.53 (9H, s).
[Step 2] tert-butyl N-[(6R) -2- [3-fluoro-5- (hydroxymethyl) phenyl] -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e ] Indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　上記工程１で得られた化合物（360mg）を用いて実施例１工程１０と同様の手法により得られたラセミ体混合物を、セミ分取カラムCHIRALPAK IC（株式会社ダイセル；イソプロピルアルコール：ヘキサン＝50：50－100：0、流速20mL/min）を用いて光学分割を行い、標題化合物（192mg）を白色固体として得た。
HPLC分析条件；CHIRALPAK IC（φ4.6mm，250mm）、1.0mL/min、ヘキサン：イソプロパノール＝50：50（v/v）、R体；5.5min、S体；20.0min
1H-NMR(CDCl3)δppm:8.17(1H,d,J=8.2Hz),7.35-7.33(4H,m),7.19(1H,d,J=9.0Hz),7.14-7.01(3H,m),6.56(1H,s),5.30-5.24(1H,m),4.79(2H,s),4.09-4.03(1H,m),3.88-3.62(1H,m),2.92-2.84(1H,m),2.71-2.66(1H,m),2.33(3H,s),1.92-1.86(1H,m),1.53(9H,s).
[工程３]　tert-ブチル N-[(6R)-2-(3-フルオロ-5-ホルミル－フェニル)-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート A racemic mixture obtained by the same procedure as in Example 1, Step 10 using the compound (360 mg) obtained in Step 1 above was prepared as a semi-preparative column CHIRALPAK IC (Daicel Corporation; isopropyl alcohol: hexane = 50: The title compound (192 mg) was obtained as a white solid by optical resolution using 50-100: 0, flow rate 20 mL / min).
HPLC analysis conditions: CHIRALPAK IC (φ4.6 mm, 250 mm), 1.0 mL / min, hexane: isopropanol = 50: 50 (v / v), R-form; 5.5 min, S-form; 20.0 min
1 H-NMR (CDCl 3 ) δppm: 8.17 (1H, d, J = 8.2Hz), 7.35-7.33 (4H, m), 7.19 (1H, d, J = 9.0Hz), 7.14-7.01 (3H, m ), 6.56 (1H, s), 5.30-5.24 (1H, m), 4.79 (2H, s), 4.09-4.03 (1H, m), 3.88-3.62 (1H, m), 2.92-2.84 (1H, m ), 2.71-2.66 (1H, m), 2.33 (3H, s), 1.92-1.86 (1H, m), 1.53 (9H, s).
[Step 3] tert-Butyl N-[(6R) -2- (3-Fluoro-5-formyl-phenyl) -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indole -6-yl] carbamate
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　上記工程２で得られた化合物（192mg）をジクロロメタン（30mL）に溶解し、0℃でデスマーチンペルヨージナン（295mg）、炭酸水素ナトリウム（87mg）を加えた。室温で2時間攪拌した後、溶媒を減圧留去した。得られた残留物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］で精製し、標題化合物（190mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:10.01(1H,d,J=1.4Hz),8.13(1H,d,J=8.6Hz),7.78(1H,t,J=1.4Hz),7.60(1H,dt,J=8.0,1.3Hz),7.48(1H,dt,J=8.7,2.1Hz),7.32(1H,d,J=8.6Hz),7.24(2H,d,J=6.1Hz),7.05(2H,d,J=8.2Hz),6.58(1H,s),5.27-5.22(1H,m),4.74(1H,d,J=8.2Hz),3.04-2.97(1H,m),2.88-2.79(1H,m),2.62-2.60(1H,m),2.28(3H,s),1.87-1.77(1H,m),1.47(9H,s).
[工程４]　tert-ブチル N-[(6R)-2-(3-フルオロ-5-ビニル-フェニル)-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート The compound obtained in Step 2 (192 mg) was dissolved in dichloromethane (30 mL), and desmartin periodinane (295 mg) and sodium bicarbonate (87 mg) were added at 0 ° C. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (190 mg) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 10.01 (1H, d, J = 1.4Hz), 8.13 (1H, d, J = 8.6Hz), 7.78 (1H, t, J = 1.4Hz), 7.60 (1H, dt, J = 8.0,1.3Hz), 7.48 (1H, dt, J = 8.7,2.1Hz), 7.32 (1H, d, J = 8.6Hz), 7.24 (2H, d, J = 6.1Hz), 7.05 ( 2H, d, J = 8.2Hz), 6.58 (1H, s), 5.27-5.22 (1H, m), 4.74 (1H, d, J = 8.2Hz), 3.04-2.97 (1H, m), 2.88-2.79 (1H, m), 2.62-2.60 (1H, m), 2.28 (3H, s), 1.87-1.77 (1H, m), 1.47 (9H, s).
[Step 4] tert-Butyl N-[(6R) -2- (3-Fluoro-5-vinyl-phenyl) -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indole -6-yl] carbamate
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　メチルトリフェニルホスホニウムブロミド（160mg）をテトラヒドロフラン（30mL）に溶解し、n-ブチルリチウム（1.6mol/l in hexane，0.30mL，0.4848mmol）を室温で加え、1時間攪拌した。反応溶液に、上記工程３で得られた化合物（190mg）のテトラヒドロフラン溶液（5mL）を加え、室温で12時間攪拌した。溶媒を減圧留去し、得られた残留物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］で精製し、標題化合物（190mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.09(1H,d,J=8.2Hz),7.26-7.19(5H,m),7.06(1H,dd,J=19.9,9.4Hz),6.99(2H,d,J=8.2Hz),6.64(1H,dd,J=17.6,10.9Hz),6.46(1H,s),5.72(1H,d,J=17.6Hz),5.29(1H,d,J=10.9Hz),5.21-5.16(1H,m),4.88(1H,d,J=8.6Hz),2.98-2.92(1H,m),2.82-2.76(1H,m),2.59-2.53(1H,m),2.22(3H,s),1.82-1.77(1H,m),1.45(9H,s).
[工程５]　tert-ブチル N-[(6R)-2-[3-(1,2-ジヒドロキシエチル)-5-フルオロ-フェニル]-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Methyltriphenylphosphonium bromide (160 mg) was dissolved in tetrahydrofuran (30 mL), n-butyllithium (1.6 mol / l in hexane, 0.30 mL, 0.4848 mmol) was added at room temperature, and the mixture was stirred for 1 hour. To the reaction solution was added a tetrahydrofuran solution (5 mL) of the compound (190 mg) obtained in Step 3 above, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (190 mg) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 8.09 (1H, d, J = 8.2Hz), 7.26-7.19 (5H, m), 7.06 (1H, dd, J = 19.9,9.4Hz), 6.99 (2H, d , J = 8.2Hz), 6.64 (1H, dd, J = 17.6,10.9Hz), 6.46 (1H, s), 5.72 (1H, d, J = 17.6Hz), 5.29 (1H, d, J = 10.9Hz) ), 5.21-5.16 (1H, m), 4.88 (1H, d, J = 8.6Hz), 2.98-2.92 (1H, m), 2.82-2.76 (1H, m), 2.59-2.53 (1H, m), 2.22 (3H, s), 1.82-1.77 (1H, m), 1.45 (9H, s).
[Step 5] tert-butyl N-[(6R) -2- [3- (1,2-dihydroxyethyl) -5-fluoro-phenyl] -3- (p-toluylsulfonyl) -7,8-dihydro- 6H-cyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
　上記工程４で得られた化合物（190mg）を1,4-ジオキサン（30mL）と水（1mL）に溶解し、四酸化オスミウム（2.5wt.% tert-ブタノール溶液，0.070mL）、4-メチルモルホリンN-オキシド（61mg）を加え、室温で4時間攪拌した。反応溶液に水を注ぎ、有機層を酢酸エチルで抽出し、食塩水で洗浄した。硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残留物を、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］で精製し、標題化合物（116mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.13(1H,d,J=8.6Hz),7.32(1H,d,J=6.7Hz),7.29-7.25(3H,m),7.17(1H,d,J=9.4Hz),7.09-7.05(3H,m),6.51(1H,s),5.26-5.20(1H,m),4.89-4.85(2H,m),3.84(1H,d,J=11.3Hz),3.71(1H,dd,J=11.3,7.8Hz),3.01(1H,ddd,J=16.1,8.9,3.6Hz),2.88-2.80(1H,m),2.62-2.60(1H,m),2.29(3H,s),1.90-1.85(1H,m),1.51(9H,s).
[工程６]　1-[3-[(6R)-6-アミノ-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-2-イル]-5-フルオロ-フェニル]エタン-1,2-ジオール The compound obtained in Step 4 (190 mg) was dissolved in 1,4-dioxane (30 mL) and water (1 mL), and osmium tetroxide (2.5 wt.% Tert-butanol solution, 0.070 mL), 4-methylmorpholine. N-oxide (61 mg) was added, and the mixture was stirred at room temperature for 4 hours. Water was poured into the reaction solution, and the organic layer was extracted with ethyl acetate and washed with brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (116 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 8.13 (1H, d, J = 8.6Hz), 7.32 (1H, d, J = 6.7Hz), 7.29-7.25 (3H, m), 7.17 (1H, d, J = 9.4Hz), 7.09-7.05 (3H, m), 6.51 (1H, s), 5.26-5.20 (1H, m), 4.89-4.85 (2H, m), 3.84 (1H, d, J = 11.3Hz) , 3.71 (1H, dd, J = 11.3,7.8Hz), 3.01 (1H, ddd, J = 16.1,8.9,3.6Hz), 2.88-2.80 (1H, m), 2.62-2.60 (1H, m), 2.29 (3H, s), 1.90-1.85 (1H, m), 1.51 (9H, s).
[Step 6] 1- [3-[(6R) -6-amino-3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-2-yl] -5-fluoro- Phenyl] ethane-1,2-diol
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
　上記工程５で得られた化合物（116mg）を用いて実施例１工程１１と同様の手法により標題化合物（85mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.11(1H,d,J=8.6Hz),7.31-7.23(4H,m),7.14(1H,d,J=9.4Hz),7.07-7.01(3H,m),6.49(1H,s),4.85-4.82(1H,m),4.41(1H,t,J=7.0Hz),3.81(1H,d,J=9.8Hz),3.68(1H,dd,J=11.3,7.4Hz),3.02-2.96(1H,m),2.83-2.74(1H,m),2.56-2.49(1H,m),2.26(3H,s),2.05-1.97(1H,m),1.77-1.68(1H,m).
[工程７]　1-[3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-5-フルオロ-フェニル]エタン-1,2-ジオール Using the compound (116 mg) obtained in Step 5 above, the title compound (85 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.11 (1H, d, J = 8.6Hz), 7.31-7.23 (4H, m), 7.14 (1H, d, J = 9.4Hz), 7.07-7.01 (3H, m ), 6.49 (1H, s), 4.85-4.82 (1H, m), 4.41 (1H, t, J = 7.0Hz), 3.81 (1H, d, J = 9.8Hz), 3.68 (1H, dd, J = 11.3, 7.4Hz), 3.02-2.96 (1H, m), 2.83-2.74 (1H, m), 2.56-2.49 (1H, m), 2.26 (3H, s), 2.05-1.97 (1H, m), 1.77 -1.68 (1H, m).
[Step 7] 1- [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-fluoro-phenyl] ethane-1,2 -Diol
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　上記工程６で得られた化合物（85mg）を用いて実施例１工程１２と同様の手法により標題化合物（21mg）を白色固体として得た。
1H-NMR(CD3OD)δppm:7.67(1H,s),7.46(1H,dt,J=10.0,2.1Hz),7.32(1H,d,J=8.2Hz),7.21(1H,d,J=8.2Hz),7.09(1H,d,J=9.4Hz),6.85(1H,s),4.79(1H,dd,J=6.7,4.7Hz),4.51(1H,t,J=6.7Hz),3.76-3.67(2H,m),3.29-3.23(1H,m),3.07-2.99(1H,m),2.65-2.59(1H,m),1.95-1.90(1H,m).
実施例６　[5-[(6S)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-2-メチルスルホニル-フェニル]メタノール
[工程１]　メチル 5-{(6R)-6-[(tert-ブトキシカルボニル)アミノ]-3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル}-2-(メチルスルホニル)ベンゾエート Using the compound (85 mg) obtained in the above Step 6, the title compound (21 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CD 3 OD) δppm: 7.67 (1H, s), 7.46 (1H, dt, J = 10.0, 2.1Hz), 7.32 (1H, d, J = 8.2Hz), 7.21 (1H, d, J = 8.2Hz), 7.09 (1H, d, J = 9.4Hz), 6.85 (1H, s), 4.79 (1H, dd, J = 6.7,4.7Hz), 4.51 (1H, t, J = 6.7Hz) 3.76-3.67 (2H, m), 3.29-3.23 (1H, m), 3.07-2.99 (1H, m), 2.65-2.59 (1H, m), 1.95-1.90 (1H, m).
Example 6 [5-[(6S) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -2-methylsulfonyl-phenyl] methanol
[Step 1] Methyl 5-{(6R) -6-[(tert-butoxycarbonyl) amino] -3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] Indol-2-yl} -2- (methylsulfonyl) benzoate
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
　後記実施例１０工程１～５の方法で得られた化合物（770mg）及び2-メチルスルホニル-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸メチル（0.67g）を用いて実施例１工程９と同様の手法により標題化合物（1.0g）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.15(1H,d,J=8.2Hz),8.12(1H,d,J=8.6Hz),7.84(1H,d,J=2.0Hz),7.81(1H,dd,J=8.2,2.0Hz),7.33(1H,d,J=8.6Hz),7.25(2H,d,J=8.2Hz),7.06(2H,d,J=8.2Hz),6.62(1H,s),5.26-5.19(1H,m),4.73(1H,d,J=8.2Hz),3.98(3H,s),3.41(3H,s),3.03-2.96(1H,m),2.87-2.79(1H,m),2.66-2.58(1H,m),2.28(3H,s),1.47(9H,s).
[工程２]　tert-ブチル N-[(6R)-2-[3-(ヒドロキシメチル)-4-メチルスルホニル-フェニル]-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル] Example 10 Compound (770 mg) obtained by the method of Example 10 steps 1 to 5 and 2-methylsulfonyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) The title compound (1.0 g) was obtained as a white solid in the same manner as in Example 1, Step 9 using methyl benzoate (0.67 g).
1 H-NMR (CDCl 3 ) δppm: 8.15 (1H, d, J = 8.2Hz), 8.12 (1H, d, J = 8.6Hz), 7.84 (1H, d, J = 2.0Hz), 7.81 (1H, dd, J = 8.2,2.0Hz), 7.33 (1H, d, J = 8.6Hz), 7.25 (2H, d, J = 8.2Hz), 7.06 (2H, d, J = 8.2Hz), 6.62 (1H, s), 5.26-5.19 (1H, m), 4.73 (1H, d, J = 8.2Hz), 3.98 (3H, s), 3.41 (3H, s), 3.03-2.96 (1H, m), 2.87-2.79 (1H, m), 2.66-2.58 (1H, m), 2.28 (3H, s), 1.47 (9H, s).
[Step 2] tert-Butyl N-[(6R) -2- [3- (hydroxymethyl) -4-methylsulfonyl-phenyl] -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] Indole-6-Ile]
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　上記工程１で得られた化合物（2.8g）を用いて実施例１工程１０と同様の手法により標題化合物（1.58g）を得た。
1H-NMR(CDCl3)δppm:8.11(1H,d,J=8.2Hz),8.07(1H,d,J=8.2Hz),7.71(1H,d,J=1.6Hz),7.66(1H,dd,J=8.2,1.6Hz),7.31(1H,d,J=8.2Hz),7.26(2H,d,J=8.2Hz),7.05(2H,d,J=8.2Hz),6.60(1H,s),5.24-5.21(1H,m),4.99(2H,d,J=6.6Hz),4.73(1H,d,J=5.9Hz),3.23(3H,s),3.03-2.96(1H,m),2.86-2.79(1H,m),2.64-2.59(1H,m),2.27(3H,s),1.85-1.79(1H,m),1.47(9H,s).
[工程３]　[5-[(6R)-6-アミノ-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-2-イル]-2-メチルスルホニル-フェニル]メタノール Using the compound (2.8 g) obtained in Step 1 above, the title compound (1.58 g) was obtained in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.11 (1H, d, J = 8.2Hz), 8.07 (1H, d, J = 8.2Hz), 7.71 (1H, d, J = 1.6Hz), 7.66 (1H, dd, J = 8.2,1.6Hz), 7.31 (1H, d, J = 8.2Hz), 7.26 (2H, d, J = 8.2Hz), 7.05 (2H, d, J = 8.2Hz), 6.60 (1H, s), 5.24-5.21 (1H, m), 4.99 (2H, d, J = 6.6Hz), 4.73 (1H, d, J = 5.9Hz), 3.23 (3H, s), 3.03-2.96 (1H, m ), 2.86-2.79 (1H, m), 2.64-2.59 (1H, m), 2.27 (3H, s), 1.85-1.79 (1H, m), 1.47 (9H, s).
[Step 3] [5-[(6R) -6-amino-3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-2-yl] -2-methylsulfonyl-phenyl ]methanol
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　上記工程２で得られた化合物（700mg）を用いて実施例１工程１１と同様の手法により標題化合物（590mg）を得た。
1H-NMR(CDCl3)δppm:8.92(2H,s),7.25(1H,d,J=8.2Hz),7.16(1H,d,J=8.2Hz),6.80(1H,s),4.42(1H,t,J=6.8Hz),4.02(3H,s),3.21-3.15(1H,m),2.98-2.90(1H,m),2.59-2.51(1H,m),1.86-1.79(1H,m).
[工程４]　[5-[(6S)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-2-メチルスルホニル-フェニル]メタノール Using the compound (700 mg) obtained in the above Step 2, the title compound (590 mg) was obtained in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.92 (2H, s), 7.25 (1H, d, J = 8.2Hz), 7.16 (1H, d, J = 8.2Hz), 6.80 (1H, s), 4.42 ( 1H, t, J = 6.8Hz), 4.02 (3H, s), 3.21-3.15 (1H, m), 2.98-2.90 (1H, m), 2.59-2.51 (1H, m), 1.86-1.79 (1H, m).
[Step 4] [5-[(6S) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -2-methylsulfonyl-phenyl] methanol
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　上記工程３で得られた化合物（660mg）を用いて実施例１工程１２と同様の手法により標題化合物（150mg）を白色固体として得た。
1H-NMR(CD3OD)δppm:8.13(1H,s),8.00(1H,d,J=8.2Hz),7.88(1H,d,J=8.6Hz),7.29(1H,d,J=8.6Hz),7.20(1H,d,J=8.6Hz),6.97(1H,s),5.04(2H,s),4.48(1H,t,J=6.1Hz),3,23-3.22(1H,m),3.20(3H,s),3.03-2.94(1H,m),2.61-2.54(1H,m),1.92-1.82(1H,m).
実施例７　(1R)-1-[3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-5-クロロ-フェニル]エタン-1,2-ジオール
[工程１]　tert-ブチル N-[(6R)-2-(3-クロロ-5-ビニル-フェニル)-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Using the compound (660 mg) obtained in Step 3 above, the title compound (150 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CD 3 OD) δppm: 8.13 (1H, s), 8.00 (1H, d, J = 8.2Hz), 7.88 (1H, d, J = 8.6Hz), 7.29 (1H, d, J = 8.6Hz), 7.20 (1H, d, J = 8.6Hz), 6.97 (1H, s), 5.04 (2H, s), 4.48 (1H, t, J = 6.1Hz), 3, 23-3.22 (1H, m), 3.20 (3H, s), 3.03-2.94 (1H, m), 2.61-2.54 (1H, m), 1.92-1.82 (1H, m).
Example 7 (1R) -1- [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-chloro-phenyl] ethane- 1,2-diol
[Step 1] tert-Butyl N-[(6R) -2- (3-Chloro-5-vinyl-phenyl) -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indole -6-yl] carbamate
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　後記実施例１０工程１～５の方法で得られた化合物（2.5g）及び2-(3-クロロ-5-ビニル-フェニル)-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン（1.00g）を用いて実施例１工程９と同様の手法により標題化合物（250mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.14(1H,d,J=8.6Hz),7.41(1H,s),7.34(1H,s),7.27-7.25(4H,m),7.05(2H,d,J=8.2Hz),6.66(1H,dd,J=17.6,10.9Hz),6.49(1H,s),5.76(1H,d,J=17.6Hz),5.33(1H,d,J=10.9Hz),5.34-5.25(1H,m),4.74(1H,d,J=7.0Hz),3.01-2.96(1H,m),2.87-2.80(1H,m),2.63-2.56(1H,m),2.28(3H,s),1.87-1.78(1H,m),1.44(9H,s).
[工程２]　tert-ブチル N-[(6R)-2-[3-クロロ-5-[(1R)-1,2-ジヒドロキシエチル]フェニル]-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Example 10 Compound (2.5 g) obtained by the method of Example 10 steps 1 to 5 and 2- (3-chloro-5-vinyl-phenyl) -4,4,5,5-tetramethyl-1,3,2 The title compound (250 mg) was obtained as a white solid in the same manner as in Example 1, Step 9 using -dioxaborolane (1.00 g).
1 H-NMR (CDCl 3 ) δ ppm: 8.14 (1H, d, J = 8.6Hz), 7.41 (1H, s), 7.34 (1H, s), 7.27-7.25 (4H, m), 7.05 (2H, d , J = 8.2Hz), 6.66 (1H, dd, J = 17.6,10.9Hz), 6.49 (1H, s), 5.76 (1H, d, J = 17.6Hz), 5.33 (1H, d, J = 10.9Hz) ), 5.34-5.25 (1H, m), 4.74 (1H, d, J = 7.0Hz), 3.01-2.96 (1H, m), 2.87-2.80 (1H, m), 2.63-2.56 (1H, m), 2.28 (3H, s), 1.87-1.78 (1H, m), 1.44 (9H, s).
[Step 2] tert-butyl N-[(6R) -2- [3-chloro-5-[(1R) -1,2-dihydroxyethyl] phenyl] -3- (p-toluylsulfonyl) -7,8 -Dihydro-6H-cyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
　上記工程１で得られた化合物（130mg）をtert-ブチルアルコール（10mL）に溶解し、AD-mix beta（1.0g）を加え、水（2mL）を加えて室温で6時間攪拌した。反応溶液を亜硫酸ナトリウム水溶液に注ぎ、有機物を酢酸エチルで抽出した。食塩水で洗浄後、硫酸ナトリウムで乾燥し、溶媒を留去した。得られた残留物をジオールシリカゲルクロマトグラフィー［ヘキサン／酢酸エチル］で精製し、標題化合物（80mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.09(1H,d,J=8.6Hz),7.41(2H,d,J=1.6Hz),7.27-7.20(4H,m),7.03(2H,d,J=8.6Hz),6.48(1H,s),5.22-5.16(1H,m),4.83-4.78(2H,m),3.83-3.78(1H,m),3.69-3.65(1H,m),3.23(1H,brs),2.97(1H,ddd,J=16.1,8.9,3.6Hz),2.84-2.76(1H,m),2.61-2.57(2H,m),2.25(3H,s),1.86-1.76(1H,m),1.46(9H,s).
[工程３]　(1R)-1-[3-[(6R)-6-アミノ-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-2-イル]-5-クロロ-フェニル]エタン-1,2-ジオール The compound (130 mg) obtained in the above step 1 was dissolved in tert-butyl alcohol (10 mL), AD-mix beta (1.0 g) was added, water (2 mL) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into an aqueous sodium sulfite solution, and the organic matter was extracted with ethyl acetate. After washing with brine, it was dried over sodium sulfate and the solvent was distilled off. The obtained residue was purified by diol silica gel chromatography [hexane / ethyl acetate] to give the title compound (80 mg) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 8.09 (1H, d, J = 8.6Hz), 7.41 (2H, d, J = 1.6Hz), 7.27-7.20 (4H, m), 7.03 (2H, d, J = 8.6Hz), 6.48 (1H, s), 5.22-5.16 (1H, m), 4.83-4.78 (2H, m), 3.83-3.78 (1H, m), 3.69-3.65 (1H, m), 3.23 ( 1H, brs), 2.97 (1H, ddd, J = 16.1,8.9,3.6Hz), 2.84-2.76 (1H, m), 2.61-2.57 (2H, m), 2.25 (3H, s), 1.86-1.76 ( 1H, m), 1.46 (9H, s).
[Step 3] (1R) -1- [3-[(6R) -6-amino-3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-2-yl]- 5-chloro-phenyl] ethane-1,2-diol
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　上記工程２で得られた化合物（80mg）を用いて実施例１工程１１と同様の手法により標題化合物（70mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.09(1H,d,J=8.6Hz),7.40(2H,s),7.27(2H,dd,J=4.9,3.3Hz),7.21(2H,d,J=8.2Hz),7.02(2H,d,J=8.2Hz),6.47(1H,s),5.26(1H,s),4.79(1H,dd,J=7.0,3.5Hz),4.39(1H,t,J=7.0Hz),3.79(1H,dd,J=11.5,3.7Hz),3.66(1H,dd,J=11.7,7.4Hz),2.97(1H,ddd,J=16.1,4.1,2.1Hz),2.81-2.73(1H,m),2.56-2.47(1H,m),2.55(3H,s),1.75-1.66(1H,m).
[工程４]　(1R)-1-[3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-5-クロロ-フェニル]エタン-1,2-ジオール Using the compound (80 mg) obtained in the above Step 2, the title compound (70 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.09 (1H, d, J = 8.6Hz), 7.40 (2H, s), 7.27 (2H, dd, J = 4.9,3.3Hz), 7.21 (2H, d, J = 8.2Hz), 7.02 (2H, d, J = 8.2Hz), 6.47 (1H, s), 5.26 (1H, s), 4.79 (1H, dd, J = 7.0, 3.5Hz), 4.39 (1H, t , J = 7.0Hz), 3.79 (1H, dd, J = 11.5,3.7Hz), 3.66 (1H, dd, J = 11.7,7.4Hz), 2.97 (1H, ddd, J = 16.1,4.1,2.1Hz) , 2.81-2.73 (1H, m), 2.56-2.47 (1H, m), 2.55 (3H, s), 1.75-1.66 (1H, m).
[Step 4] (1R) -1- [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-chloro-phenyl] ethane 1,2-diol
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　上記工程３で得られた化合物（70mg）を用いて実施例１工程１２と同様の手法により標題化合物（20mg）を薄黄色固体として得た。
MS(ESI)m/z:326(M-NH2)+
1H-NMR(CD3OD)δppm:7.68(2H,d,J=9.8Hz),7.28(1H,s),7.24(1H,d,J=8.2Hz),7.14(1H,d,J=8.2Hz),6.77(1H,s),4.70(1H,m),4.42(1H,m),3.69-3.60(2H,m),3.18(1H,ddd,J=14.7,4.9,2.4Hz),2.98-2.91(1H,m),2.57-2.49(1H,m),1.86-1.78(1H,m).
実施例８　2-(6-メトキシピリミジン-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチルN-[2-(2-メトキシピリミジン-5-イル)-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Using the compound (70 mg) obtained in the above Step 3, the title compound (20 mg) was obtained as a pale yellow solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 326 (M-NH 2 ) +
1 H-NMR (CD 3 OD) δ ppm: 7.68 (2H, d, J = 9.8 Hz), 7.28 (1 H, s), 7.24 (1 H, d, J = 8.2 Hz), 7.14 (1 H, d, J = 8.2Hz), 6.77 (1H, s), 4.70 (1H, m), 4.42 (1H, m), 3.69-3.60 (2H, m), 3.18 (1H, ddd, J = 14.7, 4.9, 2.4Hz), 2.98-2.91 (1H, m), 2.57-2.49 (1H, m), 1.86-1.78 (1H, m).
Example 8 2- (6-Methoxypyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-Butyl N- [2- (2-methoxypyrimidin-5-yl) -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-6-yl] Carbamate
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　実施例１工程８で得られた化合物（1.1g）及び2-メトキシ-5-ピリミジンボロン酸（500mg）を用い、実施例１工程９と同様の手法により標題化合物（1.1g）を白色固体として得た。
MS(ESI)m/z：535(M+H)+
1H-NMR(CDCl3)δppm:8.54(2H,d,J=1.2Hz),8.14(1H,d,J=8.6Hz),7.32(1H,d,J=8.6Hz),7.24(2H,d,J=7.8Hz),7.07(1H,d,J=8.2Hz),6.51(1H,s),5.25-5.22(1H,brm),4.81(1H,brs),4.08(3H,s),3.02(1H,ddd,J=15.9,8.7,3.6Hz),2.89-2.81(1H,m),2.63-2.61(1H,m),2.27(3H,s),1.86-1.83(1H,m),1.47(9H,s).
[工程２]　2-(2-メトキシピリミジン-5-イル)-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-アミン Using the compound (1.1 g) obtained in Step 1 of Example 1 and 2-methoxy-5-pyrimidineboronic acid (500 mg), the title compound (1.1 g) was converted to a white solid in the same manner as in Step 1 of Example 1. Obtained.
MS (ESI) m / z: 535 (M + H) +
1 H-NMR (CDCl 3 ) δ ppm: 8.54 (2H, d, J = 1.2Hz), 8.14 (1H, d, J = 8.6Hz), 7.32 (1H, d, J = 8.6Hz), 7.24 (2H, d, J = 7.8Hz), 7.07 (1H, d, J = 8.2Hz), 6.51 (1H, s), 5.25-5.22 (1H, brm), 4.81 (1H, brs), 4.08 (3H, s), 3.02 (1H, ddd, J = 15.9,8.7,3.6Hz), 2.89-2.81 (1H, m), 2.63-2.61 (1H, m), 2.27 (3H, s), 1.86-1.83 (1H, m), 1.47 (9H, s).
[Step 2] 2- (2-Methoxypyrimidin-5-yl) -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　上記工程１で得られた化合物（1.1g）を用いて実施例１工程１１と同様の手法により標題化合物（900mg）を白色固体として得た。
MS(ESI)m/z:435(M+H)+
1H-NMR(CDCl3)δppm:8.54(2H,s),8.16(1H,d,J=8.6Hz),7.33(1H,d,J=8.6Hz),7.24(2H,d,J=8.6Hz),7.06(2H,d,J=8.6Hz),6.51(1H,s),4.44(1H,t,J=7.0Hz),4.08(3H,s),3.04(1H,ddd,J=16.0,8.6,3.5Hz),2.87-2.79(1H,m),2.58-2.55(1H,m),2.27(3H,s),1.77-1.72(1H,m).
[工程３]　2-(6-メトキシピリミジン-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (1.1 g) obtained in the above Step 1, the title compound (900 mg) was obtained as a white solid by the same method as in Step 1 of Example 1.
MS (ESI) m / z: 435 (M + H) +
1 H-NMR (CDCl 3 ) δppm: 8.54 (2H, s), 8.16 (1H, d, J = 8.6Hz), 7.33 (1H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.6 Hz), 7.06 (2H, d, J = 8.6Hz), 6.51 (1H, s), 4.44 (1H, t, J = 7.0Hz), 4.08 (3H, s), 3.04 (1H, ddd, J = 16.0 , 8.6, 3.5Hz), 2.87-2.79 (1H, m), 2.58-2.55 (1H, m), 2.27 (3H, s), 1.77-1.72 (1H, m).
[Step 3] 2- (6-Methoxypyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
　上記工程２で得られた化合物（900mg）を用いて実施例１工程１２と同様の手法により標題化合物（350mg）を白色固体として得た。
MS(ESI)m/z:281(M+H)+
1H-NMR(CD3OD)δppm:8.93(2H,s),7.86(1H,s),7.26(1H,d,J=8.2Hz),7.17(1H,d,J=8.2Hz),6.80(1H,s),4.47(1H,t,J=6.6Hz),4.02(3H,s),3.22-3.19(1H,m),3.01-2.93(1H,m),2.61-2.53(1H,m),1.89-1.86(1H,m).
実施例９　2-(6-エトキシピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル N-[2-(6-エトキシピラジン-2-イル)-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Using the compound (900 mg) obtained in the above Step 2, the title compound (350 mg) was obtained as a white solid by the same method as in Step 1 of Example 1.
MS (ESI) m / z: 281 (M + H) +
1 H-NMR (CD 3 OD) δppm: 8.93 (2H, s), 7.86 (1H, s), 7.26 (1H, d, J = 8.2Hz), 7.17 (1H, d, J = 8.2Hz), 6.80 (1H, s), 4.47 (1H, t, J = 6.6Hz), 4.02 (3H, s), 3.22-3.19 (1H, m), 3.01-2.93 (1H, m), 2.61-2.53 (1H, m ), 1.89-1.86 (1H, m).
Example 9 2- (6-Ethoxypyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-butyl N- [2- (6-ethoxypyrazin-2-yl) -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-6-yl] Carbamate
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　実施例１工程８で得られた化合物（250mg）及び6-エトキシピラジン-2-ボロン酸ピナコールエステル（148mg）を用いて実施例１工程９と同様の手法により標題化合物（87mg）を黄色固体として得た。
MS(ESI)m/z:549(M+H)+
1H-NMR(CDCl3)δppm:8.38(1H,s),8.23(1H,s),8.03(1H,d,J=8.6Hz),7.54(2H,d,J=8.6Hz),7.33(1H,d,J=8.6Hz),7.13(2H,d,J=8.2Hz),6.80(1H,s),5.28-5.23(1H,m),4.79(1H,d,J=8.2Hz),4.39(2H,q,J=7.0Hz),3.07(1H,ddd,J=16.2,8.8,3.5Hz),2.94-2.86(1H,m),2.70-2.62(1H,m),2.32(3H,s),1.92-1.82(1H,m),1.50(9H,s),1.43(3H,t,J=7.0Hz).
[工程２]　2-(6-エトキシピラジン-2-イル)-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-アミン Example 1 Using the compound obtained in Step 8 (250 mg) and 6-ethoxypyrazine-2-boronic acid pinacol ester (148 mg) in the same manner as Example 1 Step 9, the title compound (87 mg) was converted to a yellow solid. Obtained.
MS (ESI) m / z: 549 (M + H) +
1 H-NMR (CDCl 3 ) δ ppm: 8.38 (1H, s), 8.23 (1H, s), 8.03 (1H, d, J = 8.6Hz), 7.54 (2H, d, J = 8.6Hz), 7.33 ( 1H, d, J = 8.6Hz), 7.13 (2H, d, J = 8.2Hz), 6.80 (1H, s), 5.28-5.23 (1H, m), 4.79 (1H, d, J = 8.2Hz), 4.39 (2H, q, J = 7.0Hz), 3.07 (1H, ddd, J = 16.2,8.8,3.5Hz), 2.94-2.86 (1H, m), 2.70-2.62 (1H, m), 2.32 (3H, s), 1.92-1.82 (1H, m), 1.50 (9H, s), 1.43 (3H, t, J = 7.0Hz).
[Step 2] 2- (6-Ethoxypyrazin-2-yl) -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
　上記工程１で得られた化合物（87mg）を用いて実施例１工程１２と同様の手法により標題化合物（40mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.35(1H,s),8.18(1H,s),8.00(1H,d,J=8.6Hz),7.51(2H,d,J=8.6Hz),7.30(1H,d,J=8.6Hz),7.08(2H,d,J=7.8Hz),6.77(1H,s),4.42(1H,m),4.34(2H,q,J=7.0Hz),3.04(1H,ddd,J=16.0,8.6,3.5Hz),2.87-2.78(1H,m),2.56-2.53(1H,m),2.28-2.25(4H,m),1.39(3H,t,J=7.0Hz).
[工程３]　2-(6-エトキシピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (87 mg) obtained in the above Step 1, the title compound (40 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.35 (1H, s), 8.18 (1H, s), 8.00 (1H, d, J = 8.6Hz), 7.51 (2H, d, J = 8.6Hz), 7.30 ( 1H, d, J = 8.6Hz), 7.08 (2H, d, J = 7.8Hz), 6.77 (1H, s), 4.42 (1H, m), 4.34 (2H, q, J = 7.0Hz), 3.04 ( 1H, ddd, J = 16.0,8.6,3.5Hz), 2.87-2.78 (1H, m), 2.56-2.53 (1H, m), 2.28-2.25 (4H, m), 1.39 (3H, t, J = 7.0 Hz).
[Step 3] 2- (6-Ethoxypyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　上記工程２で得られた化合物（40mg）を用いて実施例１工程１２と同様の手法により標題化合物（10mg）を白色固体として得た。
1H-NMR(CD3OD)δppm:8.52(1H,s),7.88(1H,s),7.31(1H,d,J=8.2Hz),7.18(1H,d,J=8.2Hz),7.01(1H,s),4.51(2H,q,J=7.0Hz),4.38(1H,t,J=6.6Hz),3.17(1H,ddd,J=16.0,4.3,2.2Hz),2.96-2.88(1H,m),2.55-2.52(1H,m),1.85-1.76(1H,m),1.41(3H,t,J=7.0Hz).
実施例１０　(6R)-2-(6-メトキシピリミジン-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　(6S)-3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-オール Using the compound (40 mg) obtained in the above Step 2, the title compound (10 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CD 3 OD) δppm: 8.52 (1H, s), 7.88 (1H, s), 7.31 (1H, d, J = 8.2Hz), 7.18 (1H, d, J = 8.2Hz), 7.01 (1H, s), 4.51 (2H, q, J = 7.0Hz), 4.38 (1H, t, J = 6.6Hz), 3.17 (1H, ddd, J = 16.0,4.3,2.2Hz), 2.96-2.88 ( 1H, m), 2.55-2.52 (1H, m), 1.85-1.76 (1H, m), 1.41 (3H, t, J = 7.0Hz).
Example 10 (6R) -2- (6-Methoxypyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] (6S) -3-[(4-Methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-ol
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
　トリエチルアミン（121mL）にギ酸（38.5mL）を0℃で加えた後、30分攪拌した。反応液を室温に戻し、3-[(4-メチルフェニル)スルホニル]-7,8-ジヒドロシクロペンタ[e]インドール-6(3H)-オン（94.1g）のジクロロメタン（940mL）溶液を15分かけて滴下した後、クロロ[(1S,2S)-N-(p-トルエンスルホニル)-1,2-ジフェニルエタンジアミン](メシチレン)ルテニウム(II)（9g）を加えて17時間攪拌した。反応液に水を加えた後、ジクロロメタンで抽出し、有機層を飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物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］で精製することにより標題化合物（84.2g；20%程度の(6R)-体を含む。）を褐色固体として得た。
[工程２]　tert-ブチル (6R)-{3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル}[(2-ニトロフェニル)スルホニル]カルバメート Formic acid (38.5 mL) was added to triethylamine (121 mL) at 0 ° C., followed by stirring for 30 minutes. The reaction solution was returned to room temperature, and a solution of 3-[(4-methylphenyl) sulfonyl] -7,8-dihydrocyclopenta [e] indol-6 (3H) -one (94.1 g) in dichloromethane (940 mL) was added for 15 minutes. After dropwise addition, chloro [(1S, 2S) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium (II) (9 g) was added and stirred for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (84.2 g; containing about 20% of (6R) -form) as a brown solid.
[Step 2] tert-Butyl (6R)-{3-[(4-Methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl} [(2-nitrophenyl ) Sulfonyl] carbamate
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
　上記工程１で得られた化合物（84.2g）を用いて実施例１工程６と同様の手法により標題化合物（178g；20%程度の(6S)-体を含む。）を褐色アモルファス状物質として得た。
[工程３]　tert-ブチル {(6R)-3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル}カルバメート Using the compound (84.2 g) obtained in Step 1 above, the title compound (178 g; containing about 20% of (6S) -form) is obtained as a brown amorphous substance by the same procedure as in Step 1 of Example 1. It was.
[Step 3] tert-butyl {(6R) -3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl} carbamate
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　上記工程２で得られた化合物（157g）を用いて実施例１工程７と同様の手法により標題化合物（62.2g；20%程度の(6S)-体を含む。）を白色固体として得た。
59.8%ee：CHIRALPAK IA（0.46 x 25cm），nHex／EtOH＝40：60，flow rate：0.5mL/min
1st peak：12.09min, 79.9%
2nd peak：14.84min, 20.1%
[工程４]　tert-ブチル N-[(6S)-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート；tert-ブチル N-[(6R)-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Using the compound (157 g) obtained in the above Step 2, the title compound (62.2 g; containing about 20% of (6S) -form) was obtained as a white solid by the same procedure as in Step 1 of Example 1.
59.8% ee: CHIRALPAK IA (0.46 x 25cm), nHex / EtOH = 40: 60, flow rate: 0.5mL / min
1st peak: 12.09min, 79.9%
2nd peak: 14.84min, 20.1%
[Step 4] tert-butyl N-[(6S) -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-6-yl] carbamate; tert-butyl N-[( 6R) -3- (p-Tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
　上記工程３で得られた化合物（67.3g）の光学分割をカラムクロマトグラフィー（株式会社ダイセル キラルセルOJ-H、メタノール100%）を用いて行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル N-[(6S)-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル］カルバメート（14.6g，光学純度>98%ee）を白色固体として得た。また、後から溶出する第二ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル N-[(6R)-3-(p-トリルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート（50.1g，光学純度>98%ee）を白色固体として得た。
分析条件：キラルセルOJ-H、MeOH、流速1.0mL/min、吸収波長297nm
1st peak；保持時間（rt）= 5.5min, >98%ee
2nd peak；保持時間（rt）= 6.8min, >98%ee
[工程５]　tert-ブチル {(6R)-2-ブロモ-3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル}カルバメート Optical resolution of the compound (67.3 g) obtained in the above Step 3 was performed using column chromatography (Daicel Chiralcel OJ-H, methanol 100%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl N-[(6S) -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] Indol-6-yl] carbamate (14.6 g, optical purity> 98% ee) was obtained as a white solid. In addition, after collecting the second peak eluting later, the solvent was distilled off under reduced pressure to obtain tert-butyl N-[(6R) -3- (p-tolylsulfonyl) -7,8-dihydro-6H. -Cyclopenta [e] indol-6-yl] carbamate (50.1 g, optical purity> 98% ee) was obtained as a white solid.
Analysis conditions: Chiralcel OJ-H, MeOH, flow rate 1.0 mL / min, absorption wavelength 297 nm
1st peak; retention time (rt) = 5.5min,> 98% ee
2nd peak; retention time (rt) = 6.8min,> 98% ee
[Step 5] tert-butyl {(6R) -2-bromo-3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl} carbamate
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　上記工程４で第二ピークとして得られた化合物（2.2g）を用いて実施例１工程８と同様の手法により標題化合物（2g）を白色固体として得た。
[工程６]　tert-ブチルN-[(6R)-2-(2-メトキシピリミジン-5-イル)-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Using the compound (2.2 g) obtained as the second peak in Step 4 above, the title compound (2 g) was obtained as a white solid in the same manner as in Step 1 of Example 1.
[Step 6] tert-Butyl N-[(6R) -2- (2-methoxypyrimidin-5-yl) -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indole- 6-yl] carbamate
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　上記工程５で得られた化合物（4.1g）及び2-メトキシ-5-ピリミジンボロン酸（1.9g）を用いて実施例１工程９と同様の手法により標題化合物（3.0g）を白色固体として得た。
MS(ESI)m/z:535(M+H)+
1H-NMR(CDCl3)δppm:8.54(2H,d,J=1.2Hz),8.15(1H,d,J=8.6Hz),7.32(1H,d,J=8.6Hz),7.24(2H,d,J=7.8Hz),7.06(1H,d,J=8.2Hz),6.51(1H,s),5.26-5.21(1H,m),4.75(1H,brs),4.08(3H,s),3.02(1H,ddd,J=16.1,8.9,3.6Hz),2.89-2.81(1H,m),2.66-2.61(1H,m),2.28(3H,s),1.88-1.79(1H,m),1.47(9H,s).
[工程７]　(6R)-2-(2-メトキシピリミジン-5-イル)-3-(p-トルイルスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-アミン Using the compound (4.1 g) obtained in the above Step 5 and 2-methoxy-5-pyrimidineboronic acid (1.9 g), the title compound (3.0 g) was obtained as a white solid by the same method as in Step 1 of Example 1. It was.
MS (ESI) m / z: 535 (M + H) +
1 H-NMR (CDCl 3 ) δ ppm: 8.54 (2H, d, J = 1.2Hz), 8.15 (1H, d, J = 8.6Hz), 7.32 (1H, d, J = 8.6Hz), 7.24 (2H, d, J = 7.8Hz), 7.06 (1H, d, J = 8.2Hz), 6.51 (1H, s), 5.26-5.21 (1H, m), 4.75 (1H, brs), 4.08 (3H, s), 3.02 (1H, ddd, J = 16.1,8.9,3.6Hz), 2.89-2.81 (1H, m), 2.66-2.61 (1H, m), 2.28 (3H, s), 1.88-1.79 (1H, m), 1.47 (9H, s).
[Step 7] (6R) -2- (2-methoxypyrimidin-5-yl) -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　上記工程６で得られた化合物（300mg）を用いて実施例１工程１１と同様の手法により標題化合物（180mg）を白色固体として得た。
MS(ESI)m/z:435(M+H)+
1H-NMR(CDCl3)δppm:8.54(2H,s),8.16(1H,d,J=8.6Hz),7.34(1H,d,J=8.6Hz),7.24(2H,d,J=8.6Hz),7.06(2H,d,J=8.6Hz),6.51(1H,s),4.44(1H,t,J=7.2Hz),4.07(3H,s),3.04(1H,ddd,J=16.0,8.6,3.5Hz),2.87-2.78(1H,m),2.60-2.52(1H,m),2.26(3H,s),1.79-1.70(1H,m).
[工程８]　(6R)-2-(6-メトキシピリミジン-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (300 mg) obtained in the above Step 6, the title compound (180 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 435 (M + H) +
1 H-NMR (CDCl 3 ) δppm: 8.54 (2H, s), 8.16 (1H, d, J = 8.6Hz), 7.34 (1H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.6 Hz), 7.06 (2H, d, J = 8.6Hz), 6.51 (1H, s), 4.44 (1H, t, J = 7.2Hz), 4.07 (3H, s), 3.04 (1H, ddd, J = 16.0 , 8.6, 3.5Hz), 2.87-2.78 (1H, m), 2.60-2.52 (1H, m), 2.26 (3H, s), 1.79-1.70 (1H, m).
[Step 8] (6R) -2- (6-Methoxypyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
　上記工程７で得られた化合物（180mg）を用いて実施例１工程１２と同様の手法により標題化合物（68mg）を白色固体として得た。
1H-NMR(CD3OD)δppm:8.92(2H,s),7.25(1H,d,J=8.2Hz),7.16(1H,d,J=8.2Hz),6.80(1H,s),4.42(1H,t,J=6.8Hz),4.02(3H,s),3.21-3.15(1H,m),2.98-2.90(1H,m),2.59-2.51(1H,m),1.86-1.79(1H,m).
実施例１１　2-(5-メトキシピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　3-[1-(フェニルスルホニル)-1H-インドール-4-イル]プロパノイックアシッド Using the compound (180 mg) obtained in the above Step 7, the title compound (68 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CD 3 OD) δppm: 8.92 (2H, s), 7.25 (1H, d, J = 8.2Hz), 7.16 (1H, d, J = 8.2Hz), 6.80 (1H, s), 4.42 (1H, t, J = 6.8Hz), 4.02 (3H, s), 3.21-3.15 (1H, m), 2.98-2.90 (1H, m), 2.59-2.51 (1H, m), 1.86-1.79 (1H , m).
Example 11 2- (5-Methoxypyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] 3- [1- (Phenylsulfonyl) -1H-indol-4-yl] propanoic acid
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
　エチル3-[1-(ベンゼンスルホニル)インドール-4-イル]プロパノエート（106.17g）を用いて実施例１工程２と同様の手法により標題化合物（95.23g）を淡紫色固体として得た。
1H-NMR(CDCl3)δppm:7.86-7.82(3H,m),7.57-7.55(1H,m),7.52-7.48(1H,m),7.43-7.39(2H,m),7.24-7.19(1H,m),7.05-7.02(1H,m),6.70-6.68(1H,m),3.11(2H,t,J=7.8Hz),2.68(2H,t,J=7.8Hz).
[工程２]　3-[1-(ベンゼンスルホニル)インドール-4-イル]プロパノイルクロリド The title compound (95.23 g) was obtained as a pale purple solid in the same manner as in Example 1, step 2 using ethyl 3- [1- (benzenesulfonyl) indol-4-yl] propanoate (106.17 g).
1 H-NMR (CDCl 3 ) δ ppm: 7.86-7.82 (3H, m), 7.57-7.55 (1H, m), 7.52-7.48 (1H, m), 7.43-7.39 (2H, m), 7.24-7.19 ( 1H, m), 7.05-7.02 (1H, m), 6.70-6.68 (1H, m), 3.11 (2H, t, J = 7.8Hz), 2.68 (2H, t, J = 7.8Hz).
[Step 2] 3- [1- (Benzenesulfonyl) indol-4-yl] propanoyl chloride
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　上記工程１で得られた化合物（95.23g）を用いて実施例１工程３と同様の手法により標題化合物（100.6g）を黒色油状物質として得た。
1H-NMR(CDCl3)δppm:7.90-7.86(3H,m),7.62-7.59(1H,m),7.56-7.51(1H,m),7.47-7.42(2H,m),7.27-7.22(1H,m),7.05-7.03(1H,m),6.69-6.67(1H,m),3.24-3.16(4H,m).
[工程３]　3-(フェニルスルホニル)-7,8-ジヒドロシクロペンタ[e]インドール-6(3H)-オン Using the compound (95.23 g) obtained in the above Step 1, the title compound (100.6 g) was obtained as a black oily substance in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 7.90-7.86 (3H, m), 7.62-7.59 (1H, m), 7.56-7.51 (1H, m), 7.47-7.42 (2H, m), 7.27-7.22 ( 1H, m), 7.05-7.03 (1H, m), 6.69-6.67 (1H, m), 3.24-3.16 (4H, m).
[Step 3] 3- (Phenylsulfonyl) -7,8-dihydrocyclopenta [e] indole-6 (3H) -one
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
　上記工程２で得られた化合物（100.6g）を用いて実施例１工程４と同様の手法により標題化合物（78.5g）を薄黄茶色固体として得た。
1H-NMR(CDCl3)δppm:8.01-7.97(1H,m),7.90-7.87(2H,m),7.70-7.65(2H,m),7.57-7.52(1H,m),7.47-7.42(2H,m),6.79-6.77(1H,m),3.23-3.18(2H,m),2.73-2.70(2H,m).
[工程４]　3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-オール Using the compound (100.6 g) obtained in the above Step 2, the title compound (78.5 g) was obtained as a light yellow brown solid by the same method as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.01-7.97 (1H, m), 7.90-7.87 (2H, m), 7.70-7.65 (2H, m), 7.57-7.52 (1H, m), 7.47-7.42 ( 2H, m), 6.79-6.77 (1H, m), 3.23-3.18 (2H, m), 2.73-2.70 (2H, m).
[Step 4] 3- (Phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-ol
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　上記工程３で得られた化合物（5.5g）を用いて実施例１工程５と同様の手法により標題化合物（4.48g）を得た。
1H-NMR(CDCl3)δppm:7.90-7.83(3H,m),7.60-7.57(1H,m),7.52-7.48(1H,m),7.43-7.38(2H,m),7.36-7.32(1H,m),6.61-6.58(1H,m),5.33-5.27(1H,m),3.20-3.11(1H,m),2.92-2.85(1H,m),2.57-2.49(1H,m),2.05-1.95(1H,m).
[工程５]　tert-ブチル [(2-ニトロフェニル)スルホニル][3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (5.5 g) obtained in the above Step 3, the title compound (4.48 g) was obtained in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 7.90-7.83 (3H, m), 7.60-7.57 (1H, m), 7.52-7.48 (1H, m), 7.43-7.38 (2H, m), 7.36-7.32 ( 1H, m), 6.61-6.58 (1H, m), 5.33-5.27 (1H, m), 3.20-3.11 (1H, m), 2.92-2.85 (1H, m), 2.57-2.49 (1H, m), 2.05-1.95 (1H, m).
[Step 5] tert-Butyl [(2-nitrophenyl) sulfonyl] [3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
　上記工程４で得られた化合物（4.48g）を用いて実施例１工程６と同様の手法により標題化合物（7.91g）を得た。
1H-NMR(CDCl3)δppm:8.45-8.41(1H,m),7.83-7.73(5H,m),7.58-7.55(1H,m),7.48-7.44(1H,m),7.40-7.34(2H,m),7.25-7.21(1H,m),6.59-6.55(1H,m),6.02-5.97(1H,m),3.21-3.12(1H,m),3.02-2.94(1H,m),2.86-2.77(1H,m),2.45-2.36(1H,m),0.83(9H,s).
[工程６]　tert-ブチル [(6R)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (4.48 g) obtained in the above Step 4, the title compound (7.91 g) was obtained in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.45-8.41 (1H, m), 7.83-7.73 (5H, m), 7.58-7.55 (1H, m), 7.48-7.44 (1H, m), 7.40-7.34 ( 2H, m), 7.25-7.21 (1H, m), 6.59-6.55 (1H, m), 6.02-5.97 (1H, m), 3.21-3.12 (1H, m), 3.02-2.94 (1H, m), 2.86-2.77 (1H, m), 2.45-2.36 (1H, m), 0.83 (9H, s).
[Step 6] tert-Butyl [(6R) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
　上記工程５で得られた化合物（9.75g）を用いて実施例１工程７と同様の手法により標題化合物（18.6g）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.86-7.82(3H,m),7.58-7.56(1H,m),7.52-7.48(1H,m),7.43-7.38(2H,m),7.25-7.23(1H,m),6.58-6.56(1H,m),5.26-5.17(1H,m),4.72-4.65(1H,m),3.10-3.00(1H,m),2.91-2.83(1H,m),2.67-2.55(1H,m),1.88-1.79(1H,m),1.45(12H,s).
[工程７]　tert-ブチル [3-(フェニルスルホニル)-2-(トリブチルスタナニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (9.75 g) obtained in the above Step 5, the title compound (18.6 g) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 7.86-7.82 (3H, m), 7.58-7.56 (1H, m), 7.52-7.48 (1H, m), 7.43-7.38 (2H, m), 7.25-7.23 ( 1H, m), 6.58-6.56 (1H, m), 5.26-5.17 (1H, m), 4.72-4.65 (1H, m), 3.10-3.00 (1H, m), 2.91-2.83 (1H, m), 2.67-2.55 (1H, m), 1.88-1.79 (1H, m), 1.45 (12H, s).
[Step 7] tert-Butyl [3- (phenylsulfonyl) -2- (tributylstannanyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　1.1M リチウムジイソプロピルアミド（in n-hexane-tetrahydrofuran，5.1mL）のテトラヒドロフラン（81mL）溶液を-78℃に冷却後、上記工程６で得られた化合物（1g）のテトラヒドロフラン（3mL）溶液をゆっくりと滴下した。同温度で20分攪拌後、ヨウ化トリブチルスズ（1.59mL）を加え、同温度で10分間攪拌した。反応液に水を加えた後、室温に昇温した。酢酸エチルで抽出後、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た後ろ過し、ろ液を減圧留去した。得られた残留物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＝1／0→0／1）で精製した。スズのカスが除去できていなかったため、目的物との混合物を酢酸エチル（200ml）に溶かした後フッ化カリウム（1.37g）の水溶液（100ml）を加えて20分攪拌した。これを酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物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］で精製することにより標題化合物（1.06g）を白色アモルファス状物質として得た。
1H-NMR(CDCl3)δppm:7.67-7.64(1H,m),7.63-7.60(2H,m),7.50-7.45(1H,m),7.39-7.34(2H,m),7.13-7.10(1H,m),6.72-6.68(1H,m),5.25-5.15(1H,m),4.71-4.63(1H,m),3.14-3.04(1H,m),2.95-2.87(1H,m),2.67-2.54(1H,m),1.86-1.81(1H,m),1.61-1.07(27H,m),1.43(9H,s),0.86(9H,t,J=7.2Hz).
[工程８]　tert-ブチル [2-(5-メトキシピラジン-2-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート 1.1M After cooling a solution of lithium diisopropylamide (in n-hexane-tetrahydrofuran, 5.1 mL) in tetrahydrofuran (81 mL) to −78 ° C., slowly add the tetrahydrofuran (3 mL) solution of the compound (1 g) obtained in step 6 above. It was dripped. After stirring at the same temperature for 20 minutes, tributyltin iodide (1.59 mL) was added and stirred at the same temperature for 10 minutes. After adding water to the reaction solution, the temperature was raised to room temperature. After extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/0 → 0/1). Since the residue of tin could not be removed, the mixture with the target product was dissolved in ethyl acetate (200 ml), and then an aqueous solution (100 ml) of potassium fluoride (1.37 g) was added and stirred for 20 minutes. This was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (1.06 g) as a white amorphous substance.
1 H-NMR (CDCl 3 ) δ ppm: 7.67-7.64 (1H, m), 7.63-7.60 (2H, m), 7.50-7.45 (1H, m), 7.39-7.34 (2H, m), 7.13-7.10 ( 1H, m), 6.72-6.68 (1H, m), 5.25-5.15 (1H, m), 4.71-4.63 (1H, m), 3.14-3.04 (1H, m), 2.95-2.87 (1H, m), 2.67-2.54 (1H, m), 1.86-1.81 (1H, m), 1.61-1.07 (27H, m), 1.43 (9H, s), 0.86 (9H, t, J = 7.2Hz).
[Step 8] tert-Butyl [2- (5-methoxypyrazin-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
　上記工程７で得られた化合物（250mg）、2-ブロモ-5-メトキシピラジン（135mg）とN,N-ジメチルホルムアミド（2mL）の混合物に、テトラキス(トリフェニルホスフィン)パラジウム(0)（61.8mg）及びヨウ化銅(I)（20.4mg）を加えて、120℃に昇温して窒素雰囲気下2時間攪拌した。反応溶液を室温に戻し、直接アミノシリカゲルにチャージし、アミノ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］により精製し、標題化合物（116mg）を白色固体として得た。
[工程９]　2-(5-メトキシピラジン-2-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン To a mixture of the compound obtained in Step 7 above (250 mg), 2-bromo-5-methoxypyrazine (135 mg) and N, N-dimethylformamide (2 mL), tetrakis (triphenylphosphine) palladium (0) (61.8 mg ) And copper (I) iodide (20.4 mg) were added, and the mixture was heated to 120 ° C. and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was returned to room temperature, directly charged onto amino silica gel, and purified by amino silica gel column chromatography [hexane / ethyl acetate] to obtain the title compound (116 mg) as a white solid.
[Step 9] 2- (5-Methoxypyrazin-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　上記工程８で得られた化合物（114mg）を用いて実施例１工程１１と同様の手法により標題化合物（75.0mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.43(1H,d,J=1.2Hz),8.30(1H,d,J=1.2Hz),8.08(1H,d,J=8.5Hz),7.67-7.65(2H,m),7.49-7.45(1H,m),7.37-7.32(3H,m),6.78(1H,s),4.47(1H,t,J=6.7Hz),4.06(3H,s),3.11-3.04(1H,m),2.89-2.81(1H,m),2.62-2.53(1H,m),1.83-1.74(1H,m).
[工程１０]　2-(5-メトキシピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン The title compound (75.0 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1 using the compound (114 mg) obtained in the above Step 8.
1 H-NMR (CDCl 3 ) δ ppm: 8.43 (1H, d, J = 1.2 Hz), 8.30 (1 H, d, J = 1.2 Hz), 8.08 (1 H, d, J = 8.5 Hz), 7.67-7.65 ( 2H, m), 7.49-7.45 (1H, m), 7.37-7.32 (3H, m), 6.78 (1H, s), 4.47 (1H, t, J = 6.7Hz), 4.06 (3H, s), 3.11 -3.04 (1H, m), 2.89-2.81 (1H, m), 2.62-2.53 (1H, m), 1.83-1.74 (1H, m).
[Step 10] 2- (5-Methoxypyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
　上記工程９で得られた化合物（73.0mg）を用いて実施例１工程１２と同様の手法により標題化合物（33.2mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.27(1H,brs),8.63(1H,d,J=1.6Hz),8.19(1H,d,J=1.6Hz),7.32-7.30(1H,m),7.22-7.19(1H,m),6.89-6.87(1H,m),4.50(1H,t,J=7.0Hz),4.02(3H,s),3.26-3.19(1H,m),3.04-2.97(1H,m),2.70-2.62(1H,m),1.89-1.79(1H,m).
MS(ESI)m/z:279(M-H)+
実施例１２　[5-(6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル)ピラジン-2-イル]メタノール
[工程１]　メチル 5-{6-[(tert-ブトキシカルボニル)アミノ]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル}ピラジン-2-カルボキシレート Using the compound (73.0 mg) obtained in the above Step 9, the title compound (33.2 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 9.27 (1H, brs), 8.63 (1H, d, J = 1.6Hz), 8.19 (1H, d, J = 1.6Hz), 7.32-7.30 (1H, m), 7.22-7.19 (1H, m), 6.89-6.87 (1H, m), 4.50 (1H, t, J = 7.0Hz), 4.02 (3H, s), 3.26-3.19 (1H, m), 3.04-2.97 ( 1H, m), 2.70-2.62 (1H, m), 1.89-1.79 (1H, m).
MS (ESI) m / z: 279 (MH) +
Example 12 [5- (6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl) pyrazin-2-yl] methanol
[Step 1] Methyl 5- {6-[(tert-butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl} pyrazine-2 -Carboxylate
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
　実施例１１工程７で得られた化合物（300mg）を用いて実施例１１工程８と同様の手法により標題化合物（140mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.37-9.35(1H,m),9.10-9.09(1H,m),8.08(1H,d,J=8.6Hz),7.60-7.58(2H,m),7.52-7.47(1H,m),7.40-7.33(3H,m),7.05(1H,s),5.28-5.22(1H,m),4.78-4.73(1H,m),4.10(3H,s),3.09-3.02(1H,m),2.92-2.84(1H,m),2.69-2.59(1H,m),1.90-1.81(1H,m),1.50(9H,s).
[工程２]　tert-ブチル {2-[5-(ヒドロキシメチル)ピラジン-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル}カルバメート The title compound (140 mg) was obtained as a white solid in the same manner as in Example 11, Step 8 using the compound (300 mg) obtained in Step 7 of Example 11.
1 H-NMR (CDCl 3 ) δppm: 9.37-9.35 (1H, m), 9.10-9.09 (1H, m), 8.08 (1H, d, J = 8.6Hz), 7.60-7.58 (2H, m), 7.52 -7.47 (1H, m), 7.40-7.33 (3H, m), 7.05 (1H, s), 5.28-5.22 (1H, m), 4.78-4.73 (1H, m), 4.10 (3H, s), 3.09 -3.02 (1H, m), 2.92-2.84 (1H, m), 2.69-2.59 (1H, m), 1.90-1.81 (1H, m), 1.50 (9H, s).
[Step 2] tert-butyl {2- [5- (hydroxymethyl) pyrazin-2-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl } Carbamate
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
　上記工程１で得られた化合物（140mg）を用いて実施例１工程１０と同様の手法により標題化合物（110mg）を淡黄色固体として得た。
1H-NMR(CDCl3)δppm:8.91(1H,s),8.70(1H,s),8.07(1H,d,J=8.2Hz),7.62(2H,d,J=7.4Hz),7.50-7.46(1H,m),7.36-7.33(3H,m),6.91(1H,s),5.28-5.21(1H,m),4.95(2H,d,J=5.5Hz),4.76-4.72(1H,m),3.09-3.01(1H,m),2.92-2.83(1H,m),2.69-2.61(1H,m),1.89-1.83(1H,m),1.50(9H,s).
[工程３]　{5-[6-アミノ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}メタノール The title compound (110 mg) was obtained as a pale yellow solid in the same manner as in Step 1 of Example 1 using the compound (140 mg) obtained in the above Step 1.
1 H-NMR (CDCl 3 ) δppm: 8.91 (1H, s), 8.70 (1H, s), 8.07 (1H, d, J = 8.2Hz), 7.62 (2H, d, J = 7.4Hz), 7.50- 7.46 (1H, m), 7.36-7.33 (3H, m), 6.91 (1H, s), 5.28-5.21 (1H, m), 4.95 (2H, d, J = 5.5Hz), 4.76-4.72 (1H, m), 3.09-3.01 (1H, m), 2.92-2.83 (1H, m), 2.69-2.61 (1H, m), 1.89-1.83 (1H, m), 1.50 (9H, s).
[Step 3] {5- [6-Amino-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} methanol
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
　上記工程２で得られた化合物（110mg）を用いて実施例１工程１１と同様の手法により標題化合物（65.2mg）を淡黄色固体として得た。
1H-NMR(CDCl3)δppm:8.91(1H,d,J=1.6Hz),8.70(1H,d,J=1.6Hz),8.08(1H,d,J=8.6Hz),7.64-7.61(2H,m),7.49-7.45(1H,m),7.38-7.32(3H,m),6.91(1H,s),4.94(2H,s),4.45(1H,t,J=7.2Hz),3.10-3.02(1H,m),2.89-2.81(1H,m),2.61-2.54(1H,m),1.82-1.73(1H,m).
[工程４]　[5-(6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル)ピラジン-2-イル]メタノール Using the compound (110 mg) obtained in the above Step 2, the title compound (65.2 mg) was obtained as a pale yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.91 (1H, d, J = 1.6 Hz), 8.70 (1 H, d, J = 1.6 Hz), 8.08 (1 H, d, J = 8.6 Hz), 7.64-7.61 ( 2H, m), 7.49-7.45 (1H, m), 7.38-7.32 (3H, m), 6.91 (1H, s), 4.94 (2H, s), 4.45 (1H, t, J = 7.2Hz), 3.10 -3.02 (1H, m), 2.89-2.81 (1H, m), 2.61-2.54 (1H, m), 1.82-1.73 (1H, m).
[Step 4] [5- (6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl) pyrazin-2-yl] methanol
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
　上記工程３で得られた化合物（65.2mg）を用いて実施例１工程１２と同様の手法により標題化合物（25.9mg）を白色固体として得た。
1H-NMR(CD3OD)δppm:9.05(1H,d,J=1.2Hz),8.71-8.70(1H,m),7.35(1H,d,J=8.2Hz),7.25(1H,d,J=8.2Hz),7.17(1H,s),4.76(2H,s),4.50(1H,t,J=6.8Hz),3.30-3.23(1H,m),3.06-2.99(1H,m),2.66-2.57(1H,m),1.95-1.87(1H,m).
MS(ESI)m/z:281(M+H)+
実施例１３　(6R)-2-[5-(メチルスルホニル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　(6S)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-オール Using the compound (65.2 mg) obtained in Step 3 above, the title compound (25.9 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CD 3 OD) δppm: 9.05 (1H, d, J = 1.2Hz), 8.71-8.70 (1H, m), 7.35 (1H, d, J = 8.2Hz), 7.25 (1H, d, J = 8.2Hz), 7.17 (1H, s), 4.76 (2H, s), 4.50 (1H, t, J = 6.8Hz), 3.30-3.23 (1H, m), 3.06-2.99 (1H, m), 2.66-2.57 (1H, m), 1.95-1.87 (1H, m).
MS (ESI) m / z: 281 (M + H) +
Example 13 (6R) -2- [5- (Methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] (6S) -3- (Phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-ol
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
　実施例１１工程３で得られた化合物（267g）を用いて実施例１０工程１と同様の手法により標題化合物（154g；15%程度の(6R)-体を含む。）を白色固体として得た。
[工程２]　tert-ブチル [(2-ニトロフェニル)スルホニル][(6R)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Example 11 Using the compound (267 g) obtained in Step 3 of Example 11, the title compound (154 g; containing about 15% of (6R) -isomer) was obtained as a white solid by the same procedure as in Step 10 of Example 10. .
[Step 2] tert-Butyl [(2-nitrophenyl) sulfonyl] [(6R) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
　上記工程１で得られた化合物（452g）を用いて実施例１工程６と同様の手法により標題化合物（730g；15%程度の(6S)-体を含む。）を淡黄色固体として得た。
[工程３]　tert-ブチル [(6R)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (452 g) obtained in the above Step 1, the title compound (730 g; containing about 15% of (6S) -form) was obtained as a pale yellow solid by the same procedure as in Step 1 of Example 1.
[Step 3] tert-Butyl [(6R) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
　上記工程２で得られた化合物（729g）を用いて実施例１工程７と同様の手法により標題化合物（397g；15%程度の(6S)-体を含む。）を淡黄色固体として得た。
[工程４]　tert-ブチル N-[(6S)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート；tert-ブチル N-[(6R)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (729 g) obtained in the above Step 2, the title compound (397 g; containing about 15% of (6S) -form) was obtained as a pale yellow solid by the same procedure as in Step 1 of Example 1.
[Step 4] tert-butyl N-[(6S) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate; tert-butyl N-[( 6R) -3- (Phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
　上記工程３で得られた化合物（383g）の光学分割をカラムクロマトグラフィー（株式会社ダイセル キラルセルOJ-H、メタノール100%）を用いて行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル N-[(6S)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート（46.9g，光学純度>98%ee）を白色固体として得た。また、後から溶出する第二ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル N-[(6R)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート（293g，光学純度>98%ee）を白色固体として得た。
分析条件：キラルセルOJ-H、MeOH、流速1.0mL/min、吸収波長297nm
1st peak；保持時間（rt）= 5.2min, >98%ee
2nd peak；保持時間（rt）= 6.5min, >98%ee
[工程５]　tert-ブチル [(6R)-3-(フェニルスルホニル)-2-(トリブチルスタナニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Optical resolution of the compound (383 g) obtained in Step 3 above was performed using column chromatography (Daicel Chiralcel OJ-H, methanol 100%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl N-[(6S) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] Indol-6-yl] carbamate (46.9 g, optical purity> 98% ee) was obtained as a white solid. In addition, after collecting the second peak eluting later, the solvent was distilled off under reduced pressure to obtain tert-butyl N-[(6R) -3- (phenylsulfonyl) -3,6,7,8-tetrahydro Cyclopenta [e] indol-6-yl] carbamate (293 g, optical purity> 98% ee) was obtained as a white solid.
Analysis conditions: Chiralcel OJ-H, MeOH, flow rate 1.0 mL / min, absorption wavelength 297 nm
1st peak; retention time (rt) = 5.2min,> 98% ee
2nd peak; retention time (rt) = 6.5min,> 98% ee
[Step 5] tert-Butyl [(6R) -3- (phenylsulfonyl) -2- (tributylstannanyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
　上記工程４で第二ピークとして得られた化合物（3.90g）を用いて実施例１１工程７と同様の手法により標題化合物（5g）を白色アモルファス状物質として得た。
1H-NMR(CDCl3)δppm:7.67-7.64(1H,m),7.63-7.60(2H,m),7.50-7.45(1H,m),7.39-7.34(2H,m),7.13-7.10(1H,m),6.72-6.68(1H,m),5.25-5.15(1H,m),4.71-4.63(1H,m),3.14-3.04(1H,m),2.95-2.87(1H,m),2.67-2.54(1H,m),1.86-1.81(1H,m),1.61-1.07(27H,m),1.43(9H,s),0.86(9H,t,J=7.2Hz).
[工程６]　tert-ブチル [(6R)-2-[5-(メチルスルホニル)ピリジン-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (3.90 g) obtained as the second peak in Step 4 above, the title compound (5 g) was obtained as a white amorphous substance in the same manner as in Step 7 of Example 11.
1 H-NMR (CDCl 3 ) δ ppm: 7.67-7.64 (1H, m), 7.63-7.60 (2H, m), 7.50-7.45 (1H, m), 7.39-7.34 (2H, m), 7.13-7.10 ( 1H, m), 6.72-6.68 (1H, m), 5.25-5.15 (1H, m), 4.71-4.63 (1H, m), 3.14-3.04 (1H, m), 2.95-2.87 (1H, m), 2.67-2.54 (1H, m), 1.86-1.81 (1H, m), 1.61-1.07 (27H, m), 1.43 (9H, s), 0.86 (9H, t, J = 7.2Hz).
[Step 6] tert-Butyl [(6R) -2- [5- (methylsulfonyl) pyridin-2-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-yl] carbamate
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
　上記工程５で得られた化合物（1.00g）及び2-ブロモ-5-(メチルスルホニル)ピリジン（673mg）を用いて実施例１１工程８の手法により標題化合物（760mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.20-9.19(1H,m),8.30-8.27(1H,m),8.06(1H,d,J=8.6Hz),7.97-7.95(1H,m),7.62-7.60(2H,m),7.50-7.46(1H,m),7.38-7.33(3H,m),7.02-7.01(1H,m),5.28-5.20(1H,m),4.76-4.71(1H,m),3.21(3H,s),3.08-3.00(1H,m),2.91-2.82(1H,m),2.69-2.60(1H,m),1.90-1.80(1H,m),1.50(9H,s).
[工程７]　(6R)-2-[5-(メチルスルホニル)ピリジン-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound obtained in the above Step 5 (1.00 g) and 2-bromo-5- (methylsulfonyl) pyridine (673 mg), the title compound (760 mg) was obtained as a white solid by the procedure in Step 11 of Example 11.
1 H-NMR (CDCl 3 ) δ ppm: 9.20-9.19 (1H, m), 8.30-8.27 (1H, m), 8.06 (1H, d, J = 8.6Hz), 7.97-7.95 (1H, m), 7.62 -7.60 (2H, m), 7.50-7.46 (1H, m), 7.38-7.33 (3H, m), 7.02-7.01 (1H, m), 5.28-5.20 (1H, m), 4.76-4.71 (1H, m), 3.21 (3H, s), 3.08-3.00 (1H, m), 2.91-2.82 (1H, m), 2.69-2.60 (1H, m), 1.90-1.80 (1H, m), 1.50 (9H, s).
[Step 7] (6R) -2- [5- (Methylsulfonyl) pyridin-2-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
　上記工程６で得られた化合物（750mg）を用いて実施例１工程１１と同様の手法により標題化合物（520mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.20-9.19(1H,m),8.28(1H,dd,J=8.6,2.3Hz),8.07(1H,d,J=8.6Hz),7.98-7.95(1H,m),7.62-7.60(2H,m),7.50-7.45(1H,m),7.40-7.32(3H,m),7.03(1H,s),4.48-4.40(1H,m),3.21(3H,s),3.09-3.02(1H,m),2.88-2.80(1H,m),2.62-2.54(1H,m),1.81-1.72(1H,m).
[工程８]　(6R)-2-[5-(メチルスルホニル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (750 mg) obtained in the above Step 6, the title compound (520 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 9.20-9.19 (1H, m), 8.28 (1H, dd, J = 8.6,2.3Hz), 8.07 (1H, d, J = 8.6Hz), 7.98-7.95 (1H , m), 7.62-7.60 (2H, m), 7.50-7.45 (1H, m), 7.40-7.32 (3H, m), 7.03 (1H, s), 4.48-4.40 (1H, m), 3.21 (3H , s), 3.09-3.02 (1H, m), 2.88-2.80 (1H, m), 2.62-2.54 (1H, m), 1.81-1.72 (1H, m).
[Step 8] (6R) -2- [5- (Methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
　上記工程７で得られた化合物（515mg）を用いて実施例１工程１２と同様の手法により標題化合物（320mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.58(1H,brs),9.07-9.06(1H,m),8.19(1H,dd,J=8.6,2.3Hz),7.94-7.91(1H,m),7.35(1H,d,J=8.2Hz),7.29(1H,d,J=8.2Hz),7.13-7.12(1H,m),4.51(1H,t,J=6.8Hz),3.27-3.20(1H,m),3.15(3H,s),3.05-2.97(1H,m),2.71-2.63(1H,m),1.89-1.80(1H,m).
MS(ESI)m/z:326(M+H)+
実施例１４　[4-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシ-2-ピリジル]メタノール
[工程１]　tert-ブチル [(6R)-2-ブロモ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (515 mg) obtained in the above Step 7, the title compound (320 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 9.58 (1H, brs), 9.07-9.06 (1H, m), 8.19 (1H, dd, J = 8.6,2.3Hz), 7.94-7.91 (1H, m), 7.35 (1H, d, J = 8.2Hz), 7.29 (1H, d, J = 8.2Hz), 7.13-7.12 (1H, m), 4.51 (1H, t, J = 6.8Hz), 3.27-3.20 (1H, m), 3.15 (3H, s), 3.05-2.97 (1H, m), 2.71-2.63 (1H, m), 1.89-1.80 (1H, m).
MS (ESI) m / z: 326 (M + H) +
Example 14 [4-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxy-2-pyridyl] methanol
[Step 1] tert-Butyl [(6R) -2-bromo-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
　実施例１３工程４で第二ピークとして得られた化合物（5.00g）を用いて実施例１工程８と同様の手法により標題化合物（5.25g）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.14-8.11(1H,m),7.88-7.83(2H,m),7.58-7.48(1H,m),7.44-7.39(2H,m),7.27-7.25(1H,m),6.66(1H,s),5.27-5.18(1H,m),4.76-4.66(1H,m),3.04-2.96(1H,m),2.86-2.79(1H,m),2.67-2.57(1H,m),1.89-1.81(2H,m),1.47(9H,s).
[工程２]　メチル4-[(6R)-3-(ベンゼンスルホニル)-6-(tert-ブトキシカルボニルアミノ)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-2-イル]-6-メトキシ-ピリミジン-2-カルボキシレート The title compound (5.25 g) was obtained as a white solid in the same manner as in Example 1, Step 8, using the compound (5.00 g) obtained as the second peak in Step 4 of Example 13.
1 H-NMR (CDCl 3 ) δ ppm: 8.14-8.11 (1H, m), 7.88-7.83 (2H, m), 7.58-7.48 (1H, m), 7.44-7.39 (2H, m), 7.27-7.25 ( 1H, m), 6.66 (1H, s), 5.27-5.18 (1H, m), 4.76-4.66 (1H, m), 3.04-2.96 (1H, m), 2.86-2.79 (1H, m), 2.67- 2.57 (1H, m), 1.89-1.81 (2H, m), 1.47 (9H, s).
[Step 2] Methyl 4-[(6R) -3- (benzenesulfonyl) -6- (tert-butoxycarbonylamino) -7,8-dihydro-6H-cyclopenta [e] indol-2-yl] -6- Methoxy-pyrimidine-2-carboxylate
Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106
　上記工程１で得られた化合物（400mg）及びメチル6-メトキシ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン-2-カルボキシレート（301mg）を用いて実施例１工程９と同様の手法により標題化合物（440mg）を黄色固体として得た。
1H-NMR(CDCl3)δppm:8.15(1H,d,J=8.6Hz),7.90(1H,d,J=1.6Hz),7.52-7.43(3H,m),7.38-7.28(3H,m),7.09(1H,s),6.68(1H,s),5.32-5.20(1H,m),4.81-4.70(1H,m),4.10(3H,s),4.00(3H,s),3.10-2.95(1H,m),2.95-2.80(1H,m),2.70-2.58(1H,m),1.93-1.80(1H.m),1.50(9H,s).
[工程３]　tert-ブチルN-[(6R)-3-(ベンゼンスルホニル)-2-[2-(ヒドロキシメチル)-6-メトキシ-4-ピリジル]-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート  The compound (400 mg) obtained in the above step 1 and methyl 6-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2-carboxylate ( 301 mg) was used to give the title compound (440 mg) as a yellow solid in the same manner as in Example 1, Step 9.
1 H-NMR (CDCl 3 ) δppm: 8.15 (1H, d, J = 8.6Hz), 7.90 (1H, d, J = 1.6Hz), 7.52-7.43 (3H, m), 7.38-7.28 (3H, m ), 7.09 (1H, s), 6.68 (1H, s), 5.32-5.20 (1H, m), 4.81-4.70 (1H, m), 4.10 (3H, s), 4.00 (3H, s), 3.10- 2.95 (1H, m), 2.95-2.80 (1H, m), 2.70-2.58 (1H, m), 1.93-1.80 (1H.m), 1.50 (9H, s).
[Step 3] tert-butyl N-[(6R) -3- (benzenesulfonyl) -2- [2- (hydroxymethyl) -6-methoxy-4-pyridyl] -7,8-dihydro-6H-cyclopenta [ e] Indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
　上記工程３で得られた化合物（430mg）を用いて実施例１工程１０と同様の手法により標題化合物（370mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.14(1H,d,J=8.6Hz),7.53-7.43(3H,m),7.37-7.28(3H,m),7.01(1H,s),6.79(1H,s),6.62(1H,s),5.30(1H,m),4.75(2H,d,J=5.5Hz),4.03(3H,s),3.44(1H,t,J=5.3Hz),3.08-2.95(1H,m),2.95-2.78(1H,m),2.70-2.55(1H,m),1.92-1.78(1H,m),1.50(9H,s).
[工程４]　[4-[(6R)-6-アミノ-3-(ベンゼンスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-2-イル]-6-メトキシ-2-ピリジル]メタノール Using the compound (430 mg) obtained in the above Step 3, the title compound (370 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.14 (1H, d, J = 8.6Hz), 7.53-7.43 (3H, m), 7.37-7.28 (3H, m), 7.01 (1H, s), 6.79 (1H , s), 6.62 (1H, s), 5.30 (1H, m), 4.75 (2H, d, J = 5.5Hz), 4.03 (3H, s), 3.44 (1H, t, J = 5.3Hz), 3.08 -2.95 (1H, m), 2.95-2.78 (1H, m), 2.70-2.55 (1H, m), 1.92-1.78 (1H, m), 1.50 (9H, s).
[Step 4] [4-[(6R) -6-amino-3- (benzenesulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-2-yl] -6-methoxy-2-pyridyl] methanol
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
　上記工程３で得られた化合物（370mg）を用いて実施例１工程１１と同様の手法により標題化合物（210mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.15(1H,d,J=8.2Hz),7.51-7.43(3H,m),7.38-7.27(3H,m),7.01(1H,s),6.79(1H,d,J=0.8Hz),6.63(1H,s),4.75(2H,s),4.44(1H,t,J=7.0Hz),4.03(3H,s),3.07-2.98(1H,m),2.90-2.76(1H,m),2.63-2.51(1H,m),1.82-1.69(1H,m).
[工程５]　[4-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシ-2-ピリジル]メタノール Using the compound (370 mg) obtained in the above Step 3, the title compound (210 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.15 (1H, d, J = 8.2 Hz), 7.51-7.43 (3H, m), 7.38-7.27 (3H, m), 7.01 (1H, s), 6.79 (1H , d, J = 0.8Hz), 6.63 (1H, s), 4.75 (2H, s), 4.44 (1H, t, J = 7.0Hz), 4.03 (3H, s), 3.07-2.98 (1H, m) 2.90-2.76 (1H, m), 2.63-2.51 (1H, m), 1.82-1.69 (1H, m).
[Step 5] [4-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxy-2-pyridyl] methanol
Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109
　上記工程４で得られた化合物（200mg）を用いて実施例１工程１２と同様の手法により標題化合物（35mg）を白色固体として得た。
1H-NMR(DMSO-d6)δppm:7.57(1H,d,J=1.2Hz),7.29(1H,d,J=8.6Hz),7.21(1H,d,J=8.2Hz),7.16(1H,d,J=1.2Hz),7.07(1H,d,J=1.6Hz),5.55-5.45(1H,m),4.55(2H,d,J=4.7Hz),4.33(1H,t,J=7.0Hz),3.91(3H,s),3.19-3.08(1H,m),2.95-2.81(1H,m),2.57-2.44(1H,m),1.80-1.64(1H,m).
実施例１５　(6R)-2-(ピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [(6R)-3-(フェニルスルホニル)-2-(ピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (200 mg) obtained in the above Step 4, the title compound (35 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (DMSO-d6) δppm: 7.57 (1H, d, J = 1.2Hz), 7.29 (1H, d, J = 8.6Hz), 7.21 (1H, d, J = 8.2Hz), 7.16 (1H , d, J = 1.2Hz), 7.07 (1H, d, J = 1.6Hz), 5.55-5.45 (1H, m), 4.55 (2H, d, J = 4.7Hz), 4.33 (1H, t, J = 7.0Hz), 3.91 (3H, s), 3.19-3.08 (1H, m), 2.95-2.81 (1H, m), 2.57-2.44 (1H, m), 1.80-1.64 (1H, m).
Example 15 (6R) -2- (pyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-Butyl [(6R) -3- (phenylsulfonyl) -2- (pyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110
　実施例１３工程５で得られた化合物（200mg）を用いて実施例１１工程８と同様の手法により標題化合物（140mg）を得た。
MS(ESI)m/z:491(M+H)+
[工程２]　(6R)-3-(フェニルスルホニル)-2-(ピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (200 mg) obtained in Example 13, Step 5, the title compound (140 mg) was obtained in the same manner as in Example 11, Step 8.
MS (ESI) m / z: 491 (M + H) +
[Step 2] (6R) -3- (Phenylsulfonyl) -2- (pyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111
　上記工程１で得られた化合物（140mg）を用いて実施例１工程１１と同様の手法により標題化合物（95mg）を淡黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.96-8.93(1H,m),8.64-8.62(1H,m),8.59-8.57(1H,m),8.07-8.04(1H,m),7.63-7.60(2H,m),7.46-7.43(1H,m),7.36-7.30(3H,m),6.89(1H,s),4.45-4.40(1H,m),3.07-3.00(1H,m),2.86-2.79(1H,m),2.58-2.52(1H,m),1.78-1.70(1H,m).
[工程３]　(6R)-2-(ピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (140 mg) obtained in the above Step 1, the title compound (95 mg) was obtained as a pale yellow oily substance in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.96-8.93 (1H, m), 8.64-8.62 (1H, m), 8.59-8.57 (1H, m), 8.07-8.04 (1H, m), 7.63-7.60 ( 2H, m), 7.46-7.43 (1H, m), 7.36-7.30 (3H, m), 6.89 (1H, s), 4.45-4.40 (1H, m), 3.07-3.00 (1H, m), 2.86- 2.79 (1H, m), 2.58-2.52 (1H, m), 1.78-1.70 (1H, m).
[Step 3] (6R) -2- (pyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112
　上記工程２で得られた化合物（95mg）を用いて実施例１工程１２と同様の手法により標題化合物（45.3mg）を淡黄色固体として得た。
1H-NMR(CDCl3)δppm:9.36(1H,brs),9.09-9.06(1H,m),8.49-8.47(1H,m),8.40-8.38(1H,m),7.32-7.29(1H,m),7.26-7.23(1H,m),7.08-7.05(1H,m),4.50-4.46(1H,m),3.25-3.18(1H,m),3.03-2.96(1H,m),2.68-2.61(1H,m),1.86-1.77(1H,m).
実施例１６　(6R)-2-(3-メチルピリジン-4-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [(6R)-2-(3-メチルピリジン-4-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound obtained in Step 2 above (95 mg), the title compound (45.3 mg) was obtained as a pale yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 9.36 (1H, brs), 9.09-9.06 (1H, m), 8.49-8.47 (1H, m), 8.40-8.38 (1H, m), 7.32-7.29 (1H, m), 7.26-7.23 (1H, m), 7.08-7.05 (1H, m), 4.50-4.46 (1H, m), 3.25-3.18 (1H, m), 3.03-2.96 (1H, m), 2.68- 2.61 (1H, m), 1.86-1.77 (1H, m).
Example 16 (6R) -2- (3-Methylpyridin-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-butyl [(6R) -2- (3-methylpyridin-4-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113
　実施例１４工程１で得られた化合物（200mg）及び3-ピコリン-4-ボロン酸（83.6mg）を用いて実施例１工程９と同様の手法により標題化合物（117mg）を淡黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.51(1H,s),8.48-8.46(1H,m),8.19-8.15(1H,m),7.51-7.44(3H,m),7.37-7.30(3H,m),7.06-6.99(1H,m),6.46(1H,s),5.31-5.22(1H,m),4.78-4.72(1H,m),3.09-3.00(1H,m),2.94-2.83(1H,m),2.70-2.60(1H,m),2.22(3H,d,J=19.5Hz),1.92-1.82(1H,m),1.48(9H,s).
[工程２]　(6R)-2-(3-メチルピリジン-4-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Example 14 Using the compound (200 mg) obtained in Step 1 and 3-picoline-4-boronic acid (83.6 mg) in the same manner as in Example 1, Step 9, the title compound (117 mg) was obtained as a pale yellow oil. Obtained.
1 H-NMR (CDCl 3 ) δ ppm: 8.51 (1H, s), 8.48-8.46 (1H, m), 8.19-8.15 (1H, m), 7.51-7.44 (3H, m), 7.37-7.30 (3H, m), 7.06-6.99 (1H, m), 6.46 (1H, s), 5.31-5.22 (1H, m), 4.78-4.72 (1H, m), 3.09-3.00 (1H, m), 2.94-2.83 ( 1H, m), 2.70-2.60 (1H, m), 2.22 (3H, d, J = 19.5Hz), 1.92-1.82 (1H, m), 1.48 (9H, s).
[Step 2] (6R) -2- (3-Methylpyridin-4-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114
　上記工程１で得られた化合物（117mg）を用いて実施例１工程１１と同様の手法により標題化合物（77mg）を淡黄色固体として得た。
1H-NMR(CDCl3)δppm:8.50(1H,s),8.47-8.45(1H,m),8.19-8.16(1H,m),7.50-7.44(3H,m),7.37-7.29(3H,m),7.03-7.00(1H,m),6.46(1H,s),4.50-4.42(1H,m),3.11-3.00(1H,m),2.90-2.79(1H,m),2.62-2.52(1H,m),2.21(3H,s),1.82-1.71(1H,m).
[工程３]　(6R)-2-(3-メチルピリジン-4-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (117 mg) obtained in the above Step 1, the title compound (77 mg) was obtained as a pale yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.50 (1H, s), 8.47-8.45 (1H, m), 8.19-8.16 (1H, m), 7.50-7.44 (3H, m), 7.37-7.29 (3H, m), 7.03-7.00 (1H, m), 6.46 (1H, s), 4.50-4.42 (1H, m), 3.11-3.00 (1H, m), 2.90-2.79 (1H, m), 2.62-2.52 ( 1H, m), 2.21 (3H, s), 1.82-1.71 (1H, m).
[Step 3] (6R) -2- (3-Methylpyridin-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115
　上記工程２で得られた化合物（77mg）を用いて実施例１工程１２と同様の手法により標題化合物（21mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.52(1H,s),8.50-8.47(1H,m),8.35(1H,s),7.37-7.35(1H,m),7.33-7.30(1H,m),7.26-7.23(1H,m),6.74-6.72(1H,m),4.50(1H,t,J=7.1Hz),3.26-3.18(1H,m),3.02-2.96(1H,m),2.68-2.61(1H,m),2.54(3H,s),1.86-1.78(1H,m).
実施例１７　[6-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル]メタノール
[工程１]　tert-ブチル N-[(6R)-3-(ベンゼンスルホニル)-2-[6-(ヒドロキシメチル)ピラジン-2-イル]-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Using the compound (77 mg) obtained in the above Step 2, the title compound (21 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3) δppm: 8.52 (1H, s), 8.50-8.47 (1H, m), 8.35 (1H, s), 7.37-7.35 (1H, m), 7.33-7.30 (1H, m) , 7.26-7.23 (1H, m), 6.74-6.72 (1H, m), 4.50 (1H, t, J = 7.1Hz), 3.26-3.18 (1H, m), 3.02-2.96 (1H, m), 2.68 -2.61 (1H, m), 2.54 (3H, s), 1.86-1.78 (1H, m).
Example 17 [6-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] methanol
[Step 1] tert-Butyl N-[(6R) -3- (Benzenesulfonyl) -2- [6- (hydroxymethyl) pyrazin-2-yl] -7,8-dihydro-6H-cyclopenta [e] indole -6-yl] carbamate
Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116
　実施例１３工程５で得られた化合物（240mg）及び(6-クロロピラジン-2-イル)メタノール（98.9mg）を用いて実施例１１工程８と同様の手法により標題化合物（190mg）を白色固体として得た。
MS(ESI)m/z:521(M+H)+
1H-NMR(CDCl3)δppm:8.82(1H,s),8.61(1H,s),8.05(1H,d,J=8.6Hz),7.56(2H,t,J=4.9Hz),7.46(1H,t,J=7.4Hz),7.33(3H,d,J=8.2Hz),6.87(1H,s),5.24-5.21(1H,m),4.88(2H,d,J=5.5Hz),4.73(1H,d,J=8.6Hz),3.07-2.99(1H,m),2.88-2.84(1H,m),2.64-2.60(1H,m),1.85-1.82(1H,m),1.46(9H,s).
[工程２]　[6-[(6R)-6-アミノ-3-(ベンゼンスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-2-イル]ピラジン-2-イル]メタノール Example 13 Using the compound obtained in Step 5 of Step (240 mg) and (6-chloropyrazin-2-yl) methanol (98.9 mg) in the same manner as in Step 11 of Example 11, the title compound (190 mg) was obtained as a white solid. Got as.
MS (ESI) m / z: 521 (M + H) +
1 H-NMR (CDCl 3 ) δ ppm: 8.82 (1H, s), 8.61 (1H, s), 8.05 (1H, d, J = 8.6Hz), 7.56 (2H, t, J = 4.9Hz), 7.46 ( 1H, t, J = 7.4Hz), 7.33 (3H, d, J = 8.2Hz), 6.87 (1H, s), 5.24-5.21 (1H, m), 4.88 (2H, d, J = 5.5Hz), 4.73 (1H, d, J = 8.6Hz), 3.07-2.99 (1H, m), 2.88-2.84 (1H, m), 2.64-2.60 (1H, m), 1.85-1.82 (1H, m), 1.46 ( 9H, s).
[Step 2] [6-[(6R) -6-amino-3- (benzenesulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-2-yl] pyrazin-2-yl] methanol
Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117
　上記工程１で得られた化合物（190mg）を用いて実施例１工程１１と同様の手法により標題化合物（160mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.81(1H,s),8.61(1H,s),8.04(1H,d,J=8.6Hz),7.57(2H,dd,J=8.4,1.4Hz),7.45(1H,t,J=7.4Hz),7.35-7.29(3H,m),6.87(1H,s),4.87(2H,s),4.42(1H,t,J=7.2Hz),3.03(1H,ddd,J=16.1,8.7,3.4Hz),2.86-2.78(1H,m),2.56-2.53(1H,m),1.73(2H,ddd,J=18.2,10.2,5.7Hz).
[工程３]　[6-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル]メタノール Using the compound (190 mg) obtained in the above Step 1, the title compound (160 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3) δppm: 8.81 (1H, s), 8.61 (1H, s), 8.04 (1H, d, J = 8.6Hz), 7.57 (2H, dd, J = 8.4,1.4Hz), 7.45 (1H, t, J = 7.4Hz), 7.35-7.29 (3H, m), 6.87 (1H, s), 4.87 (2H, s), 4.42 (1H, t, J = 7.2Hz), 3.03 (1H , ddd, J = 16.1,8.7,3.4Hz), 2.86-2.78 (1H, m), 2.56-2.53 (1H, m), 1.73 (2H, ddd, J = 18.2,10.2,5.7Hz).
[Step 3] [6-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] methanol
Figure JPOXMLDOC01-appb-C000118
Figure JPOXMLDOC01-appb-C000118
　上記工程２で得られた化合物（160mg）を用いて実施例１工程１２と同様の手法により標題化合物（10mg）を薄黄色固体として得た。
MS(ESI)m/z:264(M-NH2)+
1H-NMR(CD3OD)δppm:8.99(1H,s),8.44(1H,s),7.31(1H,d,J=8.2Hz),7.22(1H,d,J=8.6Hz),7.17(1H,s),4.79(2H,s),4.45(1H,t,J=6.8Hz),3.22-3.20(1H,m),3.01-2.96(1H,m),2.59-2.56(1H,m),1.91-1.83(1H,m).
実施例１８　(6R)-2-(6-メチルピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル N-[(6R)-3-(ベンゼンスルホニル)-2-(6-メチルピラジン-2-イル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Using the compound (160 mg) obtained in the above Step 2, the title compound (10 mg) was obtained as a pale yellow solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 264 (M-NH2) +
1 H-NMR (CD 3 OD ) δppm: 8.99 (1H, s), 8.44 (1H, s), 7.31 (1H, d, J = 8.2Hz), 7.22 (1H, d, J = 8.6Hz), 7.17 (1H, s), 4.79 (2H, s), 4.45 (1H, t, J = 6.8Hz), 3.22-3.20 (1H, m), 3.01-2.96 (1H, m), 2.59-2.56 (1H, m ), 1.91-1.83 (1H, m).
Example 18 (6R) -2- (6-Methylpyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-Butyl N-[(6R) -3- (benzenesulfonyl) -2- (6-methylpyrazin-2-yl) -7,8-dihydro-6H-cyclopenta [e] indole-6- IL] Carbamate
Figure JPOXMLDOC01-appb-C000119
Figure JPOXMLDOC01-appb-C000119
　実施例１３工程５で得られた化合物（240m）及び2-クロロ-6-メチルピラジン（88.0mg）を用いて実施例１１工程８と同様の手法により標題化合物（170mg）を白色固体として得た。
MS(ESI)m/z:505(M+H)+
1H-NMR(CDCl3)δppm:8.70(1H,s),8.45(1H,s),8.03(1H,d,J=8.6Hz),7.63(2H,d,J=7.8Hz),7.45(1H,t,J=7.4Hz),7.33-7.31(3H,m),6.84(1H,s),5.23-5.21(1H,m),4.74(1H,d,J=7.8Hz),3.02(1H,ddd,J=16.2,8.8,3.7Hz),2.86-2.82(1H,m),2.61-2.60(4H,m),1.85-1.80(1H,m),1.46(9H,s).
[工程２]　(6R)-3-(ベンゼンスルホニル)-2-(6-メチルピラジン-2-イル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-アミン Example 13 Using the compound (240m) obtained in Step 5 and 2-chloro-6-methylpyrazine (88.0 mg), the title compound (170 mg) was obtained as a white solid in the same manner as in Step 11 of Example 11. .
MS (ESI) m / z: 505 (M + H) +
1 H-NMR (CDCl 3) δppm: 8.70 (1H, s), 8.45 (1H, s), 8.03 (1H, d, J = 8.6Hz), 7.63 (2H, d, J = 7.8Hz), 7.45 ( 1H, t, J = 7.4Hz), 7.33-7.31 (3H, m), 6.84 (1H, s), 5.23-5.21 (1H, m), 4.74 (1H, d, J = 7.8Hz), 3.02 (1H , ddd, J = 16.2,8.8,3.7Hz), 2.86-2.82 (1H, m), 2.61-2.60 (4H, m), 1.85-1.80 (1H, m), 1.46 (9H, s).
[Step 2] (6R) -3- (Benzenesulfonyl) -2- (6-methylpyrazin-2-yl) -7,8-dihydro-6H-cyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000120
Figure JPOXMLDOC01-appb-C000120
　上記工程２で得られた化合物（170mg）を用いて実施例１工程１１と同様の手法により標題化合物（136mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.71(1H,s),8.44(1H,s),8.04(1H,d,J=8.6Hz),7.65-7.62(2H,m),7.44(1H,t,J=7.6Hz),7.33-7.30(3H,m),6.85(1H,s),4.42(1H,t,J=7.0Hz),3.03(1H,ddd,J=16.1,8.9,3.4Hz),2.85-2.77(1H,m),2.61(3H,s),2.56-2.53(1H,m),1.75-1.70(1H,m).
[工程３]　(6R)-2-(6-メチルピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (170 mg) obtained in the above Step 2, the title compound (136 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3) δppm: 8.71 (1H, s), 8.44 (1H, s), 8.04 (1H, d, J = 8.6Hz), 7.65-7.62 (2H, m), 7.44 (1H, t , J = 7.6Hz), 7.33-7.30 (3H, m), 6.85 (1H, s), 4.42 (1H, t, J = 7.0Hz), 3.03 (1H, ddd, J = 16.1,8.9,3.4Hz) , 2.85-2.77 (1H, m), 2.61 (3H, s), 2.56-2.53 (1H, m), 1.75-1.70 (1H, m).
[Step 3] (6R) -2- (6-Methylpyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000121
Figure JPOXMLDOC01-appb-C000121
　上記工程２で得られた化合物（136mg）を用いて実施例１工程１２と同様の手法により標題化合物（20mg）を白色固体として得た。
MS(ESI)m/z:248(M-NH2)+
1H-NMR(CD3OD)δppm:8.86(1H,s),8.23(1H,s),7.31(1H,d,J=8.6Hz),7.20(1H,d,J=8.6Hz),7.11(1H,s),4.45(1H,t,J=6.5Hz),3.23-3.19(1H,m),3.01-2.93(1H,m),2.59-2.54(4H,m),1.88-1.85(1H,m).
実施例１９　(6R)-2-(3-メチルピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル N-[(6R)-3-(ベンゼンスルホニル)-2-(3-メチルピラジン-2-イル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Using the compound (136 mg) obtained in the above Step 2, the title compound (20 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 248 (M-NH2) +
1 H-NMR (CD 3 OD) δppm: 8.86 (1H, s), 8.23 (1H, s), 7.31 (1H, d, J = 8.6Hz), 7.20 (1H, d, J = 8.6Hz), 7.11 (1H, s), 4.45 (1H, t, J = 6.5Hz), 3.23-3.19 (1H, m), 3.01-2.93 (1H, m), 2.59-2.54 (4H, m), 1.88-1.85 (1H , m).
Example 19 (6R) -2- (3-Methylpyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-Butyl N-[(6R) -3- (benzenesulfonyl) -2- (3-methylpyrazin-2-yl) -7,8-dihydro-6H-cyclopenta [e] indole-6- IL] Carbamate
Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000122
　実施例１３工程５で得られた化合物（250mg）及び2-クロロ-3-メチルピラジン（91.6mg）を用いて実施例１１工程８と同様の手法により標題化合物（190mg）を白色固体として得た。
MS(ESI)m/z:505(M+H)+
1H-NMR(CDCl3)δppm:8.53(1H,d,J=2.7Hz),8.48(1H,d,J=2.7Hz),7.98(1H,d,J=8.6Hz),7.71(2H,d,J=8.2Hz),7.44(1H,t,J=7.4Hz),7.37-7.29(3H,m),6.71(1H,s),5.23-5.21(1H,m),4.77(1H,d,J=9.4Hz),3.05-3.01(1H,m),2.89-2.81(1H,m),2.63-2.61(1H,m),2.58(3H,s),1.86-1.79(1H,m),1.46(9H,s).
[工程２]　(6R)-3-(ベンゼンスルホニル)-2-(3-メチルピラジン-2-イル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-アミン Example 13 Using the compound (250 mg) obtained in Step 5 and 2-chloro-3-methylpyrazine (91.6 mg), the title compound (190 mg) was obtained as a white solid in the same manner as in Example 11, Step 8. .
MS (ESI) m / z: 505 (M + H) +
1 H-NMR (CDCl 3 ) δ ppm: 8.53 (1H, d, J = 2.7Hz), 8.48 (1H, d, J = 2.7Hz), 7.98 (1H, d, J = 8.6Hz), 7.71 (2H, d, J = 8.2Hz), 7.44 (1H, t, J = 7.4Hz), 7.37-7.29 (3H, m), 6.71 (1H, s), 5.23-5.21 (1H, m), 4.77 (1H, d , J = 9.4Hz), 3.05-3.01 (1H, m), 2.89-2.81 (1H, m), 2.63-2.61 (1H, m), 2.58 (3H, s), 1.86-1.79 (1H, m), 1.46 (9H, s).
[Step 2] (6R) -3- (Benzenesulfonyl) -2- (3-methylpyrazin-2-yl) -7,8-dihydro-6H-cyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000123
Figure JPOXMLDOC01-appb-C000123
　上記工程１で得られた化合物（190mg）を用いて実施例１工程１１と同様の手法により標題化合物（130mg）を白色固体として得た。
MS(ESI)m/z:405(M+H)+
1H-NMR(CDCl3)δppm:8.58(1H,d,J=2.3Hz),8.52(1H,d,J=2.7Hz),8.04(1H,d,J=8.2Hz),7.76(2H,dd,J=8.4,1.4Hz),7.49(1H,tt,J=10.7,5.6Hz),7.39-7.36(3H,m),6.76(1H,s),4.47(1H,t,J=7.6Hz),3.09(1H,ddd,J=16.2,8.8,3.5Hz),2.91-2.83(1H,m),2.63(3H,s),2.60-2.58(1H,m),1.80-1.75(1H,m).
[工程３]　(6R)-2-(3-メチルピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (190 mg) obtained in the above Step 1, the title compound (130 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 405 (M + H) +
1 H-NMR (CDCl 3) δppm: 8.58 (1H, d, J = 2.3Hz), 8.52 (1H, d, J = 2.7Hz), 8.04 (1H, d, J = 8.2Hz), 7.76 (2H, dd, J = 8.4,1.4Hz), 7.49 (1H, tt, J = 10.7,5.6Hz), 7.39-7.36 (3H, m), 6.76 (1H, s), 4.47 (1H, t, J = 7.6Hz ), 3.09 (1H, ddd, J = 16.2,8.8,3.5Hz), 2.91-2.83 (1H, m), 2.63 (3H, s), 2.60-2.58 (1H, m), 1.80-1.75 (1H, m ).
[Step 3] (6R) -2- (3-Methylpyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000124
Figure JPOXMLDOC01-appb-C000124
　上記工程２で得られた化合物（130mg）を用いて実施例１工程１２と同様の手法により標題化合物（30mg）を白色固体として得た。
MS(ESI)m/z:248(M-NH2)+
1H-NMR(CD3OD)δppm:8.50(1H,d,J=2.3Hz),8.28(1H,d,J=2.7Hz),7.33(1H,d,J=8.2Hz),7.23(1H,d,J=8.6Hz),6.97(1H,s),4.42(1H,t,J=6.6Hz),3.23-3.20(1H,m),3.02-2.94(1H,m),2.84(3H,s),2.60-2.56(1H,m),1.87-1.82(1H,m).
実施例２０　[3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル]メタノール
[工程１]　tert-ブチル N-[(6R)-3-(ベンゼンスルホニル)-2-[3-(ヒドロキシメチル)ピラジン－2-イル]-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Using the compound (130 mg) obtained in the above Step 2, the title compound (30 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 248 (M-NH2) +
1 H-NMR (CD 3 OD) δ ppm: 8.50 (1H, d, J = 2.3 Hz), 8.28 (1 H, d, J = 2.7 Hz), 7.33 (1 H, d, J = 8.2 Hz), 7.23 (1 H , d, J = 8.6Hz), 6.97 (1H, s), 4.42 (1H, t, J = 6.6Hz), 3.23-3.20 (1H, m), 3.02-2.94 (1H, m), 2.84 (3H, s), 2.60-2.56 (1H, m), 1.87-1.82 (1H, m).
Example 20 [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] methanol
[Step 1] tert-butyl N-[(6R) -3- (benzenesulfonyl) -2- [3- (hydroxymethyl) pyrazin-2-yl] -7,8-dihydro-6H-cyclopenta [e] indole -6-yl] carbamate
Figure JPOXMLDOC01-appb-C000125
Figure JPOXMLDOC01-appb-C000125
　実施例１３工程５で得られた化合物（480mg）及び(3-クロロピラジン-2-イル)メタノール（198mg）を用いて実施例１１工程８と同様の手法により標題化合物（60mg）を白色固体として得た。
MS(ESI)m/z:521(M+H)+
1H-NMR(CDCl3)δppm:8.61(2H,d,J=5.9Hz),7.97(1H,d,J=8.6Hz),7.66-7.62(2H,m),7.51-7.50(1H,m),7.44-7.40(2H,m),7.33(1H,dd,J=15.6,8.2Hz),6.74(1H,s),5.22-5.20(1H,m),4.77-4.74(3H,m),3.75(1H,s),3.01(1H,ddd,J=16.3,8.9,3.6Hz),2.85-2.83(1H,m),2.60-2.56(1H,m),1.86-1.81(1H,m).
[工程２]　[3-[(6R)-6-アミノ-3-(ベンゼンスルホニル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-2-イル]ピラジン-2-イル]メタノール Example 13 Using the compound (480 mg) obtained in Step 5 and (3-chloropyrazin-2-yl) methanol (198 mg) in the same manner as Example 11 Step 8, the title compound (60 mg) was converted to a white solid. Obtained.
MS (ESI) m / z: 521 (M + H) +
1 H-NMR (CDCl 3 ) δppm: 8.61 (2H, d, J = 5.9Hz), 7.97 (1H, d, J = 8.6Hz), 7.66-7.62 (2H, m), 7.51-7.50 (1H, m ), 7.44-7.40 (2H, m), 7.33 (1H, dd, J = 15.6,8.2Hz), 6.74 (1H, s), 5.22-5.20 (1H, m), 4.77-4.74 (3H, m), 3.75 (1H, s), 3.01 (1H, ddd, J = 16.3,8.9,3.6Hz), 2.85-2.83 (1H, m), 2.60-2.56 (1H, m), 1.86-1.81 (1H, m).
[Step 2] [3-[(6R) -6-amino-3- (benzenesulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-2-yl] pyrazin-2-yl] methanol
Figure JPOXMLDOC01-appb-C000126
Figure JPOXMLDOC01-appb-C000126
　上記工程１で得られた化合物（60mg）を用いて実施例１工程１１と同様の手法により標題化合物（41mg）を白色固体として得た。
MS(ESI)m/z:421(M+H)+
1H-NMR(CDCl3)δppm:8.62(2H,dd,J=8.0,2.5Hz),7.99(1H,d,J=8.6Hz),7.69(2H,dd,J=5.9,3.9Hz),7.47-7.43(1H,m),7.36-7.33(3H,m),6.75(1H,s),4.79(2H,s),4.42(1H,t,J=7.2Hz),3.03(1H,ddd,J=16.2,8.8,3.3Hz),2.86-2.78(1H,m),2.56-2.53(1H,m),2.00(3H,s),1.76-1.71(1H,m).
[工程３]　[3-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル]メタノール Using the compound (60 mg) obtained in the above Step 1, the title compound (41 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 421 (M + H) +
1 H-NMR (CDCl 3 ) δ ppm: 8.62 (2H, dd, J = 8.0,2.5Hz), 7.99 (1H, d, J = 8.6Hz), 7.69 (2H, dd, J = 5.9,3.9Hz), 7.47-7.43 (1H, m), 7.36-7.33 (3H, m), 6.75 (1H, s), 4.79 (2H, s), 4.42 (1H, t, J = 7.2Hz), 3.03 (1H, ddd, J = 16.2,8.8,3.3Hz), 2.86-2.78 (1H, m), 2.56-2.53 (1H, m), 2.00 (3H, s), 1.76-1.71 (1H, m).
[Step 3] [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] methanol
Figure JPOXMLDOC01-appb-C000127
Figure JPOXMLDOC01-appb-C000127
　上記工程２で得られた化合物（40mg）を用いて実施例１工程１２と同様の手法により標題化合物（15mg）を白色固体として得た。
MS(ESI)m/z:264(M-NH2)+
1H-NMR(CD3OD)δppm:8.57(1H,d,J=2.3Hz),8.41(1H,d,J=2.7Hz),7.33(1H,d,J=8.6Hz),7.23(1H,d,J=8.2Hz),7.02(1H,s),4.97(2H,s),4.43(1H,t,J=6.6Hz),3.25-3.21(1H,m),3.02-2.95(1H,m),2.58-2.54(1H,m),1.86-1.83(1H,m).
実施例２１　(6R)-2-(3-フルオロピリジン-4-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [(6R)-2-(3-フルオロピリジン-4-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (40 mg) obtained in the above Step 2, the title compound (15 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 264 (M-NH2) +
1 H-NMR (CD 3 OD) δppm: 8.57 (1H, d, J = 2.3Hz), 8.41 (1H, d, J = 2.7Hz), 7.33 (1H, d, J = 8.6Hz), 7.23 (1H , d, J = 8.2Hz), 7.02 (1H, s), 4.97 (2H, s), 4.43 (1H, t, J = 6.6Hz), 3.25-3.21 (1H, m), 3.02-2.95 (1H, m), 2.58-2.54 (1H, m), 1.86-1.83 (1H, m).
Example 21 (6R) -2- (3-Fluoropyridin-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-butyl [(6R) -2- (3-fluoropyridin-4-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
Figure JPOXMLDOC01-appb-C000128
Figure JPOXMLDOC01-appb-C000128
　実施例１４工程１で得られた化合物（200mg）及び3-フルオロ-4-ピリジンボロン酸ピナコールエステル（136mg）を用いて実施例１工程９と同様の手法により標題化合物（154mg）を淡黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.57-8.55(1H,m),8.51-8.47(1H,m),8.10-8.07(1H,m),7.49-7.44(3H,m),7.40-7.37(1H,m),7.35-7.29(3H,m),6.70(1H,s),5.27-5.19(1H,m),4.79-4.72(1H,m),3.07-2.99(1H,m),2.89-2.83(1H,m),2.67-2.57(1H,m),1.88-1.82(1H,m),1.48(9H,s).
[工程２]　(6R)-2-(3-フルオロピリジン-4-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Example 14 Using the compound (200 mg) obtained in Step 1 and 3-fluoro-4-pyridineboronic acid pinacol ester (136 mg), the title compound (154 mg) was prepared as a pale yellow oil in the same manner as in Example 1, Step 9. Obtained as material.
1 H-NMR (CDCl 3 ) δ ppm: 8.57-8.55 (1H, m), 8.51-8.47 (1H, m), 8.10-8.07 (1H, m), 7.49-7.44 (3H, m), 7.40-7.37 ( 1H, m), 7.35-7.29 (3H, m), 6.70 (1H, s), 5.27-5.19 (1H, m), 4.79-4.72 (1H, m), 3.07-2.99 (1H, m), 2.89- 2.83 (1H, m), 2.67-2.57 (1H, m), 1.88-1.82 (1H, m), 1.48 (9H, s).
[Step 2] (6R) -2- (3-Fluoropyridin-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000129
Figure JPOXMLDOC01-appb-C000129
　上記工程１で得られた化合物（154mg）を用いて実施例１工程１１及び実施例１工程１２と同様の手法により表題化合物（14mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.95(1H,brs),8.55-8.52(1H,m),8.44-8.40(1H,m),7.68-7.63(1H,m),7.33-7.23(2H,m),7.10-7.06(1H,m),4.51-4.46(1H,m),3.25-3.17(1H,m),3.02-2.95(1H,m),2.68-2.61(1H,m),1.85-1.77(1H,m).
実施例２２　(6R)-2-(2-メチルピリミジン-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [(6R)-2-(2-メチルピリミジン-5-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (154 mg) obtained in the above Step 1, the title compound (14 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1 and Step 12 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.95 (1H, brs), 8.55-8.52 (1H, m), 8.44-8.40 (1H, m), 7.68-7.63 (1H, m), 7.33-7.23 (2H, m), 7.10-7.06 (1H, m), 4.51-4.46 (1H, m), 3.25-3.17 (1H, m), 3.02-2.95 (1H, m), 2.68-2.61 (1H, m), 1.85 1.77 (1H, m).
Example 22 (6R) -2- (2-Methylpyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-butyl [(6R) -2- (2-methylpyrimidin-5-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
Figure JPOXMLDOC01-appb-C000130
Figure JPOXMLDOC01-appb-C000130
　実施例１４工程１で得られた化合物（200mg）及び2-メチルピリミジン-5-ボロン酸（84.2mg）を用いて実施例１工程９と同様の手法により標題化合物（194mg）を淡黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.72-8.68(2H,m),8.18-8.14(1H,m),7.48-7.44(1H,m),7.38-7.34(3H,m),7.31-7.27(2H,m),6.57(1H,s),5.29-5.22(1H,m),4.83-4.76(1H,m),3.07-2.99(1H,m),2.90-2.84(1H,m),2.82(3H,s),2.68-2.59(1H,m),1.90-1.80(1H,m),1.48(9H,s).
[工程２]　(6R)-2-(2-メチルピリミジン-5-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Example 14 Using the compound (200 mg) obtained in Step 1 and 2-methylpyrimidine-5-boronic acid (84.2 mg), the title compound (194 mg) was obtained as a pale yellow oily substance in the same manner as in Example 1, Step 9. Got as.
1 H-NMR (CDCl 3 ) δ ppm: 8.72-8.68 (2H, m), 8.18-8.14 (1H, m), 7.48-7.44 (1H, m), 7.38-7.34 (3H, m), 7.31-7.27 ( 2H, m), 6.57 (1H, s), 5.29-5.22 (1H, m), 4.83-4.76 (1H, m), 3.07-2.99 (1H, m), 2.90-2.84 (1H, m), 2.82 ( 3H, s), 2.68-2.59 (1H, m), 1.90-1.80 (1H, m), 1.48 (9H, s).
[Step 2] (6R) -2- (2-Methylpyrimidin-5-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000131
　上記工程１で得られた化合物（194mg）を用いて実施例１工程１１と同様の手法により標題化合物（141mg）を淡黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.70(2H,s),8.19-8.16(1H,m),7.47-7.44(1H,m),7.39-7.35(3H,m),7.32-7.27(2H,m),6.58(1H,s),4.47(1H,t,J=7.1Hz),3.09-3.02(1H,m),2.88-2.82(1H,m),2.82(3H,s),2.61-2.53(1H,m),1.82-1.74(1H,m).
[工程３]　(6R)-2-(2-メチルピリミジン-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (194 mg) obtained in the above Step 1, the title compound (141 mg) was obtained as a pale yellow oily substance in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.70 (2H, s), 8.19-8.16 (1H, m), 7.47-7.44 (1H, m), 7.39-7.35 (3H, m), 7.32-7.27 (2H, m), 6.58 (1H, s), 4.47 (1H, t, J = 7.1Hz), 3.09-3.02 (1H, m), 2.88-2.82 (1H, m), 2.82 (3H, s), 2.61-2.53 (1H, m), 1.82-1.74 (1H, m).
[Step 3] (6R) -2- (2-Methylpyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000132
Figure JPOXMLDOC01-appb-C000132
　上記工程２で得られた化合物（141mg）を用いて実施例１工程１２と同様の手法により標題化合物（19mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.91(2H,s),8.44(1H,s),7.32-7.29(1H,m),7.24-7.21(1H,m),6.83-6.81(1H,m),4.48(1H,t,J=6.8Hz),3.23-3.17(1H,m),3.01-2.94(1H,m),2.76(3H,s),2.67-2.60(1H,m),1.85-1.77(1H,m).
実施例２３　1-[5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル]エタノン
[工程１]　tert-ブチル [(6R)-2-(5-アセチルピラジン-2-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (141 mg) obtained in the above Step 2, the title compound (19 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3) δppm: 8.91 (2H, s), 8.44 (1H, s), 7.32-7.29 (1H, m), 7.24-7.21 (1H, m), 6.83-6.81 (1H, m) , 4.48 (1H, t, J = 6.8Hz), 3.23-3.17 (1H, m), 3.01-2.94 (1H, m), 2.76 (3H, s), 2.67-2.60 (1H, m), 1.85-1.77 (1H, m).
Example 23 1- [5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] ethanone
[Step 1] tert-Butyl [(6R) -2- (5-acetylpyrazin-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
Figure JPOXMLDOC01-appb-C000133
Figure JPOXMLDOC01-appb-C000133
　実施例１３工程５で得られた化合物（7.0g）及び1-(5-クロロピラジン-2-イル)エタノン（1.7g）を用いて実施例１１工程８と同様の手法により標題化合物（5.3g）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.24(1H,s),9.02(1H,s),8.05(1H,d,J=8.6Hz),7.54(2H,d,J=8.2Hz),7.45(1H,t,J=7.6Hz),7.36-7.29(3H,m),7.01(1H,s),5.22-5.21(1H,m),4.71(1H,d,J=7.0Hz),3.02(1H,ddd,J=16.5,4.2,2.1Hz),2.86-2.84(1H,m),2.76(3H,s),2.64-2.59(1H,m),1.84-1.81(1H,m),1.46(9H,s).
[工程２]　1-{5-[(6R)-6-アミノ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノン Example 13 Using the compound (7.0 g) obtained in Step 5 and 1- (5-chloropyrazin-2-yl) ethanone (1.7 g), the title compound (5.3 g) was prepared in the same manner as in Example 11, Step 8. ) Was obtained as a white solid.
1 H-NMR (CDCl 3 ) δppm: 9.24 (1H, s), 9.02 (1H, s), 8.05 (1H, d, J = 8.6Hz), 7.54 (2H, d, J = 8.2Hz), 7.45 ( 1H, t, J = 7.6Hz), 7.36-7.29 (3H, m), 7.01 (1H, s), 5.22-5.21 (1H, m), 4.71 (1H, d, J = 7.0Hz), 3.02 (1H , ddd, J = 16.5,4.2,2.1Hz), 2.86-2.84 (1H, m), 2.76 (3H, s), 2.64-2.59 (1H, m), 1.84-1.81 (1H, m), 1.46 (9H , s).
[Step 2] 1- {5-[(6R) -6-amino-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl } Ethanon
Figure JPOXMLDOC01-appb-C000134
Figure JPOXMLDOC01-appb-C000134
　上記工程１で得られた化合物（200mg）を用いて実施例１工程１１と同様の手法により標題化合物（30mg）を白色固体として得た。
MS(ESI)m/z:416(M-NH2)+
1H-NMR(CDCl3)δppm:9.23(1H,d,J=1.6Hz),9.02(1H,s),8.06(1H,d,J=7.8Hz),7.54(2H,d,J=7.4Hz),7.44(1H,t,J=7.2Hz),7.38-7.29(3H,m),7.02(1H,s),4.42(1H,t,J=7.0Hz),3.03(1H,ddd,J=16.2,8.6,3.5Hz),2.83-2.81(1H,m),2.76(3H,s),2.56-2.52(1H,m),1.75-1.66(1H,m).
[工程３]　1-[5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル]エタノン Using the compound (200 mg) obtained in the above Step 1, the title compound (30 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 416 (M-NH2) +
1 H-NMR (CDCl 3) δppm: 9.23 (1H, d, J = 1.6Hz), 9.02 (1H, s), 8.06 (1H, d, J = 7.8Hz), 7.54 (2H, d, J = 7.4 Hz), 7.44 (1H, t, J = 7.2Hz), 7.38-7.29 (3H, m), 7.02 (1H, s), 4.42 (1H, t, J = 7.0Hz), 3.03 (1H, ddd, J = 16.2,8.6,3.5Hz), 2.83-2.81 (1H, m), 2.76 (3H, s), 2.56-2.52 (1H, m), 1.75-1.66 (1H, m).
[Step 3] 1- [5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000135
Figure JPOXMLDOC01-appb-C000135
　上記工程２で得られた化合物（30mg）を用いて実施例１工程１２と同様の手法により標題化合物（10mg）を白色固体として得た。
MS(ESI)m/z:276(M-NH2)+
1H-NMR(CD3OD)δppm:9.18(1H,d,J=1.6Hz),9.08(1H,d,J=1.6Hz),7.35(2H,d,J=5.5Hz),7.27(1H,d,J=8.6Hz),4.53(1H,t,J=6.3Hz),3.24-3.21(1H,m),3.09-3.00(1H,m),2.65(3H,s),2.62-2.61(1H,m),1.98-1.91(1H,m).
実施例２４　(1S)-1-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール
[工程１]　tert-ブチル [(6R)-2-{5-[(1S)-1-ヒドロキシエチル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (30 mg) obtained in the above Step 2, the title compound (10 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 276 (M-NH2) +
1 H-NMR (CD 3 OD) δppm: 9.18 (1H, d, J = 1.6Hz), 9.08 (1H, d, J = 1.6Hz), 7.35 (2H, d, J = 5.5Hz), 7.27 (1H , d, J = 8.6Hz), 4.53 (1H, t, J = 6.3Hz), 3.24-3.21 (1H, m), 3.09-3.00 (1H, m), 2.65 (3H, s), 2.62-2.61 ( 1H, m), 1.98-1.91 (1H, m).
Example 24 (1S) -1- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} ethanol
[Step 1] tert-Butyl [(6R) -2- {5-[(1S) -1-hydroxyethyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6,7,8-tetrahydro Cyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000136
Figure JPOXMLDOC01-appb-C000136
　実施例２３工程１で得られた化合物（60mg）を用いて実施例１０工程１と同様の手法により標題化合物（40mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.84(1H,d,J=1.2Hz),8.70(1H,d,J=1.6Hz),8.03(1H,d,J=8.2Hz),7.59(2H,d,J=8.2Hz),7.44(1H,t,J=7.4Hz),7.33-7.29(3H,m),6.87(1H,s),5.21(1H,q,J=7.8Hz),5.07-5.05(1H,m),4.73(1H,d,J=8.6Hz),3.43(1H,s),3.01(1H,ddd,J=16.1,8.7,3.4Hz),2.88-2.80(1H,m),2.62-2.59(1H,m),1.85-1.80(1H,m),1.62(3H,d,J=6.6Hz),1.46(9H,s).
分析条件；CHIRALPAK OD-H，ヘキサン：イソプロパノール＝1：1，1.0mL/min
tert-ブチル [(6R)-2-{5-[(1S)-1-ヒドロキシエチル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート：7.001min
[工程２]　(1S)-1-{5-[(6R)-6-アミノ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール  The title compound (40 mg) was obtained as a white solid in the same manner as in Example 10, Step 1, using the compound (60 mg) obtained in Step 1, Example 23.
1 H-NMR (CDCl 3) δppm: 8.84 (1H, d, J = 1.2Hz), 8.70 (1H, d, J = 1.6Hz), 8.03 (1H, d, J = 8.2Hz), 7.59 (2H, d, J = 8.2Hz), 7.44 (1H, t, J = 7.4Hz), 7.33-7.29 (3H, m), 6.87 (1H, s), 5.21 (1H, q, J = 7.8Hz), 5.07- 5.05 (1H, m), 4.73 (1H, d, J = 8.6Hz), 3.43 (1H, s), 3.01 (1H, ddd, J = 16.1,8.7,3.4Hz), 2.88-2.80 (1H, m) , 2.62-2.59 (1H, m), 1.85-1.80 (1H, m), 1.62 (3H, d, J = 6.6Hz), 1.46 (9H, s).
Analysis conditions: CHIRALPAK OD-H, hexane: isopropanol = 1: 1, 1.0 mL / min
tert-butyl [(6R) -2- {5-[(1S) -1-hydroxyethyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e ] Indol-6-yl] Carbamate: 7.001min
[Step 2] (1S) -1- {5-[(6R) -6-amino-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazine -2-yl} ethanol
Figure JPOXMLDOC01-appb-C000137
Figure JPOXMLDOC01-appb-C000137
　上記工程１で得られた化合物（124mg）を用いて実施例１工程１１と同様の手法により標題化合物（100mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.83(1H,d,J=1.6Hz),8.70(1H,d,J=1.6Hz),8.03(1H,d,J=8.6Hz),7.59(2H,d,J=8.4Hz),7.43(1H,t,J=7.4Hz),7.33-7.29(3H,m),6.86(1H,d,J=0.8Hz),5.04(1H,q,J=6.6Hz),4.41(1H,t,J=7.0Hz),3.02(1H,ddd,J=16.3,8.7,3.6Hz),2.84-2.76(1H,m),2.55-2.52(1H,m),1.77-1.70(1H,m),1.61(3H,d,J=6.6Hz).
[工程３]　(1S)-1-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール Using the compound (124 mg) obtained in Step 1 above, the title compound (100 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.83 (1H, d, J = 1.6Hz), 8.70 (1H, d, J = 1.6Hz), 8.03 (1H, d, J = 8.6Hz), 7.59 (2H, d, J = 8.4Hz), 7.43 (1H, t, J = 7.4Hz), 7.33-7.29 (3H, m), 6.86 (1H, d, J = 0.8Hz), 5.04 (1H, q, J = 6.6 Hz), 4.41 (1H, t, J = 7.0Hz), 3.02 (1H, ddd, J = 16.3,8.7,3.6Hz), 2.84-2.76 (1H, m), 2.55-2.52 (1H, m), 1.77 -1.70 (1H, m), 1.61 (3H, d, J = 6.6Hz).
[Step 3] (1S) -1- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} ethanol
Figure JPOXMLDOC01-appb-C000138
Figure JPOXMLDOC01-appb-C000138
　上記工程２で得られた化合物（100mg）を用いて実施例１工程１２と同様の手法により標題化合物（30mg）を白色固体として得た。
MS(ESI)m/z:278(M-NH2)+
1H-NMR(CD3OD)δppm:9.04(1H,d,J=1.2Hz),8.74(1H,d,J=0.8Hz),7.35(1H,d,J=8.2Hz),7.24(1H,d,J=8.6Hz),7.16(1H,s),4.95(1H,q,J=6.5Hz),4.47(1H,t,J=6.7Hz),3.27-3.22(1H,m),3.05-2.97(1H,m),2.62-2.59(1H,m),1.90-1.87(1H,m),1.55(3H,d,J=6.7Hz).
実施例２５　(1R)-1-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール
[工程１]　tert-ブチル [(6R)-2-{5-[(1R)-1-ヒドロキシエチル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (100 mg) obtained in the above Step 2, the title compound (30 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 278 (M-NH2) +
1 H-NMR (CD 3 OD) δppm: 9.04 (1H, d, J = 1.2Hz), 8.74 (1H, d, J = 0.8Hz), 7.35 (1H, d, J = 8.2Hz), 7.24 (1H , d, J = 8.6Hz), 7.16 (1H, s), 4.95 (1H, q, J = 6.5Hz), 4.47 (1H, t, J = 6.7Hz), 3.27-3.22 (1H, m), 3.05 -2.97 (1H, m), 2.62-2.59 (1H, m), 1.90-1.87 (1H, m), 1.55 (3H, d, J = 6.7Hz).
Example 25 (1R) -1- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} ethanol
[Step 1] tert-Butyl [(6R) -2- {5-[(1R) -1-hydroxyethyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6,7,8-tetrahydro Cyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000139
　実施例２３工程１で得られた化合物（5.80g）及びクロロ[(1R,2R)-N-(p-トルエンスルホニル)-1,2-ジフェニルエタンジアミン](メシチレン)ルテニウム(II)（350mg）を用いて実施例１０工程１と同様の手法により標題化合物（4.98g）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.85(1H,s),8.70(1H,s),8.03(1H,d,J=8.6Hz),7.60(2H,d,J=8.2Hz),7.44(1H,t,J=7.4Hz),7.34-7.30(3H,m),6.87(1H,s),5.22-5.21(1H,m),5.07(1H,d,J=4.3Hz),4.72(1H,d,J=9.0Hz),3.01(1H,ddd,J=16.4,9.0,3.5Hz),2.88-2.80(1H,m),2.63-2.59(1H,m),1.85-1.80(1H,m),1.63(3H,d,J=6.6Hz),1.46(9H,s).
分析条件；CHIRALPAK OD-H，ヘキサン：イソプロパノール＝1：1，1.0mL/min
tert-ブチル [(6R)-2-{5-[(1R)-1-ヒドロキシエチル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート:8.215min
[工程２]　(1R)-1-{5-[(6R)-6-アミノ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール Example 23 Compound (5.80 g) obtained in Step 1 and chloro [(1R, 2R) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium (II) (350 mg) Was used to give the title compound (4.98 g) as a white solid in the same manner as in Step 10 of Example 10.
1 H-NMR (CDCl 3 ) δppm: 8.85 (1H, s), 8.70 (1H, s), 8.03 (1H, d, J = 8.6Hz), 7.60 (2H, d, J = 8.2Hz), 7.44 ( 1H, t, J = 7.4Hz), 7.34-7.30 (3H, m), 6.87 (1H, s), 5.22-5.21 (1H, m), 5.07 (1H, d, J = 4.3Hz), 4.72 (1H , d, J = 9.0Hz), 3.01 (1H, ddd, J = 16.4,9.0,3.5Hz), 2.88-2.80 (1H, m), 2.63-2.59 (1H, m), 1.85-1.80 (1H, m ), 1.63 (3H, d, J = 6.6Hz), 1.46 (9H, s).
Analysis conditions: CHIRALPAK OD-H, hexane: isopropanol = 1: 1, 1.0 mL / min
tert-Butyl [(6R) -2- {5-[(1R) -1-hydroxyethyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e ] Indol-6-yl] Carbamate: 8.215min
[Step 2] (1R) -1- {5-[(6R) -6-amino-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazine -2-yl} ethanol
Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000140
　上記工程１で得られた化合物（6.60g）を用いて実施例１工程１１と同様の手法により標題化合物（4.90g）を白色固体として得た。
MS(ESI)m/z:418(M-NH2)+
1H-NMR(CDCl3)δppm:8.85(1H,s),8.69(1H,s),8.04(1H,d,J=8.6Hz),7.60(2H,d,J=8.6Hz),7.43(1H,t,J=9.9Hz),7.34-7.32(3H,m),6.87(1H,s),5.06(1H,q,J=6.5Hz),4.41(1H,t,J=7.2Hz),3.02(1H,ddd,J=16.4,8.8,3.7Hz),2.85-2.77(1H,m),2.56-2.53(1H,m),1.75-1.71(1H,m),1.62(3H,d,J=6.6Hz).
[工程３]　(1R)-1-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール The title compound (4.90 g) was obtained as a white solid in the same manner as in Step 1 of Example 1 using the compound (6.60 g) obtained in Step 1 above.
MS (ESI) m / z: 418 (M-NH2) +
1 H-NMR (CDCl 3 ) δ ppm: 8.85 (1H, s), 8.69 (1H, s), 8.04 (1H, d, J = 8.6Hz), 7.60 (2H, d, J = 8.6Hz), 7.43 ( 1H, t, J = 9.9Hz), 7.34-7.32 (3H, m), 6.87 (1H, s), 5.06 (1H, q, J = 6.5Hz), 4.41 (1H, t, J = 7.2Hz), 3.02 (1H, ddd, J = 16.4,8.8,3.7Hz), 2.85-2.77 (1H, m), 2.56-2.53 (1H, m), 1.75-1.71 (1H, m), 1.62 (3H, d, J = 6.6Hz).
[Step 3] (1R) -1- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} ethanol
Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000141
　上記工程２で得られた化合物（4.50g）を用いて実施例１工程１２と同様の手法により標題化合物（1.10g）を白色固体として得た。
MS(ESI)m/z:278(M-NH2)+
1H-NMR(CD3OD)δppm:9.00(1H,d,J=1.6Hz),8.70(1H,d,J=1.2Hz),7.30(1H,d,J=8.6Hz),7.20(1H,d,J=8.6Hz),7.11(1H,s),4.91(1H,q,J=6.6Hz),4.41(1H,t,J=6.6Hz),3.24-3.18(1H,m),3.00-2.92(1H,m),2.57-2.54(1H,m),1.88-1.79(1H,m),1.51(3H,d,J=6.6Hz).
実施例２６　{4-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリミジン-2-イル}メタノール
[工程１]　{4-[(6R)-6-[(tert-ブトキシカルボニル)アミノ]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリミジン-2-イル}メチルアセテート Using the compound (4.50 g) obtained in Step 2 above, the title compound (1.10 g) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 278 (M-NH2) +
1 H-NMR (CD 3 OD) δppm: 9.00 (1H, d, J = 1.6Hz), 8.70 (1H, d, J = 1.2Hz), 7.30 (1H, d, J = 8.6Hz), 7.20 (1H , d, J = 8.6Hz), 7.11 (1H, s), 4.91 (1H, q, J = 6.6Hz), 4.41 (1H, t, J = 6.6Hz), 3.24-3.18 (1H, m), 3.00 -2.92 (1H, m), 2.57-2.54 (1H, m), 1.88-1.79 (1H, m), 1.51 (3H, d, J = 6.6Hz).
Example 26 {4-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyrimidin-2-yl} methanol
[Step 1] {4-[(6R) -6-[(tert-butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl ] -6-Methoxypyrimidin-2-yl} methyl acetate
Figure JPOXMLDOC01-appb-C000142
Figure JPOXMLDOC01-appb-C000142
　実施例１３工程５で得られた化合物（400mg）及び(4-クロロ-6－メトキシ-ピリミジン-2-イル)メチルアセテート（247mg）を用いて実施例１１工程８と同様の手法により標題化合物（230mg）を黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.03(1H,d,J=8.2Hz),7.77-7.70(2H,m),7.55-7.46(1H,m),7.42-7.33(3H,m),6.97(1H,s),6.90(1H,s),5.36-5.18(3H,m),4.76-4.67(1H,m),4.03(3H,s),3.10-3.00(1H,m),2.92-2.81(1H,m),2.70-2.59(1H,m),2.20(3H,s),1.92-1.80(1H,m),1.49(9H,s).
[工程２]　tert-ブチル [(6R)-2-[2-(ヒドロキシメチル)-6-メトキシピリミジン-4-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Example 13 Using the compound obtained in Step 5 (400 mg) and (4-chloro-6-methoxy-pyrimidin-2-yl) methyl acetate (247 mg) in the same manner as in Example 11, Step 8, the title compound ( 230 mg) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δppm: 8.03 (1H, d, J = 8.2Hz), 7.77-7.70 (2H, m), 7.55-7.46 (1H, m), 7.42-7.33 (3H, m), 6.97 (1H, s), 6.90 (1H, s), 5.36-5.18 (3H, m), 4.76-4.67 (1H, m), 4.03 (3H, s), 3.10-3.00 (1H, m), 2.92-2.81 (1H, m), 2.70-2.59 (1H, m), 2.20 (3H, s), 1.92-1.80 (1H, m), 1.49 (9H, s).
[Step 2] tert-butyl [(6R) -2- [2- (hydroxymethyl) -6-methoxypyrimidin-4-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] Indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000143
　上記工程１で得られた化合物（220mg）のテトラヒドロフラン（1.86mL）及びメタノール（1.86mL）溶液に炭酸カリウム（0.111g）を加え、0℃で1時間攪拌した。水を加えて反応を停止した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物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］で精製することにより標題化合物（140mg）を黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.05(1H,d,J=8.6Hz),7.69-7.64(2H,m),7.53-7.47(1H,m),7.40-7.34(3H,m),6.99(1H,s),6.95(1H,s),5.30-5.20(1H,m),4.80-4.70(3H,m),4.06(3H,s),3.10-3.00(1H,m),2.94-2.82(1H,m),2.70-2.58(1H,m),1.92-1.80(1H,m),1.50(9H,s).
[工程３]　{4-[(6R)-6-アミノ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリミジン-2-イル}メタノール To a solution of the compound obtained in Step 1 (220 mg) in tetrahydrofuran (1.86 mL) and methanol (1.86 mL) was added potassium carbonate (0.111 g), and the mixture was stirred at 0 ° C. for 1 hour. The reaction was stopped by adding water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (140 mg) as a yellow oil.
1 H-NMR (CDCl 3 ) δppm: 8.05 (1H, d, J = 8.6Hz), 7.69-7.64 (2H, m), 7.53-7.47 (1H, m), 7.40-7.34 (3H, m), 6.99 (1H, s), 6.95 (1H, s), 5.30-5.20 (1H, m), 4.80-4.70 (3H, m), 4.06 (3H, s), 3.10-3.00 (1H, m), 2.94-2.82 (1H, m), 2.70-2.58 (1H, m), 1.92-1.80 (1H, m), 1.50 (9H, s).
[Step 3] {4-[(6R) -6-amino-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyrimidine-2 -Il} methanol
Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000144
　上記工程２で得られた化合物（135mg）を用いて実施例１工程１１と同様の手法により標題化合物（85mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:8.06(1H,d,J=8.6Hz),7.68-7.65(2H,m),7.53-7.47(1H,m),7.40-7.34(3H,m),6.99(1H,s),6.96(1H,s),4.75(2H,s),4.44(1H,dd,J=7.2,7.2Hz),3.10-3.00(1H,m),2.90-2.80(1H,m),2.64-2.53(1H,m),1.82-1.70(1H,m).
[工程４]　{4-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリミジン-2-イル}メタノール Using the compound (135 mg) obtained in the above Step 2, the title compound (85 mg) was obtained as a colorless oily substance in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.06 (1H, d, J = 8.6Hz), 7.68-7.65 (2H, m), 7.53-7.47 (1H, m), 7.40-7.34 (3H, m), 6.99 (1H, s), 6.96 (1H, s), 4.75 (2H, s), 4.44 (1H, dd, J = 7.2,7.2Hz), 3.10-3.00 (1H, m), 2.90-2.80 (1H, m ), 2.64-2.53 (1H, m), 1.82-1.70 (1H, m).
[Step 4] {4-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyrimidin-2-yl} methanol
Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000145
　上記工程３で得られた化合物（80mg）を用いて実施例１工程１２と同様の手法により標題化合物（28mg）を白色固体として得た。
1H-NMR(MeOH-d4)δppm:7.37-7.17(4H,m),4.74(2Hs),4.48(1H,dd,J=6.6,6.6Hz),4.05(3H,s),3.35-3.24(1H,m),3.06-2.98(1H,m),2.67-2.58(1H,m),1.94-1.86(1H,m).
実施例２７　(6S)-2-[5-(メチルスルホニル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [(6S)-3-[(4-メチルフェニル)スルホニル]-2-(トリブチルスタナニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (80 mg) obtained in the above Step 3, the title compound (28 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δ ppm: 7.37-7.17 (4H, m), 4.74 (2Hs), 4.48 (1H, dd, J = 6.6, 6.6Hz), 4.05 (3H, s), 3.35-3.24 ( 1H, m), 3.06-2.98 (1H, m), 2.67-2.58 (1H, m), 1.94-1.86 (1H, m).
Example 27 (6S) -2- [5- (Methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-butyl [(6S) -3-[(4-methylphenyl) sulfonyl] -2- (tributylstannanyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
Figure JPOXMLDOC01-appb-C000146
Figure JPOXMLDOC01-appb-C000146
　実施例１０工程４で第一ピークとして得られた化合物（2g）を用いて実施例１１工程７と同様の手法により標題化合物（2.6g）を白色固体として得た。
[工程２]　tert-ブチル {(6S)-3-[(4-メチルフェニル)スルホニル]-2-[5-(メチルスルホニル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル}カルバメート The title compound (2.6 g) was obtained as a white solid in the same manner as in Example 11, Step 7 using the compound (2 g) obtained as the first peak in Step 4 of Example 10.
[Step 2] tert-butyl {(6S) -3-[(4-methylphenyl) sulfonyl] -2- [5- (methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclo Penta [e] indol-6-yl} carbamate
Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000147
　上記工程１で得られた化合物（500mg）及び2-ブロモ-5-メチルスルホニル-ピリジン（330mg）を用いて実施例１１工程８と同様の手法により標題化合物（310mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.21-9.17(1H,m),8.27(1H,d,J=8.2,2.3Hz),8.06(1H,d,J=8.6Hz),7.98-7.92(1H,m),7.50-7.44(3H,m),7.36(1H,d,J=8.6Hz),7.15-7.10(2H,m),7.00(1H,s),5.30-5.17(1H,m),4.80-4.68(1H,m),3.20(3H,s),3.10-3.00(1H,m),3.00-2.80(1H,m),2.70-2.55(1H,m),2.30(3H,s),1.92-1.79(1H,m),1.50(9H,s).
[工程３]　(6S)-3-[(4-メチルフェニル)スルホニル]-2-[5-(メチルスルホニル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound obtained in Step 1 above (500 mg) and 2-bromo-5-methylsulfonyl-pyridine (330 mg), the title compound (310 mg) was obtained as a white solid in the same manner as in Step 8 of Example 11.
1 H-NMR (CDCl 3 ) δppm: 9.21-9.17 (1H, m), 8.27 (1H, d, J = 8.2,2.3Hz), 8.06 (1H, d, J = 8.6Hz), 7.98-7.92 (1H , m), 7.50-7.44 (3H, m), 7.36 (1H, d, J = 8.6Hz), 7.15-7.10 (2H, m), 7.00 (1H, s), 5.30-5.17 (1H, m), 4.80-4.68 (1H, m), 3.20 (3H, s), 3.10-3.00 (1H, m), 3.00-2.80 (1H, m), 2.70-2.55 (1H, m), 2.30 (3H, s), 1.92-1.79 (1H, m), 1.50 (9H, s).
[Step 3] (6S) -3-[(4-Methylphenyl) sulfonyl] -2- [5- (methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] Indole-6-amine
Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000148
　上記工程２で得られた化合物（305mg）を用いて実施例１工程１１と同様の手法により標題化合物（210mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:9.18(1H,d,J=2.3Hz),8.26(1H,dd,J=8.2,2.3Hz),8.07(1H,d,J=8.2Hz),7.50-7.43(2H,m),7.37(1H,d,J=8.2Hz),7.11(1H,d,J=8.6Hz),7.00(1H,s),4.44(1H,dd,J=7.2,7.2Hz),3.20(3H,s),3.10-3.00(1H,m),2.90-2.73(1H,m),2.62-2.52(1H,m),2.29(3H,s),1.82-1.70(1H,m).
[工程４]　(6S)-2-[5-(メチルスルホニル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (305 mg) obtained in the above Step 2, the title compound (210 mg) was obtained as a colorless oily substance in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 9.18 (1H, d, J = 2.3Hz), 8.26 (1H, dd, J = 8.2,2.3Hz), 8.07 (1H, d, J = 8.2Hz), 7.50- 7.43 (2H, m), 7.37 (1H, d, J = 8.2Hz), 7.11 (1H, d, J = 8.6Hz), 7.00 (1H, s), 4.44 (1H, dd, J = 7.2,7.2Hz ), 3.20 (3H, s), 3.10-3.00 (1H, m), 2.90-2.73 (1H, m), 2.62-2.52 (1H, m), 2.29 (3H, s), 1.82-1.70 (1H, m) ).
[Step 4] (6S) -2- [5- (Methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000149
Figure JPOXMLDOC01-appb-C000149
　上記工程３で得られた化合物（200mg）を用いて実施例１工程１２と同様の手法により標題化合物（65mg）を白色固体として得た。
1H-NMR(MeOH-d4)δppm:9.08(1H,dd,J=2.3,0.8Hz),8.28(1H,dd,J=8.6,2.3Hz),8.12(1H,d,J=8.6,0.8Hz),7.38(1H,d,J=8.2Hz),7.30(1H,d,J=8.2Hz),7.26(1H,s),4.49(1H,dd,J=6.6,6.6Hz),3.35-3.20(4H,m),3.09-2.98(1H,m),2.68-2.57(1H,m),1.96-1.85(1H,m).
実施例２８　(1R)-1-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}プロパン-1-オール
[工程１]　tert-ブチル [(6R)-2-{5-[メトキシ(メチル)カルバモイル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (200 mg) obtained in the above Step 3, the title compound (65 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δ ppm: 9.08 (1H, dd, J = 2.3,0.8Hz), 8.28 (1H, dd, J = 8.6,2.3Hz), 8.12 (1H, d, J = 8.6,0.8 Hz), 7.38 (1H, d, J = 8.2Hz), 7.30 (1H, d, J = 8.2Hz), 7.26 (1H, s), 4.49 (1H, dd, J = 6.6, 6.6Hz), 3.35- 3.20 (4H, m), 3.09-2.98 (1H, m), 2.68-2.57 (1H, m), 1.96-1.85 (1H, m).
Example 28 (1R) -1- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} propane-1 -All
[Step 1] tert-Butyl [(6R) -2- {5- [methoxy (methyl) carbamoyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [ e] Indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000150
Figure JPOXMLDOC01-appb-C000150
　実施例１３工程５で合成した化合物（1.11g）及び5-クロロ-N-メトキシ-N-メチルピラジン-2-カルボキサミド（319mg）を用いて実施例１１工程８と同様の手法により標題化合物（910mg）を白色固体として得た。
MS(ESI)m/z:578(M+H)+
1H-NMR(CDCl3)δppm:8.95(2H,s),8.04(1H,d,J=8.6Hz),7.56(2H,d,J=7.8Hz),7.44(1H,t,J=7.4Hz),7.34-7.30(3H,m),6.96(1H,s),5.24-5.20(1H,m),4.70(1H,d,J=9.0Hz),3.82(3H,s),3.02(1H,ddd,J=16.1,9.1,3.4Hz),2.86-2.82(1H,m),2.67-2.57(1H,m),1.84-1.79(1H,m),1.53(3H,s),1.46(9H,s).
[工程２]　tert-ブチル [(6R)-3-(フェニルスルホニル)-2-(5-プロパノイルピラジン-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Example 13 Using the compound synthesized in Step 5 (1.11 g) and 5-chloro-N-methoxy-N-methylpyrazine-2-carboxamide (319 mg) in the same manner as Example 11 Step 8, the title compound (910 mg ) Was obtained as a white solid.
MS (ESI) m / z: 578 (M + H) +
1 H-NMR (CDCl 3 ) δppm: 8.95 (2H, s), 8.04 (1H, d, J = 8.6Hz), 7.56 (2H, d, J = 7.8Hz), 7.44 (1H, t, J = 7.4 Hz), 7.34-7.30 (3H, m), 6.96 (1H, s), 5.24-5.20 (1H, m), 4.70 (1H, d, J = 9.0Hz), 3.82 (3H, s), 3.02 (1H , ddd, J = 16.1,9.1,3.4Hz), 2.86-2.82 (1H, m), 2.67-2.57 (1H, m), 1.84-1.79 (1H, m), 1.53 (3H, s), 1.46 (9H , s).
[Step 2] tert-butyl [(6R) -3- (phenylsulfonyl) -2- (5-propanoylpyrazin-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6 -Il] Carbamate
Figure JPOXMLDOC01-appb-C000151
Figure JPOXMLDOC01-appb-C000151
　上記工程１で得られた化合物（1.0g）をテトラヒドロフラン（30mL）に溶解し、窒素雰囲気下、0℃でエチルマグネシウムブロミドテトラヒドロフラン溶液（1.0M，1.53mL）を滴下した。室温で30分攪拌後、反応溶液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。食塩水で洗浄後、硫酸ナトリウムで乾燥した。溶媒を留去し、残留物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］で精製し、標題化合物（149mg）を白色固体として得た。
MS(ESI)m/z:547(M+H)+
1H-NMR(CDCl3)δppm:9.23(1H,d,J=1.2Hz),9.00(1H,d,J=1.6Hz),8.05(1H,d,J=8.6Hz),7.54(2H,d,J=8.2Hz),7.44(1H,t,J=7.6Hz),7.36-7.29(3H,m),7.00(1H,s),5.23-5.21(1H,m),4.71(1H,d,J=8.6Hz),3.25(2H,q,J=7.2Hz),3.02(1H,ddd,J=16.5,4.2,2.1Hz),2.88-2.80(1H,m),2.63-2.59(1H,m),1.85-1.77(1H,m),1.46(9H,s),1.24(3H,t,J=7.2Hz).
[工程３]　tert-ブチル [(6R)-2-{5-[(1R)-1-ヒドロキシプロピル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート The compound (1.0 g) obtained in the above step 1 was dissolved in tetrahydrofuran (30 mL), and an ethylmagnesium bromide tetrahydrofuran solution (1.0 M, 1.53 mL) was added dropwise at 0 ° C. in a nitrogen atmosphere. After stirring at room temperature for 30 minutes, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing with brine, it was dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (149 mg) as a white solid.
MS (ESI) m / z: 547 (M + H) +
1 H-NMR (CDCl 3 ) δppm: 9.23 (1H, d, J = 1.2Hz), 9.00 (1H, d, J = 1.6Hz), 8.05 (1H, d, J = 8.6Hz), 7.54 (2H, d, J = 8.2Hz), 7.44 (1H, t, J = 7.6Hz), 7.36-7.29 (3H, m), 7.00 (1H, s), 5.23-5.21 (1H, m), 4.71 (1H, d , J = 8.6Hz), 3.25 (2H, q, J = 7.2Hz), 3.02 (1H, ddd, J = 16.5,4.2,2.1Hz), 2.88-2.80 (1H, m), 2.63-2.59 (1H, m), 1.85-1.77 (1H, m), 1.46 (9H, s), 1.24 (3H, t, J = 7.2Hz).
[Step 3] tert-butyl [(6R) -2- {5-[(1R) -1-hydroxypropyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6,7,8-tetrahydro Cyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000152
Figure JPOXMLDOC01-appb-C000152
　トリエチルアミン（0.0945mL）、ギ酸（0.0442mL）を攪拌し、クロロ[(1R,2R)-N-(2',6'-ジメチルベンジルスルホニル)-1,2-ジフェニルエタンジアミン](メシチレン)ルテニウム(II)（8.8mg）、上記工程２で得られた化合物（149mg）のジクロロメタン溶液（3mL）を加え、室温で2時間攪拌した。溶媒を留去し、残留物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］で精製し、標題化合物（118mg）を白色固体として得た。
MS(ESI)m/z:549(M+H)+
1H-NMR(CDCl3)δppm:8.85(1H,s),8.67(1H,s),8.03(1H,d,J=8.6Hz),7.59(2H,d,J=8.2Hz),7.44(1H,t,J=7.4Hz),7.33-7.29(3H,m),6.87(1H,d,J=0.8Hz),5.21(1H,q,J=7.6Hz),4.84(1H,t,J=5.1Hz),4.72(1H,d,J=9.0Hz),3.01(1H,ddd,J=16.2,9.0,3.5Hz),2.88-2.80(1H,m),2.63-2.59(1H,m),1.97-1.96(1H,m),1.87-1.84(2H,m),1.46(9H,s),1.01(3H,t,J=7.4Hz).
[工程４]　(1R)-1-{5-[(6R)-6-アミノ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}プロパン-1-オール Triethylamine (0.0945 mL) and formic acid (0.0442 mL) were stirred and chloro [(1R, 2R) -N- (2 ', 6'-dimethylbenzylsulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium ( II) (8.8 mg) and a dichloromethane solution (3 mL) of the compound obtained in Step 2 above (149 mg) were added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (118 mg) as a white solid.
MS (ESI) m / z: 549 (M + H) +
1 H-NMR (CDCl 3 ) δ ppm: 8.85 (1H, s), 8.67 (1H, s), 8.03 (1H, d, J = 8.6Hz), 7.59 (2H, d, J = 8.2Hz), 7.44 ( 1H, t, J = 7.4Hz), 7.33-7.29 (3H, m), 6.87 (1H, d, J = 0.8Hz), 5.21 (1H, q, J = 7.6Hz), 4.84 (1H, t, J = 5.1Hz), 4.72 (1H, d, J = 9.0Hz), 3.01 (1H, ddd, J = 16.2,9.0,3.5Hz), 2.88-2.80 (1H, m), 2.63-2.59 (1H, m) 1.91.9.96 (1H, m), 1.87-1.84 (2H, m), 1.46 (9H, s), 1.01 (3H, t, J = 7.4Hz).
[Step 4] (1R) -1- {5-[(6R) -6-amino-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazine -2-yl} propan-1-ol
Figure JPOXMLDOC01-appb-C000153
Figure JPOXMLDOC01-appb-C000153
　上記工程３で得られた化合物（118mg）を用いて実施例１工程１１と同様の手法により標題化合物（60mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.85(1H,d,J=1.2Hz),8.66(1H,d,J=1.6Hz),8.04(1H,d,J=8.6Hz),7.60(2H,dd,J=8.4,1.4Hz),7.43(1H,t,J=7.4Hz),7.34-7.31(3H,m),6.88(1H,s),4.84(1H,dd,J=7.4,5.1Hz),4.41(1H,t,J=7.2Hz),3.02(1H,ddd,J=16.1,8.9,3.6Hz),2.85-2.77(1H,m),2.56-2.53(1H,m),2.00-1.95(1H,m),1.88-1.80(1H,m),1.75-1.68(1H,m),1.01(3H,t,J=7.2Hz).
[工程５]　(1R)-1-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}プロパン-1-オール Using the compound (118 mg) obtained in Step 3 above, the title compound (60 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.85 (1H, d, J = 1.2Hz), 8.66 (1H, d, J = 1.6Hz), 8.04 (1H, d, J = 8.6Hz), 7.60 (2H, dd, J = 8.4,1.4Hz), 7.43 (1H, t, J = 7.4Hz), 7.34-7.31 (3H, m), 6.88 (1H, s), 4.84 (1H, dd, J = 7.4,5.1Hz ), 4.41 (1H, t, J = 7.2Hz), 3.02 (1H, ddd, J = 16.1,8.9,3.6Hz), 2.85-2.77 (1H, m), 2.56-2.53 (1H, m), 2.00- 1.95 (1H, m), 1.88-1.80 (1H, m), 1.75-1.68 (1H, m), 1.01 (3H, t, J = 7.2Hz).
[Step 5] (1R) -1- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} propane- 1-all
Figure JPOXMLDOC01-appb-C000154
Figure JPOXMLDOC01-appb-C000154
　上記工程４で得られた化合物（60mg）を用いて実施例１工程１２と同様の手法により標題化合物（20mg）を薄黄色固体として得た。
MS(ESI)m/z:292(M-NH2)+
1H-NMR(CD3OD)δppm:9.08(1H,d,J=1.6Hz),8.74(1H,d,J=1.2Hz),7.38(1H,d,J=8.2Hz),7.27(1H,d,J=8.6Hz),7.19(1H,s),4.74(1H,dd,J=7.4,5.1Hz),4.50(1H,t,J=6.7Hz),3.29-3.27(1H,m),3.08-3.00(1H,m),2.66-2.61(1H,m),1.97-1.87(3H,m),1.02(3H,t,J=7.4Hz).
実施例２９　(6R)-2-{5-[(1Z)-N-ヒドロキシエタンイミドイル]ピラジン-2-イル}-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [(6R)-2-{5-[(1Z)-N-ヒドロキシエタンイミドイル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (60 mg) obtained in the above Step 4, the title compound (20 mg) was obtained as a pale yellow solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 292 (M-NH2) +
1 H-NMR (CD 3 OD) δppm: 9.08 (1H, d, J = 1.6Hz), 8.74 (1H, d, J = 1.2Hz), 7.38 (1H, d, J = 8.2Hz), 7.27 (1H , d, J = 8.6Hz), 7.19 (1H, s), 4.74 (1H, dd, J = 7.4, 5.1Hz), 4.50 (1H, t, J = 6.7Hz), 3.29-3.27 (1H, m) , 3.08-3.00 (1H, m), 2.66-2.61 (1H, m), 1.97-1.87 (3H, m), 1.02 (3H, t, J = 7.4Hz).
Example 29 (6R) -2- {5-[(1Z) -N-hydroxyethaneimidoyl] pyrazin-2-yl} -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-butyl [(6R) -2- {5-[(1Z) -N-hydroxyethaneimidoyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6,7,8 -Tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000155
Figure JPOXMLDOC01-appb-C000155
　実施例２３工程１で得られた化合物（50mg）をメタノール（5mL）に溶解し、ヒドロキシルアミン塩酸塩（9.8mg）、酢酸ナトリウム（12mg）を加え、80℃で1時間攪拌した。反応溶液に水を注ぎ、有機物を酢酸エチルで抽出した。食塩水で洗浄後、硫酸ナトリウムで乾燥した。溶媒を留去し、残留物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］で精製し、標題化合物（28mg）を白色固体として得た。
MS(ESI)m/z:548(M+H)+
1H-NMR(CDCl3)δppm:9.10(1H,s),8.87(1H,s),8.03(1H,d,J=8.2Hz),7.55(2H,d,J=7.8Hz),7.42(1H,t,J=7.4Hz),7.30(3H,dd,J=14.7,6.8Hz),6.89(1H,s),5.24-5.22(1H,m),4.78(1H,d,J=8.6Hz),3.00(1H,ddd,J=16.3,9.1,3.6Hz),2.87-2.79(1H,m),2.63-2.58(1H,m),2.38(3H,s),1.84-1.79(1H,m),1.47(9H,s).
[工程２]　(6R)-2-{5-[(1Z)-N-ヒドロキシエタンイミドイル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Example 23 The compound (50 mg) obtained in Step 1 was dissolved in methanol (5 mL), hydroxylamine hydrochloride (9.8 mg) and sodium acetate (12 mg) were added, and the mixture was stirred at 80 ° C. for 1 hr. Water was poured into the reaction solution, and the organic matter was extracted with ethyl acetate. After washing with brine, it was dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (28 mg) as a white solid.
MS (ESI) m / z: 548 (M + H) +
1 H-NMR (CDCl 3 ) δ ppm: 9.10 (1H, s), 8.87 (1H, s), 8.03 (1H, d, J = 8.2Hz), 7.55 (2H, d, J = 7.8Hz), 7.42 ( 1H, t, J = 7.4Hz), 7.30 (3H, dd, J = 14.7,6.8Hz), 6.89 (1H, s), 5.24-5.22 (1H, m), 4.78 (1H, d, J = 8.6Hz ), 3.00 (1H, ddd, J = 16.3, 9.1, 3.6 Hz), 2.87-2.79 (1H, m), 2.63-2.58 (1H, m), 2.38 (3H, s), 1.84-1.79 (1H, m ), 1.47 (9H, s).
[Step 2] (6R) -2- {5-[(1Z) -N-hydroxyethaneimidoyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] Indole-6-amine
Figure JPOXMLDOC01-appb-C000156
Figure JPOXMLDOC01-appb-C000156
　上記工程１で得られた化合物（28mg）を用いて実施例１工程１１と同様の手法により標題化合物（19mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.08(1H,s),8.11(1H,d,J=7.8Hz),7.67-7.62(2H,m),7.53(2H,d,J=8.6Hz),7.43-7.41(3H,brm),6.88(1H,s),4.53-4.50(1H,m),3.02(1H,ddd,J=16.4,8.6,3.7Hz),2.86-2.78(1H,m),2.60-2.52(1H,m),2.35(3H,s),1.86-1.84(1H,m).
[工程３]　(6R)-2-{5-[(1Z)-N-ヒドロキシエタンイミドイル]ピラジン-2-イル}-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (28 mg) obtained in the above Step 1, the title compound (19 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 9.08 (1H, s), 8.11 (1H, d, J = 7.8Hz), 7.67-7.62 (2H, m), 7.53 (2H, d, J = 8.6Hz), 7.43-7.41 (3H, brm), 6.88 (1H, s), 4.53-4.50 (1H, m), 3.02 (1H, ddd, J = 16.4,8.6,3.7Hz), 2.86-2.78 (1H, m), 2.60-2.52 (1H, m), 2.35 (3H, s), 1.86-1.84 (1H, m).
[Step 3] (6R) -2- {5-[(1Z) -N-hydroxyethaneimidoyl] pyrazin-2-yl} -3,6,7,8-tetrahydrocyclopenta [e] indole-6- Amine
Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000157
　上記工程２で得られた化合物（19mg）を用いて実施例１工程１２と同様の手法により標題化合物（5.0mg）を白色固体として得た。
MS(ESI)m/z:291(M-NH2)+
1H-NMR(CD3OD)δppm:9.04(2H,s),7.32(1H,d,J=8.2Hz),7.22(1H,d,J=8.2Hz),7.15(1H,s),4.47(1H,t,J=5.9Hz),3.23-3.21(1H,m),3.04-2.96(1H,m),2.60-2.56(1H,m),2.26(3H,s),1.90-1.86(1H,m).
実施例３０　(6R)-2-{5-[(Z)-(ヒドロキシイミノ)メチル]ピラジン-2-イル}-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　メチル 5-[(6R)-6-[(tert-ブトキシカルボニル)アミノ]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-カルボキシレート Using the compound (19 mg) obtained in the above Step 2, the title compound (5.0 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 291 (M-NH2) +
1 H-NMR (CD 3 OD) δppm: 9.04 (2H, s), 7.32 (1H, d, J = 8.2Hz), 7.22 (1H, d, J = 8.2Hz), 7.15 (1H, s), 4.47 (1H, t, J = 5.9Hz), 3.23-3.21 (1H, m), 3.04-2.96 (1H, m), 2.60-2.56 (1H, m), 2.26 (3H, s), 1.90-1.86 (1H , m).
Example 30 (6R) -2- {5-[(Z)-(Hydroxyimino) methyl] pyrazin-2-yl} -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] Methyl 5-[(6R) -6-[(tert-butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl Pyrazine-2-carboxylate
Figure JPOXMLDOC01-appb-C000158
Figure JPOXMLDOC01-appb-C000158
　実施例１３工程５で合成した化合物（1.15g）及びメチル 5-ブロモピラジン-2-カルボキシレート（711mg）を用いて実施例１１工程８と同様の手法により標題化合物（890mg）を白色固体として得た。
MS(ESI)m/z:549(M+H)+
1H-NMR(CDCl3)δppm:9.32(1H,d,J=1.2Hz),9.06(1H,d,J=1.6Hz),8.04(1H,d,J=8.6Hz),7.55(2H,d,J=8.2Hz),7.45(1H,t,J=7.4Hz),7.36-7.29(3H,m),7.01(1H,s),5.22(1H,q,J=7.7Hz),4.72(1H,d,J=9.0Hz),4.06(3H,s),3.02(1H,ddd,J=16.3,4.2,2.1Hz),2.89-2.81(1H,m),2.64-2.60(1H,m),1.87-1.78(1H,m),1.46(9H,s).
[工程２]　tert-ブチル [(6R)-2-[5-(ヒドロキシメチル)ピラジン-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Example 13 Using the compound synthesized in Step 5 (1.15 g) and methyl 5-bromopyrazine-2-carboxylate (711 mg), the title compound (890 mg) was obtained as a white solid in the same manner as in Step 11 of Example 11. It was.
MS (ESI) m / z: 549 (M + H) +
1 H-NMR (CDCl 3 ) δppm: 9.32 (1H, d, J = 1.2Hz), 9.06 (1H, d, J = 1.6Hz), 8.04 (1H, d, J = 8.6Hz), 7.55 (2H, d, J = 8.2Hz), 7.45 (1H, t, J = 7.4Hz), 7.36-7.29 (3H, m), 7.01 (1H, s), 5.22 (1H, q, J = 7.7Hz), 4.72 ( 1H, d, J = 9.0Hz), 4.06 (3H, s), 3.02 (1H, ddd, J = 16.3,4.2,2.1Hz), 2.89-2.81 (1H, m), 2.64-2.60 (1H, m) , 1.87-1.78 (1H, m), 1.46 (9H, s).
[Step 2] tert-Butyl [(6R) -2- [5- (hydroxymethyl) pyrazin-2-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-yl] carbamate
Figure JPOXMLDOC01-appb-C000159
Figure JPOXMLDOC01-appb-C000159
　上記工程１で得られた化合物（1.03g）を用いて実施例１工程１０と同様の手法により標題化合物（254mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.85(1H,s),8.68(1H,s),8.03(1H,d,J=8.6Hz),7.58(2H,dd,J=8.4,1.4Hz),7.44(1H,t,J=7.4Hz),7.33-7.29(3H,m),6.87(1H,s),5.21(1H,q,J=7.6Hz),4.91(2H,s),4.75(1H,d,J=7.8Hz),3.21(1H,s),3.05-2.99(1H,m),2.88-2.80(1H,m),2.63-2.59(1H,m),1.84-1.80(1H,m),1.46(9H,s).
[工程３]　tert-ブチル [(6R)-2-(5-ホルミルピラジン-2-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (1.03 g) obtained in the above Step 1, the title compound (254 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.85 (1H, s), 8.68 (1H, s), 8.03 (1H, d, J = 8.6Hz), 7.58 (2H, dd, J = 8.4, 1.4Hz), 7.44 (1H, t, J = 7.4Hz), 7.33-7.29 (3H, m), 6.87 (1H, s), 5.21 (1H, q, J = 7.6Hz), 4.91 (2H, s), 4.75 (1H , d, J = 7.8Hz), 3.21 (1H, s), 3.05-2.99 (1H, m), 2.88-2.80 (1H, m), 2.63-2.59 (1H, m), 1.84-1.80 (1H, m ), 1.46 (9H, s).
[Step 3] tert-Butyl [(6R) -2- (5-formylpyrazin-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
Figure JPOXMLDOC01-appb-C000160
Figure JPOXMLDOC01-appb-C000160
　上記工程３で得られた化合物（254mg）を用いて実施例５工程３と同様の手法により標題化合物（230mg）を得た。
1H-NMR(CDCl3)δppm:10.20(1H,s),9.18(1H,s),9.12(1H,d,J=1.6Hz),8.04(1H,d,J=8.6Hz),7.53(2H,d,J=8.2Hz),7.45(1H,t,J=7.6Hz),7.37-7.29(3H,m),7.06(1H,s),5.23-5.20(1H,m),4.73(1H,d,J=10.2Hz),3.02(1H,ddd,J=16.4,9.0,3.5Hz),2.89-2.81(1H,m),2.64-2.60(1H,m),1.85-1.80(1H,m),1.46(9H,s).
[工程４]　tert-ブチル [(6R)-2-{5-[(Z)-(ヒドロキシイミノ)メチル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (254 mg) obtained in Step 3 above, the title compound (230 mg) was obtained in the same manner as in Step 3 of Example 5.
1 H-NMR (CDCl 3 ) δ ppm: 10.20 (1H, s), 9.18 (1H, s), 9.12 (1H, d, J = 1.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 7.53 ( 2H, d, J = 8.2Hz), 7.45 (1H, t, J = 7.6Hz), 7.37-7.29 (3H, m), 7.06 (1H, s), 5.23-5.20 (1H, m), 4.73 (1H , d, J = 10.2Hz), 3.02 (1H, ddd, J = 16.4,9.0,3.5Hz), 2.89-2.81 (1H, m), 2.64-2.60 (1H, m), 1.85-1.80 (1H, m ), 1.46 (9H, s).
[Step 4] tert-butyl [(6R) -2- {5-[(Z)-(hydroxyimino) methyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6,7,8- Tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000161
Figure JPOXMLDOC01-appb-C000161
　上記工程３で得られた化合物（230mg）を用いて実施例２９工程１と同様の手法により標題化合物（234mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.06(1H,s),8.93(1H,s),8.35(1H,s),8.09(1H,d,J=8.2Hz),7.61(2H,d,J=7.4Hz),7.49(1H,t,J=7.0Hz),7.37(3H,dd,J=18.0,8.2Hz),7.00(1H,s),5.33-5.31(1H,m),4.89(1H,d,J=5.9Hz),3.10-3.07(1H,m),2.95-2.87(1H,m),2.69-2.65(1H,m),1.91-1.80(1H,m),1.54(9H,s).
[工程５]　(6R)-2-{5-[(Z)-(ヒドロキシイミノ)メチル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン The title compound (234 mg) was obtained as a white solid in the same manner as in Example 29, Step 1 using the compound (230 mg) obtained in Step 3 above.
1 H-NMR (CDCl 3 ) δ ppm: 9.06 (1H, s), 8.93 (1H, s), 8.35 (1H, s), 8.09 (1H, d, J = 8.2 Hz), 7.61 (2H, d, J = 7.4Hz), 7.49 (1H, t, J = 7.0Hz), 7.37 (3H, dd, J = 18.0, 8.2Hz), 7.00 (1H, s), 5.33-5.31 (1H, m), 4.89 (1H , d, J = 5.9Hz), 3.10-3.07 (1H, m), 2.95-2.87 (1H, m), 2.69-2.65 (1H, m), 1.91-1.80 (1H, m), 1.54 (9H, s ).
[Step 5] (6R) -2- {5-[(Z)-(Hydroxyimino) methyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [ e] Indole-6-amine
Figure JPOXMLDOC01-appb-C000162
Figure JPOXMLDOC01-appb-C000162
　上記工程４で得られた化合物（234mg）を用いて実施例１工程１１と同様の手法により標題化合物（200mg）を得た。得られた化合物は精製せず工程６に用いた。
[工程６]　(6R)-2-{5-[(Z)-(ヒドロキシイミノ)メチル]ピラジン-2-イル}-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン The title compound (200 mg) was obtained in the same manner as in Step 1 of Example 1 using the compound (234 mg) obtained in the above Step 4. The obtained compound was used in Step 6 without purification.
[Step 6] (6R) -2- {5-[(Z)-(Hydroxyimino) methyl] pyrazin-2-yl} -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000163
Figure JPOXMLDOC01-appb-C000163
　上記工程５で得られた化合物（200mg）を用いて実施例１工程１２と同様の手法により標題化合物（40mg）を白色固体として得た。
MS(ESI)m/z:294(M+H)+
1H-NMR(CD3OD)δppm:9.05(1H,s),8.96(1H,s),8.11(1H,s),7.32(1H,d,J=7.8Hz),7.23(1H,d,J=8.2Hz),7.19(1H,s),4.51-4.45(1H,m),3.22-3.20(1H,m),3.06-2.96(1H,m),2.64-2.55(1H,m),1.94-1.86(1H,m).
実施例３１　2-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール
[工程１]　tert-ブチル [(6R)-2-(5-エテニルピラジン-2-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (200 mg) obtained in Step 5 above, the title compound (40 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 294 (M + H) +
1 H-NMR (CD 3 OD) δ ppm: 9.05 (1H, s), 8.96 (1H, s), 8.11 (1H, s), 7.32 (1H, d, J = 7.8Hz), 7.23 (1H, d, J = 8.2Hz), 7.19 (1H, s), 4.51-4.45 (1H, m), 3.22-3.20 (1H, m), 3.06-2.96 (1H, m), 2.64-2.55 (1H, m), 1.94 -1.86 (1H, m).
Example 31 2- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} ethanol
[Step 1] tert-Butyl [(6R) -2- (5-ethenylpyrazin-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl ] Carbamate
Figure JPOXMLDOC01-appb-C000164
Figure JPOXMLDOC01-appb-C000164
　実施例３０工程３で得られた化合物（450mg）を用いて実施例５工程４と同様の手法により標題化合物（160mg）を黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.90(1H,d,J=1.6Hz),8.64(1H,d,J=1.6Hz),8.0(1H,d,J=9.0Hz),7.66-7.56(2H,m),7.50-7.44(1H,m),7.38-7.30(3H,m),6.95-6.85(2H,m),6.46(1H,dd,J=17.6,1.2Hz),5.69(1H,dd,J=10.9,1.2Hz),5.30-5.17(1H,m),4.80-4.65(1H,m),3.10-2.95(1H,m),2.95-2.80(1H,m),2.70-2.55(1H,m),1.93-1.77(1H,m),1.50(9H,s).
[工程２]　tert-ブチル [(6R)-2-{5-[(1S)-1,2-ジヒドロキシエチル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート The title compound (160 mg) was obtained as a yellow oily substance in the same manner as in Step 5 of Example 5 using the compound (450 mg) obtained in Step 3 of Example 30.
1 H-NMR (CDCl 3 ) δ ppm: 8.90 (1H, d, J = 1.6 Hz), 8.64 (1 H, d, J = 1.6 Hz), 8.0 (1 H, d, J = 9.0 Hz), 7.66-7.56 ( 2H, m), 7.50-7.44 (1H, m), 7.38-7.30 (3H, m), 6.95-6.85 (2H, m), 6.46 (1H, dd, J = 17.6,1.2Hz), 5.69 (1H, dd, J = 10.9, 1.2Hz), 5.30-5.17 (1H, m), 4.80-4.65 (1H, m), 3.10-2.95 (1H, m), 2.95-2.80 (1H, m), 2.70-2.55 ( 1H, m), 1.93-1.77 (1H, m), 1.50 (9H, s).
[Step 2] tert-butyl [(6R) -2- {5-[(1S) -1,2-dihydroxyethyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6,7,8 -Tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000165
Figure JPOXMLDOC01-appb-C000165
　上記工程１で得られた化合物（3.00g）及びAD-mix alpha（15.0g）を用い実施例７工程２と同様の手法により標題化合物（2.10g）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.90(1H,d,J=1.6Hz),8.80(1H,d,J=1.6Hz),8.06(1H,d,J=8.6Hz),7.65-7.58(2H,m),7.53-7.45(1H,m),7.40-7.30(3H,m),5.30-5.18(1H,m),5.05-4.94(1H,m),4.28-4.15(1H,m),4.10-4.01(1H,m),4.01-3.90(1H,m),3.73-3.65(1H,m),3.10-2.95(1H,m),2.95-2.75(1H,m),2.68-2.53(1H,m),2.45-2.36(1H,m),1.92-1.75(1H,m),1.50(9H,s).
[工程３]　tert-ブチル [(6R)-2-{5-[(1S)-1-ヒドロキシ-2-{[トリ(プロパン-2-イル)シリル]オキシ}エチル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート The title compound (2.10 g) was obtained as a white solid in the same manner as in Step 2 of Example 7 using the compound (3.00 g) obtained in Step 1 above and AD-mix alpha (15.0 g).
1 H-NMR (CDCl 3 ) δ ppm: 8.90 (1H, d, J = 1.6 Hz), 8.80 (1 H, d, J = 1.6 Hz), 8.06 (1 H, d, J = 8.6 Hz), 7.65-7.58 ( 2H, m), 7.53-7.45 (1H, m), 7.40-7.30 (3H, m), 5.30-5.18 (1H, m), 5.05-4.94 (1H, m), 4.28-4.15 (1H, m), 4.10-4.01 (1H, m), 4.01-3.90 (1H, m), 3.73-3.65 (1H, m), 3.10-2.95 (1H, m), 2.95-2.75 (1H, m), 2.68-2.53 (1H , m), 2.45-2.36 (1H, m), 1.92-1.75 (1H, m), 1.50 (9H, s).
[Step 3] tert-Butyl [(6R) -2- {5-[(1S) -1-hydroxy-2-{[tri (propan-2-yl) silyl] oxy} ethyl] pyrazin-2-yl} -3- (Phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000166
Figure JPOXMLDOC01-appb-C000166
　上記工程２で得られた化合物（800mg）のジクロロメタン（14.5mL）溶液にイミダゾール（415mg）、4-ジメチルアミノピリジン（17.8mg）及びトリイソプロピルシリルクロリド（0.560g）を加え、室温で6時間攪拌した。飽和塩化アンモニウム水溶液を加えて反応を停止し、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物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］で精製することにより標題化合物（913mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.89(1H,d,J=1.6Hz),8.86(1H,d,J=1.6Hz),8.09(1H,1H,d,J=8.6Hz),7.65-7.56(2H,m),7.50-7.43(1H,m),7.38-7.30(3H,m),6.89(1H,s),5.30-5.17(1H,m),5.03-4.90(1H,m),4.80-4.66(1H,m),4.10-3.96(2H,m),3.68-3.60(1H,m),3.10-2.96(1H,m),2.96-2.77(1H,m),2.70-2.50(1H,m),1.90-1.75(1H,m),1.50(9H,s),1.30-0.80(21H,m).
[工程４]　tert-ブチル [(6R)-2-[5-(1-ブロモ-2-{[トリ(プロパン-2-イル)シリル]オキシ}エチル)ピラジン-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Add imidazole (415 mg), 4-dimethylaminopyridine (17.8 mg) and triisopropylsilyl chloride (0.560 g) to a solution of the compound obtained in step 2 (800 mg) in dichloromethane (14.5 mL) and stir at room temperature for 6 hours. did. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (913 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 8.89 (1H, d, J = 1.6 Hz), 8.86 (1 H, d, J = 1.6 Hz), 8.09 (1 H, 1 H, d, J = 8.6 Hz), 7.65 7.56 (2H, m), 7.50-7.43 (1H, m), 7.38-7.30 (3H, m), 6.89 (1H, s), 5.30-5.17 (1H, m), 5.03-4.90 (1H, m), 4.80-4.66 (1H, m), 4.10-3.96 (2H, m), 3.68-3.60 (1H, m), 3.10-2.96 (1H, m), 2.96-2.77 (1H, m), 2.70-2.50 (1H , m), 1.90-1.75 (1H, m), 1.50 (9H, s), 1.30-0.80 (21H, m).
[Step 4] tert-butyl [(6R) -2- [5- (1-bromo-2-{[tri (propan-2-yl) silyl] oxy} ethyl) pyrazin-2-yl] -3- ( Phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000167
Figure JPOXMLDOC01-appb-C000167
　上記工程３で得られた化合物（550mg）のジクロロメタン（7.78mL）溶液に四臭化炭素（748mg）及びトリフェニルホスフィン（612mg）を加え、室温で1時間攪拌した。水を加えて反応を停止し、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物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］で精製することにより標題化合物（510mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:8.95(1H,d,J=1.2Hz),8.75(1H,d,J=1.2Hz),8.09(1H,d,J=8.2Hz),7.64-7.55(2H,m),7.52-7.44(1H,m),7.40-7.30(3H,m),6.91(1H,s),5.30-5.20(1H,m),5.15-5.08(1H,m),4.78-4.70(1H,m),4.46(1H,dd,J=10.4,8.0Hz),4.34(1H,dd,J=10.4,3.8Hz),3.10-2.97(1H,m),2.93-2.8(1H,m),2.70-2.55(1H,m),1.93-1.78(1H,m),1.50(9H,s),1.13-0.90(21H,m).
[工程５]　tert-ブチル {(6R)-3-(フェニルスルホニル)-2-[5-(2-{[トリ(プロパン-2-イル)シリル]オキシ}エチル)ピラジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル}カルバメート Carbon tetrabromide (748 mg) and triphenylphosphine (612 mg) were added to a dichloromethane (7.78 mL) solution of the compound (550 mg) obtained in Step 3 above, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by adding water and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (510 mg) as a colorless oil.
1 H-NMR (CDCl 3 ) δ ppm: 8.95 (1H, d, J = 1.2 Hz), 8.75 (1 H, d, J = 1.2 Hz), 8.09 (1 H, d, J = 8.2 Hz), 7.64-7.55 ( 2H, m), 7.52-7.44 (1H, m), 7.40-7.30 (3H, m), 6.91 (1H, s), 5.30-5.20 (1H, m), 5.15-5.08 (1H, m), 4.78- 4.70 (1H, m), 4.46 (1H, dd, J = 10.4,8.0Hz), 4.34 (1H, dd, J = 10.4,3.8Hz), 3.10-2.97 (1H, m), 2.93-2.8 (1H, m), 2.70-2.55 (1H, m), 1.93-1.78 (1H, m), 1.50 (9H, s), 1.13-0.90 (21H, m).
[Step 5] tert-butyl {(6R) -3- (phenylsulfonyl) -2- [5- (2-{[tri (propan-2-yl) silyl] oxy} ethyl) pyrazin-2-yl]- 3,6,7,8-Tetrahydrocyclopenta [e] indol-6-yl} carbamate
Figure JPOXMLDOC01-appb-C000168
Figure JPOXMLDOC01-appb-C000168
　上記工程４で得られた化合物（500mg）のテトラヒドロフラン（10mL）及びメタノール（10mL）溶液に、トリエチルアミン（2mL）及び10% 炭素パラジウム触媒（0.300g）を加え、水素雰囲気下、30分間攪拌した。反応終結後、セライトろ過でパラジウム触媒を除いた溶液を減圧濃縮し、得られた残留物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］で精製することにより標題化合物（410mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.87(1H,d,J=1.6Hz),8.61(1H,d,J=1.2Hz),8.08(1H,d,J=8.6Hz),7.65-7.58(2H,m),7.50-7.43(1H,m),7.37-7.30(3H,m),6.84(1H,d,J=0.8Hz),5.30-5.19(1H,m),4.78-4.70(1H,m),4.17-4.07(2H,m),3.17-3.08(2H,m),3.08-2.98(1H,m),2.94-2.80(1H,m),2.70-2.55(1H,m),1.91-1.78(1H,m),1.49(9H,s),1.15-0.90(21H,m).
[工程６]　2-{5-[(6R)-6-アミノ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール Triethylamine (2 mL) and a 10% carbon palladium catalyst (0.300 g) were added to a solution of the compound obtained in Step 4 (500 mg) in tetrahydrofuran (10 mL) and methanol (10 mL), and the mixture was stirred for 30 minutes in a hydrogen atmosphere. After completion of the reaction, the solution from which the palladium catalyst had been removed by Celite filtration was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to obtain the title compound (410 mg) as a white solid. .
1 H-NMR (CDCl 3 ) δ ppm: 8.87 (1H, d, J = 1.6 Hz), 8.61 (1 H, d, J = 1.2 Hz), 8.08 (1 H, d, J = 8.6 Hz), 7.65-7.58 ( 2H, m), 7.50-7.43 (1H, m), 7.37-7.30 (3H, m), 6.84 (1H, d, J = 0.8Hz), 5.30-5.19 (1H, m), 4.78-4.70 (1H, m), 4.17-4.07 (2H, m), 3.17-3.08 (2H, m), 3.08-2.98 (1H, m), 2.94-2.80 (1H, m), 2.70-2.55 (1H, m), 1.91 1.78 (1H, m), 1.49 (9H, s), 1.15-0.90 (21H, m).
[Step 6] 2- {5-[(6R) -6-amino-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl }ethanol
Figure JPOXMLDOC01-appb-C000169
Figure JPOXMLDOC01-appb-C000169
　上記工程５で得られた化合物（0.405g）を用いて実施例１工程１１と同様の手法により標題化合物（230mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.85(1H,d,J=1.2Hz),8.56(1H,d,J=1.6Hz),8.07(1H,d,J=7.8Hz),7.67-7.61(2H,m),7.50-7.43(1H,m),7.38-7.31(3H,m),6.88(1H,d,J=0.8Hz),4.44(1H,t,J=7.2Hz),4.16-4.06(2H,m),3.16(2H,t,J=5.7Hz),3.05(1H,ddd,J=16.1,8.9,3.4Hz),2.88-2.80(1H,m),2.63-2.51(1H,m),1.82-1.69(1H,m).
[工程７]　2-{5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール Using the compound (0.405 g) obtained in the above Step 5, the title compound (230 mg) was obtained as a white solid by the same method as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.85 (1H, d, J = 1.2 Hz), 8.56 (1 H, d, J = 1.6 Hz), 8.07 (1 H, d, J = 7.8 Hz), 7.67-7.61 ( 2H, m), 7.50-7.43 (1H, m), 7.38-7.31 (3H, m), 6.88 (1H, d, J = 0.8Hz), 4.44 (1H, t, J = 7.2Hz), 4.16-4.06 (2H, m), 3.16 (2H, t, J = 5.7Hz), 3.05 (1H, ddd, J = 16.1, 8.9, 3.4Hz), 2.88-2.80 (1H, m), 2.63-2.51 (1H, m ), 1.82-1.69 (1H, m).
[Step 7] 2- {5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} ethanol
Figure JPOXMLDOC01-appb-C000170
Figure JPOXMLDOC01-appb-C000170
　上記工程６で得られた化合物（230mg）を用いて実施例１工程１２と同様の手法により標題化合物（28mg）を黄色固体として得た。
1H-NMR(MeOH-d4)δppm:9.07(1H,d,J=1.6Hz),8.57(1H,d,J=1.6Hz),7.37(1H,d,J=8.2Hz),7.27(1H,d,J=8.2Hz),7.16(1H,s),4.50(1H,t,J=6.6Hz),3.98(2H,t,J=6.5Hz),3.35(1H,m),3.09-2.08(3H,m),2.68-2.57(1H,m),1.97-1.85(1H,m).
実施例３２　(6R)-2-[5-(S-メチルスルホンイミドイル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [(6R)-2-[5-(メチルスルフィニル)ピリジン-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (230 mg) obtained in the above Step 6, the title compound (28 mg) was obtained as a yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δppm: 9.07 (1H, d, J = 1.6Hz), 8.57 (1H, d, J = 1.6Hz), 7.37 (1H, d, J = 8.2Hz), 7.27 (1H , d, J = 8.2Hz), 7.16 (1H, s), 4.50 (1H, t, J = 6.6Hz), 3.98 (2H, t, J = 6.5Hz), 3.35 (1H, m), 3.09-2.08 (3H, m), 2.68-2.57 (1H, m), 1.97-1.85 (1H, m).
Example 32 (6R) -2- [5- (S-methylsulfonimidoyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-butyl [(6R) -2- [5- (methylsulfinyl) pyridin-2-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-yl] carbamate
Figure JPOXMLDOC01-appb-C000171
Figure JPOXMLDOC01-appb-C000171
　実施例１３工程５で合成した化合物（500mg）を用いて実施例１１工程８と同様の手法により標題化合物（371mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.89(1H,dd,J=2.3,0.8Hz),8.11-8.03(2H,m),7.94-7.88(1H,m),7.66-7.58(2H,m),7.50-7.43(1H,m),7.37-7.27(3H,m),6.94(1H,s),5.30-5.17(1H,m),4.80-4.66(1H,m),3,10-2.94(1Hm),2.90-2.79(4H,m),2.70-2.55(1H,m),1.92-1.78(1H,m),1.49(9H,s).
[工程２]　tert-ブチル [{6-[(6R)-6-[(tert-ブトキシカルボニル)アミノ]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピリジン-3-イル}(メチル)オキシド-λ6-スルファニリデン]カルバメート The title compound (371 mg) was obtained as a white solid in the same manner as in Step 11 of Example 11 using the compound (500 mg) synthesized in Step 13 of Example 13.
1 H-NMR (CDCl 3 ) δ ppm: 8.89 (1H, dd, J = 2.3,0.8Hz), 8.11-8.03 (2H, m), 7.94-7.88 (1H, m), 7.66-7.58 (2H, m) , 7.50-7.43 (1H, m), 7.37-7.27 (3H, m), 6.94 (1H, s), 5.30-5.17 (1H, m), 4.80-4.66 (1H, m), 3,10-2.94 ( 1Hm), 2.90-2.79 (4H, m), 2.70-2.55 (1H, m), 1.92-1.78 (1H, m), 1.49 (9H, s).
[Step 2] tert-butyl [{6-[(6R) -6-[(tert-butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -2-yl] pyridin-3-yl} (methyl) oxide-λ 6 -sulfanilidene] carbamate
Figure JPOXMLDOC01-appb-C000172
Figure JPOXMLDOC01-appb-C000172
　上記工程１で得られた化合物（153mg）のジクロロメタン（2.77mL）の溶液にtert-ブチル カルバメート（97.5mg）、酸化マグネシウム（224mg）、ロジウム(II)アセテートダイマー（0.0184g）、ヨードベンゼンジアセテート（0.268g）を加え、1時間攪拌した。反応終結後にセライトろ過を行い、不溶物を除いて得られた溶液に飽和炭酸水素ナトリウム水溶液及び飽和チオ硫酸ナトリウム水溶液を加えた。その後、有機層をジクロロメタンで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物をアミノ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］で精製することにより標題化合物（145mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.19(1H,dd,J=3.7,1.4Hz),8.33-8.26(1H,m),8.05(1H,d,J=8.6Hz),7.97(1H,d,J=8.6Hz),7.62-7.55(2H,m),7.51-7.43(1H,m),7.38-7.31(3H,m),7.02(1H,s),5.30-5.18(1H,m),4.79-4.68(1H,m),3.39(3H,s),3.10-3.00(1H,m),2.91-2.82(1H,m),2.70(1H,m),1.92-1.78(1H,m),1.50(9H,s),1.43(9H,s).
[工程３]　(6R)-2-[5-(S-メチルスルホンイミドイル)ピリジン-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン To a solution of the compound obtained in Step 1 above (153 mg) in dichloromethane (2.77 mL), tert-butyl carbamate (97.5 mg), magnesium oxide (224 mg), rhodium (II) acetate dimer (0.0184 g), iodobenzene diacetate (0.268 g) was added and stirred for 1 hour. After completion of the reaction, celite filtration was performed, and a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium thiosulfate solution were added to the solution obtained by removing insolubles. Thereafter, the organic layer was extracted with dichloromethane, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography [hexane / ethyl acetate] to give the title compound (145 mg) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 9.19 (1H, dd, J = 3.7,1.4Hz), 8.33-8.26 (1H, m), 8.05 (1H, d, J = 8.6Hz), 7.97 (1H, d , J = 8.6Hz), 7.62-7.55 (2H, m), 7.51-7.43 (1H, m), 7.38-7.31 (3H, m), 7.02 (1H, s), 5.30-5.18 (1H, m), 4.79-4.68 (1H, m), 3.39 (3H, s), 3.10-3.00 (1H, m), 2.91-2.82 (1H, m), 2.70 (1H, m), 1.92-1.78 (1H, m), 1.50 (9H, s), 1.43 (9H, s).
[Step 3] (6R) -2- [5- (S-methylsulfonimidoyl) pyridin-2-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-Amine
Figure JPOXMLDOC01-appb-C000173
Figure JPOXMLDOC01-appb-C000173
　上記工程２で得られた化合物（105mg）を用いて実施例１工程１１と同様の手法により標題化合物（44mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.24(1H,dd,J=2.3,0.8Hz),8.33(1H,dd,J=8.6,2.3Hz),8.07(1H,d,J=7.8Hz),7.93(1H,dd,J=8.2,0.8Hz),7.65-7.59(2H,m),7.50-7.43(1H,m),7.40-7.30(3H,m),7.00(1H,s),4.44(1H,dd,J=7.0,7.0Hz),3.24(3H,s),3.10-3.00(1H,m),2.90-2.78(2H,m),2.62-2.53(1H,m),1.80-1.90(1H,m).
[工程４]　(6R)-2-[5-(S-メチルスルホンイミドイル)ピリジン-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (105 mg) obtained in the above Step 2, the title compound (44 mg) was obtained as a white solid by the same method as in Step 1 of Example 1.
1 H-NMR (CDCl 3) δppm: 9.24 (1H, dd, J = 2.3,0.8Hz), 8.33 (1H, dd, J = 8.6,2.3Hz), 8.07 (1H, d, J = 7.8Hz), 7.93 (1H, dd, J = 8.2,0.8Hz), 7.65-7.59 (2H, m), 7.50-7.43 (1H, m), 7.40-7.30 (3H, m), 7.00 (1H, s), 4.44 ( 1H, dd, J = 7.0,7.0Hz), 3.24 (3H, s), 3.10-3.00 (1H, m), 2.90-2.78 (2H, m), 2.62-2.53 (1H, m), 1.80-1.90 ( 1H, m).
[Step 4] (6R) -2- [5- (S-Methylsulfonimidoyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000174
Figure JPOXMLDOC01-appb-C000174
　上記工程３で得られた化合物（40mg）を用いて実施例１工程１２と同様の手法により標題化合物（21mg）を黄色固体として得た。
1H-NMR(MeOH-d4)δppm:9.13(1H,d,J=2.0Hz),8.32(1H,dd,J=8.6,2.3Hz),8.12(1H,dd,J=7.6,0.8Hz),7.39(1H,d,J=9.0Hz),7.33-7.24(2H,m),4.51(1H,dd,J=6.7,6.7Hz),3.47-3.24(4H,m),3.10-3.00(1H,m),2.70-2.60(1H,m),1.98-1.87(1H,m).
実施例３３　2-[5-(2-メトキシピリジン-4-イル)-1,3,4-オキサジアゾール-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　メチル 6-[(tert-ブトキシカルボニル)アミノ]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-カルボキシレート Using the compound (40 mg) obtained in the above Step 3, the title compound (21 mg) was obtained as a yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δ ppm: 9.13 (1H, d, J = 2.0 Hz), 8.32 (1 H, dd, J = 8.6, 2.3 Hz), 8.12 (1 H, dd, J = 7.6, 0.8 Hz) , 7.39 (1H, d, J = 9.0Hz), 7.33-7.24 (2H, m), 4.51 (1H, dd, J = 6.7,6.7Hz), 3.47-3.24 (4H, m), 3.10-3.00 (1H , m), 2.70-2.60 (1H, m), 1.98-1.87 (1H, m).
Example 33 2- [5- (2-Methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole- 6-amine
[Step 1] Methyl 6-[(tert-butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-2-carboxylate
Figure JPOXMLDOC01-appb-C000175
Figure JPOXMLDOC01-appb-C000175
　リチウムジイソプロピルアミド（in n-hexane-tetrahydrofuran，12mL）のテトラヒドロフラン（190mL）溶液を-78℃に冷却し、窒素雰囲気下、実施例１１工程６で得られた化合物（2.35g）のテトラヒドロフラン（6mL）溶液を加えた。25分間攪拌した後、クロロギ酸メチル（0.968mL）を滴下して10分攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加えた後、室温に戻して酢酸エチルで3回抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残留物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］で精製し、標題化合物（1.77g）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.02-7.94(3H,m),7.57-7.52(1H,m),7.48-7.43(2H,m),7.39-7.35(1H,m),7.10(1H,s),5.29-5.20(1H,m),4.75-4.67(1H,m).
[工程２]　6-[(tert-ブトキシカルボニル)アミノ]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-カルボキシリックアシッド A solution of lithium diisopropylamide (in n-hexane-tetrahydrofuran, 12 mL) in tetrahydrofuran (190 mL) was cooled to −78 ° C., and tetrahydrofuran (6 mL) of the compound (2.35 g) obtained in Step 11 of Example 11 under a nitrogen atmosphere. The solution was added. After stirring for 25 minutes, methyl chloroformate (0.968 mL) was added dropwise and stirred for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was returned to room temperature and extracted three times with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (1.77 g) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 8.02-7.94 (3H, m), 7.57-7.52 (1H, m), 7.48-7.43 (2H, m), 7.39-7.35 (1H, m), 7.10 (1H, s), 5.29-5.20 (1H, m), 4.75-4.67 (1H, m).
[Step 2] 6-[(tert-Butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-2-carboxylic acid
Figure JPOXMLDOC01-appb-C000176
Figure JPOXMLDOC01-appb-C000176
　上記工程１で得られた化合物（1.74g）とエタノール（24mL）及びテトラヒドロフラン（8mL）の混合物に2N 水酸化ナトリウム（9.24mL）を室温にて加えた。室温にて終夜攪拌した。反応溶液に1規定塩酸を加えて酢酸エチルで3回抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮することにより標題化合物（1.68g）を粗精製物として得た。
[工程３]　tert-ブチル [2-({2-[(2-メトキピリジン-4-イル)カルボニル]ヒドラジニル}カルボニル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート 2N sodium hydroxide (9.24 mL) was added to a mixture of the compound obtained in Step 1 (1.74 g), ethanol (24 mL) and tetrahydrofuran (8 mL) at room temperature. Stir at room temperature overnight. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.68 g) as a crude product.
[Step 3] tert-butyl [2-({2-[(2-methoxypyridin-4-yl) carbonyl] hydrazinyl} carbonyl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] Indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000177
Figure JPOXMLDOC01-appb-C000177
　上記工程２で得られた化合物（330mg）、2-メトキシピリジン-4-カルボヒドラジド塩酸塩（191mg）とN,N-ジメチルホルムアミド（2.4mL）の混合物に、O-(7-アザ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ホスファート（357mg）とN,N-ジイソプロピルエチルアミン（0.369mL）を加え、室温にて6時間攪拌した。反応溶液に水を加えて酢酸エチルで3回抽出した。抽出液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残留物をアミノ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］で精製し、標題化合物（187mg）を粗精製物として得た。
[工程４]　tert-ブチル {2-[5-(2-メトキピリジン-4-イル)-1,3,4-オキサジアゾール-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル｝カルバメート To a mixture of the compound obtained in Step 2 above (330 mg), 2-methoxypyridine-4-carbohydrazide hydrochloride (191 mg) and N, N-dimethylformamide (2.4 mL), O- (7-azabenzotriazole- 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (357 mg) and N, N-diisopropylethylamine (0.369 mL) were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography [hexane / ethyl acetate] to give the title compound (187 mg) as a crude product.
[Step 4] tert-butyl {2- [5- (2-methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl] -3- (phenylsulfonyl) -3,6, 7,8-Tetrahydrocyclopenta [e] indol-6-yl} carbamate
Figure JPOXMLDOC01-appb-C000178
Figure JPOXMLDOC01-appb-C000178
　上記工程３で得られた化合物（183mg）、トリフェニルホスフィン（127mg）とアセトニトリル（3.0mL）の混合物に、N,N-ジイソプロピルエチルアミン（0.154mL）とヘキサクロロエタン（107mg）を加え、室温にて3時間攪拌した。反応溶液に水を加えて酢酸エチルで3回抽出した。抽出液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残留物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］で精製し、標題化合物（160mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.37(1H,d,J=5.1Hz),8.07(1H,d,J=8.6Hz),7.81(2H,d,J=7.8Hz),7.61-7.60(1H,m),7.56-7.52(1H,m),7.46-7.41(4H,m),7.23(1H,s),5.30-5.25(1H,m),4.77-4.75(1H,m),4.02(3H,s),3.13-3.06(1H,m),2.96-2.88(1H,m),2.71-2.63(1H,m),1.94-1.84(1H,m),1.50(9H,s).
[工程５]　2-[5-(2-メトキシピリジン-4-イル)-1,3,4-オキサジアゾール-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン To a mixture of the compound obtained in Step 3 above (183 mg), triphenylphosphine (127 mg) and acetonitrile (3.0 mL), N, N-diisopropylethylamine (0.154 mL) and hexachloroethane (107 mg) were added, and at room temperature. Stir for 3 hours. Water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (160 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 8.37 (1H, d, J = 5.1 Hz), 8.07 (1 H, d, J = 8.6 Hz), 7.81 (2 H, d, J = 7.8 Hz), 7.61-7.60 ( 1H, m), 7.56-7.52 (1H, m), 7.46-7.41 (4H, m), 7.23 (1H, s), 5.30-5.25 (1H, m), 4.77-4.75 (1H, m), 4.02 ( 3H, s), 3.13-3.06 (1H, m), 2.96-2.88 (1H, m), 2.71-2.63 (1H, m), 1.94-1.84 (1H, m), 1.50 (9H, s).
[Step 5] 2- [5- (2-Methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl] -3- (phenylsulfonyl) -3,6,7,8- Tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000179
Figure JPOXMLDOC01-appb-C000179
　上記工程４で得られた化合物（158mg）を用いて実施例１工程１１と同様の手法により標題化合物（94.3mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.38-8.37(1H,m),8.08(1H,d,J=8.6Hz),7.84-7.81(2H,m),7.60(1H,dd,J=5.3,1.4Hz),7.56-7.51(1H,m),7.48-7.40(4H,m),7.26-7.24(1H,m),4.48(1H,t,J=7.2Hz),4.02(3H,s),3.15-3.08(1H,m),2.94-2.86(1H,m),2.65-2.57(1H,m),1.85-1.76(1H,m).
[工程６]　2-[5-(2-メトキシピリジン-4-イル)-1,3,4-オキサジアゾール-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (158 mg) obtained in Step 4 above, the title compound (94.3 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.38-8.37 (1H, m), 8.08 (1H, d, J = 8.6Hz), 7.84-7.81 (2H, m), 7.60 (1H, dd, J = 5.3, 1.4Hz), 7.56-7.51 (1H, m), 7.48-7.40 (4H, m), 7.26-7.24 (1H, m), 4.48 (1H, t, J = 7.2Hz), 4.02 (3H, s), 3.15-3.08 (1H, m), 2.94-2.86 (1H, m), 2.65-2.57 (1H, m), 1.85-1.76 (1H, m).
[Step 6] 2- [5- (2-Methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole -6-Amine
Figure JPOXMLDOC01-appb-C000180
Figure JPOXMLDOC01-appb-C000180
　上記工程５で得られた化合物（89.1mg）を用いて実施例１工程１２と同様の手法により標題化合物（45.3mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.42(1H,brs),8.38-8.36(1H,m),7.60(1H,dd,J=5.3,1.4Hz),7.45-7.43(1H,m),7.41(1H,d,J=8.6Hz),7.37(1H,d,J=8.6Hz),4.53(1H,t,J=6.8Hz),4.03(3H,s),3.29-3.23(1H,m),3.07-2.99(1H,m),2.73-2.65(1H,m),1.91-1.82(1H,m).
MS(ESI)m/z:348(M+H)+
実施例３４　2-[5-(3,4-ジメトキシフェニル)-1,3,4-オキサジアゾール-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [2-{[2-(3,4-ジメトキシベンゾイル)ヒドラジニル]カルボニル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル)]カルバメート Using the compound (89.1 mg) obtained in the above Step 5, the title compound (45.3 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 9.42 (1H, brs), 8.38-8.36 (1H, m), 7.60 (1H, dd, J = 5.3,1.4Hz), 7.45-7.43 (1H, m), 7.41 (1H, d, J = 8.6Hz), 7.37 (1H, d, J = 8.6Hz), 4.53 (1H, t, J = 6.8Hz), 4.03 (3H, s), 3.29-3.23 (1H, m) 3.07-2.99 (1H, m), 2.73-2.65 (1H, m), 1.91-1.82 (1H, m).
MS (ESI) m / z: 348 (M + H) +
Example 34 2- [5- (3,4-Dimethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6- Amine
[Step 1] tert-butyl [2-{[2- (3,4-dimethoxybenzoyl) hydrazinyl] carbonyl} -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole- 6-yl)] carbamate
Figure JPOXMLDOC01-appb-C000181
Figure JPOXMLDOC01-appb-C000181
　実施例３３工程２で得られた化合物（330mg）及び3,4-ジメトキシベンゾヒドラジド（184mg）を用いて実施例３３工程３と同様の手法により標題化合物（501mg）を粗精製物として得た。
[工程２]　tert-ブチル {2-[5-(3,4-ジメトキシフェニル)-1,3,4-オキサジアゾール-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル}カルバメート Using the compound obtained in Example 33, Step 2 (330 mg) and 3,4-dimethoxybenzohydrazide (184 mg), the title compound (501 mg) was obtained as a crude product in the same manner as in Example 33, Step 3.
[Step 2] tert-butyl {2- [5- (3,4-dimethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3- (phenylsulfonyl) -3,6,7, 8-tetrahydrocyclopenta [e] indol-6-yl} carbamate
Figure JPOXMLDOC01-appb-C000182
Figure JPOXMLDOC01-appb-C000182
　上記工程１で得られた化合物（501mg）を用いて実施例３３工程４と同様の手法により標題化合物（264mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.08(1H,d,J=8.6Hz),7.85-7.82(2H,m),7.75-7.72(1H,m),7.68(1H,d,J=2.0Hz),7.55-7.51(1H,m),7.44-7.40(3H,m),7.20-7.19(1H,m),7.00(1H,d,J=8.2Hz),5.30-5.24(1H,m),4.77-4.74(1H,m),4.00(3H,s),3.98(3H,s),3.13-3.06(1H,m),2.96-2.88(1H,m),2.71-2.61(1H,m),1.94-1.84(1H,m),1.50(9H,s).
[工程３]　2-[5-(3,4-ジメトキシフェニル)-1,3,4-オキサジアゾール-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン The title compound (264 mg) was obtained as a white solid in the same manner as in Step 33 of Example 33 using the compound (501 mg) obtained in the above Step 1.
1 H-NMR (CDCl 3 ) δppm: 8.08 (1H, d, J = 8.6Hz), 7.85-7.82 (2H, m), 7.75-7.72 (1H, m), 7.68 (1H, d, J = 2.0Hz ), 7.55-7.51 (1H, m), 7.44-7.40 (3H, m), 7.20-7.19 (1H, m), 7.00 (1H, d, J = 8.2Hz), 5.30-5.24 (1H, m), 4.77-4.74 (1H, m), 4.00 (3H, s), 3.98 (3H, s), 3.13-3.06 (1H, m), 2.96-2.88 (1H, m), 2.71-2.61 (1H, m), 1.94-1.84 (1H, m), 1.50 (9H, s).
[Step 3] 2- [5- (3,4-Dimethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclo Penta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000183
Figure JPOXMLDOC01-appb-C000183
　上記工程２で得られた化合物（264mg）を用いて実施例１工程１１と同様の手法により標題化合物（226mg）を得た。
[工程４]　2-[5-(3,4-ジメトキシフェニル)-1,3,4-オキサジアゾール-2-イル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (264 mg) obtained in Step 2 above, the title compound (226 mg) was obtained in the same manner as in Step 1 of Example 1.
[Step 4] 2- [5- (3,4-Dimethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6 -Amine
Figure JPOXMLDOC01-appb-C000184
Figure JPOXMLDOC01-appb-C000184
　上記工程３で得られた化合物（226mg）を用いて実施例１工程１２と同様の手法により標題化合物（61.5mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.33(1H,brs),7.73(1H,dd,J=8.2,2.0Hz),7.66(1H,d,J=2.0Hz),7.40(1H,d,J=8.6Hz),7.34(1H,d,J=8.6Hz),7.23-7.21(1H,m),7.01(1H,d,J=8.6Hz),4.53(1H,t,J=6.8Hz),4.02(3H,s),3.99(3H,s),3.29-3.21(1H,m),3.07-2.99(1H,m),2.72-2.63(1H,m),1.90-1.82(1H,m).
MS(ESI)m/z：377(M+H)+
実施例３５　1-{2-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1,3-チアゾール-5-イル}エタノン
[工程１]　tert-ブチル [(6R)-2-{5-[メトキシ(メチル)カルバモイル]-1,3－チアゾール-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (226 mg) obtained in the above Step 3, the title compound (61.5 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 9.33 (1H, brs), 7.73 (1H, dd, J = 8.2,2.0Hz), 7.66 (1H, d, J = 2.0Hz), 7.40 (1H, d, J = 8.6Hz), 7.34 (1H, d, J = 8.6Hz), 7.23-7.21 (1H, m), 7.01 (1H, d, J = 8.6Hz), 4.53 (1H, t, J = 6.8Hz), 4.02 (3H, s), 3.99 (3H, s), 3.29-3.21 (1H, m), 3.07-2.99 (1H, m), 2.72-2.63 (1H, m), 1.90-1.82 (1H, m).
MS (ESI) m / z: 377 (M + H) +
Example 35 1- {2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazol-5-yl} ethanone
[Step 1] tert-butyl [(6R) -2- {5- [methoxy (methyl) carbamoyl] -1,3-thiazol-2-yl} -3- (phenylsulfonyl) -3,6,7,8 -Tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000185
Figure JPOXMLDOC01-appb-C000185
　実施例１３工程５で得られた化合物（300mg）及び2-ブロモ-N-メトキシ-N-メチル-チアゾール-5-カルボキサミド（215mg）を用いて実施例１１工程８と同様の手法により標題化合物（210mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.64(1H,s),8.03(1H,d,J=8.6Hz),7.80(2H,d,J=7.4Hz),7.49-7.45(1H,m),7.38-7.33(3H,m),6.95(1H,s),5.25-5.19(1H,m),4.74(1H,d,J=8.6Hz),3.80(3H,s),3.37(3H,s),3.02(1H,ddd,J=16.2,4.2,2.1Hz),2.89-2.81(1H,m),2.66-2.52(1H,m),1.87-1.78(1H,m),1.47(9H,s).
[工程２]　tert-ブチル [(6R)-2-(5-アセチル-1,3-チアゾール-2-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Example 13 Using the compound obtained in Step 5 (300 mg) and 2-bromo-N-methoxy-N-methyl-thiazole-5-carboxamide (215 mg) in the same manner as Example 11 Step 8, the title compound ( 210 mg) was obtained as a white solid.
1 H-NMR (CDCl 3 ) δppm: 8.64 (1H, s), 8.03 (1H, d, J = 8.6Hz), 7.80 (2H, d, J = 7.4Hz), 7.49-7.45 (1H, m), 7.38-7.33 (3H, m), 6.95 (1H, s), 5.25-5.19 (1H, m), 4.74 (1H, d, J = 8.6Hz), 3.80 (3H, s), 3.37 (3H, s) , 3.02 (1H, ddd, J = 16.2,4.2,2.1Hz), 2.89-2.81 (1H, m), 2.66-2.52 (1H, m), 1.87-1.78 (1H, m), 1.47 (9H, s) .
[Step 2] tert-Butyl [(6R) -2- (5-acetyl-1,3-thiazol-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e ] Indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000186
Figure JPOXMLDOC01-appb-C000186
　上記工程１で得られた化合物（210mg）及びで1.09M 塩化メチルマグネシウム テトラヒドロフラン溶液（1.2mL）を用いて実施例２８工程２と同様の手法により標題化合物（200mg）を得た。
MS(ESI)m/z：538(M+H)+
1H-NMR(CDCl3)δppm:8.31(1H,s),8.01(1H,d,J=8.6Hz),7.80(2H,d,J=7.4Hz),7.51-7.49(1H,m),7.39-7.34(3H,m),6.95(1H,s),5.24-5.19(1H,m),4.77(1H,d,J=8.2Hz),3.03(1H,ddd,J=16.3,8.9,3.8Hz),2.89-2.81(1H,m),2.66-2.57(4H,m),1.85-1.81(1H,m),1.46(9H,s).
[工程３]　1-{2-[(6R)-6-アミノ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1,3-チアゾール-5-イル}エタノン The title compound (200 mg) was obtained in the same manner as in Step 28 of Example 28 using the compound (210 mg) obtained in the above Step 1 and 1.09 M methylmagnesium chloride in tetrahydrofuran (1.2 mL).
MS (ESI) m / z: 538 (M + H) +
1 H-NMR (CDCl 3 ) δ ppm: 8.31 (1H, s), 8.01 (1H, d, J = 8.6Hz), 7.80 (2H, d, J = 7.4Hz), 7.51-7.49 (1H, m), 7.39-7.34 (3H, m), 6.95 (1H, s), 5.24-5.19 (1H, m), 4.77 (1H, d, J = 8.2Hz), 3.03 (1H, ddd, J = 16.3,8.9,3.8 Hz), 2.89-2.81 (1H, m), 2.66-2.57 (4H, m), 1.85-1.81 (1H, m), 1.46 (9H, s).
[Step 3] 1- {2-[(6R) -6-amino-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3- Thiazol-5-yl} ethanone
Figure JPOXMLDOC01-appb-C000187
Figure JPOXMLDOC01-appb-C000187
　上記工程２で得られた化合物（50mg）を用いて実施例１工程１１と同様の手法により標題化合物（25mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.39(1H,s),8.02(1H,d,J=8.6Hz),7.81(2H,dd,J=8.4,1.4Hz),7.50-7.45(1H,m),7.38-7.34(3H,m),6.96(1H,s),4.43-4.39(1H,m),3.03(1H,ddd,J=16.2,8.8,3.5Hz),2.86-2.78(1H,m),2.62(3H,s),2.59-2.51(1H,m),1.77-1.70(1H,m).
[工程４]　1-{2-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1,3-チアゾール-5-イル}エタノン Using the compound (50 mg) obtained in the above Step 2, the title compound (25 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.39 (1H, s), 8.02 (1H, d, J = 8.6Hz), 7.81 (2H, dd, J = 8.4, 1.4Hz), 7.50-7.45 (1H, m ), 7.38-7.34 (3H, m), 6.96 (1H, s), 4.43-4.39 (1H, m), 3.03 (1H, ddd, J = 16.2, 8.8, 3.5Hz), 2.86-2.78 (1H, m ), 2.62 (3H, s), 2.59-2.51 (1H, m), 1.77-1.70 (1H, m).
[Step 4] 1- {2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazol-5-yl} ethanone
Figure JPOXMLDOC01-appb-C000188
Figure JPOXMLDOC01-appb-C000188
　上記工程３で得られた化合物（25mg）を用いて実施例１工程１２と同様の手法により標題化合物（10mg）を黄色固体として得た。
MS(ESI)m/z:298(M+H)+
1H-NMR(CD3OD)δppm:8.45(1H,d,J=2.7Hz),7.29(2H,dd,J=13.9,8.8Hz),7.12(1H,s),4.45(1H,m),3.20-3.17(1H,m),3.01-2.93(1H,m),2.52-2.61(4H,m),1.90-1.84(1H,m).
実施例３６　(6R)-2-(1-メチル-1H-ピラゾール-4-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [(6R)-2-(1-メチル-1H-ピラゾール-4-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (25 mg) obtained in Step 3 above, the title compound (10 mg) was obtained as a yellow solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 298 (M + H) +
1 H-NMR (CD 3 OD) δ ppm: 8.45 (1H, d, J = 2.7Hz), 7.29 (2H, dd, J = 13.9,8.8Hz), 7.12 (1H, s), 4.45 (1H, m) 3.20-3.17 (1H, m), 3.01-2.93 (1H, m), 2.52-2.61 (4H, m), 1.90-1.84 (1H, m).
Example 36 (6R) -2- (1-Methyl-1H-pyrazol-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-Butyl [(6R) -2- (1-methyl-1H-pyrazol-4-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-yl] carbamate
Figure JPOXMLDOC01-appb-C000189
Figure JPOXMLDOC01-appb-C000189
　実施例１４工程１で得られた化合物（200mg）及び1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボラン-2-イル)-1Hピラゾール（127mg）を用いて実施例１工程９と同様の手法により標題化合物（171mg）を淡黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.18-8.14(1H,m),7.64(1H,s),7.48(1H,s),7.44-7.38(3H,m),7.29-7.23(3H,m),6.42(1H,s),5.28-5.20(1H,m),4.79-4.71(1H,m),3.96(3H,s),3.06-2.97(1H,m),2.87-2.81(1H,m),2.67-2.56(1H,m),1.89-1.80(1H,m),1.47(9H,s).
[工程２]　(6R)-2-(1-メチル-1H-ピラゾール-4-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Example 14 Compound obtained in Step 1 (200 mg) and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -1H pyrazole (127 mg) Was used to give the title compound (171 mg) as a pale-yellow oil in the same manner as in Example 1, Step 9.
1 H-NMR (CDCl 3 ) δppm: 8.18-8.14 (1H, m), 7.64 (1H, s), 7.48 (1H, s), 7.44-7.38 (3H, m), 7.29-7.23 (3H, m) , 6.42 (1H, s), 5.28-5.20 (1H, m), 4.79-4.71 (1H, m), 3.96 (3H, s), 3.06-2.97 (1H, m), 2.87-2.81 (1H, m) 2.67-2.56 (1H, m), 1.89-1.80 (1H, m), 1.47 (9H, s).
[Step 2] (6R) -2- (1-Methyl-1H-pyrazol-4-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000190
Figure JPOXMLDOC01-appb-C000190
　上記工程１で得られた化合物（171mg）を用いて実施例１工程１１と同様の手法により標題化合物（118mg）を淡黄色固体として得た。
1H-NMR(CDCl3)δppm:8.17-8.14(1H,m),7.65-7.62(1H,m),7.48-7.47(1H,m),7.44-7.37(3H,m),7.27-7.22(3H,m),6.43-6.41(1H,m),4.43(1H,t,J=7.0Hz),3.96(3H,s),3.06-2.96(1H,m),2.84-2.76(1H,m),2.59-2.51(1H,m),1.78-1.68(1H,m).
[工程３]　(6R)-2-(1-メチル-1H-ピラゾール-4-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (171 mg) obtained in the above Step 1, the title compound (118 mg) was obtained as a pale yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.17-8.14 (1H, m), 7.65-7.62 (1H, m), 7.48-7.47 (1H, m), 7.44-7.37 (3H, m), 7.27-7.22 ( 3H, m), 6.43-6.41 (1H, m), 4.43 (1H, t, J = 7.0Hz), 3.96 (3H, s), 3.06-2.96 (1H, m), 2.84-2.76 (1H, m) , 2.59-2.51 (1H, m), 1.78-1.68 (1H, m).
[Step 3] (6R) -2- (1-Methyl-1H-pyrazol-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
　上記工程２で得られた化合物（118mg）を用いて実施例１工程１２と同様の手法により標題化合物（31mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.13(1H,brs),7.74-7.72(1H,m),7.62-7.60(1H,m),7.25-7.21(1H,m),7.14-7.10(1H,m),6.47-6.45(1H,m),4.46(1H,t,J=6.8Hz),3.94(3H,s),3.20-3.12(1H,m),2.97-2.90(1H,m),2.65-2.57(1H,m),1.82-1.75(1H,m).
実施例３７　(6R)-2-(1,3-チアゾール-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [(6R)-3-(フェニルスルホニル)-2-(1,3-チアゾール-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (118 mg) obtained in the above Step 2, the title compound (31 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.13 (1H, brs), 7.74-7.72 (1H, m), 7.62-7.60 (1H, m), 7.25-7.21 (1H, m), 7.14-7.10 (1H, m), 6.47-6.45 (1H, m), 4.46 (1H, t, J = 6.8Hz), 3.94 (3H, s), 3.20-3.12 (1H, m), 2.97-2.90 (1H, m), 2.65 -2.57 (1H, m), 1.82-1.75 (1H, m).
Example 37 (6R) -2- (1,3-thiazol-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-butyl [(6R) -3- (phenylsulfonyl) -2- (1,3-thiazol-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6 -Il] Carbamate
Figure JPOXMLDOC01-appb-C000192
Figure JPOXMLDOC01-appb-C000192
　実施例１３工程５で得られた化合物（200mg）及び5-ブロモチアゾール（93.5mg）を用いて実施例１１工程８と同様の手法により標題化合物（141mg）を粗精製物として得た。
[工程２]　(6R)-3-(フェニルスルホニル)-2-(1,3-チアゾール-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Example 13 Using the compound (200 mg) obtained in Step 5 and 5-bromothiazole (93.5 mg), the title compound (141 mg) was obtained as a crude product in the same manner as in Example 11, Step 8.
[Step 2] (6R) -3- (Phenylsulfonyl) -2- (1,3-thiazol-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000193
Figure JPOXMLDOC01-appb-C000193
　上記工程１で得られた化合物（141mg）を用いて実施例１工程１１と同様の手法により標題化合物（67mg）を淡黄色固体として得た。
1H-NMR(CDCl3)δppm:8.91(1H,s),8.21-8.16(1H,m),7.85(1H,s),7.49-7.44(3H,m),7.38-7.34(1H,m),7.32-7.29(2H,m),6.65(1H,s),4.46(1H,t,J=7.1Hz),3.08-3.00(1H,m),2.87-2.80(1H,m),2.62-2.52(1H,m),1.81-1.73(1H,m).
[工程３]　(6R)-2-(1,3-チアゾール-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (141 mg) obtained in the above Step 1, the title compound (67 mg) was obtained as a pale yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.91 (1H, s), 8.21-8.16 (1H, m), 7.85 (1H, s), 7.49-7.44 (3H, m), 7.38-7.34 (1H, m) , 7.32-7.29 (2H, m), 6.65 (1H, s), 4.46 (1H, t, J = 7.1Hz), 3.08-3.00 (1H, m), 2.87-2.80 (1H, m), 2.62-2.52 (1H, m), 1.81-1.73 (1H, m).
[Step 3] (6R) -2- (1,3-thiazol-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000194
Figure JPOXMLDOC01-appb-C000194
　上記工程２で得られた化合物（67mg）を用いて実施例１工程１２と同様の手法により標題化合物（19mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.73(1H,s),8.34(1H,s),8.04(1H,s),7.26-7.19(2H,m),6.68(1H,s),4.47(1H,t,J=7.1Hz),3.21-3.13(1H,m),2.98-2.92(1H,m),2.65-2.59(1H,m),1.85-1.75(1H,m).
実施例３８　(1S)-1-{2-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1,3-チアゾール-5-イル}エタノール
[工程１]　tert-ブチル N-[(6R)-3-(ベンゼンスルホニル)-2-[5-[(1S)-1-ヒドロキシエチル]チアゾール-2-イル]-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Using the compound (67 mg) obtained in the above Step 2, the title compound (19 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.73 (1H, s), 8.34 (1H, s), 8.04 (1H, s), 7.26-7.19 (2H, m), 6.68 (1H, s), 4.47 (1H , t, J = 7.1Hz), 3.21-3.13 (1H, m), 2.98-2.92 (1H, m), 2.65-2.59 (1H, m), 1.85-1.75 (1H, m).
Example 38 (1S) -1- {2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazol-5- Il} ethanol
[Step 1] tert-butyl N-[(6R) -3- (benzenesulfonyl) -2- [5-[(1S) -1-hydroxyethyl] thiazol-2-yl] -7,8-dihydro-6H -Cyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000195
Figure JPOXMLDOC01-appb-C000195
　実施例３５工程２で得られた化合物（150mg）を用いて実施例１０工程１と同様の手法により標題化合物（100mg）を白色固体として得た。
MS(ESI)m/z：540(M+H)+
1H-NMR(CDCl3)δppm:8.00(1H,d,J=8.6Hz),7.81(2H,d,J=8.2Hz),7.74(1H,s),7.45(1H,t,J=7.4Hz),7.36-7.29(3H,m),6.77(1H,s),5.21(1H,q,J=6.4Hz),4.47(1H,s),2.99(1H,ddd,J=16.1,8.9,3.6Hz),2.86-2.78(1H,m),2.60-2.58(1H,m),1.83-1.78(1H,m),1.64(3H,d,J=6.6Hz),1.45(9H,s).
分析条件；CHIRALPAK OD-H,ヘキサン:イソプロパノール=95：5－50：50，1.0mL/min
6.553min
[工程２]　(1S)-1-{2-[(6R)-6-アミノ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1,3-チアゾール-5-イル}エタノール Using the compound (150 mg) obtained in Example 35, Step 2, the title compound (100 mg) was obtained as a white solid in the same manner as in Example 10, Step 1.
MS (ESI) m / z: 540 (M + H) +
1 H-NMR (CDCl 3 ) δppm: 8.00 (1H, d, J = 8.6Hz), 7.81 (2H, d, J = 8.2Hz), 7.74 (1H, s), 7.45 (1H, t, J = 7.4 Hz), 7.36-7.29 (3H, m), 6.77 (1H, s), 5.21 (1H, q, J = 6.4Hz), 4.47 (1H, s), 2.99 (1H, ddd, J = 16.1, 8.9, 3.6Hz), 2.86-2.78 (1H, m), 2.60-2.58 (1H, m), 1.83-1.78 (1H, m), 1.64 (3H, d, J = 6.6Hz), 1.45 (9H, s).
Analysis conditions: CHIRALPAK OD-H, hexane: isopropanol = 95: 5-50: 50, 1.0 mL / min
6.553min
[Step 2] (1S) -1- {2-[(6R) -6-amino-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl]- 1,3-thiazol-5-yl} ethanol
Figure JPOXMLDOC01-appb-C000196
Figure JPOXMLDOC01-appb-C000196
　上記工程１で得られた化合物（220mg）を用いて実施例１工程１１と同様の手法により標題化合物（145mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.01(1H,d,J=8.6Hz),7.82(2H,dd,J=8.4,1.4Hz),7.73(1H,s),7.44(1H,ddd,J=10.0,4.9,2.2Hz),7.36-7.30(3H,m),6.83(1H,s),5.20(1H,q,J=6.5Hz),4.39(1H,t,J=7.2Hz),3.43(2H,s),3.03(1H,ddd,J=20.0,12.6,7.3Hz),2.84-2.76(1H,m),2.56-2.48(1H,m),1.76-1.71(1H,m),1.64(3H,d,J=6.6Hz).
[工程３]　(1S)-1-{2-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1,3-チアゾール-5-イル}エタノール Using the compound (220 mg) obtained in the above Step 1, the title compound (145 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.01 (1H, d, J = 8.6Hz), 7.82 (2H, dd, J = 8.4,1.4Hz), 7.73 (1H, s), 7.44 (1H, ddd, J = 10.0,4.9,2.2Hz), 7.36-7.30 (3H, m), 6.83 (1H, s), 5.20 (1H, q, J = 6.5Hz), 4.39 (1H, t, J = 7.2Hz), 3.43 (2H, s), 3.03 (1H, ddd, J = 20.0,12.6,7.3Hz), 2.84-2.76 (1H, m), 2.56-2.48 (1H, m), 1.76-1.71 (1H, m), 1.64 (3H, d, J = 6.6Hz).
[Step 3] (1S) -1- {2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazole-5 -Il} ethanol
Figure JPOXMLDOC01-appb-C000197
Figure JPOXMLDOC01-appb-C000197
　上記工程２で得られた化合物（145mg）を用いて実施例１工程１２と同様の手法により標題化合物（50mg）を白色固体として得た。
MS(ESI)m/z：300(M+H)+
1H-NMR(CD3OD)δppm:7.64(1H,s),7.32(1H,d,J=8.5Hz),7.25(1H,d,J=8.5Hz),6.94(1H,s),5.14(1H,q,J=6.5Hz),4.48(1H,t,J=6.4Hz),3.34(2H,s),3.27-3.20(1H,m),3.04-2.96(1H,m),2.65-2.58(1H,m),1.92-1.87(1H,m),1.59(3H,d,J=6.7Hz).
実施例３９　(1R)-1-{2-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1,3-チアゾール-5-イル}エタノール
[工程１]　tert-ブチル [(6R)-2-{5-[(1R)-1-ヒドロキシエチル]-1,3-チアゾール-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (145 mg) obtained in the above Step 2, the title compound (50 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 300 (M + H) +
1 H-NMR (CD 3 OD) δppm: 7.64 (1H, s), 7.32 (1H, d, J = 8.5Hz), 7.25 (1H, d, J = 8.5Hz), 6.94 (1H, s), 5.14 (1H, q, J = 6.5Hz), 4.48 (1H, t, J = 6.4Hz), 3.34 (2H, s), 3.27-3.20 (1H, m), 3.04-2.96 (1H, m), 2.65- 2.58 (1H, m), 1.92-1.87 (1H, m), 1.59 (3H, d, J = 6.7Hz).
Example 39 (1R) -1- {2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazol-5- Il} ethanol
[Step 1] tert-Butyl [(6R) -2- {5-[(1R) -1-hydroxyethyl] -1,3-thiazol-2-yl} -3- (phenylsulfonyl) -3,6, 7,8-Tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000198
Figure JPOXMLDOC01-appb-C000198
　実施例３５工程２で得られた化合物（230mg）及びクロロ[(1R,2R)-N-(p-トルエンスルホニル)-1,2-ジフェニルエタンジアミン](メシチレン)ルテニウム(II)（13.3mg）を用い実施例１０工程１と同様の手法により標題化合物（200mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.01(1H,d,J=8.6Hz),7.82(2H,d,J=8.2Hz),7.76(1H,s),7.46(1H,t,J=7.4Hz),7.37-7.30(3H,m),6.83(1H,s),5.26-5.20(1H,m),4.71(1H,d,J=9.4Hz),3.03-2.99(1H,m),2.88-2.80(1H,m),2.61-2.58(1H,m),2.27(1H,d,J=5.1Hz),1.85-1.79(1H,m),1.66(3H,d,J=6.6Hz),1.46(9H,s).
分析条件；CHIRALPAK OD-H，ヘキサン：イソプロパノール＝95：5－50：50，1.0mL/min
8.526min
[工程２]　(1R)-1-{2-[(6R)-6-アミノ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1,3-チアゾール-5-イル}エタノール Example 35 Compound (230 mg) obtained in Step 2 and chloro [(1R, 2R) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium (II) (13.3 mg) Was used to give the title compound (200 mg) as a white solid in the same manner as in Step 1 of Example 10.
1 H-NMR (CDCl 3 ) δppm: 8.01 (1H, d, J = 8.6Hz), 7.82 (2H, d, J = 8.2Hz), 7.76 (1H, s), 7.46 (1H, t, J = 7.4 Hz), 7.37-7.30 (3H, m), 6.83 (1H, s), 5.26-5.20 (1H, m), 4.71 (1H, d, J = 9.4Hz), 3.03-2.99 (1H, m), 2.88 -2.80 (1H, m), 2.61-2.58 (1H, m), 2.27 (1H, d, J = 5.1Hz), 1.85-1.79 (1H, m), 1.66 (3H, d, J = 6.6Hz), 1.46 (9H, s).
Analysis conditions: CHIRALPAK OD-H, hexane: isopropanol = 95: 5-50: 50, 1.0 mL / min
8.526min
[Step 2] (1R) -1- {2-[(6R) -6-amino-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl]- 1,3-thiazol-5-yl} ethanol
Figure JPOXMLDOC01-appb-C000199
Figure JPOXMLDOC01-appb-C000199
　上記工程１で得られた化合物（200mg）を用いて実施例１工程１１と同様の手法により標題化合物（140mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.02(1H,d,J=8.6Hz),7.83(2H,d,J=8.2Hz),7.75(1H,s),7.45(1H,t,J=7.4Hz),7.37-7.31(3H,m),6.85(1H,s),5.22(1H,q,J=6.3Hz),4.40(1H,t,J=7.0Hz),3.02(1H,ddd,J=16.2,8.8,3.7Hz),2.85-2.77(1H,m),2.55-2.52(1H,m),1.77-1.70(1H,m),1.66(3H,d,J=6.3Hz).
[工程３]　(1R)-1-{2-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1,3-チアゾール-5-イル}エタノール Using the compound (200 mg) obtained in the above Step 1, the title compound (140 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.02 (1H, d, J = 8.6Hz), 7.83 (2H, d, J = 8.2Hz), 7.75 (1H, s), 7.45 (1H, t, J = 7.4 Hz), 7.37-7.31 (3H, m), 6.85 (1H, s), 5.22 (1H, q, J = 6.3Hz), 4.40 (1H, t, J = 7.0Hz), 3.02 (1H, ddd, J = 16.2,8.8,3.7Hz), 2.85-2.77 (1H, m), 2.55-2.52 (1H, m), 1.77-1.70 (1H, m), 1.66 (3H, d, J = 6.3Hz).
[Step 3] (1R) -1- {2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazole-5 -Il} ethanol
Figure JPOXMLDOC01-appb-C000200
Figure JPOXMLDOC01-appb-C000200
　上記工程２で得られた化合物（140mg）を用いて実施例１工程１２と同様の手法により標題化合物（60mg）を白色固体として得た。
MS(ESI)m/z：300(M+H)+
1H-NMR(CD3OD)δppm:7.60(1H,s),7.27(1H,d,J=8.6Hz),7.21(1H,d,J=8.6Hz),6.89(1H,s),5.10(1H,q,J=6.5Hz),4.42-4.40(1H,m),3.20-3.16(1H,m),2.95-2.91(1H,m),2.56-2.53(1H,m),1.83-1.81(1H,m),1.54(3H,s).
実施例４０　(6R)-2-(5-メチル-1,3,4-チアジアゾール-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [(6R)-2-(5-メチル-1,3,4-チアジアゾール-2-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (140 mg) obtained in the above Step 2, the title compound (60 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 300 (M + H) +
1 H-NMR (CD 3 OD) δppm: 7.60 (1H, s), 7.27 (1H, d, J = 8.6Hz), 7.21 (1H, d, J = 8.6Hz), 6.89 (1H, s), 5.10 (1H, q, J = 6.5Hz), 4.42-4.40 (1H, m), 3.20-3.16 (1H, m), 2.95-2.91 (1H, m), 2.56-2.53 (1H, m), 1.83-1.81 (1H, m), 1.54 (3H, s).
Example 40 (6R) -2- (5-Methyl-1,3,4-thiadiazol-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-butyl [(6R) -2- (5-methyl-1,3,4-thiadiazol-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] Indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000201
Figure JPOXMLDOC01-appb-C000201
　実施例１３工程５で得られた化合物（3.00g）の及び2-ブロモ-5-メチル-1,3,4-チアジアゾール（1.15g）を用いて実施例１１工程８と同様の手法により標題化合物（1.12g）を淡黄色固体として得た。
1H-NMR(CDCl3)δppm:8.06-8.03(1H,m),7.78-7.75(2H,m),7.49-7.45(1H,m),7.38-7.34(3H,m),6.97(1H,s),5.28-5.19(1H,m),4.74-4.67(1H,m),3.06-2.98(1H,m),2.88-2.82(1H,m),2.87(3H,s),2.67-2.57(1H,m),1.89-1.77(1H,m),1.47(9H,s).
[工程２]　(6R)-2-(5-メチル-1,3,4-チアジアゾール-2-イル)-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Example 13 Using the compound obtained in Step 5 of Step (3.00 g) and 2-bromo-5-methyl-1,3,4-thiadiazole (1.15 g) in the same manner as in Step 11 of Example 11, the title compound (1.12 g) was obtained as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ ppm: 8.06-8.03 (1H, m), 7.78-7.75 (2H, m), 7.49-7.45 (1H, m), 7.38-7.34 (3H, m), 6.97 (1H, s), 5.28-5.19 (1H, m), 4.74-4.67 (1H, m), 3.06-2.98 (1H, m), 2.88-2.82 (1H, m), 2.87 (3H, s), 2.67-2.57 ( 1H, m), 1.89-1.77 (1H, m), 1.47 (9H, s).
[Step 2] (6R) -2- (5-Methyl-1,3,4-thiadiazol-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-Amine
Figure JPOXMLDOC01-appb-C000202
Figure JPOXMLDOC01-appb-C000202
　上記工程１で得られた化合物（1.12g）を用いて実施例１工程１１と同様の手法により標題化合物（1.05g）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.07-8.04(1H,m),7.78-7.75(2H,m),7.48-7.45(1H,m),7.38-7.34(3H,m),6.98(1H,s),4.42(1H,t,J=7.3Hz),3.07-2.99(1H,m),2.87(3H,s),2.86-2.79(1H,m),2.58-2.52(1H,m),1.77-1.69(1H,m).
[工程３]　(6R)-2-(5-メチル-1,3,4-チアジアゾール-2-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (1.12 g) obtained in the above Step 1, the title compound (1.05 g) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.07-8.04 (1H, m), 7.78-7.75 (2H, m), 7.48-7.45 (1H, m), 7.38-7.34 (3H, m), 6.98 (1H, s), 4.42 (1H, t, J = 7.3Hz), 3.07-2.99 (1H, m), 2.87 (3H, s), 2.86-2.79 (1H, m), 2.58-2.52 (1H, m), 1.77 -1.69 (1H, m).
[Step 3] (6R) -2- (5-Methyl-1,3,4-thiadiazol-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000203
Figure JPOXMLDOC01-appb-C000203
　上記工程２で得られた化合物（850mg）の1-プロパノール（16.11g，20mL）溶液に炭酸セシウム（5.4g）を加え、80℃で1時間攪拌した。反応液をそのままアミノ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］で精製することにより標題化合物（580mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.39(1H,brs),7.32-7.25(2H,m),6.88-6.85(1H,m),4.47(1H,t,J=7.1Hz),3.21-3.14(1H,m),2.98-2.92(1H,m),2.80(3H,s),2.66-2.59(1H,m),1.84-1.77(1H,m).
実施例４１　5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1-メチルピリジン-2(1H)-オン
[工程１]　tert-ブチル N-[(6R)-3-(ベンゼンスルホニル)-2-(1-メチル-6－オキソ-3-ピリジル)-7,8-ジヒドロ-6H-シクロペンタ[e]インドール-6-イル]カルバメート Cesium carbonate (5.4 g) was added to a 1-propanol (16.11 g, 20 mL) solution of the compound (850 mg) obtained in Step 2 above, and the mixture was stirred at 80 ° C. for 1 hour. The reaction solution was directly purified by amino silica gel column chromatography [ethyl acetate / methanol] to obtain the title compound (580 mg) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 9.39 (1H, brs), 7.32-7.25 (2H, m), 6.88-6.85 (1H, m), 4.47 (1H, t, J = 7.1Hz), 3.21-3.14 (1H, m), 2.98-2.92 (1H, m), 2.80 (3H, s), 2.66-2.59 (1H, m), 1.84-1.77 (1H, m).
Example 41 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1-methylpyridin-2 (1H) -one
[Step 1] tert-Butyl N-[(6R) -3- (benzenesulfonyl) -2- (1-methyl-6-oxo-3-pyridyl) -7,8-dihydro-6H-cyclopenta [e] indole -6-yl] carbamate
Figure JPOXMLDOC01-appb-C000204
Figure JPOXMLDOC01-appb-C000204
　実施例１４工程１で得られた化合物（250mg）及びN-メチル-1H-ピリドン-2-オン-5-ボロン酸ピナコールエステル（239mg）を用いて実施例１工程９と同様の手法により標題化合物（160mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:8.16(1H,d,J=8.6Hz),7.53-7.46(1H,m),7.46-7.38(3H,m),7.36-7.28(4H,m),6.59(1H,d,J=7.4Hz),6.46(1H,s),5.32-5.20(1H,m),4.85-4.70(1H,m),3.60(3H,s),3.10-2.96(1H,m),2.92-2.80(1H,m),2.73-2.57(1H,m),1.95-1.82(1H,m),1.50(9H,s).
[工程２]　5-[(6R)-6-アミノ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1-メチルピリジン-2(1H)-オン Example 14 Using the compound obtained in Step 1 of Step 1 (250 mg) and N-methyl-1H-pyridone-2-one-5-boronic acid pinacol ester (239 mg) in the same manner as in Step 1 of Example 1, the title compound (160 mg) was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ ppm: 8.16 (1H, d, J = 8.6 Hz), 7.53-7.46 (1H, m), 7.46-7.38 (3H, m), 7.36-7.28 (4H, m), 6.59 (1H, d, J = 7.4Hz), 6.46 (1H, s), 5.32-5.20 (1H, m), 4.85-4.70 (1H, m), 3.60 (3H, s), 3.10-2.96 (1H, m ), 2.92-2.80 (1H, m), 2.73-2.57 (1H, m), 1.95.82 (1H, m), 1.50 (9H, s).
[Step 2] 5-[(6R) -6-amino-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1-methylpyridine-2 ( 1H) -ON
Figure JPOXMLDOC01-appb-C000205
Figure JPOXMLDOC01-appb-C000205
　上記工程１で得られた化合物（160mg）を用いて実施例１工程１１と同様の手法により（115mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.18(1H,d,J=8.6Hz),7.54-7.30(8H,m),6.59(1H,d,J=9.4Hz),6.46(1H,s),4.47(1H,t,J=7.0Hz),3.60(3H,s),3.11-2.98(1H,m),2.90-2.77(1H,m),2.64-2.52(1H,m),1.84-1.70(1H,m).
[工程３]　5-[(6R)-6-アミノ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-1-メチルピリジン-2(1H)-オン (115 mg) was obtained as a white solid in the same manner as in Example 1, Step 11 using the compound (160 mg) obtained in Step 1 above.
1 H-NMR (CDCl 3 ) δppm: 8.18 (1H, d, J = 8.6Hz), 7.54-7.30 (8H, m), 6.59 (1H, d, J = 9.4Hz), 6.46 (1H, s), 4.47 (1H, t, J = 7.0Hz), 3.60 (3H, s), 3.11-2.98 (1H, m), 2.90-2.77 (1H, m), 2.64-2.52 (1H, m), 1.84-1.70 ( 1H, m).
[Step 3] 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1-methylpyridin-2 (1H) -one
Figure JPOXMLDOC01-appb-C000206
Figure JPOXMLDOC01-appb-C000206
　上記工程２で得られた化合物（115mg）を用いて実施例１工程１２と同様の手法により標題化合物（41mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.09(1H,d,J=2.3Hz),8.01(1H,dd,J=9.4,2.7Hz),7.27(1H,d,J=7.8Hz),7.19(1H,d,J=8.2Hz),6.70-6.62(2H,m),4.47(1H,t,J=6.7Hz),3.67(3H,s),3.28-3.18(1H,m),3.05-2.93(1H,m),2.67-2.54(1H,m),1.94-1.83(1H,m).
実施例４２　(6R*,7S*)-7-フルオロ-2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　7-フルオロ-3-[(4-メチルフェニル)スルホニル]-7,8-ジヒドロシクロペンタ[e]インドール-6(3H)-オン Using the compound (115 mg) obtained in the above Step 2, the title compound (41 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.09 (1H, d, J = 2.3 Hz), 8.01 (1 H, dd, J = 9.4, 2.7 Hz), 7.27 (1 H, d, J = 7.8 Hz), 7.19 ( 1H, d, J = 8.2Hz), 6.70-6.62 (2H, m), 4.47 (1H, t, J = 6.7Hz), 3.67 (3H, s), 3.28-3.18 (1H, m), 3.05-2.93 (1H, m), 2.67-2.54 (1H, m), 1.94-1.83 (1H, m).
Example 42 (6R * , 7S * )-7-Fluoro-2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] 7-Fluoro-3-[(4-methylphenyl) sulfonyl] -7,8-dihydrocyclopenta [e] indole-6 (3H) -one
Figure JPOXMLDOC01-appb-C000207
Figure JPOXMLDOC01-appb-C000207
　実施例１工程４で得られた化合物のメタノール（30.7mL）溶液に1-フルオロ-4-ヒドロキシ-1,4-ジアゾニアビシクロ[2,2,2]オクタンビス(テトラフルオロボレート)（1.09g）を加え、80℃で5時間攪拌した。水を加えて反応を停止した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物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］で精製することにより標題化合物（280mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.06(1H,d,J=8.6Hz),7.83-7.70(4H,m),7.30-7.25(2H,m),6.78(1H,d,J=3.5Hz),5.30(1H,ddd,J=51.0,3.8,3.8Hz),3.80-3.70(1H,m),3.37-3.22(1H,m),2.36(3H,s).
[工程２]　(6R*,7S*)-7-フルオロ-3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-オール Example 1 1-fluoro-4-hydroxy-1,4-diazoniabicyclo [2,2,2] octanebis (tetrafluoroborate) (1.09 g) in a methanol (30.7 mL) solution of the compound obtained in Step 4 And stirred at 80 ° C. for 5 hours. The reaction was stopped by adding water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (280 mg) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 8.06 (1H, d, J = 8.6Hz), 7.83-7.70 (4H, m), 7.30-7.25 (2H, m), 6.78 (1H, d, J = 3.5Hz ), 5.30 (1H, ddd, J = 51.0, 3.8, 3.8Hz), 3.80-3.70 (1H, m), 3.37-3.22 (1H, m), 2.36 (3H, s).
[Step 2] (6R * , 7S * )-7-fluoro-3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-ol
Figure JPOXMLDOC01-appb-C000208
Figure JPOXMLDOC01-appb-C000208
　上記工程１で得られた化合物（280mg）を用いて実施例１工程５と同様の手法により標題化合物（260mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.94(1H,d,J=8.2Hz),7.79-7.74(2H,m),7.63(1H,d,J=3.5Hz),7.41(1H,d,J=8.2Hz),7.25-7.20(2H,m),6.63-6.58(1H,m),5.47-5.28(1H,m),5.24-5.13(1H,m),3.40-3.10(2H,m),2.40-2.25(4H,m).
[工程３]　(6R*,7S*)-2-ブロモ-7-フルオロ-3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-オール Using the compound (280 mg) obtained in the above Step 1, the title compound (260 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 7.94 (1H, d, J = 8.2Hz), 7.79-7.74 (2H, m), 7.63 (1H, d, J = 3.5Hz), 7.41 (1H, d, J = 8.2Hz), 7.25-7.20 (2H, m), 6.63-6.58 (1H, m), 5.47-5.28 (1H, m), 5.24-5.13 (1H, m), 3.40-3.10 (2H, m), 2.40-2.25 (4H, m).
[Step 3] (6R * , 7S * )-2-bromo-7-fluoro-3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6- Oar
Figure JPOXMLDOC01-appb-C000209
Figure JPOXMLDOC01-appb-C000209
　上記工程２で得られた化合物（280mg）を用いて実施例１工程８と同様の手法により標題化合物（320mg）を黄色固体として得た。
1H-NMR(CDCl3)δppm:8.27(1H,m),7.81-7.76(2H,m),7.43(1H,d,J=8.6Hz),7.26-7.20(2H,m),6.68(1H,s),5.46-5.28(1H,m),5.25-5.14(1H,m),3.37-3.05(2H,m),2.43-2.30(4H,m).
[工程４]　(6R*,7S*)-7-フルオロ-3-[(4-メチルフェニル)スルホニル]-2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-オール Using the compound (280 mg) obtained in the above Step 2, the title compound (320 mg) was obtained as a yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.27 (1H, m), 7.81-7.76 (2H, m), 7.43 (1H, d, J = 8.6Hz), 7.26-7.20 (2H, m), 6.68 (1H , s), 5.46-5.28 (1H, m), 5.25-5.14 (1H, m), 3.37-3.05 (2H, m), 2.43-2.30 (4H, m).
[Step 4] (6R * , 7S * )-7-fluoro-3-[(4-methylphenyl) sulfonyl] -2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclo Penta [e] indole-6-ol
Figure JPOXMLDOC01-appb-C000210
Figure JPOXMLDOC01-appb-C000210
　上記工程３で得られた化合物（270mg）を用いて実施例１工程９と同様の手法により標題化合物（220mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.26(1H,d,J=8.6Hz),8.03-7.98(2H,m),7.76-7.71(2H,m),7.51(1H,d,J=8.6Hz),7.31-7.20(2H,m),7.12-7.05(2H,m),6.60(1H,s),5.48-5.28(1H,m),5.28-5.13(1H,m),3.40-3.07(4H,m),2.45-2.37(1H,m),2.31(3H,s).
[工程５]　(6R*,7S*)-6-アジド-7-フルオロ-3-[(4-メチルフェニル)スルホニル]-2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール Using the compound (270 mg) obtained in the above Step 3, the title compound (220 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.26 (1H, d, J = 8.6Hz), 8.03-7.98 (2H, m), 7.76-7.71 (2H, m), 7.51 (1H, d, J = 8.6Hz ), 7.31-7.20 (2H, m), 7.12-7.05 (2H, m), 6.60 (1H, s), 5.48-5.28 (1H, m), 5.28-5.13 (1H, m), 3.40-3.07 (4H) , m), 2.45-2.37 (1H, m), 2.31 (3H, s).
[Step 5] (6R * , 7S * )-6-azido-7-fluoro-3-[(4-methylphenyl) sulfonyl] -2- [4- (methylsulfonyl) phenyl] -3,6,7, 8-tetrahydrocyclopenta [e] indole
Figure JPOXMLDOC01-appb-C000211
Figure JPOXMLDOC01-appb-C000211
　上記工程４で得られた化合物（0.220g）のテトラヒドロフラン（4.40mL）溶液にDPPA（0.114mL）及びジアザビシクロウンデセン（DBU；0.0789mL）を加え、室温で3時間攪拌した。反応液を直接ゲルろ過することにより標題化合物（231mg）を粗精製物として得た。
[工程６]　(6R*,7S*)-7-フルオロ-3-[(4-メチルフェニル)スルホニル]-2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン DPPA (0.114 mL) and diazabicycloundecene (DBU; 0.0789 mL) were added to a tetrahydrofuran (4.40 mL) solution of the compound (0.220 g) obtained in Step 4 above, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was directly gel filtered to give the titled compound (231 mg) as a crude product.
[Step 6] (6R * , 7S * )-7-fluoro-3-[(4-methylphenyl) sulfonyl] -2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclo Penta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000212
Figure JPOXMLDOC01-appb-C000212
　上記工程５で得られた化合物（231mg）のテトラヒドロフラン（4.40mL）溶液に水（0.440ml）及びトリフェニルホスフィン（0.231g）を加え、室温で16時間攪拌した。反応液を直接ゲルろ過することにより標題化合物（200mg）を得た。
[工程７]　(6R*,7S*)-7-フルオロ-2-[4-(メチルスルホニル)フェニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Water (0.440 ml) and triphenylphosphine (0.231 g) were added to a tetrahydrofuran (4.40 mL) solution of the compound (231 mg) obtained in Step 5 above, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was directly gel filtered to give the title compound (200 mg).
[Step 7] (6R * , 7S * )-7-Fluoro-2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000213
Figure JPOXMLDOC01-appb-C000213
　上記工程６で得られた化合物（200mg）を用いて実施例１工程１２と同様の手法により標題化合物（26mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.03-7.96(2H,m),7.87-7.81(2H,m),7.37(1H,d,J=7.8Hz),7.29-7.24(1H,m),6.90(1H,d,J=1.2Hz),5.22-5.03(1H,m),4.59(1H,dd,J=19.6,3.9Hz),3.60(1H,ddd,J=16.4,6.6,6.6Hz),3.42-3.16(1H,m),3.10(3H,s).
実施例４３　(6R*,7S*)-7-フルオロ-2-(2-メトキシピリミジン-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　(6R*,7S*)-7-フルオロ-2-(2-メトキシピリミジン-5-イル)-3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-オール Using the compound (200 mg) obtained in the above Step 6, the title compound (26 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.03-7.96 (2H, m), 7.87-7.81 (2H, m), 7.37 (1H, d, J = 7.8Hz), 7.29-7.24 (1H, m), 6.90 (1H, d, J = 1.2Hz), 5.22-5.03 (1H, m), 4.59 (1H, dd, J = 19.6,3.9Hz), 3.60 (1H, ddd, J = 16.4,6.6,6.6Hz), 3.42-3.16 (1H, m), 3.10 (3H, s).
Example 43 (6R * , 7S * )-7-Fluoro-2- (2-methoxypyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] (6R *, 7S *)-7-Fluoro-2- (2-methoxypyrimidin-5-yl) -3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydro Cyclopenta [e] indole-6-ol
Figure JPOXMLDOC01-appb-C000214
Figure JPOXMLDOC01-appb-C000214
　実施例４２工程３で得られた化合物（600mg）及び、(2-メトキシミリミジン-5-イル)ボロン酸（283mg）を用いて実施例１工程９と同様の手法により標題化合物（450mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.57(2H,s),8.29(1H,d,J=8.6Hz),7.51(1H,d,J=9.0Hz),7.32-7.24(2H,m),7.14-7.07(2H,m),6.55(1H,d,J=0.8Hz),5.49-5.29(1H,m),5.29-5.16(1H,m),4.12(3H,s),3.40-3.10(2H,m),2.48-2.40(1H,m),2.31(3H,s).
[工程２]　(6R*,7S*)-6-アジド-7-フルオロ-2-(2-メトキシピリミジン-5-イル)-3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール Example 42 Using the compound (600 mg) obtained in Step 3 and (2-methoxymyrimidin-5-yl) boronic acid (283 mg), the title compound (450 mg) was prepared in the same manner as in Example 1, Step 9. Obtained as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 8.57 (2H, s), 8.29 (1H, d, J = 8.6Hz), 7.51 (1H, d, J = 9.0Hz), 7.32-7.24 (2H, m), 7.14-7.07 (2H, m), 6.55 (1H, d, J = 0.8Hz), 5.49-5.29 (1H, m), 5.29-5.16 (1H, m), 4.12 (3H, s), 3.40-3.10 ( 2H, m), 2.48-2.40 (1H, m), 2.31 (3H, s).
[Step 2] (6R * , 7S * )-6-azido-7-fluoro-2- (2-methoxypyrimidin-5-yl) -3-[(4-methylphenyl) sulfonyl] -3,6,7 , 8-Tetrahydrocyclopenta [e] indole
Figure JPOXMLDOC01-appb-C000215
Figure JPOXMLDOC01-appb-C000215
　上記工程１で得られた化合物（400mg）を用いて実施例４２工程５と同様の手法により標題化合物（140mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:8.57(2H,s),8.35-8.29(1H,m),7.45(1H,d,J=8.6Hz),7.30-7.22(2H,m),7.14-7.08(2H,m),6.55(1H,d,J=0.8Hz),5.42-5.23(1H,m),5.05(1H,dd,J=17.4,2.5Hz),4.12(3H,s),3.57-3.42(1H,m),3.30-3.14(1H,m),2.32(3H,s).
[工程３]　(6R*,7S*)-7-フルオロ-2-(2-メトキシピリミジン-5-イル)-3-[(4-メチルフェニル)スルホニル]-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (400 mg) obtained in the above Step 1, the title compound (140 mg) was obtained as a colorless oily substance in the same manner as in Example 42, Step 5.
1 H-NMR (CDCl 3 ) δppm: 8.57 (2H, s), 8.35-8.29 (1H, m), 7.45 (1H, d, J = 8.6Hz), 7.30-7.22 (2H, m), 7.14-7.08 (2H, m), 6.55 (1H, d, J = 0.8Hz), 5.42-5.23 (1H, m), 5.05 (1H, dd, J = 17.4,2.5Hz), 4.12 (3H, s), 3.57- 3.42 (1H, m), 3.30-3.14 (1H, m), 2.32 (3H, s).
[Step 3] (6R * , 7S * )-7-fluoro-2- (2-methoxypyrimidin-5-yl) -3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydro Cyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000216
Figure JPOXMLDOC01-appb-C000216
　上記工程２で得られた化合物（130mg）を用いて実施例４２工程６と同様の手法により標題化合物（200mg）を得た。
[工程４]　(6R*,7S*)-7-フルオロ-2-(2-メトキシピリミジン-5-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン The title compound (200 mg) was obtained in the same manner as in Example 42, Step 6 using the compound (130 mg) obtained in Step 2 above.
[Step 4] (6R * , 7S * )-7-Fluoro-2- (2-methoxypyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000217
Figure JPOXMLDOC01-appb-C000217
　上記工程３で得られた化合物（200mg）を用いて実施例１工程１２と同様の手法により標題化合物（12mg）を白色固体として得た。
1H-NMR(MeOH-d4)δppm:9.01(2H,s),7.38(1H,d,J=8.2Hz),7.24(1H,d,J=8.2Hz),6.89(1H,s),5.29-5.10(1H,m),4.50(1H,dd,J=20.0,3.1Hz),3.72-3.57(1H,m),3.30-3.14(1H,m).
実施例４４　{4-[(6S,7R)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリジン-2-イル}メタノール
[工程１]　7-フルオロ-3-(フェニルスルホニル)-7,8-ジヒドロシクロペンタ[e]インドール-6(3H)-オン Using the compound (200 mg) obtained in Step 3 above, the title compound (12 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δ ppm: 9.01 (2H, s), 7.38 (1H, d, J = 8.2 Hz), 7.24 (1H, d, J = 8.2 Hz), 6.89 (1H, s), 5.29 -5.10 (1H, m), 4.50 (1H, dd, J = 20.0,3.1Hz), 3.72-3.57 (1H, m), 3.30-3.14 (1H, m).
Example 44 {4-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyridin-2-yl }methanol
[Step 1] 7-Fluoro-3- (phenylsulfonyl) -7,8-dihydrocyclopenta [e] indole-6 (3H) -one
Figure JPOXMLDOC01-appb-C000218
Figure JPOXMLDOC01-appb-C000218
　実施例１１工程３で得られた化合物（3.00g）を用いて実施例４２工程１と同様の手法により標題化合物（2.60g）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.12-8.05(1H,m),7.95-7.90(2H,m),7.78-7.70(2H,m),7.64-7.55(1H,m),7.53-7.45(2H,m),6.83-6.75(1H,m),5.31(1H,ddd,J=50.8,7.6,3.7Hz),3.75(1H,ddd,J=17.3,7.5,7.5Hz),3.36-3.19(1H,m).
[工程２]　(6Z)-7-フルオロ-N-メトキシ-3-(フェニルスルホニル)-7,8-ジヒドロシクロペンタ[e]インドール-6(3H)-イミン The title compound (2.60 g) was obtained as a white solid in the same manner as in Example 42, Step 1 using the compound (3.00 g) obtained in Step 3 of Example 11.
1 H-NMR (CDCl 3 ) δ ppm: 8.12-8.05 (1H, m), 7.95-7.90 (2H, m), 7.78-7.70 (2H, m), 7.64-7.55 (1H, m), 7.53-7.45 ( 2H, m), 6.83-6.75 (1H, m), 5.31 (1H, ddd, J = 50.8,7.6,3.7Hz), 3.75 (1H, ddd, J = 17.3,7.5,7.5Hz), 3.36-3.19 ( 1H, m).
[Step 2] (6Z) -7-Fluoro-N-methoxy-3- (phenylsulfonyl) -7,8-dihydrocyclopenta [e] indole-6 (3H) -imine
Figure JPOXMLDOC01-appb-C000219
Figure JPOXMLDOC01-appb-C000219
　上記工程１で得られた化合物（2.50g）のエタノール（19.0mL）溶液に酢酸ナトリウム（1.90g）、O-メチルヒドロキシアミン塩酸塩（1.90g）、水（19.0mL）及びテトラヒドロフラン（19.0mL）を加え、85℃で3時間攪拌した。水を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去することにより標題化合物（2.5g）を粗精製物として得た。
[工程３]　tert-ブチル [(6R*,7S*)-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Sodium acetate (1.90 g), O-methylhydroxyamine hydrochloride (1.90 g), water (19.0 mL) and tetrahydrofuran (19.0 mL) were added to an ethanol (19.0 mL) solution of the compound (2.50 g) obtained in Step 1 above. And stirred at 85 ° C. for 3 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure to give the title compound (2.5 g) as a crude product.
[Step 3] tert-Butyl [(6R * , 7S * )-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000220
Figure JPOXMLDOC01-appb-C000220
　上記工程２で得られた化合物（2.5g）のテトラヒドロフラン（35mL）溶液に0.9M ボラン－テトラヒドロフラン錯体（20mL）を加え、85℃で1時間攪拌した。2規定塩酸水溶液を加えて反応を停止し、10分間攪拌した後に、2規定水酸化ナトリウム水溶液、酢酸エチル及びジ-t-ブチルジカルボネート（2.3g）を加えて30分間攪拌した。酢酸エチルで抽出して有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。ろ過後、ろ液を減圧留去し、得られた残留物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]にて精製し、標題化合物（1.70g）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.95-7.83(3H,m),7.64-7.58(1H,m),7.56-7.48(1H,m),7.48-7.38(2H,m),7.30-7.22(1H,m),6.60(1H,d,J=3.9Hz),5.55-5.23(2H,m),5.23-5.00(1H,m),3.40-3.10(2H,m),1.52(9H,s).
[工程４]　tert-ブチル[((6R*,7S*)-2-ブロモ-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート To a tetrahydrofuran (35 mL) solution of the compound (2.5 g) obtained in the above Step 2, 0.9M borane-tetrahydrofuran complex (20 mL) was added and stirred at 85 ° C. for 1 hour. 2N hydrochloric acid aqueous solution was added to stop the reaction, and the mixture was stirred for 10 minutes. Then, 2N sodium hydroxide aqueous solution, ethyl acetate and di-t-butyl dicarbonate (2.3 g) were added and stirred for 30 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (1.70 g) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 7.95-7.83 (3H, m), 7.64-7.58 (1H, m), 7.56-7.48 (1H, m), 7.48-7.38 (2H, m), 7.30-7.22 ( 1H, m), 6.60 (1H, d, J = 3.9Hz), 5.55-5.23 (2H, m), 5.23-5.00 (1H, m), 3.40-3.10 (2H, m), 1.52 (9H, s) .
[Step 4] tert-Butyl [((6R * , 7S * )-2-bromo-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
Figure JPOXMLDOC01-appb-C000221
Figure JPOXMLDOC01-appb-C000221
　上記工程３で得られた化合物（1.10g）を用いて実施例１工程８と同様の手法により標題化合物（1.05g）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.21(1H,d,J=9.0Hz),7.93-7.83(2H,m),7.57(1H,dd,J=7.4,7.4Hz),7.50-7.40(2H,m),7.32-7.22(1H,m),6.69(1H,s),5.53-5.04(2H,m),3.33-3.02(2H,m),1.53(9H,m).
[工程５]　メチル 4-[(6R*,7S*)-6-[(tert-ブトキシカルボニル)アミノ]-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリジン-2-カルボキシレート The title compound (1.05 g) was obtained as a white solid in the same manner as in Step 1 of Example 1 using the compound (1.10 g) obtained in the above Step 3.
1 H-NMR (CDCl 3 ) δppm: 8.21 (1H, d, J = 9.0Hz), 7.93-7.83 (2H, m), 7.57 (1H, dd, J = 7.4,7.4Hz), 7.50-7.40 (2H , m), 7.32-7.22 (1H, m), 6.69 (1H, s), 5.53-5.04 (2H, m), 3.33-3.02 (2H, m), 1.53 (9H, m).
[Step 5] Methyl 4-[(6R * , 7S * )-6-[(tert-butoxycarbonyl) amino] -7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] Indol-2-yl] -6-methoxypyridine-2-carboxylate
Figure JPOXMLDOC01-appb-C000222
Figure JPOXMLDOC01-appb-C000222
　上記工程４で得られた化合物（600mg）及びメチル 6-メトキシ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン-2-カルボキシレート（414mg）を用いて実施例１工程９と同様の手法により標題化合物（600mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.22(1H,d,J=9.0Hz),7.89(1H,d,J=1.6Hz),7.53-7.42(3H,m),7.42-7.28(3H,m),5.50-5.10(3H,m),4.10(3H,s),4.00(3H,s),3.33-3.06(2H,m),1.54(9H,s).
[工程６]　tert-ブチル[(6R*,7S*)-7-フルオロ-2-[2-(ヒドロキシメチル)-6-メトキシピリジン-4-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート The compound (600 mg) obtained in the above Step 4 and methyl 6-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2-carboxylate ( The title compound (600 mg) was obtained as a white solid in the same manner as in Example 1, Step 9.
1 H-NMR (CDCl 3 ) δ ppm: 8.22 (1H, d, J = 9.0Hz), 7.89 (1H, d, J = 1.6Hz), 7.53-7.42 (3H, m), 7.42-7.28 (3H, m ), 5.50-5.10 (3H, m), 4.10 (3H, s), 4.00 (3H, s), 3.33-3.06 (2H, m), 1.54 (9H, s).
[Step 6] tert-Butyl [(6R * , 7S * )-7-fluoro-2- [2- (hydroxymethyl) -6-methoxypyridin-4-yl] -3- (phenylsulfonyl) -3,6 , 7,8-Tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000223
Figure JPOXMLDOC01-appb-C000223
　上記工程５で得られた化合物（600mg）を用いて実施例１工程１０と同様の手法により標題化合物（500mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.20(1H,d,J=8.6Hz),7.53-7.43(3H,m),7.33-7.28(3H,m),7.00(1H,s),6.78(1H,s),6.61(1H,s),5.50-5.12(3H,m),4.75(2H,d,J=5.1Hz),4.03(3H,s),3.43(1H,t,J=5.3Hz),3.33-3.04(2H,m),1.53(9H,s).
[工程７]　tert-ブチル [(6S,7R)-7-フルオロ-2-[2-(ヒドロキシメチル)-6-メトキシピリジン-4-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート；tert-ブチル [(6R,7S)-7-フルオロ-2-[2-(ヒドロキシメチル)-6-メトキシピリジン-4-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (600 mg) obtained in the above Step 5, the title compound (500 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.20 (1H, d, J = 8.6Hz), 7.53-7.43 (3H, m), 7.33-7.28 (3H, m), 7.00 (1H, s), 6.78 (1H , s), 6.61 (1H, s), 5.50-5.12 (3H, m), 4.75 (2H, d, J = 5.1Hz), 4.03 (3H, s), 3.43 (1H, t, J = 5.3Hz) 3.33-3.04 (2H, m), 1.53 (9H, s).
[Step 7] tert-butyl [(6S, 7R) -7-fluoro-2- [2- (hydroxymethyl) -6-methoxypyridin-4-yl] -3- (phenylsulfonyl) -3,6,7 , 8-tetrahydrocyclopenta [e] indol-6-yl] carbamate; tert-butyl [(6R, 7S) -7-fluoro-2- [2- (hydroxymethyl) -6-methoxypyridin-4-yl] -3- (Phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000224
Figure JPOXMLDOC01-appb-C000224
　上記工程６で得られた化合物（500mg）の光学分割をカラムクロマトグラフィー（株式会社ダイセルキラルフラッシュIC、ヘキサン／イソプロピルアルコール＝50%→100%）を用いて行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル [(6S,7R)-7-フルオロ-2-[2-(ヒドロキシメチル)-6-メトキシピリジン-4-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート（0.200g）を無色油状物質として得た。また、後から溶出する第二ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル [(6R,7S)-7-フルオロ-2-[2-(ヒドロキシメチル)-6-メトキシピリジン-4-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート（0.205g）を無色油状物質として得た。
分析条件：キラルカラムIC、Hexane/IPA = 20/80、流速1.0mL/min、吸収波長254nm
1st peak；保持時間（rt）=15.6min, >98%ee
2nd peak；保持時間（rt）=20.8min, >98%ee
[工程８]　{4-[(6S,7R)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリジン-2-イル}メタノール Optical resolution of the compound (500 mg) obtained in the above Step 6 was performed using column chromatography (Daicel Chiral Flash IC, hexane / isopropyl alcohol = 50% → 100%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl [(6S, 7R) -7-fluoro-2- [2- (hydroxymethyl) -6-methoxypyridine] was collected. -4-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate (0.200 g) was obtained as a colorless oil. In addition, after collecting the second peak eluting later, the solvent was distilled off under reduced pressure, and tert-butyl [(6R, 7S) -7-fluoro-2- [2- (hydroxymethyl) -6- Methoxypyridin-4-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate (0.205 g) was obtained as a colorless oil.
Analysis conditions: Chiral column IC, Hexane / IPA = 20/80, flow rate 1.0 mL / min, absorption wavelength 254 nm
1st peak; retention time (rt) = 15.6min,> 98% ee
2nd peak; retention time (rt) = 20.8min,> 98% ee
[Step 8] {4-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyridine-2- Il} methanol
Figure JPOXMLDOC01-appb-C000225
Figure JPOXMLDOC01-appb-C000225
　上記工程７で第一ピークとして得られた化合物（150mg）を用いて実施例１工程１２と同様の手法により標題化合物（50mg）を白色固体として得た。
1H-NMR(DMSO-d6)δppm:7.58(1H,d,J=1.2Hz),7.36(1H,d,J=8.2Hz),7.25(1H,d,J=8.2Hz),7.17(1H,d,J=1.6Hz),7.12(1H,d,J=1.2Hz),5.51(1H,t,J=5.7Hz),5.40-5.20(1H,m),4.56(2H,d,J=5.5Hz),4.37(1H,dd,J=23.7,4.1Hz),3.91(3H,s),3.43-3.17(2H,m).
実施例４５　{4-[(6R,7S)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリジン-2-イル}メタノール
[工程１]　{4-[(6R,7S)-6-アミノ-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリジン-2-イル}メタノール Using the compound (150 mg) obtained as the first peak in Step 7 above, the title compound (50 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (DMSO-d6) δppm: 7.58 (1H, d, J = 1.2Hz), 7.36 (1H, d, J = 8.2Hz), 7.25 (1H, d, J = 8.2Hz), 7.17 (1H , d, J = 1.6Hz), 7.12 (1H, d, J = 1.2Hz), 5.51 (1H, t, J = 5.7Hz), 5.40-5.20 (1H, m), 4.56 (2H, d, J = 5.5Hz), 4.37 (1H, dd, J = 23.7,4.1Hz), 3.91 (3H, s), 3.43-3.17 (2H, m).
Example 45 {4-[(6R, 7S) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyridin-2-yl }methanol
[Step 1] {4-[(6R, 7S) -6-amino-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl]- 6-Methoxypyridin-2-yl} methanol
Figure JPOXMLDOC01-appb-C000226
Figure JPOXMLDOC01-appb-C000226
　実施例４４工程７で第二ピークとして得られた化合物（200mg）を用いて実施例１工程１１と同様の手法により標題化合物（150mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.21(1Hmd,J=8.6Hz),7.49-7.43(4Hm),7.35-7.28(2H,m),7.00(1H,s),6.78(1H,d,J=1.2Hz),6.61(1H,s),5.35-5.17(1H,m),4.75(2H,s),4.41(1H,dd,J=21.9,4.3Hz),4.03(3H,s),3.32-3.04(2H,m).
[工程２]　{4-[(6R,7S)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリジン-2-イル}メタノール The title compound (150 mg) was obtained as a white solid in the same manner as in Example 1, Step 11, using the compound (200 mg) obtained as the second peak in Step 44 of Example 44.
1 H-NMR (CDCl 3 ) δppm: 8.21 (1Hmd, J = 8.6Hz), 7.49-7.43 (4Hm), 7.35-7.28 (2H, m), 7.00 (1H, s), 6.78 (1H, d, J = 1.2Hz), 6.61 (1H, s), 5.35-5.17 (1H, m), 4.75 (2H, s), 4.41 (1H, dd, J = 21.9,4.3Hz), 4.03 (3H, s), 3.32 -3.04 (2H, m).
[Step 2] {4-[(6R, 7S) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyridine-2- Il} methanol
Figure JPOXMLDOC01-appb-C000227
Figure JPOXMLDOC01-appb-C000227
　上記工程１で得られた化合物（150ｍg）を用いて実施例１工程１２と同様の手法により標題化合物（50mg）を白色固体として得た。
1H-NMR(DMSO-d6)δppm:7.58(1H,d,J=1.2Hz),7.36(1H,d,J=8.2Hz),7.25(1H,d,J=8.2Hz),7.17(1H,d,J=1.6Hz),7.12(1H,d,J=1.2Hz),5.51(1H,t,J=5.7Hz),5.40-5.20(1H,m),4.56(2H,d,J=5.5Hz),4.37(1H,dd,J=23.7,4.1Hz),3.91(3H,s),3.43-3.17(2H,m).
実施例４６　{5-[(6R*,7S*)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}メタノール
[工程１]　tert-ブチル[(6R*,7S*)-7-フルオロ-3-(フェニルスルホニル)-2-(トリブチルスタナニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (150 mg) obtained in the above Step 1, the title compound (50 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (DMSO-d 6 ) δ ppm: 7.58 (1H, d, J = 1.2 Hz), 7.36 (1 H, d, J = 8.2 Hz), 7.25 (1 H, d, J = 8.2 Hz), 7.17 ( 1H, d, J = 1.6Hz), 7.12 (1H, d, J = 1.2Hz), 5.51 (1H, t, J = 5.7Hz), 5.40-5.20 (1H, m), 4.56 (2H, d, J = 5.5Hz), 4.37 (1H, dd, J = 23.7,4.1Hz), 3.91 (3H, s), 3.43-3.17 (2H, m).
Example 46 {5-[(6R * , 7S * )-6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} methanol
[Step 1] tert-Butyl [(6R * , 7S * )-7-fluoro-3- (phenylsulfonyl) -2- (tributylstannanyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-yl] carbamate
Figure JPOXMLDOC01-appb-C000228
Figure JPOXMLDOC01-appb-C000228
　実施例４４工程３で得られた化合物（1.10g）を用いて実施例１１工程７と同様の手法により標題化合物（1.20g）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:7.73(1H,d,J=8.2Hz),7.67-7.59(2H,m),7.54-7.42(1H,m),7.43-7.34(2H,m),7.16-7.08(1H,m),6.75-6.68(1H,m),5.53-5.00(2H,m),3.45-3.10(2H,m),1.65-1.45(6H,m),1.51(9H,s),1.40-1.30(6H,m),1.23-1.20(6H,m),0.90(9H,t,J=7.2Hz).
[工程２]　メチル 5-[(6R*,7S*)-6-[(tert-ブトキシカルボニル)アミノ]-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-カルボキシレート Example 44 Using the compound (1.10 g) obtained in Step 3 of Example 44 and the procedure of Example 11 Step 7, the title compound (1.20 g) was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δppm: 7.73 (1H, d, J = 8.2Hz), 7.67-7.59 (2H, m), 7.54-7.42 (1H, m), 7.43-7.34 (2H, m), 7.16 -7.08 (1H, m), 6.75-6.68 (1H, m), 5.53-5.00 (2H, m), 3.45-3.10 (2H, m), 1.65-1.45 (6H, m), 1.51 (9H, s) 1.40-1.30 (6H, m), 1.23-1.20 (6H, m), 0.90 (9H, t, J = 7.2Hz).
[Step 2] Methyl 5-[(6R * , 7S * )-6-[(tert-butoxycarbonyl) amino] -7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] Indol-2-yl] pyrazine-2-carboxylate
Figure JPOXMLDOC01-appb-C000229
Figure JPOXMLDOC01-appb-C000229
　上記工程１で得られた化合物（1.00g）及びメチル 5-ブロモピラジン-2-カルボキシレート（603mg）を用いて実施例１１工程８と同様の手法により標題化合物（300mg）を黄色油状物質として得た。
1H-NMR(CDCl3)δppm:9.36(1H,d,J=1.6Hz),9.09(1H,d,J=1.6Hz),8.14(1H,d,J=8.6Hz),7.63-7.54(2H,m),7.54-7.45(1H,m),7.40-7.30(3H,m),7.03(1H,s),5.50-5.10(3H,m),4.09(3H,s),3.38-3.07(2H,m),1.53(9H,s).
[工程３]　tert-ブチル [(6R*,7S*)-7-フルオロ-2-[5-(ヒドロキシメチル)ピラジン-2-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (1.00 g) obtained in the above Step 1 and methyl 5-bromopyrazine-2-carboxylate (603 mg), the title compound (300 mg) was obtained as a yellow oily substance in the same manner as in Step 8 of Example 11. It was.
1 H-NMR (CDCl 3 ) δ ppm: 9.36 (1H, d, J = 1.6 Hz), 9.09 (1 H, d, J = 1.6 Hz), 8.14 (1 H, d, J = 8.6 Hz), 7.63-7.54 ( 2H, m), 7.54-7.45 (1H, m), 7.40-7.30 (3H, m), 7.03 (1H, s), 5.50-5.10 (3H, m), 4.09 (3H, s), 3.38-3.07 ( 2H, m), 1.53 (9H, s).
[Step 3] tert-butyl [(6R * , 7S * )-7-fluoro-2- [5- (hydroxymethyl) pyrazin-2-yl] -3- (phenylsulfonyl) -3,6,7,8 -Tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000230
Figure JPOXMLDOC01-appb-C000230
　上記工程２で得られた化合物（300mg）を用いて実施例１工程１０と同様の手法により標題化合物（140mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.91(1H,d,1.6Hz),8.71(1H,d,1.6Hz),8.13(1H,d,8.6Hz),7.66-7.58(2H,m),7.52-7.45(1H,m),7.39-7.32(3H,m),6.90(1H,s),5.48-5.15(3H,m),4.96(2H,m,5.9Hz),3.35-3.09(2H,m),3.05(1H,t,5.5Hz),1.53(9H,s).
[工程４]　{5-[(6R*,7S*)-6-アミノ-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}メタノール Using the compound (300 mg) obtained in the above Step 2, the title compound (140 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.91 (1H, d, 1.6 Hz), 8.71 (1 H, d, 1.6 Hz), 8.13 (1 H, d, 8.6 Hz), 7.66-7.58 (2H, m), 7.52 -7.45 (1H, m), 7.39-7.32 (3H, m), 6.90 (1H, s), 5.48-5.15 (3H, m), 4.96 (2H, m, 5.9Hz), 3.35-3.09 (2H, m ), 3.05 (1H, t, 5.5Hz), 1.53 (9H, s).
[Step 4] {5-[(6R * , 7S * )-6-amino-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl ] Pyrazin-2-yl} methanol
Figure JPOXMLDOC01-appb-C000231
Figure JPOXMLDOC01-appb-C000231
　上記工程３で得られた化合物（130mg）を用いて実施例１工程１１と同様の手法により標題化合物（50mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.91(1H,d,J=1.2Hz),8.72-8.68(1H,m),8.14(1H,d,J=8.6Hz),7.67-7.61(2H,m),7.51-7.43(2H,m),7.38-7.32(2H,m),6.90(1H,d,J=0.8Hz),5.34-5.18(1H,m),4.95(2H,s),4.41(1H,dd,J=21.9,3.9Hz),3.35-3.05(2H,m).
[工程５]　{5-[(6R*,7S*)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}メタノール Using the compound (130 mg) obtained in the above Step 3, the title compound (50 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.91 (1H, d, J = 1.2Hz), 8.72-8.68 (1H, m), 8.14 (1H, d, J = 8.6Hz), 7.67-7.61 (2H, m ), 7.51-7.43 (2H, m), 7.38-7.32 (2H, m), 6.90 (1H, d, J = 0.8Hz), 5.34-5.18 (1H, m), 4.95 (2H, s), 4.41 ( 1H, dd, J = 21.9,3.9Hz), 3.35-3.05 (2H, m).
[Step 5] {5-[(6R * , 7S * )-6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl} methanol
Figure JPOXMLDOC01-appb-C000232
Figure JPOXMLDOC01-appb-C000232
　上記工程４で得られた化合物（50mg）を用いて実施例１工程１２と同様の手法により標題化合物（13mg）を白色固体として得た。
1H-NMR(MeOH-d4)δppm:9.11(1H,d,J=1.2Hz),8.77-8.74(1H,m),7.43(1H,d,J=8.2Hz),7.32(1H,d,J=8.2Hz),7.22(1H,s),5.51-5.33(1H,m),4.80(2H,s),3.53-3.13(2H,m).
実施例４７　(1R)-1-{5-[(6S,7R)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール
[工程１]　tert-ブチル [(6R,7S)-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート；tert-ブチル [(6S,7R)-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (50 mg) obtained in the above Step 4, the title compound (13 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δ ppm: 9.11 (1H, d, J = 1.2 Hz), 8.77-8.74 (1 H, m), 7.43 (1 H, d, J = 8.2 Hz), 7.32 (1 H, d, J = 8.2Hz), 7.22 (1H, s), 5.51-5.33 (1H, m), 4.80 (2H, s), 3.53-3.13 (2H, m).
Example 47 (1R) -1- {5-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazine-2 -Il} ethanol
[Step 1] tert-butyl [(6R, 7S) -7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate; tert-butyl [(6S, 7R) -7-Fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000233
Figure JPOXMLDOC01-appb-C000233
　実施例４４工程３で得られた化合物（165g）の光学分割をカラムクロマトグラフィー（株式会社ダイセル キラルパックIA、ヘキサン／イソプロピルアルコール＝20%）を用いて行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル [(6R,7S)-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート（91.2g，光学純度＞98%ee）を白色固体として得た。また、後から溶出する第二ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル [(6S,7R)-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート（68.6g，光学純度＞98%ee）を白色固体として得た。
分析条件：CHIRALPAK IA、hexane/IPA = 80/20、流速1.0mL/min、吸収波長251nm
1st peak；保持時間（rt）= 6.9min, >98%ee
2nd peak；保持時間（rt）= 11.4min, >98%ee
[工程２]　tert-ブチル[(6R,7S)-7-フルオロ-3-(フェニルスルホニル)-2-(トリブチルスタナニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Example 44 Optical resolution of the compound (165 g) obtained in Step 3 of the process was performed using column chromatography (Daicel Chiralpak IA, hexane / isopropyl alcohol = 20%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl [(6R, 7S) -7-fluoro-3- (phenylsulfonyl) -3,6,7,8 -Tetrahydrocyclopenta [e] indol-6-yl] carbamate (91.2 g, optical purity> 98% ee) was obtained as a white solid. Further, after collecting the second peak eluting later, the solvent was distilled off under reduced pressure, and tert-butyl [(6S, 7R) -7-fluoro-3- (phenylsulfonyl) -3,6,7 , 8-tetrahydrocyclopenta [e] indol-6-yl] carbamate (68.6 g, optical purity> 98% ee) was obtained as a white solid.
Analysis conditions: CHIRALPAK IA, hexane / IPA = 80/20, flow rate 1.0 mL / min, absorption wavelength 251 nm
1st peak; retention time (rt) = 6.9min,> 98% ee
2nd peak; retention time (rt) = 11.4min,> 98% ee
[Step 2] tert-Butyl [(6R, 7S) -7-fluoro-3- (phenylsulfonyl) -2- (tributylstannanyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6 -Il] Carbamate
Figure JPOXMLDOC01-appb-C000234
Figure JPOXMLDOC01-appb-C000234
　上記工程１で第一ピークとして得られた化合物（3g）を用いて実施例１１工程７と同様の手法により標題化合物（4.3g）を白色固体として得た。
[工程３]　tert-ブチル[(6S,7R)-2-(5-アセチルピラジン-2-イル)-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート The title compound (4.3 g) was obtained as a white solid in the same manner as in Step 11 of Example 11 using the compound (3 g) obtained as the first peak in Step 1 above.
[Step 3] tert-Butyl [(6S, 7R) -2- (5-acetylpyrazin-2-yl) -7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [ e] Indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000235
Figure JPOXMLDOC01-appb-C000235
　上記工程２で得られた化合物（3.00g）及び1-(5-クロロピラジン-2-イル)エタノン（849mg）を用いて実施例１１工程８と同様の手法により標題化合物（2.05g）を黄色固体として得た。
1H-NMR(CDCl3)δppm:9.28-(1H,d,J=1.2Hz),9.05(1H,d,J=1.6Hz),8.15(1H,d,J=8.6Hz),7.60-7.52(2H,m),7.52-7.45(1H,m),7.10-7.30(3H,m),7.03(1H,s),5.50-5.10(3H,m),3.37-3.09(2H,m),2.79(3H,s),1.54(9H,s).
[工程４]　tert-ブチル [(6S,7R)-7-フルオロ-2-{5-[(1R)-1-ヒドロキシエチル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (3.00 g) obtained in the above Step 2 and 1- (5-chloropyrazin-2-yl) ethanone (849 mg), the title compound (2.05 g) was yellowed in the same manner as in Step 8 of Example 11. Obtained as a solid.
1 H-NMR (CDCl 3 ) δppm: 9.28- (1H, d, J = 1.2Hz), 9.05 (1H, d, J = 1.6Hz), 8.15 (1H, d, J = 8.6Hz), 7.60-7.52 (2H, m), 7.52-7.45 (1H, m), 7.10-7.30 (3H, m), 7.03 (1H, s), 5.50-5.10 (3H, m), 3.37-3.09 (2H, m), 2.79 (3H, s), 1.54 (9H, s).
[Step 4] tert-butyl [(6S, 7R) -7-fluoro-2- {5-[(1R) -1-hydroxyethyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6 , 7,8-Tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000236
Figure JPOXMLDOC01-appb-C000236
　上記工程３で得られた化合物（1.00g）を用いて実施例２８工程３と同様の手法により標題化合物（950mg）を黄色固体として得た。
1H-NMR(CDCl3)δppm:8.89(1H,d,J=1.2Hz),8.74(1H,d,J=1.6Hz),8.13(1H,d,J=8.6Hz),7.66-7.50(2H,m),7.52-7.45(1H,m),7.40-7.32(3H,m),6.90(1H,s),5.50-5.05(4H,m),3.41-3.07(3H,m),1.66(3H,d,J=6.6Hz),1.53(9H,s).
[工程５]　(1R)-1-{5-[(6S,7R)-6-アミノ-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール The title compound (950 mg) was obtained as a yellow solid in the same manner as in Step 28 of Example 28 using the compound (1.00 g) obtained in the above Step 3.
1 H-NMR (CDCl 3 ) δ ppm: 8.89 (1H, d, J = 1.2 Hz), 8.74 (1 H, d, J = 1.6 Hz), 8.13 (1 H, d, J = 8.6 Hz), 7.66-7.50 ( 2H, m), 7.52-7.45 (1H, m), 7.40-7.32 (3H, m), 6.90 (1H, s), 5.50-5.05 (4H, m), 3.41-3.07 (3H, m), 1.66 ( 3H, d, J = 6.6Hz), 1.53 (9H, s).
[Step 5] (1R) -1- {5-[(6S, 7R) -6-amino-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -2-yl] pyrazin-2-yl} ethanol
Figure JPOXMLDOC01-appb-C000237
Figure JPOXMLDOC01-appb-C000237
　上記工程４で得られた化合物（240mg）を用いて実施例１工程１１と同様の手法により標題化合物（160mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.88(1H,d,J=1.6Hz),8.73(1H,d,J=1.6Hz),8.14(1H,d,J=8.2Hz),7.67-7.62(2H,m),7.52-7.43(2H,m),7.49-7.42(2H,m),6.89(1H,d,J=0.8Hz),5.34-5.07(2H,m),4.41(1H,dd,J=22.3,4.3Hz),3.33-3.08(2H,m),1.66(3H,d,J=6.6Hz).
[工程６]　(1R)-1-{5-[(6S,7R)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール Using the compound (240 mg) obtained in the above Step 4, the title compound (160 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.88 (1H, d, J = 1.6 Hz), 8.73 (1 H, d, J = 1.6 Hz), 8.14 (1 H, d, J = 8.2 Hz), 7.67-7.62 ( 2H, m), 7.52-7.43 (2H, m), 7.49-7.42 (2H, m), 6.89 (1H, d, J = 0.8Hz), 5.34-5.07 (2H, m), 4.41 (1H, dd, J = 22.3, 4.3Hz), 3.33-3.08 (2H, m), 1.66 (3H, d, J = 6.6Hz).
[Step 6] (1R) -1- {5-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazine- 2-yl} ethanol
Figure JPOXMLDOC01-appb-C000238
Figure JPOXMLDOC01-appb-C000238
　上記工程５で得られた化合物（160mg）を用いて実施例１工程１２と同様の手法により標題化合物（35mg）を黄色固体として得た。
1H-NMR(MeOH-d4)δppm:9.09(1H,d,J=1.6Hz),8.78(1H,d,J=1.6Hz),7.43(1H,d,J=8.2Hz),7.32(1H,d,J=8.2Hz),7.21(1H,d,J=0.8Hz),5.48-5.32(1H,m),4.99(1H,q,J=6.6Hz),4.46(1H,d,J=20.3,4.3Hz),3.43-3.30(1H,m),1.58(3H,d,J=6.3Hz).
実施例４８　(1S)-1-{5-[(6S,7R)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール
[工程１]　tert-ブチル[(6S,7R)-7-フルオロ-2-{5-[(1S)-1-ヒドロキシエチル]ピラジン-2-イル}-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (160 mg) obtained in the above Step 5, the title compound (35 mg) was obtained as a yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δ ppm: 9.09 (1H, d, J = 1.6 Hz), 8.78 (1 H, d, J = 1.6 Hz), 7.43 (1 H, d, J = 8.2 Hz), 7.32 (1 H , d, J = 8.2Hz), 7.21 (1H, d, J = 0.8Hz), 5.48-5.32 (1H, m), 4.99 (1H, q, J = 6.6Hz), 4.46 (1H, d, J = 20.3, 4.3Hz), 3.43-3.30 (1H, m), 1.58 (3H, d, J = 6.3Hz).
Example 48 (1S) -1- {5-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazine-2 -Il} ethanol
[Step 1] tert-Butyl [(6S, 7R) -7-fluoro-2- {5-[(1S) -1-hydroxyethyl] pyrazin-2-yl} -3- (phenylsulfonyl) -3,6 , 7,8-Tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000239
Figure JPOXMLDOC01-appb-C000239
　実施例４７工程３で得られた化合物（250mg）及びクロロ[(1S,2S)-N-(2',6'-ジメチルベンゼンスルホニル)-1,2-ジフェニルエタンジアミン](メシチレン)ルテニウム(II)（0.0150g）を用いて実施例２８工程３と同様の手法により標題化合物（245mg）を粗精製物として得た。
[工程２]　(1S)-1-{5-[(6S,7R)-6-アミノ-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール Example 47 Compound (250 mg) obtained in Step 3 and chloro [(1S, 2S) -N- (2 ', 6'-dimethylbenzenesulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium (II ) (0.0150 g) to give the title compound (245 mg) as a crude product by the same procedure as in Example 28, step 3.
[Step 2] (1S) -1- {5-[(6S, 7R) -6-amino-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -2-yl] pyrazin-2-yl} ethanol
Figure JPOXMLDOC01-appb-C000240
Figure JPOXMLDOC01-appb-C000240
　上記工程１で得られた化合物（0.240g）を用いて実施例１工程１１と同様の手法により標題化合物（145mg）を粗精製物として得た。
[工程３]　(1S)-1-{5-[(6S,7R)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]ピラジン-2-イル}エタノール Using the compound (0.240 g) obtained in the above Step 1, the title compound (145 mg) was obtained as a crude product by the same method as in Step 1 of Example 1.
[Step 3] (1S) -1- {5-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazine- 2-yl} ethanol
Figure JPOXMLDOC01-appb-C000241
Figure JPOXMLDOC01-appb-C000241
　上記工程２で得られた化合物（140mg）を用いて実施例１工程１２と同様の手法により標題化合物（63mg）を白色固体として得た。
1H-NMR(MeOH-d4)δppm:9.09(1H,d,J=1.6Hz),8.78(1H,d,J=1.2Hz),7.43(1H,d,J=8.6Hz),7.32(1H,d,J=8.2Hz),7.21(1H,s),5.50-5.30(1H,m),4.96(1H,q,J=6.4Hz),4.47(1H,dd,J=19.9,4.3Hz),3.50-3.20(2H,m),1.58(3H,d,J=6.6Hz).
実施例４９　(6S,7R)-7-フルオロ-2-(1-メチル-1H-ピラゾール-4-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン
[工程１]　tert-ブチル [(6S,7R)-2-ブロモ-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート Using the compound (140 mg) obtained in the above Step 2, the title compound (63 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δ ppm: 9.09 (1H, d, J = 1.6 Hz), 8.78 (1 H, d, J = 1.2 Hz), 7.43 (1 H, d, J = 8.6 Hz), 7.32 (1 H , d, J = 8.2Hz), 7.21 (1H, s), 5.50-5.30 (1H, m), 4.96 (1H, q, J = 6.4Hz), 4.47 (1H, dd, J = 19.9, 4.3Hz) 3.50-3.20 (2H, m), 1.58 (3H, d, J = 6.6Hz).
Example 49 (6S, 7R) -7-Fluoro-2- (1-methyl-1H-pyrazol-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
[Step 1] tert-Butyl [(6S, 7R) -2-bromo-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000242
Figure JPOXMLDOC01-appb-C000242
　実施例４７工程１で第二ピークとして得られた化合物（2.00g）を用いて実施例１工程８と同様の手法により標題化合物（1.94g）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.21-8.17(1H,m),7.88-7.84(2H,m),7.56-7.52(1H,m),7.44-7.40(2H,m),7.27-7.24(1H,m),6.66(1H,s),5.47-5.27(2H,m),5.15-5.10(1H,m),3.28-3.05(2H,m),1.51(9H,s).
[工程２]　tert-ブチル [(6S,7R)-2-ブロモ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール－6-イル]カルバメート The title compound (1.94 g) was obtained as a white solid in the same manner as in Example 1, Step 8, using the compound (2.00 g) obtained as the second peak in Step 47 of Example 47.
1 H-NMR (CDCl 3 ) δ ppm: 8.21-8.17 (1H, m), 7.88-7.84 (2H, m), 7.56-7.52 (1H, m), 7.44-7.40 (2H, m), 7.27-7.24 ( 1H, m), 6.66 (1H, s), 5.47-5.27 (2H, m), 5.15-5.10 (1H, m), 3.28-3.05 (2H, m), 1.51 (9H, s).
[Step 2] tert-Butyl [(6S, 7R) -2-bromo-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000243
Figure JPOXMLDOC01-appb-C000243
　上記工程１で得られた化合物（1.00g）を用いて実施例１工程１２と同様の手法により標題化合物（530mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:8.68-8.48(1H,m),7.21-7.17(1H,m),7.11-7.05(1H,m),6.42(1H,s),5.49-5.30(1H,m),5.19-5.11(1H,m),3.36-3.11(2H,m),1.50(9H,s).
[工程３]　ベンジル (6S,7R)-2-ブロモ-6-[(tert-ブトキシカルボニル)アミノ]-7-フルオロ-7,8-ジヒドロシクロペンタ[e]インドール-3(6H)-カルボキシレート Using the compound (1.00 g) obtained in the above Step 1, the title compound (530 mg) was obtained as a colorless oily substance in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.68-8.48 (1H, m), 7.21-7.17 (1H, m), 7.11-7.05 (1H, m), 6.42 (1H, s), 5.49-5.30 (1H, m), 5.19-5.11 (1H, m), 3.36-3.11 (2H, m), 1.50 (9H, s).
[Step 3] Benzyl (6S, 7R) -2-bromo-6-[(tert-butoxycarbonyl) amino] -7-fluoro-7,8-dihydrocyclopenta [e] indole-3 (6H) -carboxylate
Figure JPOXMLDOC01-appb-C000244
Figure JPOXMLDOC01-appb-C000244
　上記工程２で得られた化合物（530mg）のジクロロメタン（15mL）溶液に、N,N-ジイソプロピルエチルアミン（0.38mL）、クロロギ酸ベンジル（0.25mL）を加えて室温で14時間攪拌した。反応液をジクロロメタンで希釈後、有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後ろ過し、ろ液を減圧留去した。得られた残留物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］で精製することにより標題化合物（708mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.99-7.94(1H,m),7.51-7.47(2H,m),7.41-7.34(3H,m),7.20-7.16(1H,m),6.69(1H,s),5.49-5.43(2H,m),5.38-5.28(2H,m),5.13-5.07(1H,m),3.34-3.11(2H,m),1.49(9H,s).
[工程４]　ベンジル (6S,7R)-6-[(tert-ブトキシカルボニル)アミノ]-7-フルオロ-2-(1-メチル-1H-ピラゾール-4-イル)-7,8-ジヒドロシクロペンタ[e]インドール-3(6H)-カルボキシレート N, N-Diisopropylethylamine (0.38 mL) and benzyl chloroformate (0.25 mL) were added to a dichloromethane (15 mL) solution of the compound (530 mg) obtained in Step 2 above, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (708 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 7.99-7.94 (1H, m), 7.51-7.47 (2H, m), 7.41-7.34 (3H, m), 7.20-7.16 (1H, m), 6.69 (1H, s), 5.49-5.43 (2H, m), 5.38-5.28 (2H, m), 5.13-5.07 (1H, m), 3.34-3.11 (2H, m), 1.49 (9H, s).
[Step 4] Benzyl (6S, 7R) -6-[(tert-butoxycarbonyl) amino] -7-fluoro-2- (1-methyl-1H-pyrazol-4-yl) -7,8-dihydrocyclopenta [e] Indole-3 (6H) -carboxylate
Figure JPOXMLDOC01-appb-C000245
Figure JPOXMLDOC01-appb-C000245
　上記工程３で得られた化合物（708mg）及び1-メチルピラゾール-4-ボロン酸ピナコールエステル（0.439g）を用いて実施例１工程９と同様の手法により標題化合物（420mg）を淡黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.05-8.01(1H,m),7.57(1H,s),7.39-7.29(6H,m),7.21-7.18(1H,m),6.47(1H,s),5.48-5.31(4H,m),5.16-5.11(1H,m),3.38-3.14(2H,m).
[工程５]　ベンジル (6S,7R)-6-アミノ-7-フルオロ-2-(1-メチル-1H-ピラゾール-4-イル)-7,8-ジヒドロシクロペンタ[e]インドール-3(6H)-カルボキシレート Using the compound obtained in Step 3 above (708 mg) and 1-methylpyrazole-4-boronic acid pinacol ester (0.439 g), the title compound (420 mg) was obtained as a pale yellow oily substance in the same manner as in Step 9 of Example 1. Got as.
1 H-NMR (CDCl 3 ) δ ppm: 8.05-8.01 (1H, m), 7.57 (1H, s), 7.39-7.29 (6H, m), 7.21-7.18 (1H, m), 6.47 (1H, s) 5.48-5.31 (4H, m), 5.16-5.11 (1H, m), 3.38-3.14 (2H, m).
[Step 5] Benzyl (6S, 7R) -6-amino-7-fluoro-2- (1-methyl-1H-pyrazol-4-yl) -7,8-dihydrocyclopenta [e] indole-3 (6H ) -Carboxylate
Figure JPOXMLDOC01-appb-C000246
Figure JPOXMLDOC01-appb-C000246
　上記工程４で得られた化合物（420mg）を用いて実施例１工程１１と同様の手法により標題化合物（241mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.08-8.04(1H,m),7.58(1H,s),7.39-7.29(7H,m),6.47(1H,s),5.34-5.22(1H,m),5.35-5.33(2H,m),4.42(1H,dd,J=21.2,4.1Hz),3.79(3H,s),3.36-3.13(2H,m).
[工程６]　(6S,7R)-7-フルオロ-2-(1-メチル-1H-ピラゾール-4-イル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-アミン Using the compound (420 mg) obtained in the above Step 4, the title compound (241 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.08-8.04 (1H, m), 7.58 (1H, s), 7.39-7.29 (7H, m), 6.47 (1H, s), 5.34-5.22 (1H, m) , 5.35-5.33 (2H, m), 4.42 (1H, dd, J = 21.2,4.1Hz), 3.79 (3H, s), 3.36-3.13 (2H, m).
[Step 6] (6S, 7R) -7-Fluoro-2- (1-methyl-1H-pyrazol-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
Figure JPOXMLDOC01-appb-C000247
Figure JPOXMLDOC01-appb-C000247
　上記工程５で得られた化合物（191mg）のメタノール（10mL）溶液に10% パラジウム炭素触媒(M)wet（0.18g）、ギ酸アンモニウム（0.0893g）を加えて室温で18時間攪拌した。反応液をろ過後、アミノ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］で精製することにより標題化合物（84mg）を白色固体として得た。
1H-NMR(DMSO-D6)δppm:11.23(1H,s),8.06(1H,s),7.85(1H,s),7.20(1H,d,J=8.3Hz),7.05(1H,d,J=8.3Hz),6.45-6.42(1H,m),5.30-5.16(1H,m),4.31-4.24(1H,m),3.87(3H,s),3.20-3.12(2H,m).
実施例５０　{4-[(6S,7R)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリミジン-2-イル}メタノール
[工程１]　{4-[(6S,7R)-6-[(tert-ブトキシカルボニル)アミノ]-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリミジン-2-イル}メチルアセテート To a solution of the compound obtained in the above Step 5 (191 mg) in methanol (10 mL) were added 10% palladium carbon catalyst (M) wet (0.18 g) and ammonium formate (0.0893 g), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and purified by amino silica gel column chromatography [ethyl acetate / methanol] to give the title compound (84 mg) as a white solid.
1 H-NMR (DMSO-D 6 ) δppm: 11.23 (1H, s), 8.06 (1H, s), 7.85 (1H, s), 7.20 (1H, d, J = 8.3Hz), 7.05 (1H, d , J = 8.3Hz), 6.45-6.42 (1H, m), 5.30-5.16 (1H, m), 4.31-4.24 (1H, m), 3.87 (3H, s), 3.20-3.12 (2H, m).
Example 50 {4-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyrimidin-2-yl }methanol
[Step 1] {4-[(6S, 7R) -6-[(tert-butoxycarbonyl) amino] -7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e ] Indol-2-yl] -6-methoxypyrimidin-2-yl} methyl acetate
Figure JPOXMLDOC01-appb-C000248
Figure JPOXMLDOC01-appb-C000248
　実施例４７工程２で得られた化合物（1.50g）及び(4-クロロ-6-メトキシピリミジン-2-イル)メチルアセテート（0.540g）を用いて実施例１１工程８と同様の手法により標題化合物（910mg）を黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.10(1H,d,J=8.6Hz),7.80-7.68(2H,m),7.53-7.47(1H,m),7.41-7.31(3H,m),6.97(1H,m),6.89(1H,m),5.50-5.10(5H,m),4.04(3H,s),3.35-3.06(2H,m),2.21(3H,s),1.52(9H,s).
[工程２]　tert-ブチル[(6S,7R)-7-フルオロ-2-[2-(ヒドロキシメチル)-6-メトキシピリミジン-4-イル]-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-6-イル]カルバメート The title compound was prepared in the same manner as in Step 11 of Example 11 using the compound (1.50 g) obtained in Example 47, Step 2 and (4-chloro-6-methoxypyrimidin-2-yl) methyl acetate (0.540 g). (910 mg) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δppm: 8.10 (1H, d, J = 8.6Hz), 7.80-7.68 (2H, m), 7.53-7.47 (1H, m), 7.41-7.31 (3H, m), 6.97 (1H, m), 6.89 (1H, m), 5.50-5.10 (5H, m), 4.04 (3H, s), 3.35-3.06 (2H, m), 2.21 (3H, s), 1.52 (9H, s ).
[Step 2] tert-butyl [(6S, 7R) -7-fluoro-2- [2- (hydroxymethyl) -6-methoxypyrimidin-4-yl] -3- (phenylsulfonyl) -3,6,7 , 8-Tetrahydrocyclopenta [e] indol-6-yl] carbamate
Figure JPOXMLDOC01-appb-C000249
Figure JPOXMLDOC01-appb-C000249
　上記工程１で得られた化合物（910mg）を用いて実施例２６工程２と同様の手法により標題化合物（140mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.12(1H,d,J=8.6Hz),7.68-7.63(2H,m),7.54-7.46(1H,m),7.40-7.32(3H,m),6.99(1H,s),6.94(1H,s),5.50-5.10(3H,m),4.76(2H,d,J=4.7Hz),4.06(3H,s),3.60(1H,t,J=4.7Hz),3.36-3.06(2H,m),1.53(9H,s).
[工程３]　{4-[(6S,7R)-6-アミノ-7-フルオロ-3-(フェニルスルホニル)-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリミジン-2-イル}メタノール Using the compound (910 mg) obtained in the above Step 1, the title compound (140 mg) was obtained as a white solid in the same manner as in Step 26 of Example 26.
1 H-NMR (CDCl 3 ) δ ppm: 8.12 (1H, d, J = 8.6Hz), 7.68-7.63 (2H, m), 7.54-7.46 (1H, m), 7.40-7.32 (3H, m), 6.99 (1H, s), 6.94 (1H, s), 5.50-5.10 (3H, m), 4.76 (2H, d, J = 4.7Hz), 4.06 (3H, s), 3.60 (1H, t, J = 4.7 Hz), 3.36-3.06 (2H, m), 1.53 (9H, s).
[Step 3] {4-[(6S, 7R) -6-amino-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl]- 6-Methoxypyrimidin-2-yl} methanol
Figure JPOXMLDOC01-appb-C000250
Figure JPOXMLDOC01-appb-C000250
　上記工程２で得られた化合物（150mg）を用いて実施例１工程１１と同様の手法により標題化合物（115mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.13(1H,d,J=8.6Hz),7.70-7.65(2H,m),7.54-7.44(2H,m),7.42-7.34(2H,m),6.99(1H,m),6.94(1H,d,J=0.8Hz),5.35-5.15(1H,m),4.75(2H,s),4.46-4.34(1H,m),4.06(3H,s),3.35-3.06(2H,m).
[工程４]　{4-[(6S,7R)-6-アミノ-7-フルオロ-3,6,7,8-テトラヒドロシクロペンタ[e]インドール-2-イル]-6-メトキシピリミジン-2-イル}メタノール Using the compound (150 mg) obtained in the above Step 2, the title compound (115 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.13 (1H, d, J = 8.6 Hz), 7.70-7.65 (2H, m), 7.54-7.44 (2H, m), 7.42-7.34 (2H, m), 6.99 (1H, m), 6.94 (1H, d, J = 0.8Hz), 5.35-5.15 (1H, m), 4.75 (2H, s), 4.46-4.34 (1H, m), 4.06 (3H, s), 3.35-3.06 (2H, m).
[Step 4] {4-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyrimidine-2- Il} methanol
Figure JPOXMLDOC01-appb-C000251
Figure JPOXMLDOC01-appb-C000251
　上記工程３で得られた化合物（110mg）を用いて実施例１工程１２と同様の手法により標題化合物（32mg）を黄色固体として得た。
1H-NMR(MeOH-d4)δppm:7.45-7.18(4H,m),5.50-5.30(1H,m),4.75(2H,s),4.48(1H,dd,J=19.9,4.3Hz),4.06(3H,s),3.50-3.20(2H,m).
（製剤例１）
　実施例１３の化合物（5g）、乳糖（90g）、トウモロコシデンプン（34g）、結晶セルロース（20g）及びステアリン酸マグネシウム（1g）をブレンダーで混合した後、錠剤機で打錠することにより、錠剤が得られる。
（製剤例２）
　実施例２５の化合物（5g）、乳糖（90g）、トウモロコシデンプン（34g）、結晶セルロース（20g）及びステアリン酸マグネシウム（1g）をブレンダーで混合した後、錠剤機で打錠することにより、錠剤が得られる。
評価例１：ASICのin vitro評価法
　Human ASIC3発現細胞は、Millipore社から購入した（カタログ番号：CYL3055）。 Using the compound (110 mg) obtained in Step 3 above, the title compound (32 mg) was obtained as a yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δppm: 7.45-7.18 (4H, m), 5.50-5.30 (1H, m), 4.75 (2H, s), 4.48 (1H, dd, J = 19.9,4.3Hz), 4.06 (3H, s), 3.50-3.20 (2H, m).
(Formulation example 1)
The compound of Example 13 (5 g), lactose (90 g), corn starch (34 g), crystalline cellulose (20 g) and magnesium stearate (1 g) were mixed in a blender, and then tableted to form a tablet. can get.
(Formulation example 2)
The compound of Example 25 (5 g), lactose (90 g), corn starch (34 g), crystalline cellulose (20 g) and magnesium stearate (1 g) were mixed in a blender and then tableted to form a tablet. can get.
Evaluation Example 1: In vitro evaluation method of ASIC Human ASIC3-expressing cells were purchased from Millipore (catalog number: CYL3055).
　Human ASIC1a、human ASIC2a、及びmouse ASIC1aの安定発現細胞株は、GeneSwitch System Complate kit（Invitrogen）を用いて作製したV5-His-ASICs-vectorを、Lipofectamine 2000 Transfection Reagent（Invitrogen）を用いて、GeneSwitch-CHO Cells（Invitrogen）に遺伝子導入して作製した。ベクター作成方法および遺伝子導入方法は、それぞれのキットに添付のマニュアルに準拠した。 The stable expression cell lines of Human ASIC1a, human ASIC2a, and mouse 発 現 ASIC1a are V5-His-ASICs-vector prepared using GeneSwitch System Complate kit (Invitrogen), and GeneSwitch-2000 Transfection Reagent (Invitrogen). A gene was introduced into CHO Cells (Invitrogen). The vector preparation method and gene introduction method were in accordance with the manual attached to each kit.
　Mouse ASIC3発現細胞は、Lipofectamine 2000 Transfection Reagent（Invitrogen）を用いて、キット添付のマニュアルに準拠した方法で、HEK293A細胞（Invitrogen）に遺伝子導入して安定発現細胞株を作製した。 Mouse ASIC3-expressing cells were transfected into HEK293A cells (Invitrogen) using Lipofectamine 2000 Transfection Reagent (Invitrogen) according to the method attached to the kit to produce a stable expression cell line.
　遺伝子名とホスト細胞の関係を表１に示す。 Table 1 shows the relationship between gene names and host cells.
　Human ASIC1a 発現細胞は1nM Mifepristone（Sigma-Aldrich）を18時間処理して発現誘導させた後、測定に用いた。Human ASIC2a発現細胞及びMouse ASIC1a発現細胞は10nM Mifepristone（Sigma-Aldrich）を18時間処理して発現誘導させた後、測定に用いた。 Human ASIC1a-expressing cells were treated with 1 nM Mifepristone (Sigma-Aldrich) for 18 hours to induce expression, and then used for measurement. Human ASIC2a-expressing cells and Mouse ASIC1a-expressing cells were treated with 10 nM Mifepristone (Sigma-Aldrich) for 18 hours to induce expression and then used for measurement.
　細胞と化合物とを接触させ、ホールセル自動パッチクランプ法（Patchliner, Nanion Technologies GmBH）を用いて、酸誘発電流のピーク変化を測定することにより、ASIC阻害活性を評価した。保持電位は-60mVとした。内液及び外液の組成を以下に記す。
内液（mM）：50 CsCl, 60 CsF, 10 NaCl, 20 EGTA, and 10 HEPES, pH 7.2。
標準外液（mM）: 135 NaCl, 4 KCl, 5 CaCl2, 1 MgCl2, 5 glucose, and 10 HEPES, pH 7.4。
酸刺激外液（mM）: 135 NaCl, 4 KCl, 5 CaCl2, 1 MgCl2, 5 glucose, and 10 HEPES, pH 6.4（ASIC1a, 3機能測定）, or 10 MES, pH 4.0（ASIC2a 機能測定）。 The ASIC inhibitory activity was evaluated by contacting the cells with the compound and measuring the peak change of the acid-induced current using the whole cell automatic patch clamp method (Patchliner, Nanion Technologies GmBH). The holding potential was -60 mV. The composition of the inner liquid and the outer liquid is described below.
Internal solution (mM): 50 CsCl, 60 CsF, 10 NaCl, 20 EGTA, and 10 HEPES, pH 7.2.
Nonstandard solution (mM): 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, and 10 HEPES, pH 7.4.
Acid-stimulated external solution (mM): 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, and 10 HEPES, pH 6.4 (ASIC1a, 3 function measurement), or 10 MES, pH 4.0 (ASIC2a function measurement) .
　酸誘発電流の基準値は、標準外液から0.1% DMSOを含む酸刺激外液へ置換した際に生じる電流ピークにより規定した。化合物のASIC電流阻害率は、基準値に対する、化合物を含む酸刺激外液へ置換した際の電流ピーク変化により規定した。各濃度の阻害率をプロットし、Hill式を用いてフィッティングした濃度反応曲線からIC50値を算出した。 The reference value of the acid-induced current was defined by the current peak generated when the non-standard solution was replaced with an acid-stimulated solution containing 0.1% DMSO. The ASIC current inhibition rate of the compound was defined by the change in the current peak when substituting the acid-stimulated external solution containing the compound with respect to the reference value. The inhibition rate at each concentration was plotted, and the IC 50 value was calculated from the concentration response curve fitted using the Hill equation.
　本発明の各化合物のヒトASIC3に対する阻害作用を表２に結果を示す。 Table 2 shows the inhibitory action of each compound of the present invention on human ASIC3.
Figure JPOXMLDOC01-appb-T000252
Figure JPOXMLDOC01-appb-T000252
Figure JPOXMLDOC01-appb-T000253
Figure JPOXMLDOC01-appb-T000253
評価例２：ENacのin vitro評価法
　LipofectamineTM LTX Reagent（Invitrogen）を用い、キット添付のマニュアルに準拠した方法で、Human ENaCα、Human ENaCβ、Human ENaCγを機能的に共発現するCHOK1細胞（DS pharma biochemical）を作製して試験に用いた。導入した遺伝子を表３に記す。 Evaluation Example 2: ENac In Vitro Evaluation Method CHOK1 cells functionally co-expressing Human ENaCα, Human ENaCβ, and Human ENaCγ using Lipofectamine ™ LTX Reagent (Invitrogen) according to the manual attached to the kit (DS pharma biochemical) was prepared and used for testing. The introduced genes are shown in Table 3.
　測定原理は、Krummらの方法（Bioorg. Med. Chem., 2012, 20, 3979-3984）に基づいたものである。細胞と化合物とを接触させ、ホールセル自動パッチクランプ法（Syncropatch384PE, Nanion Technologies GmBH）を用いて電流のピーク変化を測定することによりENaC阻害活性を評価した。保持電位は-60mVとした。内液及び外液の組成を以下に記す。
内液（mM）： 140 CsF, 10 NaCl, 20 sucrose, 10 HEPES, 1 EGTA, pH 7.3。
標準外液（mM）: 135 NaCl, 4 KCl, 5 CaCl2, 1 MgCl2, 5 glucose, 100 amiloride and 10 HEPES, pH 7.4。
評価外液（mM）: 135 NaCl, 4 KCl, 5 CaCl2, 1 MgCl2, 5 glucose, and 10 HEPES, pH 7.4。 The measurement principle is based on the method of Krumm et al. (Bioorg. Med. Chem., 2012, 20, 3979-3984). The ENaC inhibitory activity was evaluated by contacting the cells with the compound and measuring the peak change in current using the whole cell automatic patch clamp method (Syncropatch384PE, Nanion Technologies GmBH). The holding potential was -60 mV. The composition of the inner liquid and the outer liquid is described below.
Internal solution (mM): 140 CsF, 10 NaCl, 20 sucrose, 10 HEPES, 1 EGTA, pH 7.3.
Nonstandard solution (mM): 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, 100 amiloride and 10 HEPES, pH 7.4.
External solution for evaluation (mM): 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, and 10 HEPES, pH 7.4.
　ENaC電流の基準値は、標準外液から0.1% DMSOを含む評価外液へ置換した際に生じる電流ピークにより規定した。化合物のENaC電流阻害率は、基準値に対する、化合物を含む評価外液へ置換した際の電流ピーク変化により規定した。各濃度の阻害率をプロットし、Hill式を用いてフィッティングした濃度反応曲線からIC50値を算出した。 The standard value of ENaC current was defined by the current peak generated when the non-standard solution was replaced with an evaluation solution containing 0.1% DMSO. The ENaC current inhibition rate of the compound was defined by the change in current peak when the compound was replaced with an evaluation liquid containing the compound with respect to the reference value. The inhibition rate at each concentration was plotted, and the IC 50 value was calculated from the concentration response curve fitted using the Hill equation.
　実施例２５の化合物での測定結果を表４に示した。同化合物は、ENacに対しては阻害作用を示さず、一方でASICに対しては選択的な強い阻害作用が確認された。 The measurement results with the compound of Example 25 are shown in Table 4. The compound showed no inhibitory action against ENac, while a strong selective inhibitory action against ASIC was confirmed.
Figure JPOXMLDOC01-appb-T000254
Figure JPOXMLDOC01-appb-T000254
Figure JPOXMLDOC01-appb-T000255
Figure JPOXMLDOC01-appb-T000255
評価例３：経口吸収性の確認
　4週齢の雄性ddyマウス（n=3）に実施例２５の化合物を3mg/kg又は10mg/kgの用量で単回経口投与し、投与後の血漿中濃度をliquid chromatography-tandem mass spectrometry（LC-MS/MS）によって測定し、得られた血漿中濃度データからファーマコキネティックパラメータを算出した。投与基剤として、0.5% メチルセルロースを用いた。結果を図１に示した。 Evaluation Example 3: Confirmation of Oral Absorption The compound of Example 25 was orally administered once to a 4-week-old male ddy mouse (n = 3) at a dose of 3 mg / kg or 10 mg / kg, and the plasma concentration after administration Was measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS), and pharmacokinetic parameters were calculated from the plasma concentration data obtained. 0.5% methylcellulose was used as the administration base. The results are shown in FIG.
　本発明の３，６，７，８－テトラヒドロシクロペンタ［ｅ］インドール化合物、その塩、又はそれらの水和物は優れた経口性酸感受性イオンチャネル阻害剤であり、医薬として有用である。 The 3,6,7,8-tetrahydrocyclopenta [e] indole compound of the present invention, a salt thereof, or a hydrate thereof is an excellent oral acid-sensitive ion channel inhibitor and useful as a medicine.
配列番号１：ヒトENaCαサブユニットの塩基配列
配列番号２：ヒトENaCβサブユニットの塩基配列
配列番号３：ヒトENaCγサブユニットの塩基配列 SEQ ID NO: 1: Base sequence of human ENaCα subunit SEQ ID NO: 2: Base sequence of human ENaCβ subunit SEQ ID NO: 3: Base sequence of human ENaCγ subunit

Claims (11)

  1. 式（I）で示される化合物又はその薬学的に許容される塩：
    Figure JPOXMLDOC01-appb-C000001
     （式中、Rは、水素原子又はハロゲン原子を示し、次式：
    Figure JPOXMLDOC01-appb-C000002
     で示される構造は、R1及びR2が置換した芳香族基を示し、R1及びR2は、次の群：
    水素原子、C1-C6-アルキル基、C1-C6-アルコキシ基、ヒドロキシC1-C6-アルキル基、ジヒドロキシC2-C6-アルキル基、ハロゲノC1-C6-アルキル基、C3-C6-シクロアルキル(ヒドロキシ)C1-C6-アルキル基、C1-C6-アルキルスルホニル基、(N-ヒドロキシイミノ)C1-C6-アルキル基、ハロゲン原子、シアノ基及びC2-C6-アシル基
    から独立して選ばれる基を示す。）。     Compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
    Figure JPOXMLDOC01-appb-C000001
     (In the formula, R represents a hydrogen atom or a halogen atom, and the following formula:
    Figure JPOXMLDOC01-appb-C000002
     Structure shown in represents an aromatic group represented by R 1 or R 2 is substituted, R 1 and R 2, the following group:
    Hydrogen atom, C1-C6-alkyl group, C1-C6-alkoxy group, hydroxy C1-C6-alkyl group, dihydroxy C2-C6-alkyl group, halogeno C1-C6-alkyl group, C3-C6-cycloalkyl (hydroxy) A group independently selected from a C1-C6-alkyl group, a C1-C6-alkylsulfonyl group, a (N-hydroxyimino) C1-C6-alkyl group, a halogen atom, a cyano group, and a C2-C6-acyl group. ).
  2. 芳香族基が、窒素原子及び硫黄原子から選ばれる1～3の複素原子を有する5又は6員環の芳香族複素環基及び炭化水素系芳香族基から選ばれる基である請求項１に記載の化合物又はその薬学的に許容される塩。 2. The aromatic group is a group selected from a 5- or 6-membered aromatic heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom and a sulfur atom and a hydrocarbon aromatic group. Or a pharmaceutically acceptable salt thereof.
  3. 芳香族基が、フェニル基、ピロリル基、ピラゾリル基、イミダゾリル基、チアゾリル基、チアジアゾリル基、ピリジル基、ピリダジニル基、ピリミジル基、又はピラジニル基である請求項１に記載の化合物又はその薬学的に許容される塩。 2. The compound according to claim 1, wherein the aromatic group is a phenyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidyl group, or a pyrazinyl group. Salt.
  4. R1及びR2が、次の群：
    水素原子、C1-C6-アルキル基、C1-C6-アルコキシ基、ヒドロキシC1-C6-アルキル基、ジヒドロキシC2-C6-アルキル基、C1-C6-アルキルスルホニル基及びハロゲン原子
    から独立して選ばれる基である請求項１から３のいずれか一項に記載の化合物又はその薬学的に許容される塩。     R 1 and R 2 are in the following groups:
    A group independently selected from a hydrogen atom, a C1-C6-alkyl group, a C1-C6-alkoxy group, a hydroxy C1-C6-alkyl group, a dihydroxy C2-C6-alkyl group, a C1-C6-alkylsulfonyl group and a halogen atom The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.
  5. R1及びR2が、次の群：
    水素原子、メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、2-シクロプロピル-1-ヒドロキシエチル基、(1R)-2-シクロプロピル-1-ヒドロキシエチル基、(1S)-2-シクロプロピル-1-ヒドロキシエチル基、メチルスルホニル基、シアノ基、アセチル基、1,1-ジメトキシエチル基、1-(N-ヒドロキシイミノ)エチル基及び(N-ヒドロキシイミノ)メチル基
    から独立して選ばれる基である請求項１から３のいずれか一項に記載の化合物又はその薬学的に許容される塩。     R 1 and R 2 are in the following groups:
    Hydrogen atom, methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxy Ethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2 -Dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclo Independently selected from propyl-1-hydroxyethyl group, methylsulfonyl group, cyano group, acetyl group, 1,1-dimethoxyethyl group, 1- (N-hydroxyimino) ethyl group and (N-hydroxyimino) methyl group The group according to any one of claims 1 to 3, wherein Things or a pharmaceutically acceptable salt thereof.
  6. R1及びR2の一方が水素原子であって、他方が次の群：
    メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、2-シクロプロピル-1-ヒドロキシエチル基、(1R)-2-シクロプロピル-1-ヒドロキシエチル基、(1S)-2-シクロプロピル-1-ヒドロキシエチル基、メチルスルホニル基、シアノ基、アセチル基、1,1-ジメトキシエチル基、1-(N-ヒドロキシイミノ)エチル基及び(N-ヒドロキシイミノ)メチル基
    から選ばれる基である請求項１から３のいずれか一項に記載の化合物又はその薬学的に許容される塩。     One of R 1 and R 2 is a hydrogen atom and the other is in the following group:
    Methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl Group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1 A group selected from -hydroxyethyl group, methylsulfonyl group, cyano group, acetyl group, 1,1-dimethoxyethyl group, 1- (N-hydroxyimino) ethyl group and (N-hydroxyimino) methyl group The compound according to any one of 1 to 3 or a pharmaceutical thereof Acceptable salt thereof.
  7. R1及びR2が、
    一方がヒドロキシメチル基であって、他方がメチルスルホニル基、メトキシ基、シアノ基、又はフッ素原子であるか、或は、
    一方が1,2-ジヒドロキシエチル基であって、他方がフッ素原子又は塩素原子である
    請求項１から３のいずれか一項に記載の化合物又はその薬学的に許容される塩。     R 1 and R 2 are
    One is a hydroxymethyl group and the other is a methylsulfonyl group, a methoxy group, a cyano group, or a fluorine atom, or
    The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein one is a 1,2-dihydroxyethyl group and the other is a fluorine atom or a chlorine atom.
  8. 式（I）で示される化合物が、次の群： 
    Figure JPOXMLDOC01-appb-C000003
     （式中、A部分、R、R1及びR2は先の定義に等しい。）
    のいずれかである請求項１から７のいずれか一項に記載の化合物又はその薬学的に許容される塩。     The compound of formula (I) has the following group:
    Figure JPOXMLDOC01-appb-C000003
     (Wherein the A moiety, R, R 1 and R 2 are equivalent to the previous definition.)
    The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.
  9. Rが、水素原子又はフッ素原子である請求項８に記載の化合物又はその薬学的に許容される塩。 The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom or a fluorine atom.
  10. 請求項１から９のいずれかに記載の化合物又はその薬学的に許容される塩と薬学的に許容し得る担体とを含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  11. 請求項１から９のいずれかに記載の化合物又はその薬学的に許容される塩を含有する酸感受性イオンチャネル阻害剤。
     
          An acid-sensitive ion channel inhibitor comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

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