WO2021107125A1 - リゾホスファチジン酸受容体作動活性を有する化合物およびその医薬用途 - Google Patents

リゾホスファチジン酸受容体作動活性を有する化合物およびその医薬用途 Download PDF

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WO2021107125A1
WO2021107125A1 PCT/JP2020/044318 JP2020044318W WO2021107125A1 WO 2021107125 A1 WO2021107125 A1 WO 2021107125A1 JP 2020044318 W JP2020044318 W JP 2020044318W WO 2021107125 A1 WO2021107125 A1 WO 2021107125A1
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Prior art keywords
methyl
carboxylic acid
indole
group
cyclopentylamino
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PCT/JP2020/044318
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English (en)
French (fr)
Japanese (ja)
Inventor
雄三 岩城
俊充 遠藤
健介 久須美
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小野薬品工業株式会社
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Application filed by 小野薬品工業株式会社 filed Critical 小野薬品工業株式会社
Priority to US17/779,260 priority Critical patent/US20230014137A1/en
Priority to JP2021561567A priority patent/JPWO2021107125A1/ja
Priority to EP20892362.3A priority patent/EP4066895A1/en
Publication of WO2021107125A1 publication Critical patent/WO2021107125A1/ja

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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Definitions

  • Lysophosphatidic acid is a physiologically active lipid produced by phosphatidic acid (PA) present on the cell membrane or lysophosphatidylcholine (LPC) present extracellularly, and is an endothelial differentiation gene (LPC).
  • GPCR Gprotein-coupled receptor
  • LPA3 is a molecule identified as the third LPA receptor in 1999 and has been reported to be involved in platelet differentiation.
  • R 5A SO 2 R 5A , NH 2 , NHR 5A, etc .
  • R 5A is R 6A , R 7A , R 8A, etc .
  • R 6A is uncondensed or benzene, heteroallene or Phenyl that is condensed with R 6AA
  • R 7A is uncondensed or benzene, hetero allene or heteroaryl that is condensed with R 7AA
  • R 8A is uncondensed or benzene, hetero allene or The compound represented by cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl condensed with R8AA.
  • the definition of the group is an excerpt of the necessary part) or a therapeutically acceptable salt of the compound. , It is described that it inhibits the activity of anti-apparent Mcl-1 protein and is useful for the treatment of acute myeloid leukemia, cervical cancer, colorectal cancer, gastric cancer, multiple myeloma, non-hodgkin lymphoma and the like.
  • a 1B and A 2B is an (CH 2) mB, etc.; mB is an integer of 0 or 1 ⁇ 6; B B is an (CH 2) nB like; nB is 0 or 1 X B is an integer of ⁇ 6; X B is NR 5B etc .; Y B is R 6B etc .; oB is an integer of 0 or 1-3; pB is an integer of 0 or 1-4.
  • R 1Y represents a C1 to 4 alkyl group, or -CR 8 R 9 to ring 1, and R 8 and R 9 each independently represent a hydrogen atom or a C1 to 4 alkyl group
  • ring 1 represents a 1-5 R carbocycle 15 membered or 3 ⁇
  • R 13Y may 3 to 15-membered optionally substituted with,
  • R 13Y is halogen, C1-4 alkyl group, C1-4 alkoxy group, C1-4 haloalkyl group, C1-4 haloalkyl group, C3-6 cycloalkyl group, hydroxyl group, carboxyl group, amino group, (C1-4 alkyl).
  • Carbonylamino group (C1-4 alkyl) carbonyl group, carbamoyl group, (C1-4 alkyl) aminocarbonyl group, di (C1-4 alkyl) aminocarbonyl group, cyano group, C1-4 alkylsulfonyl group, C1 ⁇ It represents a 4-alkylthio group, a C1-4 haloalkylthio group, a nitro group, a 5- to 6-membered heterocycle, or —O— (CH 2 ) r Y— R 17 , where R 17 is a carboxyl group, C1 to 4 alkoxycarbonyl.
  • R 13Y may be the same or different
  • r Y represents an integer of 1 to 5
  • a plurality of R 18 may be the same or different may
  • R 2Y is a carboxyl group, C1 ⁇ 4 alkoxycarbonyl group, -CONHSO 2 R 10Y, -CONHR 19 , a sulfo group (-SO 3 H group), - SO 2 NHCOR 20, or high acidity of hydrogen
  • R 10Y is, C1 ⁇ 4 alkyl, C1 ⁇ 4 haloalkyl group, C3 ⁇ 6 cycloalkyl, di - (C1 ⁇ 4 alkyl) amino group, with 1-3 R 16 5-6 members that may be replaced Represents a carbocyclic or 1-3 heterocyclic ring may also be 5-6 membered substituted with R 16, R 16 represents a halogen, C
  • R 21 represents a halogen, C1 to 4 alkyl group, or C1 to 4 alkoxy group, and the plurality of R 21s may be the same or different, and R 21 may be the same or different.
  • R 11 may be substituted with R 11 3-5 membered saturated carbocyclic ring, or 1-5 saturated heterocyclic 3-5 membered optionally substituted by R 11 Represented,
  • R 11 is a halogen, C1-4 alkyl group, C1-4 alkoxy group, C1-4 alkylthio group, C1-4 haloalkyl group, C1-4 haloalkyl group, hydroxyl group, cyano group, C1-4 alkylsulfonyl group.
  • a plurality of R 11 may be the same or different, may form two R 11 are C1 ⁇ 3 alkylene together, R 4Y and R 5Y are each independently Te, halogen, C1 ⁇ 4 alkyl, C1 ⁇ 4 haloalkyl group, C3 ⁇ 6 cycloalkyl, C2 ⁇ 4 alkenyl group, or 1 to 3 carbons of which may be 5-6 membered substituted with R 15 a heterocyclic ring or one to three R 15 may also be 5-6 membered substituted with, R 15 is halogen, represents C1 ⁇ 4 alkyl or C1 ⁇ 4 alkoxy group, a plurality of R 15 May be the same or different, and the carbon atoms at the 4th and 5th positions of the pyrrole ring, R 4Y , and R 5Y may be combined and substituted with 1 to 3 R 12 members.
  • R 1 represents a C1 to 4 alkyl group, or -CR 8 R 9 to ring 1, and R 8 and R 9 each independently represent a hydrogen atom or a C1 to 4 alkyl group, ring 1.
  • R Reference numeral 13 is halogen, C1-4 alkyl group, C1-4 alkoxy group, C1-4 haloalkyl group, C1-4 haloalkoxy group, C3-6 cycloalkyl group, hydroxyl group, cyano group, C1-4 alkylsulfonyl group, or -O- (CH 2 ) represents an r-COOH group, and a plurality of R 13s may be the same or different, r represents an integer of 2 to 5, R 2 is a carboxyl group, and C1 to 4 alkoxycarbonyl.
  • R 16 represents a halogen, a C1-4 alkyl group, or a C1-4 alkoxy group, a plurality of R 16s may be the same or different, and R 3 may be 1-5.
  • R 11 represents a saturated heterocycle number of saturated carbon ring may 3-5 membered optionally substituted with R 11 or 1-5 may be substituted with R 11 3-5 membered,
  • R 11 is Represents a halogen, a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 alkylthio group, a C1-4 haloalkyl group, a C1-4 haloalkoxy group, a hydroxyl group, a cyano group, a C1-4 alkylsulfonyl group, or an amino group.
  • a plurality of R 11s may be the same or different, and two R 11s may be combined to form C1 to 3 alkylene, and R 4 and R 5 are independently halogens, C1 to C1 to 4 alkyl group, C2 ⁇ 4 alkenyl group, or one to three R 15 carbon ring may also be 5-6 membered substituted or 1-3 may be substituted with R 15 5-6 membered R 15 represents a halogen, a C1-4 alkyl group, or a C1-4 alkoxy group, and a plurality of R 15s may be the same or different, and the carbons at the 4- and 5-positions of the pyrrole ring.
  • R 4 may be optionally substituted with one to three carbon ring may be 5- to 6-membered substituted with R 12 or one to three R 12, 5
  • R 12 is also a halogen, C1-4 alkyl group, C2-4 alkenyl group, C2-4 alkynyl group, C1-4 alkoxy group, C1-4 haloalkyl group, C1-4 haloalkoxy group, C3-6 cyclo.
  • a plurality of R 12s may be the same or different, and R 6 and R 7 are independent of each other.
  • each hydrogen atom may be a deuterium atom or a tritium atom.
  • R 4-1 represents a halogen, a C1 to 4 alkyl group, or a C2 to 4 alkenyl group
  • p represents an integer of 0 to 5
  • m represents an integer of 0 to 5, and others.
  • the symbol has the same meaning as [1] or [2]), which is the compound according to any one of [1] to [3], or a salt thereof.
  • the compound is (1) 3-[(Cyclobutylamino) methyl] -1- (cyclopropylmethyl) -1H-indole-2-carboxylic acid, (2) 3-[(Cyclobutylamino) methyl] -1-[(2,2-difluorocyclopropyl) methyl] -1H-indole-2-carboxylic acid, (3) 3-[(Cyclobutylamino) methyl] -1-ethyl-1H-indole-2-carboxylic acid, (4) 3-[(Cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid, (5) 1- (2-chlorobenzyl) -3-[(cyclobutylamino) methyl] -1H-indole-2-carboxylic acid, (6) 5-Bromo-3-[(cyclobutylamino) methyl] -4-methyl-1- (4
  • [12-1] The compound represented by the general formula (IY) or a salt thereof is the general formula (I-1-2).
  • R 3-1 represents a saturated carbocyclic ring of 1-5 R 11 may 3-5 membered optionally substituted by, other symbols [1], [2], [5] or [6
  • the pharmaceutical composition according to [12] or [12-1] which is an LPA3 agonist.
  • the pharmaceutical composition according to [12], [12-1] or [13] which is a prophylactic and / or therapeutic agent for LPA3-related diseases.
  • LPA3-related disease is essential thrombocythemia, reactive thrombocytosis, aplastic anemia, myelodysplastic syndrome, or sepsis.
  • a method for preventing and / or treating an LPA3-related disease which comprises administering an effective amount of the compound represented by the general formula (IY) according to the above [1] or a salt thereof to a mammal.
  • the compound of the present invention has operative activity against LPA3, it can be used as an active ingredient of a prophylactic and / or therapeutic agent for essential thrombocythemia, reactive thrombocytosis and the like.
  • halogen includes, for example, fluorine, chlorine, bromine, and iodine atoms.
  • the "C1-4 alkyl group” includes methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and 2,2-dimethylethyl group.
  • the "C2-4 alkenyl group” includes ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-ethyl-1-ethenyl, 1-. Includes methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, and 2-methyl-2-propenyl groups.
  • the "C2-4 alkynyl group” includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl groups.
  • C1-4 haloalkyl group includes fluoromethyl, fluoroethyl, fluoropropyl, fluoro-1-methylethyl, fluorobutyl, fluoro-1-methylpropyl, fluoro-2-methylpropyl, fluoro-2.
  • the "(C1-4 alkyl) carbonylamino group” includes methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, 1-methylethylcarbonylamino, butylcarbonylamino, 1-methylpropylcarbonylamino, 2-. Includes methylpropylcarbonylamino and 2,2-dimethylethylcarbonylamino groups.
  • the "(C1-4 alkyl) carbonyl group” includes methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl, and 2, Contains a 2-dimethylethylcarbonyl group.
  • the "(C1-4 alkyl) aminocarbonyl group” includes methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 1-methylethylaminocarbonyl, butylaminocarbonyl, 1-methylpropylaminocarbonyl, 2-. Includes methylpropylaminocarbonyl and 2,2-dimethylethylaminocarbonyl groups.
  • the "di- (C1-4 alkyl) amino group” includes dimethylamino, diethylamino, dipropylamino, di (1-methylethyl) amino, dibutylamino, di (1-methylpropyl) amino, and di. Includes (2-methylpropyl) amino and di (2,2-dimethylethyl) amino groups.
  • the "di (C1-4 alkyl) aminocarbonyl group” includes dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, di (1-methylethyl) aminocarbonyl, dibutylaminocarbonyl, and di (1-methyl). Includes propyl) aminocarbonyl, di (2-methylpropyl) aminocarbonyl, and di (2,2-dimethylethyl) aminocarbonyl groups.
  • the "di- (C1-4 alkyl) -hydroxymethyl group” includes dimethylhydroxymethyl, diethylhydroxymethyl, dipropylhydroxymethyl, di (1-methylethyl) hydroxymethyl, dibutylhydroxymethyl and di (di). Includes 1-methylpropyl) hydroxymethyl, di (2-methylpropyl) hydroxymethyl, and di (2,2-dimethylethyl) hydroxymethyl groups.
  • the "C1 to 3 alkylene group” includes a methylene, ethylene, propylene, or methylethylene group.
  • the "C1-4 alkoxy group” includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, and 2,2-dimethylethoxy group.
  • the "C1-4 alkoxycarbonyl group” includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-methylethoxycarbonyl, butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl, and 2,2-. Includes a dimethylethoxycarbonyl group.
  • C1-4 haloalkoxy groups include fluoromethoxy, fluoroethoxy, fluoropropoxy, fluoro-1-methylethoxy, fluorobutoxy, fluoro-1-methylpropoxy, fluoro-2-methylpropoxy, fluoro-.
  • C1-4 alkylthio groups include methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, and 2,2-dimethylethylthio groups. included.
  • C1-4 haloalkylthio groups include monofluoromethylthio, monofluoroethylthio, monofluoropropylthio, monofluoro-1-methylethylthio, monofluorobutylthio, and monofluoro-1-methylpropyl.
  • the "3 to 15-membered carbocycle” includes a monocyclic, bicyclic or tricyclic, unsaturated, partially saturated, or saturated 3 to 15-membered carbocycle.
  • Monocyclic, bicyclic or tricyclic, unsaturated 3- to 15-membered carbocycles include, for example, benzene, pentalene, naphthalene, azulene, phenanthrene, anthracene, acenaphthylene, biphenylene and the like.
  • Monocyclic, bicyclic or tricyclic, partially saturated or saturated 3- to 15-membered carbocycles include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cyclopentadiene.
  • Cyclohexadiene, indene, fluorene, perhydropentane, perhydroinden, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenantrain, perhydroanthracene, perhydroacenaftylene, perhydrobiphenylene, and adamantan Rings and the like can be mentioned.
  • the "3 to 15-membered heterocycle” includes monocyclic, bicyclic or tricyclic 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom. Includes unsaturated, partially saturated, or saturated 3- to 15-membered heterocycles containing. As a monocyclic, bicyclic or tricyclic, unsaturated 3- to 15-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom.
  • the heterocycle include azidine, oxylan, azetidine, oxetane, thiirane, thietan, pyrrolin, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazin, tetrahydropyridine, tetrahydropyrimidine Tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyrane), tetrahydrothiain (t
  • the "5- to 6-membered carbocycle” includes a monocyclic, unsaturated, partially saturated, or saturated 5- to 6-membered carbocycle.
  • the unsaturated 5- to 6-membered carbon ring of a monocycle include a benzene ring.
  • the partially saturated or saturated 5- to 6-membered carbon ring of a monocycle include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, and cyclohexadiene ring.
  • the "5- to 6-membered heterocycle” contains an unsaturated single ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom. It contains partially saturated or saturated 5- to 6-membered heterocycles.
  • An unsaturated 5- to 6-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom of a monocycle includes, for example, pyrrole, imidazole, and the like.
  • a partially saturated or saturated 5- to 6-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom in a monocycle may be, for example, Pyrrolin, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazin, tetrahydropyridine, tetrahydropyranidin, tetrahydropyrandazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene , Dihydrothiain (dihydrothiopyran), tetrahydropyran (tetrahydropyran), oxazoline (dihydrooxazole), oxazolidine (tetrahydrooxazole), dihydroisoxazo
  • the "3- to 5-membered saturated carbocycle” includes cyclopropane, cyclobutane, and cyclopentane ring.
  • the "3- to 5-membered saturated heterocycle” includes aziridine, oxylan, azetidine, oxetane, thirane, thietan, pyrrolidine, imidazolidine, triazolidine, tetraziridine, pyrazolidine, tetrahydrofuran, tetrahydrothiophene, oxazolidine (tetrahydrooxazole). , Tetrahydroisothiazole, oxadiaziridine (tetrahydrooxadiazole), thiaziridine (tetrahydrothiazole), tetrahydroisothiazole, and a dioxolan ring.
  • the "C3-6 cycloalkyl group” includes cyclopropane, cyclobutane, cyclopentane, and cyclohexane ring.
  • the "C1-4 alkylsulfonyl groups” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1-methylethylsulfonyl, butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, and 2,2-. Includes a dimethylethylsulfonyl group.
  • the "C1-4 dialkylphosphoryl group” includes methylphosphoryl, ethylphosphoryl, propylphosphoryl, 1-methylethylphosphoryl, butylphosphoryl, 1-methylpropylphosphoryl, 2-methylpropylphosphoryl, and 2,2-. Includes dimethylethylphosphoryl group.
  • the "sulfur atom which may be oxidized" includes -S-, -S (O)-, and -SO 2- .
  • 4-position and 5-position carbon atoms of the pyrrole ring, R 4 or R 4Y, and R 5 or R 5Y together form Examples of the 5- to 6-membered carbon ring include cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, and a benzene ring.
  • a pyrrole ring represented by the general formula (I) or the general formula (IY) and its substituents R 4 or R 4Y and R 5 or R 5Y are formed together to form a bicyclic heterocycle.
  • the ring include indole, tetrahydrocyclopentapyrrole, tetrahydroindole, pyrrolopyridine, pyrrolopyrimidine, thienopyrrole, and pyrrolothiazole ring.
  • R 11 when two R 11 form a C1 ⁇ 3 alkylene together, R 11 two R 11 that can be a R 11 to replace the same element, substituting a different element But it may be.
  • R 11 two R 11 that can be a R 11 to replace the same element, substituting a different element But it may be.
  • two cyclobutane rings R 11 has formed a C1 ⁇ 3 alkylene together, the following structures are exemplified.
  • the 5-membered ring having hydrogen having a high acidity includes a 5-membered ring having hydrogen having a pKa of 10 or less.
  • Examples of the 5-membered ring having highly acidic hydrogen include a 4-hydroxy-1,2,5-oxadiazol-3-yl group and a 4-hydroxy-1,2,5-thiadiazol-3-yl group.
  • 5-oxo-4,5-dihydro-1H-tetrazole-1-yl group 3,5-dioxo-1,2,4-oxadiazolidine-2-yl group, 5-oxo-4,5-dihydro -1,2,4-thiasiazol-3-yl group, 5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl group, 5-thioxo-4,5-dihydro-1H -1,2,4-triazole-3-yl group, 5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl group, 1H-1,2,3-triazole-5 -Il group, 2,4-dioxo-1,3-oxazolidine-5-yl group, 2,4-dioxo-1,3-thiazolidine-5-yl group, 3-hydroxy-1,2-oxazol-5-yl group Il group, 3-hydroxy-1,2-thiazole-5-yl group, 3-hydroxy-1,2-
  • This 5-membered ring having highly acidic hydrogen may be substituted with 1 or 2 substituents.
  • substituents include methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, isopropylmethyl, trifluoromethyl, difluoromethyl group and the like.
  • the two substituents may be the same or different.
  • the two substituents may also be combined to form a cyclopropyl, cyclobutyl, and cyclopentyl ring.
  • R 1Y is preferably R 1 , more preferably R 1 or R 1 is preferably -CR 8 R 9- ring 1, more preferably -CH 2- ring 1, and even more preferably -CH 2-ring 1. It is a benzyl group that may be substituted with 1 to 5 R 13Ys (preferably 1 to 5 R 13s).
  • a hydrogen atom preferably as R 8 a hydrogen atom.
  • R 9 is preferably a hydrogen atom.
  • 1 to 5 amino R 13Y are optionally also be 5-6 membered carbocycle or a 5-6 membered heterocyclic ring as ring1 Yes, more preferably 5-6 membered carbocycles which may be substituted with 1-3 R 13Ys (preferably 1-3 R 13s), most preferably 1-5.
  • Benzene which may be substituted with R 13Y (preferably 1 to 5 R 13).
  • 1-3 R 13Y preferably one to three R 13
  • heterocyclic ring may 5-6 membered substituted also preferred.
  • 1-3 R 13Y (preferably one to three R 13) may be substituted with, carbocycle saturated 3-15 membered preferred.
  • the saturated 3- to 15-membered carbocycles are more preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, or cycloheptane, and most preferably cyclopropane, cyclobutane, or cyclopentane.
  • a 1-3 R 13 carbocyclic ring is optionally may 5-6 membered substituted with, most preferably, optionally substituted with 1-5 R 13 It may be benzene.
  • R 13Y is preferably R 13 , and more preferably R 13 is a halogen, a C1 to 4 alkyl group, a C1 to 4 haloalkyl group, a C1 to 4 haloalkoxy group, and a C3 to 6 cycloalkyl. Group or cyano group.
  • R 2Y is preferably R 2 , more preferably or R 2 is preferably a carboxyl group.
  • a 1-5-3 may be substituted with R 11 5 membered saturated carbocyclic ring, more preferably, substituted with 1-5 R 11 It is a cyclobutane ring which may be used.
  • the hydrogen atom on the 3- to 5-membered saturated carbocycle may be a deuterium atom or a tritium atom.
  • the R 11 is preferably a halogen, a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 alkylthio group, or a cyano group.
  • R 10Y is preferably R 10 , and more preferably R 10 is a C1 to 4 alkyl group, a C3 to 6 cycloalkyl group, or a di- (C1 to 4 alkyl) amino group. ..
  • R 19 is preferably a hydrogen atom or a C1 to 4 alkoxy group.
  • R 4Y is preferably R 4 , more preferably or R 4 is preferably a halogen, a C1-4 alkyl group, or a C2-4 alkenyl group, more preferably a halogen, or C1 to. It is a 4-alkyl group. Further, preferred one to three heterocyclic carbocyclic or 5-6 membered also be 5-6 membered substituted with R 15.
  • R 5Y is preferably R 5 , more preferably or R 5 is preferably a halogen, or a C1-4 alkyl group.
  • the 5- to 6-membered carbocycle or 5- to 6-membered heterocycle formed by R 4 and R 5 or R 4Y and R 5Y together is preferably benzene, cyclopentane, cyclohexane or pyridine. , Pyrimidine, thiophene, or thiazole ring, more preferably benzene, cyclopentane, cyclohexane, or thiophene ring, most preferably benzene ring.
  • halogen preferably as R 12, halogen, C1 ⁇ 4 alkyl group, C2 ⁇ 4 alkynyl, C1 ⁇ 4 alkoxy group, a cyano group or a C1 ⁇ 4 alkylsulfonyl group,.
  • a hydrogen atom or a C1 ⁇ 4 alkyl group preferably as R 6, a hydrogen atom or a C1 ⁇ 4 alkyl group, more preferably a hydrogen atom.
  • R 7 is preferably a hydrogen atom or a C1 to 4 alkyl group, and more preferably a hydrogen atom.
  • R 14-1 is preferably a hydrogen atom, a halogen, a C1-4 alkyl group, a C2-4 alkynyl group, a C1-4 alkoxy group, a cyano group, or a C1-4 alkylsulfonyl group.
  • R 14-2 is preferably a hydrogen atom, a halogen, a C1-4 alkyl group, a C2-4 alkynyl group, a C1-4 alkoxy group, a cyano group, or a C1-4 alkylsulfonyl group.
  • R 14-3 is preferably a hydrogen atom, a halogen, a C1-4 alkyl group, a C2-4 alkynyl group, a C1-4 alkoxy group, a cyano group, or a C1-4 alkylsulfonyl group.
  • R 14-4 is preferably a hydrogen atom, a halogen, a C1-4 alkyl group, a C2-4 alkynyl group, a C1-4 alkoxy group, a cyano group, or a C1-4 alkylsulfonyl group.
  • R 14-5 is preferably a hydrogen atom, a halogen, a C1-4 alkyl group, a C2-4 alkynyl group, a C1-4 alkoxy group, a cyano group, or a C1-4 alkylsulfonyl group.
  • R 14-6 is preferably a hydrogen atom, a halogen, a C1-4 alkyl group, a C2-4 alkynyl group, a C1-4 alkoxy group, a cyano group, or a C1-4 alkylsulfonyl group.
  • R 14-7 is preferably a hydrogen atom, a halogen, a C1-4 alkyl group, a C2-4 alkynyl group, a C1-4 alkoxy group, a cyano group, or a C1-4 alkylsulfonyl group.
  • a 1-3 carbon ring may also be 5-6 membered substituted with R 15, more preferably, 1-3 benzene substituted with R 15 It is a ring.
  • RING2 also preferably one to three heterocyclic ring may also be 5-6 membered substituted with R 15.
  • p is preferably an integer of 0 to 3.
  • m is preferably an integer of 0 to 2.
  • n is preferably an integer of 0 to 1.
  • q is preferably an integer of 0 to 1.
  • r Y is preferably an integer of 1 to 4.
  • the 5-membered ring having highly acidic hydrogen is preferably a 5-tetrazolyl group or a 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl group. ..
  • the compound represented by the general formula (IY) is preferably represented by the general formula (I), more preferably the compound represented by the general formula (I-1) and represented by the general formula (I-2). It is a compound, a compound represented by the general formula (I-3), or a compound represented by the general formula (I-4), and more preferably a compound represented by the general formula (I-1-1).
  • the compound represented by the general formula (I) or the general formula (IY) includes 3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid. , Or its salt is also preferred.
  • the compound represented by the general formula (I) or the general formula (IY) includes 3-[(cyclobutylamino) methyl] -1- (3-cyclopropylbenzyl) -1H-indole-2-carboxylic acid. Acids, or salts thereof, are also preferred.
  • the compound represented by the general formula (I) or the general formula (IY) is 1- (4-methylbenzyl) -3-[(3-thietanylamino) methyl] -1H-indole-2-carboxylic acid. , Or its salt is also preferred.
  • the compound represented by the general formula (I) or the general formula (IY) is 7-cyano-3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-.
  • 2-Carboxylic acid, or a salt thereof, is also preferred.
  • the deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.), an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth. It is carried out at a temperature of 0 to 40 ° C. using a metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof.
  • an organic solvent methanol, tetrahydrofuran, dioxane, etc.
  • an alkali metal hydroxide sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.
  • alkaline earth alkaline earth. It is carried out at a temperature of 0 to 40 ° C. using a metal hydroxide (barium hydroxide, calcium hydroxide, etc.)
  • the deprotection reaction by hydrogenolysis is, for example, a solvent (ether-based solvent (tetrahexyl, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based solvent (methanol, ethanol, etc.), benzene-based solvent (benzene, etc.). , Toluene, etc.), Ketone-based solvents (acetone, methyl ethyl ketone, etc.), nitrile-based solvents (acetriform, etc.), amide-based solvents (dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixture of two or more of them.
  • a solvent ether-based solvent (tetrahexyl, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based solvent (methanol, ethanol, etc.), benzene-based solvent (benzene, etc.). , To
  • R 6 is a hydrogen atom or a deuterium atom, for example, in an organic solvent (eg, 1,2-dichloroethane, tetrahydrofuran, or a mixed solvent thereof, etc.), a dehydration chlorinating agent (eg, phosphorus oxychloride, etc.) It is produced by adding a formylating agent (eg, N, N-dimethylformamide, N-methylformamide, or a corresponding deuterium substituent) in the presence of thionyl chloride, etc. and reacting at 0 ° C. to reflux temperature. Can be done.
  • an organic solvent eg, 1,2-dichloroethane, tetrahydrofuran, or a mixed solvent thereof, etc.
  • a dehydration chlorinating agent eg, phosphorus oxychloride, etc.
  • a formylating agent eg, N, N-dimethylformamide, N-methylformamide, or a corresponding
  • 1,1'-(azodicarbonyl) dipiperidin ADDP
  • 1,1'-azobis N, N-dimethylformamide
  • phosphine compounds eg, triphenylphosphine, tributylphosphine, trimethylphosphine, polymer support triphenyl
  • the reaction is carried out at 0 to 100 ° C. in the presence of (phosphine) or (2) an ilide compound (cyanomethylenetributylphosphorane, cyanomethylenetrimethylphosphoran).
  • This reduction reaction is known.
  • a reducing agent sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, etc.
  • an organic solvent methanol, ethanol, tetrahydrofuran, hexane, etc.
  • LG is halogen
  • organic solvent eg, dichloromethane, acetonitrile, toluene
  • a halogenating agent eg, phosphorus tribromide, chloride
  • the LG is a p-toluenesulfonyloxy group, a methanesulfonyloxy group, or the like, for example, in an organic solvent (eg, tetrahydrofuran, dichloromethane, toluene), the base [alkylamine (eg, triethylamine, diisopropylethylamine, etc.), etc.
  • organic solvent eg, tetrahydrofuran, dichloromethane, toluene
  • alkylamine eg, triethylamine, diisopropylethylamine, etc.
  • the compound represented by the general formula (X) can be produced by subjecting the compound represented by the general formula (IX) to an azidation reaction.
  • the compound represented by the general formula (XI) can be produced by subjecting the compound represented by the general formula (X) to a reduction reaction.
  • silane compound for example, phenylsilane, triethylsilane, tris (trimethylsilyl) silane
  • organic solvent for example, dioxane or toluene
  • the reduction reaction using a metal is carried out in an acidic solvent (for example, a buffer solution of acetic acid, ammonium acetate, pH 4.2 to 7.2 or a mixture thereof and an organic solvent such as tetrahydrofuran) in a metal (for example,). Copper, zinc) is used to react at a temperature of 0 to 100 ° C.
  • an acidic solvent for example, a buffer solution of acetic acid, ammonium acetate, pH 4.2 to 7.2 or a mixture thereof and an organic solvent such as tetrahydrofuran
  • a metal for example, Copper, zinc
  • the reductive amination reaction is known and can be carried out using a carbonyl compound corresponding to R 3.
  • the imine produced in the reaction may be isolated and then reduced, or the imine may be produced in the reaction system and reduced without isolation (in one pot).
  • This imine production reaction is known, for example, in an organic solvent (eg, methanol, ethanol, dichloromethane, chloroform, dichloroethane, benzene, toluene, or a mixed solvent thereof, etc.) and a dehydrating agent (eg, anhydrous magnesium sulfate, molecular). It can be carried out at a temperature of 20 ° C.
  • an organic solvent eg, methanol, ethanol, dichloromethane, chloroform, dichloroethane, benzene, toluene, or a mixed solvent thereof, etc.
  • a dehydrating agent eg, anhydrous magnesium sulfate, molecular
  • Do or solvent eg ether-based (eg tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based (eg methanol, ethanol, etc.), benzene-based (eg benzene, toluene, etc.), nitrile-based (eg, benzene, toluene, etc.)
  • a catalyst eg, palladium-carbon, palladium black, palladium hydroxide, platinum oxide, etc.
  • water ethyl acetate, acetic acid, or a mixed solvent thereof, etc. It can be carried out at a temperature of 0 to 200 ° C.
  • Reductive amination reactions performed without isolating imine are also known, for example, hydrogenation in organic solvents (eg, dichloroethane, dichloromethane, dimethylformamide, acetic acid, or mixtures thereof). It can be carried out at a temperature of 0 to 40 ° C. in the presence of sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, 2-picolinborane complex, etc., or the corresponding dehydrogen substitution reagent).
  • organic solvents eg, dichloroethane, dichloromethane, dimethylformamide, acetic acid, or mixtures thereof. It can be carried out at a temperature of 0 to 40 ° C. in the presence of sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, 2-picolinborane complex, etc., or the corresponding dehydrogen substitution reagent).
  • the compound represented by the general formula (XII) can be produced by subjecting the compound represented by the general formula (II) and the compound represented by the general formula (XV) to a protecting reaction of an amino group.
  • the protecting reaction of an amino group is known, and for example, "PGM Wuts, TW Greene, Green's Protective Groups in Organic Synthesis, Willey, Fourth Edition, New York, Protected 200", New York, 200.
  • a group-introducing reaction can be used to introduce a protecting group for an amino group.
  • This hydrolysis reaction is known, and is, for example, a reaction having the same contents as the "hydrolysis reaction” described as a method for producing a compound represented by the above general formula (IA).
  • the compound represented by the general formula (IIB) can be produced by subjecting the compound represented by the general formula (XIII) and the compound represented by the general formula (XVI) to an acyl sulfonamide reaction.
  • This acyl sulfonamide reaction is known, for example.
  • the carboxylic acid is contained in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, dimethoxyethane, etc.) or without a solvent, and an acid halide agent (oxalyl chloride, thionyl chloride, etc.) is used.
  • an organic solvent chloroform, dichloromethane, diethyl ether, tetrahydrofuran, dimethoxyethane, etc.
  • an acid halide agent oxalyl chloride, thionyl chloride, etc.
  • phase transfer catalysts tetrabutylammonium chloride, triethylbenzylammonium chloride, trin-octylmethylammonium chloride, trimethyldecylammonium chloride, tetramethylammonium, etc.
  • organic solvent dioxane, tetrahydrofuran, dichloromethane, etc.
  • a quaternary ammonium salt such as bromide
  • an alkaline aqueous solution such as sodium bicarbonate solution or sodium hydroxide solution
  • the solvent amide corresponding to R 10 (NH 2 SO 2 R 10 ) and the like. It can also be carried out by reacting at 0 to 40 ° C.
  • the carboxylic acid is used in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or in a solvent-free base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropyl, etc.). It was obtained by reacting with an acid halide (pivaloyl chloride, tosilk lolide, mesil chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) at about 0 to 40 ° C. in the presence of (ethylamine, etc.).
  • an organic solvent chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.
  • a solvent-free base pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropyl, etc.
  • a mixed acid anhydride organic solvent chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.
  • a condensing agent for example, a carboxylic acid and a sulfonamide (NH 2 SO 2 R 10 ) corresponding to R 10 are mixed in an organic solvent (chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.).
  • an organic solvent chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.
  • a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3-( Dimethylamino) propyl] Carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propylphosphonic acid cyclic anhydride, PPA) Etc.
  • DCC dicyclyclohexylcarbodiimide
  • EDC 1-ethyl-3- [3-( Dimethylamino) propyl] Carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propylphosphonic acid cyclic anhydride, PPA) Etc.
  • PPA 1-hydroxybenzotriazole
  • the compound having optical activity is produced by using a starting material or a reagent having optical activity, or the racemic production intermediate is optically resolved and then derived into the compound of the present invention, or the racemic compound is produced.
  • the compound of the present invention can be produced by optical resolution.
  • the method of optical resolution is known.
  • a salt / complex or the like is formed with another optically active compound, recrystallized, and then the target compound is isolated, or directly using a chiral column or the like. Examples include a method of separation.
  • a solid-phase supporting reagent supported on a high molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • a high molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • the compounds of the present invention have operative activity against LPA3, they can be formulated as prophylactic and / or therapeutic agents for diseases associated with LPA3 in mammals, especially humans.
  • diseases associated with LPA3 include diseases in which platelets increase.
  • diseases in which platelets increase include essential thrombocythemia and reactive thrombocytosis.
  • red blood cells decrease As a disease related to LPA3, a disease in which red blood cells decrease can also be exemplified.
  • diseases in which red blood cells decrease include aplastic anemia and myelodysplastic syndrome.
  • Idiopathic interstitial pneumonia can also be exemplified as a disease related to LPA3.
  • Examples of idiopathic interstitial pneumonia include idiopathic pulmonary fibrosis.
  • Sepsis can also be exemplified as a disease related to LPA3.
  • the compound of the present invention is not only used as a single agent, but also, for example, (1) complementing and / or enhancing its preventive, therapeutic and / or symptom-improving effect, (2) its In order to improve kinetics / absorption, reduce the dose, and / or (3) reduce the side effects thereof, it may be used as a concomitant drug in combination with other active ingredients such as drugs listed below.
  • the combination drug of the compound of the present invention and these other drugs may be administered in the form of a combination drug in which both components are mixed in one preparation, or different preparations are administered in the same administration route or different administration routes. You may take.
  • the separate preparations are administered, they do not necessarily have to be co-administered at the same time, and the administration may be staggered if necessary.
  • the order of administration is not particularly limited and may be appropriately adjusted so as to obtain the desired drug effect.
  • the dose of these other drugs used in combination with the compound of the present invention can be appropriately increased or decreased based on the clinically used dose of the drug or a similar drug.
  • the compounding ratio of the compound of the present invention to another drug can be appropriately adjusted in consideration of the age and body weight of the administration subject, administration method, administration time, target disease, symptom and the like.
  • 1 part by weight of the compound of the present invention may be combined with other agents in the range of 0.01 to 100 parts by weight.
  • a plurality of other agents may be used.
  • the other drug may be a drug having the same mechanism as those listed above. Such drugs include those found to date as well as those found in the future.
  • the dose of the compound of the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually in the range of 0.1 mg to 300 mg per adult once a day. Orally administered several times, or parenterally in the range of 0.1 mg to 150 mg once to several times daily, or intravenously in the range of 1 to 24 hours per adult. It may be continuously administered to.
  • the dose varies depending on various conditions, so a dose smaller than the above dose may be sufficient, or administration beyond the range may be necessary.
  • the substance which is an active ingredient is usually used. It is formulated with a pharmaceutically acceptable carrier such as various additives or solvents, and then administered systemically or topically, orally or parenterally.
  • the pharmaceutically acceptable carrier means a substance other than the active ingredient, which is generally used in the preparation of a pharmaceutical product.
  • the pharmaceutically acceptable carrier preferably has no pharmacological action at the dose of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient.
  • the pharmaceutically acceptable carrier can be used for the purpose of enhancing the usefulness of the active ingredient and the preparation, facilitating the formulation, stabilizing the quality, improving the usability, and the like.
  • substances such as those described in Yakuji Nippo's 2000 "Encyclopedia of Pharmaceutical Additives” (edited by the Japan Pharmaceutical Additives Association) may be appropriately selected according to the purpose.
  • solid preparations for oral administration include tablets, pills, capsules, powders and granules, and capsules include hard capsules and soft capsules.
  • the solid agent may be formulated with, for example, a pharmaceutically acceptable carrier of the compound of the present invention.
  • a pharmaceutically acceptable carrier for example, lactose, mannitol, glucose, microcrystalline cellulose and starch, etc.
  • binders for example, hydroxy. Hydroxycellulose, polyvinylpyrrolidone and magnesium aluminometasilicate, etc.), disintegrants (eg, calcium fibroglycolate, etc.), lubricants (eg, magnesium stearate, etc.), stabilizers, solubilizers (eg, glutamate, etc.) Aspartic acid, etc.) and the like.
  • a coating agent for example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.
  • a coating agent for example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.
  • it may be included in a capsule containing gelatin.
  • the liquid agent for oral administration may be in any form such as a liquid agent, a suspension agent, an emulsion, a syrup agent and an elixir agent, and for example, the compound of the present invention may be used as a diluent (for example, purified water, ethanol or). It may be dissolved, suspended or emulsified in a mixed solution thereof, etc. and formulated. Further, the liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance agent, a preservative, a buffering agent and the like.
  • a diluent for example, purified water, ethanol or
  • the liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance agent, a preservative, a buffering agent and the like.
  • the sustained-release preparation for oral administration may contain, for example, a gel-forming substance, and the gel-forming substance includes, for example, gum arabic, canten, polyvinylpyrrolidone, sodium alginate, propylene glycol alginate, and carboxyvinyl polymer. , Carboxymethyl cellulose, sodium carboxymethyl cellulose, guagam, gelatin, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methyl cellulose, hydroxyethyl methyl cellulose and the like.
  • a gel-forming substance includes, for example, gum arabic, canten, polyvinylpyrrolidone, sodium alginate, propylene glycol alginate, and carboxyvinyl polymer.
  • Carboxymethyl cellulose sodium carboxymethyl cellulose, guagam, gelatin, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methyl cellulose, hydroxyethyl methyl cellulose
  • Injections or infusions for parenteral administration may be in the form of aqueous solutions, suspensions or emulsions, and at the time of use solvents (eg, distilled water for injection, saline, glucose solution and By adding an isotonic solution (eg, a solution of sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borosand, propylene glycol, etc.), the solution, suspension, or emulsion can be used. It may be formulated as a solid with a pharmaceutically acceptable carrier.
  • solvents eg, distilled water for injection, saline, glucose solution
  • an isotonic solution eg, a solution of sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borosand, propylene glycol, etc.
  • an isotonic solution eg, a solution of sodium chloride, potassium chloride,
  • examples of the "pharmaceutically acceptable carrier” include stabilizers (for example, various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sulfite).
  • stabilizers for example, various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sulfite).
  • solubilizers eg, alcohol (eg, ethanol, etc.), polyalcohol (eg, propylene glycol, polyethylene glycol, etc.) and nonionic Sexual surfactants (eg, Polysorbate 20®, Polysolvate 80® and HCO-50, etc.), suspending agents (eg, glycerin monostearate, aluminum monostearate, methylcellulose, carboxymethylcellulose, etc.) , Hydroxymethyl cellulose and sodium lauryl sulfate, etc.), emulsifiers (eg, gum arabic, sodium alginate, tragant, etc.), soothing agents (eg, benzyl alcohol, chlorobutanol, sorbitol, etc.), buffers (eg, phosphate buffer, etc.) Acetate buffer, borate buffer, carbonate buffer, citrate buffer, tris buffer,
  • Antioxidants include, for example, (1) water-soluble antioxidants such as (1) ascorbic acid, cysteine hydrochloride, sodium bicarbonate, sodium metabisulfate, sodium sulfite, etc., (2) ascorbic palmitate, butylated hydroxyanisol, Use oil-soluble antioxidants such as butylated hydroxytoluene, lecithin, propyl gallate and ⁇ -tocopherol and (3) metal chelating agents such as citric acid, ethylenediamine tetraacetic acid, sorbitol, tartaric acid and phosphoric acid. Can be done.
  • water-soluble antioxidants such as (1) ascorbic acid, cysteine hydrochloride, sodium bicarbonate, sodium metabisulfate, sodium sulfite, etc.
  • ascorbic palmitate butylated hydroxyanisol
  • Use oil-soluble antioxidants such as butylated hydroxytoluene, lecithin, propyl gallate and ⁇ -tocopherol
  • the injection or infusion solution can be produced by sterilization in the final step or by aseptic technique, for example, filtering with a filter or the like to sterilize, and then filling in a sterile container.
  • the injection or infusion solution can also be used by dissolving aseptic powder (which may contain pharmaceutically acceptable carrier powder) by vacuum drying and lyophilization in an appropriate solvent before use. ..
  • Dosage forms of external preparations for parenteral administration include, for example, sprays, inhalants, sprays, aerosols, ointments, gels, creams, poultices, patches, liniments and nasal drops. Can be mentioned.
  • the inhalant examples include an inhalation liquid and an inhalation powder, and the liquid may be used by being dissolved or suspended in water or another suitable medium at the time of use.
  • These inhalants are manufactured according to known methods, for example, in the case of inhalation liquids, preservatives (eg, benzalkonium chloride and parabens, etc.), colorants, buffers (eg, sodium phosphate, etc.). And sodium acetate, etc.), isotonic agents (eg, sodium chloride and concentrated glycerin, etc.), thickeners (eg, carboxyvinyl polymers, etc.), absorption enhancers, etc.
  • preservatives eg, benzalkonium chloride and parabens, etc.
  • colorants eg, sodium phosphate, etc.
  • buffers eg, sodium phosphate, etc.
  • sodium acetate, etc. sodium acetate, etc.
  • isotonic agents eg, sodium chloride and concentrated
  • Preservatives eg, stearic acid and salts thereof, etc.
  • binders eg, starch and dextrin, etc.
  • excipients eg, lactose and cellulose, etc.
  • colorants in the case of powders for inhalation, It is prepared by appropriately mixing preservatives (for example, benzalkonium chloride, paraben, etc.) and absorption enhancers, if necessary.
  • preservatives for example, benzalkonium chloride, paraben, etc.
  • absorption enhancers if necessary.
  • a sprayer for example, an atomizer and a nebulizer
  • an inhalation dispenser for powdered medicine is usually used.
  • the ointment is prepared according to a known or commonly used formulation, for example, the compound of the present invention is mixed or melted in an ointment base.
  • the ointment base is selected from known or commonly used ones, for example, higher fatty acids or higher fatty acid esters (eg, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, etc.
  • the gel agent is prepared according to a known or commonly used formulation, for example, the compound of the present invention is prepared by melting it in a gel base.
  • the gel base is selected from known or commonly used ones, such as lower alcohols (eg ethanol and isopropyl alcohol), gelling agents (eg carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like. Selected from ethyl cellulose, etc.), neutralizers (eg, triethanolamine, diisopropanolamine, etc.), surfactants (eg, polyethylene glycol monostearate, etc.), gums, water, absorption enhancers, and anti-rash agents. It is used by mixing seeds and above. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the cream preparation is prepared according to a known or commonly used formulation, and is produced, for example, by melting or emulsifying the compound of the present invention in a cream base.
  • the cream base is selected from known or commonly used ones, for example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol and 1,3-butylene glycol, etc.). , Higher alcohols (eg 2-hexyldecanol and cetanol, etc.), emulsifiers (eg, polyoxyethylene alkyl ethers and fatty acid esters, etc.), water, absorption enhancers and anti-rash agents. Used. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the poultice is prepared according to a known or commonly used formulation, for example, the compound of the present invention is melted in a poultice base, made into a kneaded product, and spread and applied on a support.
  • the wet cloth base is selected from those known or commonly used, for example, a thickener (for example, polyacrylic acid, polyvinylpyrrolidone, arabic rubber, starch, gelatin, methyl cellulose, etc.), a wetting agent (for example, for example).
  • fillers eg, kaolin, zinc oxide, talc, calcium and magnesium, etc.
  • water solubilizers, tackifiers and anti-rash agents. Is used. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the patch is prepared according to a known or commonly used formulation, for example, the compound of the present invention is melted in a base for a patch and spread and applied on a support.
  • the base for the patch is selected from known or commonly used ones, and for example, one or more selected from polymer bases, fats and oils, higher fatty acids, tackifiers and anti-rash agents are mixed. Is used. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • Liniment agents are prepared according to known or commonly used formulations, for example, the compounds of the present invention, such as water, alcohols (eg, ethanol and polyethylene glycol, etc.), higher fatty acids, glycerin, sucrose, emulsifiers and suspending agents It is prepared by dissolving, suspending or emulsifying in one or more selected from the above. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the compounds of the present invention such as water, alcohols (eg, ethanol and polyethylene glycol, etc.), higher fatty acids, glycerin, sucrose, emulsifiers and suspending agents It is prepared by dissolving, suspending or emulsifying in one or more selected from the above. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • LCMS was performed using a Waters i-class (A) or Shimadzu Nexera X2 (B) system under the following conditions.
  • Transfer Phase B 0.1% TFA acetonitrile solution: gradient (state the ratio of mobile phase (A): mobile phase (B)): 0 to 0.10 minutes: (95%: 5%); 0.10 to 1.20 minutes: (95%: 5%) to (5%: 95%); 1.20 to 1.50 minutes :( 5%: 95%).
  • the numerical values shown in the NMR section are 1 H-NMR measured values (chemical shift values) when the described measuring solvent is used.
  • Example 1 3-[(Cyclobutylamino) Methyl] -1- (Cyclopropylmethyl) -1H-Indole-2-carboxylic Acid Sodium hydride (60%, 2.9 mg) was added to a DMF (1 mL) solution of the compound (20 mg) prepared in Reference Example 2 under an ice bath, and the mixture was stirred at room temperature for 1 hour.
  • 1- (Bromomethyl) cyclopropane (9.9 mg) was added to the reaction mixture, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was extracted.
  • the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and methanol (0.5 mL), tetrahydrofuran (hereinafter abbreviated as THF) (0.5 mL) and 5N sodium hydroxide (0.2 mL) were added to the obtained residue.
  • THF tetrahydrofuran
  • 5N sodium hydroxide 0.2 mL
  • Example 1 (1) to Example 1 (4) Using an amino compound corresponding to cyclobutylamine instead of 1- (bromomethyl) cyclopropane and a bromo compound or iodine compound corresponding to 1- (bromomethyl) cyclopropane, the same operation as in Reference Example 2 ⁇ Example 1 was carried out to obtain the following compound. Obtained.
  • Example 1 3-[(Cyclopentylamino) methyl] -1-ethyl-1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.69; MS (ESI, Pos.): 287 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.22, 1.51-1.57, 1.64-1.74, 1.87-1.94, 3.37-3.44, 4.23, 4.67, 7.09, 7.21, 7.48, 7.71, 10.88.
  • Example 1 (2): 1-Butyl-3-[(cyclobutylamino) methyl] -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.81; MS (ESI, Pos.): 301 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.23-1.30, 1.62-1.69, 1.72-1.84, 2.12-2.24, 3.69-3.79, 4.40, 4.61, 7.22, 7.38, 7.64, 7.83, 8.94.
  • Example 1 3-[(Cyclobutylamino) methyl] -1-[(2,2-difluorocyclopropyl) methyl] -1H-indole-2-carboxylic acid LCMS (A) retention time (minutes): 0.76; MS (ESI, Pos.): 335 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.44-1.52, 1.55-1.63, 1.72-1.84, 2.12-2.25, 3.69-3.78, 4.40, 4.70, 4.89, 7.24, 7.40, 7.66, 7.85, 9.13.
  • Example 1 (4): 3-[(Cyclobutylamino) methyl] -1-ethyl-1H-indole-2-carboxylic acid LCMS (A) retention time (minutes): 0.70; MS (ESI, Pos.): 273 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.21, 1.65-1.84, 2.01-2.20, 3.50-3.64, 4.10, 4.66, 7.07, 7.20, 7.47, 7.67, 11.08.
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid
  • a 2N aqueous sodium hydroxide solution (4.5 mL) was added to a solution of the compound (330 mg) prepared in Reference Example 4 in methanol (9 mL) and 1,2-dimethoxyethane (4.5 mL), and the mixture was stirred at 50 ° C. for 3 hours.
  • the reaction mixture is cooled to room temperature, neutralized with 2N hydrochloric acid (4.5 mL), water is added, and the obtained solid is filtered and dried to obtain the title compound (250 mg) having the following physical properties. Obtained.
  • Example 2 (1) to Example 2 (82) An indole compound or pyrrole compound that replaces ethyl indole-2-carboxylate, a bromo compound or chloro compound that replaces 1- (bromomethyl) -4-methylbenzene, and an amino compound that replaces cyclobutylamine.
  • indole compound or pyrrole compound that replaces ethyl indole-2-carboxylate
  • a bromo compound or chloro compound that replaces 1- (bromomethyl) -4-methylbenzene
  • an amino compound that replaces cyclobutylamine an amino compound that replaces cyclobutylamine.
  • Example 2 1- (2-chlorobenzyl) -3-[(cyclopentylamino) methyl] -4-fluoro-1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.86; MS (ESI, Pos.): 401 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.49-1.79, 1.85-2.03, 3.41-3.57, 4.40, 6.06, 6.19, 6.83-6.94, 7.02-7.27, 7.46, 10.75.
  • Example 2 (2): 1- (2-chlorobenzyl) -3-[(cyclopentylamino) methyl] -5-methyl-1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.88; MS (ESI, Pos.): 397 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.46-1.79, 1.83-2.00, 2.37, 3.38-3.51, 4.28, 6.02, 6.12, 6.95-7.13, 7.15-7.23, 7.45, 7.56, 10.83.
  • Example 2 (3): 1- (2-chlorobenzyl) -3-[(cyclopentylamino) methyl] -7-fluoro-1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.86; MS (ESI, Pos.): 401 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.52-1.61, 1.67-1.77, 1.89-2.00, 3.43-3.51, 4.33, 6.11, 6.20, 6.94, 7.04-7.11, 7.21, 7.47, 7.65, 10.68.
  • Example 2 (4): 1- (2-chlorobenzyl) -3-[(cyclopentylamino) methyl] -4-methyl-1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.87; MS (ESI, Pos.): 397 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.53-1.61, 1.66-1.76, 1.93-2.10, 2.70, 3.50-3.57, 4.45, 6.02, 6.19, 6.85, 7.00-7.08, 7.21, 7.47, 10.64.
  • Example 2 1- (2-chlorobenzyl) -3-[(cyclopentylamino) methyl] -7-methyl-1H-indole-2-carboxylic acid
  • LCMS A) Retention time (minutes): 0.88; MS (ESI, Pos.): 397 (M + H) + .
  • Example 2 (6): 1- (2-chlorobenzyl) -3-[(cyclobutylamino) methyl] -1H-indole-2-carboxylic acid LCMS (A) retention time (minutes): 0.81; MS (ESI, Pos.): 369 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.70-1.88, 2.10-2.24, 3.60-3.70, 4.23, 6.08, 6.18, 7.07, 7.10-7.26, 7.48, 7.78, 11.10.
  • Example 2 3-[(Cyclopentylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (A) retention time (minutes): 0.82; MS (ESI, Pos.): 397 (M + H) + .
  • Example 2 1- (3-chlorobenzyl) -3-[(cyclopentylamino) methyl] -1H-indole-2-carboxylic acid
  • LCMS A) Retention time (minutes): 0.82; MS (ESI, Pos.): 383 (M + H) + .
  • Example 2 (1 (4-chlorobenzyl) -3-[(cyclopentylamino) methyl] -1H-indole-2-carboxylic acid
  • LCMS A) Retention time (minutes): 0.83; MS (ESI, Pos.): 383 (M + H) + .
  • Example 2 (11): 3-[(Cyclopentylamino) methyl] -1- (2-methoxybenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.80; MS (ESI, Pos.): 379 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.51-1.59, 1.67-1.74, 1.88-1.96, 3.40-3.47, 3.88, 4.30, 5.95, 6.23, 6.65, 6.99, 7.09, 7.11-7.16, 7.22, 7.76, 10.87.
  • Example 2 (13): 1-Benzyl-3-[(cyclopentylamino) methyl] -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.78; MS (ESI, Pos.): 349 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.49-1.60, 1.64-1.75, 1.87-1.97, 3.38-3.48, 4.29, 6.00, 7.07-7.12, 7.13-7.18, 7.19-7.24, 7.42, 7.74, 10.75.
  • Example 2 3-[(Cyclopentylamino) methyl] -1- (3-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.81; MS (ESI, Neg.): 361 (MH) - . 1 1 H-NMR (CDCl 3 ): ⁇ 1.30-1.52, 1.56-1.96, 2.22, 3.16-3.32, 4.45, 5.94, 6.81-7.00, 7.03-7.35, 7.60, 11.00.
  • Example 2 (4Chloro-1- (2-chlorobenzyl) -3-[(cyclopentylamino) methyl] -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.90; MS (ESI, Pos.): 417 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.51-1.61, 1.63-1.75, 1.92-2.02, 3.45-3.54, 4.71, 6.06, 6.17, 7.08, 7.12-7.18, 7.22, 7.26, 7.48, 10.58.
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (3,4-dimethylbenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.83; MS (ESI, Pos.): 363 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.67-1.86, 2.07-2.19, 3.53-3.67, 4.18, 5.93, 6.81, 6.93, 6.97, 7.08, 7.15, 7.40, 7.70, 11.12.
  • Example 2 3-[(Cyclopropylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (A) retention time (minutes): 0.82; MS (ESI, Pos.): 335 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 0.73-0.84, 2.20, 2.70-2.77, 4.62, 5.87, 6.95, 7.04, 7.20, 7.32, 7.56, 7.88, 9.20.
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (2-fluoro-4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.86 ; MS (ESI, Pos.): 367 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.72-1.84, 2.11-2.25, 3.63-3.72, 4.30, 5.96, 6.48, 6.79, 7.01, 7.17, 7.26, 7.44, 7.80, 10.10.
  • Example 2 3-[(cyclobutylamino) methyl] -1- [4-methyl-3- (trifluoromethyl) benzyl] -1H-indole-2-carboxylic acid
  • LCMS A) retention time ( Minutes): 0.91; MS (ESI, Pos.): 417 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (2,4-dimethylbenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.88; MS (ESI, Pos.): 363 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.73-1.85, 2.14-2.26, 2.37, 3.67-3.82, 4.36-4.48, 5.81-5.97, 6.68-6.71, 6.96-7.08, 7.14-7.26, 7.29-7.34, 7.39-7.43, 7.81-7.92, 9.12.
  • Example 2 (23): 1- (3-chloro-4-methylbenzyl) -3-[(cyclobutylamino) methyl] -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.89 ; MS (ESI, Pos.): 383 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (2-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.84; MS (ESI, Pos.): 349 (M + H) + .
  • Example 2 (25): 3-[(Cyclobutylamino) methyl] -1- (3-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.84; MS (ESI, Pos.): 349 (M + H) + .
  • Example 2 (26): 1-Benzyl-3-[(cyclobutylamino) methyl] -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.80; MS (ESI, Pos.): 335 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.72-1.84, 2.12-2.24, 3.69-3.78, 4.40, 5.94, 7.06, 7.17-7.27, 7.32, 7.57, 7.85, 9.29.
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (2-fluorobenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.81; MS (ESI, Pos.): 353 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (3-fluorobenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.81; MS (ESI, Pos.): 353 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (4-fluorobenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.81; MS (ESI, Pos.): 353 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.72-1.85, 2.12-2.24, 3.69-3.78, 4.40, 5.91, 7.07-7.15, 7.21, 7.33, 7.59, 7.85, 9.30.
  • Example 2 (4Bromo-3-[(cyclopentylamino) methyl] -1- (3-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.91; MS (ESI, Pos.): 441 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.47-1.78, 1.85-2.05, 2.18, 3.33-3.50, 4.72, 5.94, 6.83, 6.92-7.14, 7.28, 7.46, 10.59.
  • Example 2 3-[(Cyclopentylamino) methyl] -4,5-dimethyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.84; MS (ESI, Pos.): 341 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.45-1.74, 1.76-1.98, 2.22, 3.33-3.44, 3.78, 5.69, 6.83, 7.03, 11.26.
  • Example 2 3-[(cyclobutylamino) methyl] -4,5-dimethyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylic acid
  • LCMS A) retention time (minutes) : 0.81; MS (ESI, Pos.): 327 (M + H) + .
  • Example 2 4-Bromo-3-[(cyclobutylamino) methyl] -5-methyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylic acid LCMS (A) retention time ( Minutes): 0.85; MS (ESI, Pos.): 391 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.65-1.84, 1.92-2.28, 3.40-3.57, 3.76, 5.78, 6.86, 7.06, 11.25.
  • Example 2 (54): 5-bromo-3-[(cyclobutylamino) methyl] -4-methyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylic acid LCMS (A) retention time (minutes): 0.81; MS (ESI, Neg.): 389 (MH) - . 1 1 H-NMR (CD 3 OD): ⁇ 1.80-1.97, 2.05, 2.12-2.37, 3.64-3.79, 3.96, 5.79, 6.93, 7.03.
  • Example 2 (35): 3-[(Cyclobutylamino) methyl] -4-fluoro-1- (4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.83 ; MS (ESI, Pos.): 367 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.70-1.83, 2.07-2.19, 2.20, 3.60-3.67, 4.25, 5.94, 6.83, 7.00-7.05, 7.08-7.13, 7.27, 10.87.
  • Example 2 3-[(Cyclobutylamino) Methyl] -1- (2,6-difluorobenzyl) -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 0.95; MS (ESI, Pos.): 371 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.43-1.88, 2.02-2.14, 2.38-2.54, 3.44-3.58, 4.46, 6.32, 6.75-6.87, 7.09-7.28, 7.40, 7.57, 11.33.
  • Example 2 (37): 3-[(Cyclobutylamino) methyl] -1- [2- (trifluoromethoxy) benzyl] -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 1.02 ; MS (ESI, Pos.): 419 (M + H) + .
  • Example 2 (38): 3-[(Cyclobutylamino) methyl] -1- [4- (difluoromethyl) benzyl] -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 0.97; MS (ESI, Pos.): 385 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.45-2.14, 2.15-2.32, 3.37-3.53, 4.35, 5.96, 6.50, 7.09-7.62, 10.70.
  • Example 2 (39): 3-[(Cyclobutylamino) methyl] -1- [3- (trifluoromethoxy) benzyl] -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 1.02 ; MS (ESI, Pos.): 419 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.45-1.78, 1.98-2.11, 2.24-2.38, 3.40-3.52, 4.39, 5.99, 6.94-7.09, 7.13-7.32, 7.58, 11.21.
  • Example 2 3-[(Cyclobutylamino) methyl] -1- [4- (trifluoromethoxy) benzyl] -1H-indole-2-carboxylic acid
  • B Retention time (minutes): 1.02 ;
  • Example 2 (3-[(Cyclobutylamino) methyl] -1- (3-cyclopropylbenzyl) -1H-indole-2-carboxylic acid
  • LCMS B) retention time (minutes): 1.05; MS (ESI, Pos.): 375 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -5-fluoro-1- (4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 1.00 ; MS (ESI, Pos.): 367 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.50-1.82, 1.98-2.11, 2.23, 2.27-2.40, 3.38-3.50, 4.24, 5.93, 6.93, 6.97-7.04, 7.14, 7.20, 11.12.
  • Example 2 (43): 5-Bromo-3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 1.05 ; MS (ESI, Pos.): 427 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.70-1.86, 2.10-2.20, 3.56-3.68, 4.18, 5.95, 6.98-7.07, 7.26, 7.41, 7.98, 10.87.
  • Example 2 (44): Retention of 3-[(bicyclo [1.1.1] pent-1-ylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (B) Hours (minutes): 0.99; MS (ESI, Pos.): 361 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.86, 2.21, 2.53-2.58, 4.23, 5.95, 6.98, 7.03, 7.11, 7.20, 7.46, 7.77, 12.05.
  • Example 2 (45): 1- (4-methylbenzyl) -3- ⁇ [(1-methylcyclobutyl) amino] methyl ⁇ -1H-indole-2-carboxylic acid LCMS (B) retention time (minutes): 0.98; MS (ESI, Pos.): 363 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.52, 1.82-1.96, 2.21, 2.33-2.45, 4.17, 5.97, 7.00-7.07, 7.09, 7.18, 7.44, 7.77, 11.14.
  • Example 2 (46): 1- (4-methylbenzyl) -3- ⁇ [(2-methylcyclobutyl) amino] methyl ⁇ -1H-indole-2-carboxylic acid LCMS (B) retention time (minutes): 1.00; MS (ESI, Pos.): 363 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.07, 1.18, 1.28-1.40, 1.43-1.55, 1.90-2.35, 2.42-2.72, 3.10-3.22, 3.61-3.72, 4.19, 5.88-6.05, 7.01-7.05, 7.06-7.12, 7.13-7.20, 7.39-7.46, 7.69-7.74, 11.20.
  • Example 2 (47): 3- ⁇ [(3,3-dimethylcyclobutyl) amino] methyl ⁇ -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (B) retention time (minutes) ): 1.03; MS (ESI, Pos.): 377 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.11, 1.91-2.06, 2.20, 3.57-3.71, 4.16, 5.96, 7.02, 7.08, 7.16, 7.42, 7.69, 11.03.
  • Example 2 (48): 1- (4-methylbenzyl) -3-[(spiro [3.3] hept-2-ylamino) methyl] -1H-indole-2-carboxylic acid LCMS (B) retention time ( Minutes): 1.04; MS (ESI, Pos.): 389 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-pyrrolo [2,3-b] pyridin-2-carboxylic acid LCMS (B) retention time (minutes): 0.89; MS (ESI, Pos.): 350 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-pyrrolo [2,3-c] pyridin-2-carboxylic acid
  • LCMS B) retention time ( Minutes): 0.70; MS (ESI, Pos.): 350 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (4-cyclopropylbenzyl) -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 1.00; MS (ESI, Pos.): 375 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 0.52-0.60, 0.82-0.90, 1.45-1.82, 1.97-2.10, 2.25-2.40, 3.39-3.50, 4.35, 5.95, 6.89, 7.02, 7.13, 7.22, 7.32, 7.55, 11.15.
  • Example 2 3-[(Cyclobutylamino) methyl] -1- [3- (difluoromethoxy) benzyl] -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 0.98; MS (ESI, Pos.): 401 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.54-1.85, 2.00-2.12, 2.24-2.37, 3.41-3.53, 4.38, 5.97, 6.39, 6.84-7.00, 7.14-7.32, 7.58, 11.03.
  • Example 2 3-[(Cyclobutylamino) methyl] -1- [2- (difluoromethoxy) benzyl] -1H-indole-2-carboxylic acid LCMS (B) retention time (minutes): 0.98; MS (ESI, Pos.): 401 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.42-1.82, 2.02-2.13, 2.25-2.39, 3.42-3.52, 4.35, 5.95, 6.57, 6.71, 6.92, 7.10-7.28, 7.58, 11.12.
  • Example 2 3-[(cyclobutylamino) methyl] -1- [3- (difluoromethyl) benzyl] -1H-indole-2-carboxylic acid
  • LCMS B) retention time (minutes): 0.96; MS (ESI, Pos.): 385 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (2-cyclopropylbenzyl) -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 1.00; MS (ESI, Pos.): 375 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 0.76-0.86, 0.99-1.09, 1.48-1.85, 1.96-2.13, 2.18-2.33, 3.38-3.51, 4.34, 5.30, 6.15-6.25, 6.87, 7.03-7.24, 7.57, 10.99.
  • Example 2 3-[(Cyclobutylamino) Methyl] -1- [2- (difluoromethyl) benzyl] -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 0.97; MS (ESI, Pos.): 385 (M + H) + .
  • Example 2 6-Bromo-3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid
  • LCMS B) Retention time (minutes): 1.03 ;
  • Example 2 (59): 7-Bromo-3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 1.03 ; MS (ESI, Pos.): 427 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.70-1.84, 2.09-2.19, 2.20, 3.55-3.67, 4.18, 6.44, 6.72, 7.00, 7.04, 7.38, 7.79, 10.88.
  • Example 2 6-[(cyclobutylamino) methyl] -4- (4-methylbenzyl) -4H-thieno [3,2-b] pyrrole-5-carboxylic acid
  • LCMS B) retention time (minutes): 0.95; MS (ESI, Pos.): 355 (M + H) + .
  • Example 2 (51): 5-Chloro-3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 1.04 ; MS (ESI, Pos.): 383 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -1- [4- (methylsulfonyl) benzyl] -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 0.87; MS (ESI, Pos.): 413 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.71-1.86, 2.10-2.21, 3.15, 3.58-3.68, 4.21, 6.13, 7.12, 7.19, 7.31, 7.42, 7.74, 7.80, 11.06.
  • Example 2 6-Chloro-3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid
  • LCMS B) Retention time (minutes): 1.02 ; MS (ESI, Pos.): 383 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -1- [2- (methylsulfonyl) benzyl] -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 0.91; MS (ESI, Pos.): 413 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.45-1.80, 2.02-2.12, 2.15-2.28, 3.40, 3.40-3.52, 4.31, 6.26, 6.33, 7.19-7.39, 7.57, 8.07, 10.97.
  • Example 2 (35): 3-[(Cyclobutylamino) methyl] -6-fluoro-1- (4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 0.98 ; MS (ESI, Pos.): 367 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.48-1.82, 2.00-2.11, 2.23, 2.25-2.40, 3.40-3.50, 4.28, 5.88, 6.88, 6.95, 7.01, 7.45, 11.15.
  • B Retention time (minutes): 1.02 ;
  • Example 2 4-Chloro-3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 1.02 ; MS (ESI, Pos.): 383 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.55-1.83, 2.06-2.18, 2.23, 2.24-2.37, 3.54-3.65, 4.84, 5.87, 6.96-7.02, 7.03-7.10, 7.15-7.19, 10.84.
  • Example 2 3-[(Cyclobutylamino) Methyl] -1- (4-Methylbenzyl) -1,4,5,6-tetrahydrocyclopenta [b] pyrrole-2-carboxylic acid LCMS (B) ) Retention time (minutes): 1.04; MS (ESI, Pos.): 339 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.50-1.71, 1.73-1.89, 1.91-2.04, 2.18, 2.21-2.44, 2.46-2.71, 3.32-3.43, 3.94, 5.33, 6.87, 6.98, 7.16-7.22, 9.33.
  • Example 2 (70): 1- (2-chlorobenzyl) -3-[(cyclopentylamino) methyl] -1H-indole-2-carboxylic acid LCMS (A) retention time (minutes): 0.84; MS (ESI, Pos.): 383 (M + H) + .
  • Example 2 (71): 1- (4-methylbenzyl) -3-[(3-thietanylamino) methyl] -1H-indole-2-carboxylic acid LCMS (B) retention time (minutes): 0.96; MS (ESI, Pos.): 367 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 2.21, 3.10-3.17, 3.47-3.55, 4.17, 4.35-4.45, 5.94, 6.99-7.05, 7.09, 7.18, 7.44, 7.71, 11.42.
  • Example 2 (72): 1- (2-chlorobenzyl) -3-[(cyclopropylamino) methyl] -1H-indole-2-carboxylic acid LCMS (B) retention time (minutes): 0.97; MS (ESI, Pos.): 355 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 0.71-0.83, 2.62-2.69, 4.42, 6.05, 6.13, 7.05, 7.14, 7.17-7.23, 7.26, 7.47, 7.82, 11.05.
  • Example 2 (73): 3-[(Cyclobutylamino) Methyl] -1- [3- (1-pyrrolidinyl) benzyl] -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 0.98 ; MS (ESI, Pos.): 404 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.67-1.84, 1.86-1.95, 2.10-2.20, 3.07-3.14, 3.53-3.64, 4.19, 5.94, 6.30, 6.33, 6.40, 6.97, 7.08, 7.16, 7.44, 7.70, 11.16.
  • Example 2 3-[(Cyclobutylamino) Methyl] -1- (2-thienylmethyl) -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 0.92; MS (ESI, Pos.): 341 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.45-1.86, 2.01-2.13, 2.33-2.49, 3.41-3.56, 4.41, 6.15, 6.84, 7.01, 7.07, 7.17, 7.30, 7.48, 7.58, 11.25.
  • Example 2 3-[(Cyclobutylamino) methyl] -1- [2- (methylthio) benzyl] -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 0.96; MS (ESI, Pos.): 381 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.71-1.88, 2.10-2.34, 2.58, 3.60-3.70, 4.23, 6.00, 6.07, 6.89, 7.08-7.23, 7.33, 7.76, 11.10.
  • Example 2 3-[(Cyclobutylamino) methyl] -1- [3- (3-phenylpropoxy) benzyl] -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 1.00; MS (ESI, Pos.): 469 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.68-1.84, 1.92-1.99, 2.11-2.19, 2.69, 3.57-3.65, 3.87, 4.20, 5.99, 6.68-6.71, 6.74, 7.08-7.22, 7.27, 7.43, 7.72, 11.08.
  • Example 2 3-[(Cyclobutylamino) methyl] -1- (3-nitrobenzyl) -1H-indole-2-carboxylic acid LCMS (B) Retention time (minutes): 0.94; MS (ESI, Pos.): 380 (M + H) + .
  • Example 2 (81): 3-[(Cyclobutylamino) methyl] -1-[(2-isopropyl-1,3-thiazole-4-yl) methyl] -1H-indole-2-carboxylic acid LCMS (B) ) Retention time (minutes): 0.93; MS (ESI, Pos.): 384 (M + H) + .
  • Example 2 3-[(Cyclobutylamino) methyl] -1- ⁇ 4-[(3-methyl-3-oxetanyl) methoxy] benzyl ⁇ -1H-indole-2-carboxylic acid
  • LCMS A) retention time (minutes): 0.81; MS (ESI, Pos.): 435 (M + H) + .
  • Reference Example 6 Ethyl 3-[(cyclobutylamino) methyl] -1- (4-hydroxybenzyl) -1H-indole-2-carboxylate A solution of the compound (1.1 g) prepared in Reference Example 5 in methanol (50 mL). To 10% palladium-activated carbon (50% wet, 200 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated. Methanol (50 mL) and 10% palladium-activated carbon (50% wet, 200 mg) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere.
  • Example 3 3-[(Cyclobutylamino) Methyl] -1- (4-Hydroxybenzyl) -1H-Indole-2-carboxylic Acid Using the compound prepared in Reference Example 6, the same operation as in Example 2. Was carried out to obtain a title compound having the following physical property values.
  • Example 3 (1) to Example 3 (2) Using the corresponding alcohol compound instead of 4-benzyloxybenzyl alcohol, the same operation as in Reference Example 5 ⁇ Reference Example 6 ⁇ Example 3 was carried out to obtain the following compound.
  • Example 3 3-[(Cyclobutylamino) methyl] -1- (2-hydroxybenzyl) -1H-indole-2-carboxylic acid LCMS (A) Retention time (minutes): 0.74; MS (ESI, Pos.): 351 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.68-1.83, 2.07-2.20, 3.57-3.65, 4.18, 5.78, 6.64, 6.71, 6.95, 7.02, 7.07, 7.14, 7.38, 7.70, 10.32, 11.17.
  • Example 4 3-[(Cyclobutylamino) Methyl] -1- (2-ethoxybenzyl) -1H-indole-2-carboxylic acid Carbonated in a DMF (1 mL) solution of the compound (20 mg) prepared in Reference Example 10. Potassium (18 mg) and iodoethane (9.9 mg) were added, and the mixture was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction mixture for extraction. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, methanol (0.5 mL), THF (0.5 mL) and 5N sodium hydroxide (0.4 mL) were added to the obtained residue, and the mixture was stirred at 60 ° C.
  • Example 4 Methyl 5-bromovalerate instead of 1- [2- (4-carboxybutoxy) benzyl] -3-[(cyclobutylamino) methyl] -1H-indole-2-carboxylate iodoethane
  • the title compound having the following physical properties was obtained.
  • Reference Example 11 Sodium hydride (60%, 840 mg) in a DMF (50 mL) solution of ethyl 1- (4-methylbenzyl) -1H-indole-2-carboxylate indole-2-carboxylate (3.8 g). In addition, the mixture was stirred at room temperature for 30 minutes. 1- (Bromomethyl) -4-methylbenzene (3.9 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture for extraction, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine.
  • Example 5 3- [1- (cyclobutylamino) ethyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid Using the compound prepared in Reference Example 13, the same operation as in Example 2 was carried out to obtain a title compound having the following physical characteristic values.
  • Example 5 (1): Using benzyl bromide instead of 1-benzyl-3- [1- (cyclobutylamino) ethyl] -1H-indole-2-carboxylic acid 1- (bromomethyl) -4-methylbenzene , Reference Example 11 ⁇ Reference Example 12 ⁇ Reference Example 13 ⁇ The same operation as in Example 5 was carried out to obtain a title compound having the following physical properties.
  • Reference Example 16 Ethyl 4-bromo-3-iodo-5-methyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylate DMF (20 mL) of the compound (2.0 g) prepared in Reference Example 15 Sodium hydride (60%, 246 mg) was added to the solution under an ice bath and the reaction mixture was stirred under an ice bath for 10 minutes and at room temperature for 30 minutes.
  • 1- (Bromomethyl) -4-methylbenzene (1.1 g) was added under an ice bath, and the mixture was stirred under an ice bath for 10 minutes and at room temperature for 2 hours.
  • Reference Example 17 Ethyl 4-bromo-5-methyl-1- (4-methylbenzyl) -3-vinyl-1H-pyrrole-2-carboxylate
  • Tributyl (vinyl) tin (0.95 mL) and bis (triphenylphosphine) palladium (II) dichloride (152 mg) were added to the solution, and the reaction mixture was stirred at 95 ° C. for 7 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure.
  • Reference Example 19 Ethyl 3-formyl-4- (4-methoxyphenyl) -5-methyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylate
  • the compound (19 mg) prepared in Reference Example 18 Add water (0.17 mL), 4-methoxyphenylboronic acid (10 mg), potassium carbonate (11 mg), tetrakis (triphenylphosphine) palladium (0) (9 mg) to a DMF (0.7 mL) solution, and use a microwave. The mixture was stirred at 100 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, ethyl acetate and saturated brine were added, and the mixture was extracted.
  • Reference Example 20 Ethyl 3-[(cyclobutylamino) methyl] -4- (4-methoxyphenyl) -5-methyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylate
  • Reference Example 19 Using the produced compound, the same operation as in Reference Example 4 was carried out to obtain a title compound having the following physical property values.
  • Example 6 3-[(Cyclobutylamino) methyl] -4- (4-methoxyphenyl) -5-methyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylic acid Reference Example 20 The same operation as in Example 2 was carried out using the compound to obtain a title compound having the following physical property values.
  • Example 6 (1) to Example 6 (7) Using the corresponding boronic acid compound instead of 4-methoxyphenylboronic acid, the same operation as in Reference Example 19 ⁇ Reference Example 20 ⁇ Example 6 was carried out to obtain the following compound.
  • Example 6 3-[(cyclobutylamino) methyl] -5-methyl-1- (4-methylbenzyl) -4-phenyl-1H-pyrrole-2-carboxylic acid LCMS (A) retention time ( Minutes): 0.93; MS (ESI, Pos.): 389 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.60-1.80, 1.86-2.10, 2.23, 3.36-3.52, 3.64, 5.79, 6.93, 7.08, 7.15-7.22, 7.23-7.31, 7.34-7.43, 11.54.
  • Example 6 3-[(Cyclobutylamino) methyl] -4- (3-fluorophenyl) -5-methyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylic acid
  • LCMS A) retention time (minutes): 0.94; MS (ESI, Pos.): 407 (M + H) + .
  • Example 6 3-[(Cyclobutylamino) methyl] -4- (2-fluorophenyl) -5-methyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylic acid LCMS ( A) Retention time (minutes): 0.93; MS (ESI, Pos.): 407 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.59-1.76, 1.90-2.02, 2.25, 3.37-3.46, 3.57-3.74, 5.70-5.85, 6.93, 7.10, 7.19-7.32, 7.34-7.43.
  • Example 6 (4): 3-[(Cyclobutylamino) methyl] -5-methyl-1- (4-methylbenzyl) -4- (3-thienyl) -1H-pyrrole-2-carboxylic acid LCMS (A) ) Retention time (minutes): 0.92; MS (ESI, Pos.): 395 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.53-1.73, 1.74-1.90, 1.92-2.12, 2.22, 3.35-3.45, 3.56, 5.78, 6.92, 7.02-7.12, 7.21, 7.53.
  • Example 6 3-[(Cyclobutylamino) methyl] -5-methyl-1- (4-methylbenzyl) -4- (2-thienyl) -1H-pyrrole-2-carboxylic acid LCMS (A) ) Retention time (minutes): 0.92; MS (ESI, Pos.): 395 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.63-1.79, 1.89-2.13, 2.23, 3.37-3.52, 3.72, 5.79, 6.88, 6.93, 7.04-7.12, 7.52, 11.45.
  • Example 6 Retention time of 3-[(cyclobutylamino) methyl] -4-isopropenyl-5-methyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylic acid LCMS (A) (Minute): 0.88; MS (ESI, Neg.): 351 (MH) - . 1 1 H-NMR (CD 3 OD): ⁇ 1.80-1.97, 2.05, 2.10-2.34, 3.60-3.74, 3.91, 4.76-4.80, 5.28-5.32, 5.73, 6.86, 7.04.
  • Example 6 3-[(Cyclobutylamino) methyl] -5-methyl-1- (4-methylbenzyl) -4-vinyl-1H-pyrrole-2-carboxylic acid LCMS (A) retention time (minutes): 0.83; MS (ESI, Neg.): 337 (MH) - . 1 1 H-NMR (CDCl 3 ): ⁇ 1.80-1.97, 2.14, 2.15-2.37, 3.63-3.77, 4.05, 5.18, 5.28, 5.76, 6.65, 6.85, 7.05.
  • Reference Example 21 Trichloroacetyl chloride in a DCE (50 mL) solution of ethyl 4,5,6,7-tetrahydro-1H-indole-2-carboxylate 4,5,6,7-tetrahydro-1H-indole (3.0 g). (1.4 g) was added, and the mixture was stirred at 85 ° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then ethanol (40 mL) and sodium ethoxide (about 20% ethanol solution, 0.85 mL) were added.
  • Reference Example 22 Ethyl 3-formyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylate Using the compound prepared in Reference Example 21, the same operation as in Reference Example 1 was carried out, and the following was performed. A title compound having physical characteristics was obtained.
  • Reference Example 23 Ethyl 3-formyl-1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-indole-2-carboxylate DMF (1 mL) of the compound (50 mg) prepared in Reference Example 22. ) Cesium carbonate (147 mg) and 1- (bromomethyl) -4-methylbenzene (63 mg) were added to the solution, and the mixture was stirred at 100 ° C. for 30 minutes using a microwave. Water and ethyl acetate were added to the reaction mixture for extraction, and then the mixture was washed with saturated brine.
  • Reference Example 24 Ethyl 3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-indole-2-carboxylate The compound prepared in Reference Example 23. In the same manner as in Reference Example 4, the title compound having the following physical property values was obtained.
  • Example 7 3-[(Cyclobutylamino) methyl] -1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid Using the compound prepared in Reference Example 24, the same operation as in Example 2 was carried out to obtain a title compound having the following physical property values.
  • Reference Example 27 Ethyl 3-formyl-1- (4-methylbenzyl) -5- (methylsulfonyl) -1H-indole-2-carboxylate
  • NMP abbreviated as NMP
  • sodium methanesulfinate 143 mg
  • copper iodide II
  • Ethyl acetate and saturated aqueous ammonium chloride solution were added, and the reaction mixture was filtered through Celite (trade name) and extracted.
  • Reference Example 28 Ethyl 3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -5- (methylsulfonyl) -1H-indole-2-carboxylate Using the compound prepared in Reference Example 27 , The same operation as in Reference Example 4 was carried out to obtain a title compound having the following physical property values.
  • Example 8 3-[(Cyclobutylamino) Methyl] -1- (4-Methylbenzyl) -5- (Methylsulfonyl) -1H-Indole-2-carboxylic Acid Using the compound prepared in Reference Example 28, The same operation as in Example 2 was carried out to obtain a title compound having the following physical property values.
  • Example 8 (1) to Example 8 (2) Using the corresponding indole compound instead of ethyl 5-bromoindole-2-carboxylate, the same operation as in Reference Example 25 ⁇ Reference Example 26 ⁇ Reference Example 27 ⁇ Reference Example 28 ⁇ Example 8 was carried out, and the following compound was performed.
  • Example 8 3-[(Cyclobutylamino) methyl] -1- (4-methylbenzyl) -7- (methylsulfonyl) -1H-indole-2-carboxylic acid LCMS (B) retention time (minutes) ): 0.92; MS (ESI, Pos.): 427 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.68-1.82, 2.05-2.16, 2.19, 3.01, 3.53-3.63, 4.23, 6.51, 6.57, 6.97, 7.36, 7.93, 8.21, 10.87.
  • Example 8 3-[(Cyclobutylamino) methyl] -1- (4-methylbenzyl) -4- (methylsulfonyl) -1H-indole-2-carboxylic acid LCMS (B) retention time (minutes) ): 0.93; MS (ESI, Pos.): 427 (M + H) + . 1 1 H-NMR (CDCl 3 ): ⁇ 1.50-1.85, 1.90-2.37, 3.04, 3.73-3.87, 4.79, 5.72, 6.80-6.92, 7.25, 7.53, 7.82, 10.47.
  • Reference Example 31 Methyl 6-cyano-3-formyl-1- (4-methylbenzyl) -1H-indole-2-carboxylate Cyanide of the compound (120 mg) prepared in Reference Example 30 into an NMP (0.7 mL) solution. Copper (I) (83 mg) and tetrakis (triphenylphosphine) palladium (0) (36 mg) were added, and the mixture was stirred at 150 ° C. for 30 minutes using a microwave. Ethyl acetate and saturated aqueous ammonium chloride solution were added to the reaction mixture for extraction. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • Reference Example 32 Methyl 6-cyano-3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylate Using the compound prepared in Reference Example 31, Reference Example The same operation as in No. 4 was carried out to obtain a title compound having the following physical property values.
  • Example 9 6-Cyano-3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid
  • Example 2 using the compound prepared in Reference Example 32. The same operation as in the above was carried out to obtain a title compound having the following physical property values.
  • Example 9 7-Cyano-3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid Using an indole compound corresponding to methyl 6-bromoindole-2-carboxylate, the same operation as in Reference Example 29 ⁇ Reference Example 30 ⁇ Reference Example 31 ⁇ Reference Example 32 ⁇ Example 9 was carried out, and the following compound was performed.
  • Reference Example 34 Ethyl 6-bromo-4- (4-methylbenzyl) -4H-pyrrolo [2,3-d] [1,3] thiazole-5-carboxylate Using the compound prepared in Reference Example 33, The same operation as in Reference Example 3 was carried out to obtain a title compound having the following physical property values.
  • Reference Example 35 Ethyl 4- (4-methylbenzyl) -6-vinyl-4H-pyrrolo [2,3-d] [1,3] thiazole-5-carboxylate Using the compound prepared in Reference Example 34, The same operation as in Reference Example 17 was carried out to obtain a title compound having the following physical property values.
  • Reference Example 36 Ethyl 6-formyl-4- (4-methylbenzyl) -4H-pyrrolo [2,3-d] [1,3] thiazole-5-carboxylate Using the compound prepared in Reference Example 35, The same operation as in Reference Example 18 was carried out to obtain a title compound having the following physical property values.
  • Reference Example 37 Ethyl 6-[(cyclobutylamino) methyl] -4- (4-methylbenzyl) -4H-pyrrolo [2,3-d] [1,3] thiazole-5-carboxylate
  • Example 10 6-[(cyclobutylamino) methyl] -4- (4-methylbenzyl) -4H-pyrrolo [2,3-d] [1,3] thiazole-5-carboxylic acid Reference Example 37 The same operation as in Example 2 was carried out using the compound to obtain a title compound having the following physical property values.
  • Example 10 (1) to Example 10 (2) Reference Example 33 ⁇ Reference Example 34 ⁇ Reference Example 35 ⁇ Reference Example 36 ⁇ Reference using a pyrrole compound corresponding to 4H-pyrrolo [2,3-d] [1,3] thiazole-5-carboxylic acid ethyl instead.
  • Example 37 The same operation as in Example 10 was carried out to obtain the following compounds.
  • Example 10 3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-pyrrolo [3,2-c] pyridin-2-carboxylic acid LCMS (A) retention time ( Minutes): 0.56; MS (ESI, Pos.): 350 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.66-1.84, 2.07-2.28, 3.55-3.70, 4.24, 5.93, 6.99-7.07, 7.43, 8.18, 8.98, 10.91.
  • Example 10 (2): 5-[(cyclobutylamino) methyl] -7- (4-methylbenzyl) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid LCMS (B) retention time ( Minutes): 0.81; MS (ESI, Pos.): 351 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.70-1.85, 2.10-2.19, 2.21, 3.60-3.72, 4.26, 5.97, 7.03, 7.09, 8.14, 8.87, 9.23, 10.75.
  • Reference Example 38 Ethyl 5-bromo-3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylate Using the compound prepared in Reference Example 26, Reference Example The same operation as in No. 4 was carried out to obtain a title compound having the following physical property values.
  • Example 11 3-[(Cyclobutylamino) methyl] -5- (dimethylphosphoryl) -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid Using the compound prepared in Reference Example 39, The same operation as in Example 2 was carried out to obtain a title compound having the following physical property values.
  • Reference Example 43 Ethyl 3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -7-[(trimethylsilyl) ethynyl] -1H-indole-2-carboxylate
  • the compound prepared in Reference Example 42 Using the same procedure as in Reference Example 4, a title compound having the following physical property values was obtained.
  • Example 12 3-[(Cyclobutylamino) methyl] -7-ethynyl-1- (4-methylbenzyl) -1H-indole-2-carboxylic acid
  • Example 2 using the compound prepared in Reference Example 43. The same operation as in the above was carried out to obtain a title compound having the following physical property values.
  • Example 13 3-[(Cyclobutylamino) Methyl] -7-Ethyl-1- (4-Methylbenzyl) -1H-Indol-2-carboxylic Acid Ethyl (1.5 mg) of the compound (8 mg) prepared in Example 12. mL) 10% palladium-activated carbon (50% wet, 4 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated to give the title compound (8 mg) having the following physical characteristics. LCMS (B) retention time (minutes): 1.02; MS (ESI, Pos.): 377 (M + H) + .
  • Reference Example 45 Ethyl 3- (aminomethyl) -1- (4-methylbenzyl) -1H-indole-2-carboxylate
  • the compound (1.0 g) prepared in Reference Example 44 was mixed with acetic acid (9.4 mL) and zinc (768 mg). ) was added, and the mixture was stirred at 70 ° C. for 1 hour.
  • the reaction mixture was cooled to room temperature, DCM was added, the mixture was neutralized with 5N sodium hydroxide, and the mixture was extracted. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Hexane and ethyl acetate were added to the obtained residue, and the slurry was washed.
  • Reference Example 46 Ethyl 3- ⁇ [(1-duterio) cyclobutylamino] methyl ⁇ -1- (4-methylbenzyl) -1H-indole-2-carboxylate Deuterated sodium sodium (66 mg) acetonitrile ( 3 mL) Acetic acid-d4 (0.28 mL) was added to the solution under an ice bath. After stirring at room temperature for 30 minutes, cyclobutanone (65 mg), diisopropylethylamine (0.21 mL), and the compound prepared in Reference Example 45 (300 mg) were added, and the mixture was stirred at room temperature for 30 minutes.
  • Example 14 3- ⁇ [(1-Duterio) cyclobutylamino] methyl ⁇ -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid
  • Example using the compound prepared in Reference Example 46 The same operation as in No. 2 was carried out to obtain a title compound having the following physical property values.
  • Reference Example 47 Add phosphorus oxychloride (0.99 mL) to a DCE (5 mL) solution of ethyl 3- (duterio) formyl-1H-indole-2-carboxylate N, N-dimethylformamide-d7 (0.82 mL) at room temperature. After stirring for 10 minutes with, a solution of ethyl indole-2-carboxylate (1.0 g) in DCE (5 mL) was added, and the reaction mixture was stirred at 60 ° C. for 3 hours. After cooling the reaction mixture to room temperature, heavy water (1 mL), ethyl acetate, saturated brine, and saturated aqueous sodium hydrogen carbonate solution were added.
  • Example 15 3-[(Cyclobutylamino) (diduterio) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid Using the compound prepared in Reference Example 49, in Example 2 and The same operation was carried out to obtain a title compound having the following physical property values.
  • Reference Example 50 Ethyl 3-[(E)-(hydroxyimino) (duterio) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylate Using the compound prepared in Reference Example 48, The same operation as in Reference Example 44 was carried out to obtain a title compound having the following physical property values.
  • Reference Example 51 Ethyl 3- [amino (diduterio) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylate
  • the compound prepared in Reference Example 50 and acetic acid-d4 instead of acetic acid are used. Then, the same operation as in Reference Example 45 was carried out to obtain a title compound having the following physical property values.
  • Reference Example 52 Ethyl 3- ⁇ [(1-duterio) cyclobutylamino] (diduterio) methyl ⁇ -1- (4-methylbenzyl) -1H-indole-2-carboxylate Using the compound prepared in Reference Example 51. Then, the same operation as in Reference Example 46 was carried out to obtain a title compound having the following physical property values.
  • Example 16 3- ⁇ [(1-duterio) cyclobutylamino] (diduterio) methyl ⁇ -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid Using the compound prepared in Reference Example 52. , The same operation as in Example 2 was carried out to obtain a title compound having the following physical property values.
  • Example 17 3-[(Cyclobutylamino) methyl] -4-isopropyl-5-methyl-1- (4-methylbenzyl) -1H-pyrrole-2-carboxylic acid
  • the compound prepared in Example 6 (6) In the same manner as in Example 13, the title compound having the following physical property values was obtained.
  • Example 18 ( ⁇ ) -3- [1- (cyclobutylamino) ethyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid
  • the second peak (retention time: about 15.00 minutes) under the above optical resolution conditions was obtained as the title compound (8 mg) having the following physical property values.
  • Reference Example 53 Ethyl 3-( ⁇ [(benzyloxy) carbonyl] (cyclobutyl) amino ⁇ methyl) -1- (4-methylbenzyl) -1H-indole-2-carboxylate
  • the compound prepared in Reference Example 4 (4.2).
  • Benzyl chloroformate (2.3 g) and diisopropylethylamine (3.9 mL) were added to a solution of g) in acetonitrile (25 mL), and the mixture was stirred at room temperature for 4 hours.
  • Ethyl acetate and saturated aqueous ammonium chloride solution were added to the reaction mixture for extraction.
  • Reference Example 54 3-( ⁇ [(benzyloxy) carbonyl] (cyclobutyl) amino ⁇ methyl) -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid Using the compound prepared in Reference Example 53. , The same operation as in Example 2 was carried out to obtain the title compound (4.6 g) having the following physical property values.
  • Example 19 3-[(Cyclobutylamino) Methyl] -1- (4-Methylbenzyl) -N- (Methylsulfonyl) -1H-Indol-2-carboxamide Methanol of the compound (22 mg) prepared in Reference Example 55. 10% palladium-activated carbon (50% wet, 25 mg) and ammonium formate (25 mg) were added to the solution (1.5 mL), and the mixture was stirred at 50 ° C. for 4 hours.
  • the reaction mixture is filtered through Celite (trade name), the filtrate is concentrated, and the obtained residue is obtained by HPLC (column: YMC Triart C 18 50 mm ⁇ 100 mm, 5 ⁇ m; flow rate: 100 mL / min; mobile phase A: 0.1. % TFA aqueous solution; mobile phase B: 0.1% TFA acetonitrile solution: gradient (state the ratio of mobile phase (A): mobile phase (B)): 0 to 0.50 minutes: (90%: 10%); By purifying from 0.50 to 12.00 minutes: (90%: 10%) to (0%: 100%); 12.01 to 18.00 minutes: (0%: 100%)), the following The title compound (9.6 mg) having a physical property value was obtained.
  • Example 19 (1) to Example 19 (6) Using the corresponding sulfonamide compound instead of methanesulfonamide, the same operation as in Reference Example 55 ⁇ Example 19 was carried out to obtain the following compound.
  • Example 19 3-[(Cyclobutylamino) methyl] -N- (cyclopropylsulfonyl) -1- (4-methylbenzyl) -1H-indole-2-carboxamide LCMS (B) retention time (minutes) ): 1.06; MS (ESI, Pos.): 452 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 0.79-0.97, 1.68-1.83, 2.08-2.30, 2.90-3.013.63-3.70, 4.23, 5.89, 7.01-7.10, 7.14, 7.22, 7.51, 7.77, 10.02.
  • Example 19 (2): Retention of 3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -N- (4-pyridinylsulfonyl) -1H-indole-2-carboxamide LCMS (B) Hours (minutes): 1.03 MS (ESI, Pos.): 489 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.74-1.89, 2.14-2.37, 3.76-3.89, 4.33, 5.78, 6.88, 6.97, 7.15, 7.24, 7.52, 7.76-7.81, 9.70.
  • Example 19 3-[(Cyclobutylamino) methyl] -N- (dimethylsulfamoyl) -1- (4-methylbenzyl) -1H-indole-2-carboxamide
  • LCMS B) retention time ( Minutes): 1.06 MS (ESI, Pos.): 455 (M + H) + .
  • Example 19 (4): 3-[(Cyclobutylamino) methyl] -1- (4-methylbenzyl) -N- (1,3-thiazole-2-ylsulfonyl) -1H-indole-2-carboxamide LCMS (B) Holding time (minutes): 1.09 MS (ESI, Pos.): 495 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.73-1.86, 2.15-2.24, 2.29-2.40, 3.78-3.87, 4.36, 5.78, 6.96, 7.01, 7.16, 7.24, 7.51, 7.80, 7.91, 7.95, 9.62.
  • Example 19 Retention of 3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -N- (4-morpholinylsulfonyl) -1H-indole-2-carboxamide LCMS (B) Hours (minutes): 1.05 MS (ESI, Pos.): 497 (M + H) + . 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.69-1.84, 2.10-2.28, 3.00-3.11, 3.51-3.59, 3.64-3.77, 4.26, 5.92, 7.01, 7.04, 7.14, 7.23, 7.50, 7.79, 9.98.
  • Example 19 3-[(Cyclobutylamino) methyl] -1- (4-methylbenzyl) -N- (2-thienylsulfonyl) -1H-indole-2-carboxamide
  • LCMS B) retention time ( Minutes): 1.13 MS (ESI, Pos.): 494 (M + H) + .
  • Reference Example 56 Benzyl ⁇ [2-carbamoyl-1- (4-methylbenzyl) -1H-indole-3-yl] methyl ⁇ cyclobutylcarbamate
  • 1-Chloro-N, N, 2-trimethylpropenylamine 886 mg was added, and the mixture was stirred at room temperature for 1 hour.
  • Ammonia 0.5 mol / L 1,4-dioxane solution, 30 mL was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and then methanol was added.
  • Example 20 3-[(Cyclobutylamino) Methyl] -1- (4-Methylbenzyl) -1H-Indole-2-Carboxamide Using the compound (20 mg) prepared in Reference Example 56, the same as in Example 19. The title compound (0.9 mg) having the following physical properties was obtained.
  • Example 20 3-[(Cyclobutylamino) methyl] -N-methoxy-1- (4-methylbenzyl) -1H-indole-2-carboxamide Using the corresponding amino compound instead of ammonia, Reference Example 56 ⁇ The same operation as in Example 20 was carried out to obtain a title compound having the following physical properties.
  • Reference Example 57 Benzyl ⁇ [2-cyano-1- (4-methylbenzyl) -1H-indol-3-yl] methyl ⁇ cyclobutylcarbamate
  • a DCM 6 mL
  • Pyridine (0.94 mL
  • trifluoroacetic anhydride (0.81 mL) were added, and the mixture was stirred at room temperature for 2 hours.
  • Ethyl acetate and 0.5N hydrochloric acid were added to the reaction mixture for extraction.
  • Reference Example 58 Benzyl Cyclobutyl ⁇ [1- (4-methylbenzyl) -2- (1H-tetrazol-5-yl) -1H-indole-3-yl] methyl ⁇ carbamate
  • Ammonium chloride (136 mg) and sodium azide (165 mg) were added to the DMF (2.5 mL) solution of the above, and the mixture was stirred at 120 ° C. for 2 hours using a microwave. Ethyl acetate and 0.5N hydrochloric acid were added to the reaction mixture for extraction. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (250 mg) having the following physical properties.
  • Example 21 N- ⁇ [1- (4-methylbenzyl) -2- (1H-tetrazol-5-yl) -1H-indole-3-yl] methyl ⁇ cyclobutaneamine
  • the compound prepared in Reference Example 58 (50 mg). ) was carried out in the same manner as in Example 19 to obtain the title compound (12 mg) having the following physical property values.
  • Reference Example 59 Benzyl Cyclobutyl ⁇ [2- (N'-hydroxycarbamimidyl) -1- (4-methylbenzyl) -1H-indole-3-yl] methyl ⁇ carbamate
  • Hydroxylamine hydrochloride 157 mg
  • triethylamine 0.32 mL
  • the reaction mixture was cooled to room temperature, ethyl acetate and saturated brine were added, and the mixture was extracted.
  • Example 22 3- ⁇ 3-[(cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-yl ⁇ -1,2,4-oxadiazole-5 (4H) - using the compound prepared in reference example 60, the procedure of example 19 to obtain the title compound having the following physical properties (5.4 mg).
  • Reference Example 62 2-Mercapto-1- (4-methylbenzyl) -1H-indol-3-carbaldehyde Aqueous solution of sodium hydrogen sulfide (334 mg) (3 mL) in a methanol (12 mL) solution of the compound prepared in Reference Example 61. In addition, the mixture was stirred at room temperature for 5 hours. DMF (10 mL) was added to the reaction mixture, and after stirring overnight at room temperature, sodium hydrogen sulfide (334 mg) was added. The reaction mixture was stirred at 50 ° C. for 30 minutes, cooled to room temperature, and then ethyl acetate, water and hydrochloric acid were added for extraction.
  • Reference Example 63 3-formyl-1- (4-methylbenzyl) -1H-indole-2-sulfonic acid Acetic acid (7.5 mL) and 30% hydrogen peroxide in an acetonitrile (20 mL) solution of the compound prepared in Reference Example 62. Water (3.5 mL) was added and the mixture was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction mixture, and the mixture was filtered through Celite (trade name) and extracted. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • Example 23 3-[(Cyclobutylamino) Methyl] -1- (4-Methylbenzyl) -1H-Indole-2-sulfonic Acid Using the compound (5 mg) prepared in Reference Example 63, with Reference Example 4. The same operation was carried out to obtain the title compound (0.6 mg) having the following physical property values.
  • Biological Example 1 LPA3 operative activity measurement experiment using lysophosphatidic acid receptor subtype expressing cells [operation] (Method A) Each cell line (Multispan, Inc., Cat No. C1048-6, C1050-6, and C1053-) using RH7777 cells derived from rat hepatocellular carcinoma as a host and stably expressing human LPA3 receptors, respectively. 6) was subjected to the experiment. The cultured cells were exfoliated until they became subconfluent and suspended in medium (DMEM controlling 10% FBS, 1% penicillin / streptomycin, 30 ⁇ g / mL puromycin) so as to have 4 ⁇ 105 cells / mL. A 96-well optical bottom plate (96 Well Optical Bottom Plates, Asahi Technograss, MT4940-010) was seeded at 100 ⁇ L per well and cultured for 1 day under the conditions of 5% CO 2 and 37 ° C.
  • DMEM DMEM controlling 10% FBS
  • the medium On the day of measurement, the medium was removed, 100 ⁇ L of medium containing 0.2% FBS was added per well, and the cells were cultured for 4 to 6 hours. Then, the medium is removed, and the assay buffer (Hank's Balanced Salt Solution contacting 0.02 mol / L HEPES, 2.5 mmol / L probenecid, 0.1% BSA, 5 ⁇ mol / L Fluo-4, Quenching Buffer, Pluronic F-127 ) was added in an amount of 100 ⁇ L per well, and the mixture was incubated at 5% CO 2 , 37 ° C. for about 1 hour.
  • the assay buffer Hank's Balanced Salt Solution contacting 0.02 mol / L HEPES, 2.5 mmol / L probenecid, 0.1% BSA, 5 ⁇ mol / L Fluo-4, Quenching Buffer, Pluronic F-127
  • a plate is set in a fluorescent drug screening system (Hamamatsu Photonics), 25 ⁇ L of a cell-added solution containing only the test substance or dimethyl sulfoxide (hereinafter abbreviated as DMSO) is added 30 seconds after the start of measurement, and then the ligand is added 3 minutes later. 25 ⁇ L was added, and then the measurement was performed for 4 minutes.
  • DMSO dimethyl sulfoxide
  • the agonistic action of the test substance was calculated as the degree of increase in Ratio after the addition of the test substance when the ratio of increase in Ratio exhibited by the cells to which the cell-added solution containing only DMSO was added was 100%.
  • the EC 50 value was calculated from the activity (%) at a concentration before and after the agonist activity exceeding 50% using Microsoft Excel as a 50% action concentration.
  • Method B Using cells in which the LPA1 receptor of Chinese hamster ovary CHO cells was knocked down as a host, a cell line in which the human LPA3 receptor was stably expressed was used in the experiment. Thaw the cryopreserved cells and load buffer (Hank's Balanced Salt Solution contacting 0.02 mol / L HEPES, 2.5 mmol / L probenecid, 0.1% BSA, 5 ⁇ mol) to 1 ⁇ 10 5 cells / mL. / L Fluo-4, Quenching Buffer, Probenecid F-127).
  • load buffer Hank's Balanced Salt Solution contacting 0.02 mol / L HEPES, 2.5 mmol / L probenecid, 0.1% BSA, 5 ⁇ mol
  • buffer in assay buffer Hank's Balanced Salt Solution contacting 0.02 mol / L HEPES, 2.5 mmol / L probenecid, 0.1% BSA.
  • assay buffer Hank's Balanced Salt Solution contacting 0.02 mol / L HEPES, 2.5 mmol / L probenecid, 0.1% BSA.
  • a plate was set in a fluorescent drug screening system (Hamamatsu Photonics), and 10 ⁇ L of a cell-added solution containing only a positive control, a test substance or DMSO was added 15 seconds after the start of measurement, and measurement was performed for 1 minute.
  • the fluorescence wavelength of 540 nm at the excitation wavelength of 480 nm was measured, and the intracellular Ca 2+ concentration was indicated by the change in fluorescence intensity.
  • the agonistic action of the test substance was calculated as the degree of increase in Ratio after the addition of the test substance, when the ratio of increase in Ratio indicated by the cells to which the cell-added solution containing the positive control was added was 100%.
  • the EC 50 value was calculated from the activity (%) at a concentration before and after the agonist activity exceeding 50% using Microsoft Excel as a 50% action concentration.
  • the compound produced in Example 1 (3) is 0.5 ⁇ mol / L (method A) or 0.2 ⁇ mol / L (method B), and the compound produced in Example 1 (4) is 0.6 ⁇ mol / L (method A).
  • the compound produced in Example 2 is 0.06 ⁇ mol / L (method A)
  • the compound produced in Example 2 (6) is 0.05 ⁇ mol / L (method B), Example 2.
  • the compound prepared in (8) was 0.2 ⁇ mol / L (method A), the compound prepared in Example 2 (18) was 1.0 ⁇ mol / L (method A), and the compound prepared in Example 2 (34) was 0.04 ⁇ mol.
  • Example 2 the compound produced in Example 2 (41) was 0.04 ⁇ mol / L (method B), and the compound produced in Example 2 (46) was 0.1 ⁇ mol / L (method B), Example 2.
  • the compound prepared in (49) was 0.1 ⁇ mol / L (method B), the compound prepared in Example 2 (53) was 0.1 ⁇ mol / L (method B), and the compound prepared in Example 2 (60) was 0.03 ⁇ mol. / L (method B), the compound produced in Example 2 (70) was 0.2 ⁇ mol / L (method B), the compound produced in Example 2 (71) was 0.06 ⁇ mol / L (method B), Example 2.
  • the compound prepared in (72) was 0.1 ⁇ mol / L (method B), the compound prepared in Example 2 (74) was 0.03 ⁇ mol / L (method B), and the compound prepared in Example 2 (75) was 0.06 ⁇ mol. / L (method B), the compound produced in Example 5 was 0.1 ⁇ mol / L (method A), the compound produced in Example 6 (2) was 0.9 ⁇ mol / L (method A), Example 6 (7).
  • the compound produced in Example 7 was 1.0 ⁇ mol / L (method A), the compound produced in Example 7 was 0.1 ⁇ mol / L (method A), and the compound produced in Example 9 (1) was 0.2 ⁇ mol / L (method B).
  • the compound prepared in Example 19 showed an EC 50 value of 0.06 ⁇ mol / L (method B), and the compound prepared in Example 21 showed an EC 50 value of 0.04 ⁇ mol / L (method B).
  • Preparation example 1 3-[(Cyclobutylamino) methyl] -1- (3-cyclopropylbenzyl) -1H-indole-2-carboxylic acid 5 mg-containing tablet After mixing the following components by a conventional method, tablet the tablet. 10,000 tablets containing 5 mg of the active ingredient can be obtained.
  • Preparation example 2 3-[(Cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-indole-2-carboxylic acid 5 mg-containing tablet After mixing the following components by a conventional method, the tablet is beaten into one tablet. 10,000 tablets containing 5 mg of the active ingredient can be obtained.
  • Preparation example 3 3-[(Cyclobutylamino) methyl] -1- (4-methylbenzyl) -1H-pyrrolo [2,3-b] pyridin-2-carboxylic acid 20 mg-containing ampoule
  • the following components were mixed by a conventional method. After that, the solution is sterilized by a conventional method, 5 mL each is filled in ampoules, and lyophilized by a conventional method to obtain 10,000 ampoules containing 20 mg of the active ingredient in one ampoule.
  • a drug containing it as an active ingredient is useful as a prophylactic and / or therapeutic agent for essential thrombocythemia, reactive thrombocytosis and the like.

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PCT/JP2020/044318 2019-11-29 2020-11-27 リゾホスファチジン酸受容体作動活性を有する化合物およびその医薬用途 WO2021107125A1 (ja)

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Publication number Priority date Publication date Assignee Title
WO2022045183A1 (ja) * 2020-08-26 2022-03-03 小野薬品工業株式会社 特発性肺線維症予防および／または治療剤

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