US20190167672A1 - Piperazine-substituted benzothiophene derivatives as antipsychotic agents - Google Patents

Piperazine-substituted benzothiophene derivatives as antipsychotic agents Download PDF

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US20190167672A1
US20190167672A1 US16/268,827 US201916268827A US2019167672A1 US 20190167672 A1 US20190167672 A1 US 20190167672A1 US 201916268827 A US201916268827 A US 201916268827A US 2019167672 A1 US2019167672 A1 US 2019167672A1
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group
alkyl group
lower alkyl
disorder
quinolin
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Hiroshi Yamashita
Yohji Sakurai
Motoyuki Miyamoto
Yuichi Nakamura
Hideaki Kuroda
Takuya Minowa
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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Priority to US16/268,827 priority Critical patent/US20190167672A1/en
Publication of US20190167672A1 publication Critical patent/US20190167672A1/en
Priority to US16/666,546 priority patent/US20200061056A1/en
Priority to US16/896,329 priority patent/US20210052575A1/en
Priority to US17/577,465 priority patent/US20230099694A1/en
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to a novel heterocyclic compound and use thereof.
  • the above-mentioned compound (1) is an antipsychotic agent having a broader treatment spectrum as compared to conventional typical antipsychotic agents and atypical antipsychotic agents, causing less side effects, and superior in tolerability and safety.
  • this compound is associated with problems in that its application to oil injections is limited and the like, since it is poorly soluble in oil such as sesame oil and benzyl benzoate.
  • Oil injections are useful as compared to aqueous suspensions from the aspects of imparted blood concentration sustainability (control of diffusion in administration site by oily base), shortened liquid preparation time when in use (unnecessitated mixing and shaking), secured sterilization by filtration (oily base filtration), avoidance of physical stimulation at administration site (oily base stability), improved accuracy of filling into injection container (container filled with oily base) and the like.
  • the problem of the present invention is to provide a superior, novel heterocyclic compound with improved solubility in oil such as sesame oil and benzyl benzoate and use thereof.
  • the present inventors have conducted various studies in an attempt to solve the aforementioned problems and found that the liposolubility of compound (1) can be markedly improved by introducing a substituent into a particular position on ring Q.
  • the present invention has been completed based on such finding.
  • the present invention preferably provides a heterocyclic compound or a salt thereof shown in the following Items 1-4, a pharmaceutical composition shown in the Item 5, a prophylactic and/or therapeutic agent shown in the Items 6 and 7, use shown in the Item 8, a prophylactic and/or treatment method shown in the Items 9 and 10, and a production method shown in the Item 11.
  • A is a lower alkylene group
  • R 2′ is the following group
  • Y 1′ is a lower alkylene group
  • an alkyl group (2) a cycloalkyl group optionally substituted by a lower alkyl group, (3) a phenyl group, (4) a phenyl lower alkyl group (5) a lower alkoxy group, (6) a cycloalkyloxy group, (7) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a phenyl lower alkyl group, or (8) a piperidyl group optionally having a piperidyl group;
  • R 6 and R 7 are the same or different and each is a hydrogen or a lower alkyl group
  • a lower alkoxy lower alkoxy group a phosphonooxy lower alkoxy group, a phenyl lower alkoxy lower alkoxy group, a phosphonooxy group optionally having 1 or 2 lower alkyl groups, the following group
  • Aa is an alkylene group, and other symbols are as defined above, or the following group
  • R 2 is a hydrogen or the following group
  • Y 1 is a lower alkylene group optionally substituted by (1) a lower alkoxycarbonyl group or (2) a lower alkyl group
  • Y 2 is a lower alkylene group
  • Y 3 is a single bond or a lower alkylene group optionally substituted by a lower alkyl group
  • an alkyl group (2) a halogen-substituted lower alkyl group, (3) an alkenyl group, (4) an amino lower alkyl group, (5) a cycloalkyl group, (6) a phenyl group, (7) a phenyl lower alkyl group, (8) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group and a piperidyl group, (9) a halogen-substituted piperidyl group, (10) a morpholinyl group, (11) a pyrrolidinyl group, (12) a tetrahydropyranyl group, (13) a furyl group, (14) a thienyl group, (15) a pyridyl group, (16) a pyrimidinyl group, (17) a pyridazinyl group, (18) a benzofuryl group, (19) a quinolyl group
  • a hydrogen (2) a lower alkyl group, (3) a halogen-substituted lower alkyl group, (4) a phenyl lower alkyl group, (5) a phenyl lower alkoxy lower alkyl group, (6) a tri-lower alkylsilyl group, (7) a tetrahydropyranyl group, or (8) a phosphono group,
  • an alkyl group (2) an alkenyl group, (3) a phenyl group, (4) a phenyl lower alkyl group, (5) a hydroxy-substituted lower alkyl group, (6) a cycloalkyl group, (7) an amino lower alkyl group optionally having 1 or 2 substituents selected from the group consisting of an amino lower alkylcarbonyl group and a lower alkylcarbonyl group, (8) a pyrrolidinyl group optionally having an amino lower alkylcarbonyl group, (9) an alkoxy group, (10) a lower alkoxy lower alkoxy lower alkyl group, (11) a lower alkoxy lower alkoxy lower alkoxy lower alkyl group, (12) a phenyl lower alkoxy group, (13) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group, a hydroxy-substituted lower alkyl group and a phenyl lower alkyl
  • R 2 is not a hydrogen, or a salt thereof.
  • Item 2 The heterocyclic compound according to Item 1, which is represented by the formula (II)
  • R 1a is the following group
  • an alkyl group (2) a cycloalkyl group, (3) a lower alkoxy group, (4) a cycloalkyloxy group, (5) a lower alkoxy lower alkoxy group, (6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or (7) the following group
  • Aa′ is an alkylene group, and other symbol is as defined in Item 1, or the following group
  • an alkyl group (2) a hydroxy-substituted lower alkyl group, (3) a cycloalkyl group, (4) a lower alkoxy group, (5) a cycloalkyloxy group, (6) a lower alkoxy lower alkoxy group, (7) a phenyloxy group, (8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group, (9) a piperidyl group optionally having a piperidyl group, (10) a piperazinyl group optionally having a lower alkyl group, or (11) the following group
  • Ab′ is an alkylene group, and other symbol is as defined in Item 1;
  • Y 1a is a lower alkylene group
  • Y 2a is a lower alkylene group
  • an alkyl group (2) a cycloalkyl group, (3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group, (4) a tetrahydropyranyl group, (5) a lower alkoxycarbonyl lower alkyl group, (6) a lower alkoxy lower alkoxy lower alkyl group (7) an amino lower alkyl group optionally having a lower alkylcarbonyl group, or (8) the following group
  • an alkyl group (2) a cycloalkyl group, (3) a lower alkoxy group, (4) a cycloalkyloxy group, (5) a lower alkoxy lower alkoxy group, or (6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or the following group
  • an alkyl group (2) a hydroxy-substituted lower alkyl group, (3) a cycloalkyl group, (4) a lower alkoxy group, (5) a cycloalkyloxy group, (6) a lower alkoxy lower alkoxy group, (7) a phenyloxy group, (8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group, (9) a piperidyl group optionally having a piperidyl group, or (10) a piperazinyl group optionally having a lower alkyl group;
  • Y 1a is a lower alkylene group
  • Y 2a is a lower alkylene group
  • an alkyl group (2) a cycloalkyl group (3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group, (4) a tetrahydropyranyl group, (5) a lower alkoxycarbonyl lower alkyl group, (6) a lower alkoxy lower alkoxy lower alkyl group (7) an amino lower alkyl group optionally having a lower alkylcarbonyl group,
  • a pharmaceutical composition comprising the heterocyclic compound according to Item 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and/or a carrier.
  • a prophylactic and/or therapeutic agent for a central neurological disease comprising the heterocyclic compound according to Item 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the central neurological disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, emotional disturbance, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, Alzheimer's disease, Parkinson disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder, Tourette's disorder, tic disorder, attention deficit hyperactivity disorder, conduct disorder and Down's syndrome.
  • Item 8 Use of the heterocyclic compound according to Item 1 or a pharmaceutically acceptable salt thereof as a medicament.
  • Item 9. A method of preventing and/or treating a central neurological disease, comprising administering the heterocyclic compound according to Item 1 or a pharmaceutically acceptable salt thereof to a human or an so animal.
  • the central neurological disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, emotional disturbance, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, Alzheimer's disease, Parkinson disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder, Tourette's disorder, tic disorder, attention deficit hyperactivity disorder, conduct disorder and Down's syndrome.
  • Item 11 A method of producing a heterocyclic compound represented by the formula (I)
  • X 1 is a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined in Item 1, or a salt thereof, with a compound represented by
  • FIG. 1 is a graph showing the transition of blood concentration of test preparations 1, 2 and 3 after administration.
  • halogen atom a fluorine atom, a chlorine atom, a bromine atom and an iodine atom can be mentioned.
  • alkyl group a straight chain or branched chain alkyl group having a carbon number of 1-30 (preferably 1-20) can be mentioned. More specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, l-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 1-methyl,
  • a linear or branched chain alkyl group having a carbon number of 1-6 can be mentioned. More specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl group and the like.
  • alkenyl group a straight chain or branched chain alkenyl group having 1-10 double bonds and a carbon number of 2-30 can be mentioned, including both a trans form and a cis form. More specific examples thereof include ethenyl(vinyl), 1-propenyl, 2-propenyl, l-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-pentene-4-ynyl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-he
  • alkenyl group a straight chain or branched chain alkenyl group having 1-3 double bonds and a carbon number of 2-6 can be mentioned, including both a trans form and a cis form. More specific examples thereof include vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-pentene-4-ynyl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl, 1,3-hexeny
  • cycloalkyl group cyclo C3-C20 alkyl group having 3-20 carbon atoms can be mentioned. More specific examples thereof include monocycloalkyl such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclodecyl group, cyclododecyl group and the like, bicycloalkyl, tricycloalkyl, polycycloalkyl and the like.
  • bicycloalkyl norbornyl, pinanyl, bicyclo[2,2,2]octyl group and the like can be mentioned, and as the tricycloalkyl and polycycloalkyl, adamantyl group and the like can be mentioned.
  • cycloalkyloxy group a cyclo C3-C20 alkyl having 3-20 carbon atoms—oxy group can be mentioned. More specific examples thereof include monocycloalkyloxy such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclooctyloxy group, cyclodecyloxy group, cyclododecyloxy group and the like, bicycloalkyloxy, tricycloalkyloxy, polycycloalkyloxy and the like.
  • monocycloalkyloxy such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclooctyloxy group, cyclodecyloxy group, cyclododecyloxy group and the like, bi
  • cycloalkyloxy norbornyloxy, pinanyloxy, bicyclo[2,2,2]octyloxy group and the like can be mentioned, and as the tricycloalkyloxy and polycycloalkyloxy, adamantyloxy group and the like can be mentioned.
  • a straight chain or branched chain alkoxy group having a carbon number of 1-6 can be mentioned. More specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy group and the like.
  • halogen-substituted lower alkyl group the aforementioned lower alkyl group, which is substituted by 1-7, more preferably 1-3, halogen atoms can be mentioned. More specific examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2-chloroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl, 4,4,4,3,3-p
  • hydroxy-substituted lower alkyl group the aforementioned lower alkyl group, which is substituted by 1-7, more preferably 1-3, hydroxy groups can be mentioned. More specific examples thereof include hydroxymethyl, 2-hydroxyethyl, 1,1-dimethyl-2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxybutyl, 5-hydroxypentyl, 1-hydroxypentyl, 6-hydroxyhexyl and the like.
  • the aforementioned lower alkyl group (preferably a straight chain or branched chain alkyl group having a carbon number of 1-6), which has 1-3, preferably 1, cycloalkyl group mentioned above can be mentioned. It may be substituted with a lower alkyl group on the cycloalkyl group.
  • cycloalkyl lower alkyl group examples include cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, cyclopentylmethyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 5-cycloheptylpentyl, 6-cyclooctylhexyl, 1,1-dimethyl-2-cyclohexylethyl, 2-methyl-3-cyclopropylpropyl group and the like.
  • the amino lower alkyl group As the amino lower alkyl group, the aforementioned lower alkyl group (preferably a straight chain or branched chain alkyl group having a carbon number of 1-6), which has 1-5, preferably 1-3, amino group can be mentioned.
  • Specific examples of the amino lower alkyl group include aminomethyl, diaminomethyl, triaminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1-amino-2-methylethyl, 1-aminobutyl, 1-amino-2-methylpropyl, l-amino-2,2-dimethylethyl, 1-amino-2-methylbutyl, 1-amino-3-methylbutyl, 1-aminohexyl, 1-amino-2-methylpentyl group and the like
  • the phenyl lower alkyl group As the phenyl lower alkyl group, the aforementioned lower alkyl group, which has 1-3, preferably 1, phenyl group can be mentioned. It may be substituted with a lower alkyl group on the phenyl group.
  • Specific examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, diphenylmethyl, 2,2-diphenylethyl group and the like.
  • the furyl lower alkyl group As the furyl lower alkyl group, the aforementioned lower alkyl group, which has 1-3, preferably 1, furyl group can be mentioned. It may be substituted with a lower alkyl group on the furyl group.
  • Specific examples of the furyl lower alkyl group include (2-furyl)methyl, 2-(3-furyl)ethyl, l-(2-furyl)ethyl, 3-(3-furyl)propyl, 4-(2-furyl)butyl, 5-(3-furyl)pentyl, 6-(2-furyl)hexyl, 1,1-dimethyl-2-(3-furyl)ethyl, 2-methyl-3-(2-furyl)propyl group and the like.
  • the aforementioned lower alkyl group which has 1-3, preferably 1, pyridyl group can be mentioned. It may be substituted with a lower alkyl group on the pyridyl group.
  • pyridyl lower alkyl group examples include (4-pyridyl)methyl, 1-(3-pyridyl)ethyl, 2-(2-pyridyl)ethyl, 3-(2-pyridyl)propyl, 4-(3-pyridyl)butyl, 5-(4-pyridyl)pentyl, 6-(2-pyridyl)hexyl, 1,1-dimethyl-2-(3-pyridyl)ethyl, 2-methyl-3-(4-pyridyl)propyl group and the like.
  • the aforementioned lower alkyl group (preferably a straight chain or branched chain alkyl group having a carbon number of 1-6), which has 1-3, preferably 1, lower alkoxy group (preferably a straight chain or branched chain alkoxy group having a carbon number of 1-6) mentioned above can be mentioned.
  • Specific examples of the lower alkoxy lower alkyl group include methoxymethyl, ethoxymethyl, propoxymethyl, hexyloxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxymethyl, butoxy methyl, tert-butoxy methyl, pentyloxymethyl, hexyloxymethyl group and the like.
  • lower alkoxycarbonyl group a straight chain or branched chain alkoxycarbonyl group having a carbon number of 1-6, wherein the lower alkoxy moiety is the aforementioned lower alkoxy group can be mentioned. More specific examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxy, n-hexyloxycarbonyl, isohexyloxycarbonyl, 3-methylpentyloxycarbonyl group and the like.
  • lower alkylcarbonyl group a straight chain or branched chain alkylcarbonyl group having a carbon number of 1-6, wherein the lower alkyl moiety is the aforementioned lower alkyl group can be mentioned. More specific examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like.
  • amino lower alkylcarbonyl group the aforementioned lower alkylcarbonyl group having 1-5, preferably 1 or 2, amino groups, can be mentioned. More specific examples thereof include aminomethylcarbonyl, 2-aminoethylcarbonyl, 1-aminoethylcarbonyl, 3-aminopropylcarbonyl, 4-aminobutylcarbonyl, 5-aminopentylcarbonyl, 6-aminohexylcarbonyl, 1,1-dimethyl-2-aminoethylcarbonyl, 2-methyl-3-aminopropylcarbonyl group and the like.
  • the aforementioned lower alkyl group (preferably straight chain or branched chain alkyl group having a carbon number of 1-6), which has 1-3, preferably 1, lower alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxy, n-hexyloxycarbonyl, isohexyloxycarbonyl, 3-methylpentyloxycarbonyl group etc.) can be mentioned.
  • lower alkoxycarbonyl group e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbon
  • lower alkoxycarbonyl lower alkyl group examples include methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, isopropoxycarbonylmethyl group, butoxycarbonylmethyl group, isobutoxycarbonylmethyl group, sec-butoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group, 2-propoxycarbonylethyl group, 3-methoxycarbonylpropyl group, 3-ethoxycarbonylpropyl group, 4-methoxycarbonylbutyl group, 4-ethoxycarbonylbutyl group and the like.
  • the aforementioned lower alkoxy group (preferably straight chain or branched chain alkoxy group having a carbon number of 1-6), which has 1-3, preferably 1, lower alkoxy group (preferably straight chain or branched chain alkoxy group having a carbon number of 1-6) mentioned above can be mentioned.
  • lower alkoxy lower alkoxy group examples include methoxymethoxy, ethoxymethoxy, propoxymethoxy, hexyloxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, isopropoxymethoxy, butoxymethoxy, tert-butoxymethoxy, pentyloxymethoxy, hexyloxymethoxy group and the like.
  • the phenyl lower alkoxy lower alkoxy group the aforementioned lower alkoxy lower alkoxy group having 1-3, preferably 1, phenyl group can be mentioned.
  • Specific examples of the phenyl lower alkoxy lower alkoxy group include benzyloxymethoxy, 2-phenylethoxymethoxy, 1-phenylethoxymethoxymethoxy, 3-phenylpropoxymethoxy, 4-phenylbutoxymethoxy, 1,1-dimethyl-2-phenylethoxymethoxy, 5-phenylpentyloxymethoxy, 6-phenylhexyloxymethoxy, 2-benzyloxyethoxy, 3-benzyloxypropoxy, 4-benzyloxybutoxy, 1,1-dimethyl-2-benzyloxyethoxy, 5-benzyloxypentoxy, 6-benzyloxyhexyloxy, 2-methyl-3-benzyloxypropoxy group and the like.
  • the aforementioned lower alkyl group (preferably straight chain or branched chain alkyl group having a carbon number of 1-6), which has 1-3, preferably 1, lower alkoxy lower alkoxy group mentioned above can be mentioned.
  • lower alkoxy lower alkoxy lower alkyl group examples include methoxymethoxymethyl, 3-(3-methoxypropoxy)propyl, ethoxymethoxymethyl, 3-(3-ethoxypropoxy)propyl, 4-(4-ethoxybutoxy)butyl, 5-(5-isopropoxypentyloxy)pentyl, 6-(6-propoxyhexyloxy)hexyl, 1,1-dimethyl-2-(2-butoxyethoxy)ethyl, 2-methyl-3-(3-tert-butoxypropoxy)propyl, 2-(2-pentyloxyethoxy)ethyl, hexyloxymethoxymethyl group and the like.
  • the aforementioned lower alkoxy lower alkoxy lower alkyl group having 1-3, preferably 1, lower alkoxy lower alkoxy group mentioned above can be mentioned.
  • Specific examples of the lower alkoxy lower alkoxy lower alkoxy lower alkyl group include methoxyethoxyethoxyethyl, ethoxyethoxyethoxyethyl group and the like.
  • the phenyl lower alkoxy group the aforementioned lower alkoxy group having 1-3, preferably 1, phenyl group can be mentioned.
  • Specific examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1,1-dimethyl-2-phenylethoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 2-benzyloxy, 3-benzyloxy, 4-benzyloxy, 1,1-dimethyl-2-benzyloxy, 5-benzyloxy, 6-benzyloxy, 2-methyl-3-benzyloxy group and the like.
  • the aforementioned lower alkoxy group (preferably straight chain or branched chain alkoxy group having a carbon number of 1-6), which has 1-3, preferably 1, phosphono group can be mentioned.
  • Specific examples of the phosphono lower alkoxy group include phosphonomethoxy, phosphonoethoxy, phosphonopropoxy, phosphonobutoxy, phosphonopentyloxy, phosphonohexyloxy group and the like.
  • piperidyl group optionally having a lower alkyl group a piperidyl group optionally having 1-3, preferably 1, lower alkyl group mentioned above can be mentioned.
  • Specific examples of the piperidyl group optionally having a lower alkyl group include piperidyl, 2-methylpiperidyl, 3-methylpiperidyl, 2-ethylpiperidyl, 3-ethylpiperidyl group and the like.
  • halogen-substituted piperidyl group a piperidyl group substituted by 1-7, more preferably 1-3, halogen atoms can be mentioned. More specific examples thereof include fluoropiperidyl, difluoropiperidyl, chloropiperidyl, dichloropiperidyl, bromopiperidyl, dibromopiperidyl group and the like.
  • the tri-lower alkylsilyl group is a silyl group substituted by 3 lower alkyl groups mentioned above. Specific examples thereof include trimethylsilyl, ethyldimethylsilyl, n-propyldimethylsilyl, tert-butyldimethylsilyl, triethylsilyl, methyldiethylsilyl, dimethylethylsilyl, triisopropylsilyl group and the like.
  • a straight chain or branched chain alkylene group having a carbon number of 1-6 can be mentioned. More specific examples thereof include methylene, ethylene, trimethylene, 2-methyltrimethylene, 3-methyltetramethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene group and the like.
  • alkylene group a straight chain or branched chain alkylene group having a carbon number of 1-30 can be mentioned. More specific examples thereof include methylene, ethylene, trimethylene, tetramethylene, hexamethylene, heptamethylene, octamethylene, decamethylene, undecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene, hexadecamethylene, octadecamethylene, tricosamethylene, hexacosamethylene, triacontamethylene, 1-methylethylene, 2-ethyltrimethylene, 1-methylheptamethylene, 2-methylheptamethylene, 1-butylhexamethylene, 2-methyl-5-ethylheptamethylene, 2,3,6-trimethylheptamethylene, 6-ethyldecamethylene, 7-methyltetradecamethylene, 7-ethylhexadecamethylene, 7,12-dimethyloctadecamethylene, 8,11-dimethyloctadecam
  • the heterocyclic compound represented by the formula (I) is a cation, it is preferably present as a salt together with anion.
  • the anion includes a halogen ion (e.g., Cl—, I—) and the like.
  • R 1 is preferably the following group
  • an alkyl group (2) a cycloalkyl group, (3) a lower alkoxy group, (4) a cycloalkyloxy group, (5) a lower alkoxy lower alkoxy group, (6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or (7) the following group
  • Aa′ is an alkylene group and A is a lower alkylene group, or the following group
  • an alkyl group (2) a hydroxy-substituted lower alkyl group, (3) a cycloalkyl group, (4) a lower alkoxy group, (5) a cycloalkyloxy group, (6) a lower alkoxy lower alkoxy group, (7) a phenyloxy group, (8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group, (9) a piperidyl group optionally having a piperidyl group, (10) a piperazinyl group optionally having a lower alkyl group, or (11) the following group
  • Ab′ is an alkylene group and A is a lower alkylene group, more preferably, the following group
  • an alkyl group (2) a cycloalkyl group, (3) a lower alkoxy group, (4) a cycloalkyloxy group, (5) a lower alkoxy lower alkoxy group, or (6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or the following group
  • an alkyl group (2) a hydroxy-substituted lower alkyl group, (3) a cycloalkyl group, (4) a lower alkoxy group, (5) a cycloalkyloxy group, (6) a lower alkoxy lower alkoxy group, (7) a phenyloxy group, (8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group, (9) a piperidyl group optionally having a piperidyl group, or (10) a piperazinyl group optionally having a lower alkyl group.
  • Y 1a is a lower alkylene group
  • Y 2a is a lower alkylene group
  • an alkyl group (2) a cycloalkyl group, (3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group, (4) a tetrahydropyranyl group, (5) a lower alkoxycarbonyl lower alkyl group, (6) a lower alkoxy lower alkoxy lower alkyl group, (7) an amino lower alkyl group optionally having a lower alkylcarbonyl group, or (8) the following group
  • Ac′ is an alkylene group
  • Y 1a is a lower alkylene group
  • A is a lower alkylene group
  • R 2 is the following group
  • Y 1a is a lower alkylene group
  • Y 2a is a lower alkylene group
  • an alkyl group (2) a cycloalkyl group, (3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group, (4) a tetrahydropyranyl group, (5) a lower alkoxycarbonyl lower alkyl group, (6) a lower alkoxy lower alkoxy lower alkyl group, or (7) an amino lower alkyl group optionally having a lower alkylcarbonyl group,
  • the heterocyclic compound represented by the formula (I) is preferably a heterocyclic compound represented by the following formula (II)
  • a heterocyclic compound represented by the above-mentioned formula (I) (hereinafter sometimes to be referred to as compound (I)) can be produced by various methods. For example, it can be produced by a method shown by the following reaction scheme.
  • the halogen atom for X 1 is as defined above.
  • Examples of the group that causes a substitution reaction similar to that by a halogen atom include a lower alkanesulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group and the like.
  • lower alkanesulfonyloxy group for X 1 include a straight chain or branched chain alkanesulfonyloxy group having a carbon number of 1-6 such as methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy, isopropanesulfonyloxy, n-butanesulfonyloxy, tert-butanesulfonyloxy, n-pentanesulfonyloxy, n-hexanesulfonyloxy group and the like.
  • arylsulfonyloxy group for X 1 examples include phenylsulfonyloxy, naphthylsulfonyloxy group and the like, which optionally have, as a substituent on the phenyl ring, 1-3 groups selected from the group consisting of a straight chain or branched chain alkyl group having a carbon number of 1-6, a straight chain or branched chain alkoxy group having a carbon number of 1-6, a nitro group and a halogen atom.
  • phenylsulfonyloxy group optionally having substituent(s) include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy group and the like.
  • the naphthylsulfonyloxy group include ⁇ -naphthylsulfonyloxy, ⁇ -naphthylsulfonyloxy group and the like.
  • Examples of the aralkylsulfonyloxy group for X 1 include a straight chain or branched chain alkanesulfonyloxy group having a carbon number of 1-6 and substituted by a phenyl group, which optionally have, as a substituent on the phenyl ring, 1-3 groups selected from the group consisting of a straight chain or branched chain alkyl group having a carbon number of 1-6, a straight chain or branched chain alkoxy group having a carbon number of 1-6, a nitro group and a halogen atom, a straight chain or branched chain alkanesulfonyloxy group having a carbon number of 1-6 and substituted by a naphthyl group and the like.
  • alkanesulfonyloxy group substituted by a phenyl group examples include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy group and the like.
  • alkanesulfonyloxy group substituted by a naphthyl group examples include ⁇ -naphthylmethylsulfonyloxy, ⁇ -naphthylmethylsulfonyloxy group and the like.
  • reaction of a compound represented by the formula (I-a) and a compound represented by the formula (I-b) is performed without solvent or in an inert solvent, in the presence or absence of a basic compound.
  • the inert solvent examples include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethylether, ethylene glycol dimethylether and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; lower alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methylethyl ketone and the like; polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric acid triamide, acetonitrile and the like.
  • ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethylether, ethylene glycol dimethylether and the like
  • aromatic hydrocarbons such as benzene, toluene, xylene and the like
  • lower alcohols such as
  • alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide and the like
  • alkali metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate and the like
  • alkali metal hydrogen carbonate such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like
  • alkali metal such as sodium, potassium and the like
  • inorganic base such as sodium amide, sodium hydride, potassium hydride and the like, and alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and the like
  • organic base such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-di
  • One kind alone from these basic compounds is used, or two or more kinds thereof are mixed and used.
  • the amount of the basic compound to be used is generally 0.5-10-fold mol, preferably 0.5-6-fold mol, relative to the compound of the formula (I-a).
  • the above-mentioned reaction can be performed by adding, as necessary, an alkali metal iodide such as potassium iodide, sodium iodide and the like as a reaction promoter.
  • an alkali metal iodide such as potassium iodide, sodium iodide and the like as a reaction promoter.
  • the proportion of the compound of the formula (I-a) and the compound of the formula (I-b) to be used in the above-mentioned reaction scheme-1 is generally at least 0.5-fold mol, preferably about 0.5- to 5-fold mol, of the latter relative to the former.
  • the above-mentioned reaction is performed generally at room temperature-200° C., preferably room temperature-150° C., and completes in about 1-30 hr.
  • X 2 is a hydroxyl group, a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined above.
  • halogen atom or group that causes a substitution reaction similar to that by a halogen atom for X 2 is as defined above.
  • reaction of a compound represented by the formula (I-c) and a compound represented by the formula (I-d) is performed under the reaction conditions similar to those of the reaction of a compound represented by the formula (I-a) and a compound represented by the formula (I-b) in the aforementioned reaction scheme-1.
  • reaction of compound (I-c) and compound (I-d) can also be performed in a suitable solvent, in the presence of a condensing agent.
  • the solvent to be used here include water; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate and the like; alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve, methylcellosolve and the like; aprotic polar solvent such as acetonitrile, pyridine, acetone, DMF, DMSO, hexamethylphosphoric acid triamide and the like, and a mixed solvent such
  • azocarboxylate such as diethylazodicarboxylate and the like
  • phosphorus compound such as triphenylphosphine and the like, and the like
  • the amount of the condensing agent to be used is generally at least an equimolar amount, preferably equimole to 2-fold molar amount, relative to compound (I-c).
  • the amount of compound (I-d) to be used is generally at least an equimolar amount, preferably equimole to 2-fold molar amount, relative to compound (I-c).
  • This reaction preferably proceeds generally at 0-200° C., preferably about 0-150° C., and generally completes in about 1-10 hr.
  • the compound of the formula (I-a) to be used as a starting material is produced, for example, by of the method shown in the following reaction scheme-3, and the compound represented by the formula (I-d) is produced, for example, by of the method shown in the following reaction scheme-4.
  • X 3 is a hydroxyl group, a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined above.
  • halogen atom or group that causes a substitution reaction similar to that by a halogen atom for X 3 is as defined above.
  • reaction of a compound represented by the formula (I-c) and a compound represented by X 3 -A-X 1 is performed under the reaction conditions similar to those of the reaction of a compound represented by the formula (I-c) and a compound represented by the formula (I-d) in the aforementioned reaction scheme-2.
  • X 4 is a hydroxyl group, a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined above.
  • halogen atom or group that causes a substitution reaction similar to that by a halogen atom for X 4 is as defined above.
  • reaction of a compound represented by the formula (I-b) and a compound represented by X 2 -A-X 4 is performed under the reaction conditions similar to those of the reaction of a compound represented by the formula (I-a) and a compound represented by the formula (I-b) in the aforementioned reaction scheme-1. Both the compound of the formula (I-b) and a compound represented by X 2 -A-X 4 are easily-available known compounds.
  • X 5 is a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined above.
  • halogen atom or group that causes a substitution reaction similar to that by a halogen atom for X 5 is as defined above.
  • reaction of a compound represented by the formula (I-e) and a compound represented by R 2 —X 5 is performed under the reaction conditions similar to those of the reaction of a compound represented by the formula (I-a) and a compound represented by the formula (I-b) in the aforementioned reaction scheme-1.
  • a compound (I) having a hydroxyl group on the bicyclic heterocycle skeleton containing Z and W is produced by treating a compound (I) having a methoxy group on the skeleton in a suitable solvent or without solvent, in the presence of an acid.
  • solvent used here examples include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; fatty acid such as acetic acid and the like; esters such as ethyl acetate, methyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; acetonitrile, pyridine, DMF, DMSO, hexamethylphosphoric acid triamide and a mixed solvent thereof and the like.
  • aromatic hydrocarbons such as benzene, toluene, xylene and the like
  • ethers such as diethyl ether, tetrahydrofuran, diox
  • the acid examples include mineral acid such as hydrobromic acid, hydrochloric acid, conc. sulfuric acid and the like, fatty acid such as formic acid, acetic acid and the like, organic acid such as p-toluenesulfonic acid and the like, Lewis acid such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron trifluoride, boron tribromide and the like, iodide such as sodium iodide, potassium iodide and the like, a mixture of the above-mentioned Lewis acid and iodide and the like.
  • mineral acid such as hydrobromic acid, hydrochloric acid, conc. sulfuric acid and the like
  • fatty acid such as formic acid, acetic acid and the like
  • organic acid such as p-toluenesulfonic acid and the like
  • Lewis acid such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron trifluoride,
  • Such acid is preferably used in an amount of generally 0.1- to 15-fold molar amount, preferably 0.5- to 10-fold molar amount, relative to compound (I).
  • an acid is generally used in an excess amount.
  • This reaction is performed generally at 0-150° C., preferably about 0-100° C., and generally completes in about 0.5-75 hr.
  • the starting compound used for each of the above-mentioned reaction schemes may be a preferable salt, and the object compound obtained in each reaction may form a preferable salt.
  • the preferable salt thereof may be similar to the preferable salts of compound (I) shown below.
  • the preferable salt of compound (I) is a pharmaceutically acceptable salt and, for example, metal salts such as alkali metal salt (e.g., sodium salt, potassium salt etc.), alkaline earth metal salt (e.g., calcium salt, magnesium salt etc.) and the like; salts with inorganic bases such as ammonium salt, alkali metal carbonate (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate etc.), alkali metal hydrogen carbonate (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate etc.), alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide etc.) and the like; salts with organic bases such as tri(lower)alkylamine (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine etc.), pyridine, quinoline, piperidine, imidazole, picoline
  • compound (I) and a salt thereof are sometimes to be generically referred to as the compound of the present invention.
  • a compound wherein a solvate e.g., hydrate, ethanolate etc.
  • a solvate e.g., hydrate, ethanolate etc.
  • hydrate can be mentioned.
  • Each object compound obtained in each of the above-mentioned reaction schemes can be isolated and purified from the reaction mixture by for example, cooling the reaction mixture, applying an isolation operation of filtration, concentration, extraction and the like to separate a crude reaction product, and applying a general purification operation such as column chromatography, recrystallization and the like.
  • Compound (I) naturally encompasses isomers such as a geometric isomer, a stereoisomer, an optical isomer and the like.
  • Compound (I) usable in the present invention is also encompasses same compounds labeled with the isotope, wherein one or plural atoms is(are) replaced by one or plural atoms having a particular atomic mass or mass number.
  • isotope that can be incorporated into compound (I) include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 36 Cl and the like.
  • Compound (I) labeled with particular isotope which contains the above-mentioned isotope and/or other isotope of other atom, for example, compound (I) incorporating a radioactive isotope such as 3 H, 14 C and the like, is useful for drug tissue distribution assay and/or substrate tissue distribution assay.
  • Tritiated (i.e., 3 H) or carbon-14 (i.e., 14 C) isotope are particularly preferred because of easiness of preparation and detectability.
  • substitution with a heavier isotope such as deuterium (i.e., 2 H) and the like is expected to provide improved metabolic stability and particular therapeutic advantage attributable to increased in vivo half-time or decreased amount of necessary administration.
  • An isotope-labeled compound of compound (I) can be generally prepared according to the method disclosed in WO2006/112464, by substituting a non-isotope-labeled reagent with an easily available isotope-labeled reagent.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or a cocrystal salt.
  • the cocrystal or cocrystal salt means a crystalline substance, which is constituted from two or more kinds of specific solids each having different physical properties (e.g., structure, melting point, heat of fusion and the like) at room temperature.
  • the cocrystal and cocrystal salt can be produced by applying a cocrystallization method known per se.
  • Compound (I) and a salt thereof are used in the form of a general pharmaceutical preparation.
  • Such preparation is prepared using a diluent or excipient generally used such as filler, extender, binder, humidifying agent, disintegrant, surface activating agent, lubricant and the like.
  • the pharmaceutical preparation can have various forms depending on the treatment object, and representative examples include tablet, pill, powder, liquid, suspension, emulsion, granule, capsule, suppository, injection (liquid, suspension etc.) and the like.
  • a carrier for formulation of a tablet, various ones conventionally known as a carrier in this field can be widely used.
  • excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like
  • binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and the like
  • disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and the like
  • disintegration inhibitors such as sucrose, stearin, cacao butter, hydrogenation oil and the like
  • absorption promoters such as qua
  • a carrier for formulation of a pill, various ones conventionally known as a carrier in this field can be widely used.
  • excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc and the like, binders such as gum arabic powder, tragacanth powder, gelatin, ethanol and the like, disintegrants such as laminaran, agar and the like; and the like.
  • a carrier for formulation of a suppository, various ones conventionally known as a carrier in this field can be widely used.
  • examples thereof include polyethylene glycol, cacao butter, higher alcohol, higher alcohol esters, gelatin, semisynthetic glyceride and the like.
  • a capsule is prepared by a conventional method by generally mixing an active ingredient compound with various carriers mentioned above and filling the mixture in a hard gelatin capsule, a soft capsule and the like.
  • a liquid, an emulsion and a suspension are preferably sterilized and isotonic with blood.
  • various ones conventionally known as a diluent in this field can be widely used. Examples thereof include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like.
  • sodium chloride, glucose or glycerol in an amount sufficient for the preparation of an isotonic solution may be contained in a pharmaceutical preparation, or general solubilizing agent, buffering agent, soothing agent and the like may be further added.
  • colorant, preservative, fragrant material, flavor, sweetening agent and the like and other pharmaceutical products may be further contained in the pharmaceutical preparation.
  • the amount of compound (I) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range. It is generally about 1-70 wt %, preferably about 1-30 wt %, of the preparation composition.
  • the administration method of the pharmaceutical preparation of the present invention is not particularly limited, and a method suitable for various dosage forms, age, sex and other conditions of patients, level of disease and the like is employed for administration.
  • tablet, pill, liquid, suspension, emulsion, granule and capsule are orally administered.
  • An injection is intravenously administered singly or as a mixture with a general fluid replacement such as glucose, amino acid and the like. Where necessary, it is administered singly by intramuscular, intradermal, subcutaneous or intraperitoneal administration.
  • a suppository is intrarectally administered.
  • the amount of the active ingredient compound is generally about 0.1-10 mg per day and per 1 kg body weight.
  • the active ingredient compound in the range of about 1-200 mg is desirably contained in a unit administration form of preparation.
  • the compound of the present invention has a D 2 receptor partial agonist effect, a 5-HT 2A receptor antagonist effect and a serotonin uptake inhibitory effect (or serotonin reuptake inhibitory effect).
  • the D 2 receptor partial agonist effect suppresses dopaminergic (DA) neurotransmission when it is enhanced, and accelerates the DAergic neurotransmission when it is lowered and thus has a function to stabilize the DA neurotransmission to a normal state (dopamine system stabilizer).
  • DA dopaminergic
  • lowering excellent clinically improving effect on the abnormal DA neurotransmission (enhancement and lowering), for example, improving effect on positive and negative symptoms, improving effect on cognitive impairment, improving effect on depressive symptom etc. are developed without causing side effects (see Michio Toru: Clinical Psychiatry, vol. 46, pages 855-864 (2004), Tetsuro Kikuchi and Tsuyoshi Hirose: Brain Science, vol. 25, pages 579-583 (2004), and Harrison, T. S. and Perry, C. M.: Drugs 64: 1715-1736, 2004).
  • 5-HT 2A receptor antagonist effect reduces extrapyramidal side effects, develops superior clinical effects, and is effective, for example, for improvement of negative symptoms, improvement of cognitive impairment, improvement of depressive symptom, improvement of insomnia and the like (see Jun Ishigooka and Ken Inada: Japanese Journal of Clinical Psychopharmacology, vol. 4, pages 1653-1664 (2001), Mitsukuni Murasaki: Japanese Journal of Clinical Psychopharmacology, vol. 1, pages 5-22 (1998), Pullar, I. A. et al.: Eur. J. Pharmacol., 407: 39-46, 2000, and Meltzer, H. Y. et al.: Prog. Neuro-psychopharmacol. Biol. Psychiatry 27: 1159-1172, 2003).
  • Serotonin uptake inhibitory effect (or serotonin reuptake inhibitory effect) is effective, for example, for improvement of depressive symptom (see Mitsukuni Murasaki: Japanese Journal of Clinical Psychopharmacology, vol. 1, pages 5-22 (1998)).
  • the compound of the present invention is excellent in all of these three effects, or remarkably excellent in one or two of these effects.
  • ⁇ 1 receptor antagonist effect is effective for improving positive symptoms of schizophrenia (see Svensson, T. H.: Prog. Neuro-psychopharmacol. Biol. Psychiatry 27: 1145-1158, 2003).
  • the compound of the present invention has a wide treatment spectrum for and excellent clinical effect on schizophrenia and other central nervous system diseases.
  • the compound, the medicament, and pharmaceutical composition of the present invention are extremely effective for the improvement of various central nervous system disorders including schizophrenia, treatment-resistant, refractory or chronic schizophrenia, emotional disturbance, psychotic disorder, mood disorder, bipolar disorder (e.g., bipolar disorder type I and bipolar disorder type II), mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder (e.g., panic attack, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.), somatoform disorder (e.g., hysteria, somatization disorder, conversion disorder, pain disorder, hypochondriasis, etc.), factitious disorder, dissociative disorder, sexual disorder (e.g., sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction, etc.), eating disorder (e.g., an
  • the compound of the present invention scarcely shows side effects and is superior in the tolerability and safety.
  • the compound of the present invention is markedly superior in the solubility in oil such as sesame oil and benzyl benzoate, and can be applied to an oil injection.
  • An oil preparation of the compound of the present invention shows superior blood concentration sustainability. Since the compound of the present invention changes, in blood, to a compound (compound (1)) disclosed in patent document 1, the compound of the present invention is also superior in the long-term maintenance of the blood concentration of compound (1) having desired efficacy.
  • the compound of the present invention is easily crystallized, superior in the operability, and also superior in the chemical stability.
  • the compound (I) of the present invention can exert effects such as decreasing the amount of administration, improving side effects, enhancing therapeutic efficacy or the like which could not attained by conventional treatment by administering with at least one clinically used drug(s) selected from the group consisting of (1) mood stabilizers, (2) serotonin reuptake inhibitors, (3) norepinephrine reuptake inhibitors, (4) serotonin and norepinephrine reuptake inhibitors and (5) antidepressants.
  • at least one clinically used drug(s) selected from the group consisting of (1) mood stabilizers, (2) serotonin reuptake inhibitors, (3) norepinephrine reuptake inhibitors, (4) serotonin and norepinephrine reuptake inhibitors and (5) antidepressants.
  • the compound was synthesized in the same manner as in Reference Example 2.
  • the compound was synthesized in the same manner as in Reference Example 2.
  • the compound was synthesized in the same manner as in Reference Example 10.
  • the compound was synthesized in the same manner as in Reference Example 12.
  • Acetic acid 7-(4-chlorobutoxy)-2-oxo-2H-quinolin-1-ylmethyl ester (299 mg), 1-benzo[b]thiophen-4-ylpiperazine hydrochloride (235 mg), potassium carbonate (319 mg) and sodium iodide (152 mg) were suspended in DMF (5 ml), and this was stirred at 70° C. for 3 hr and further at 80° C. for 4 hr. After cooling to room temperature, to the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure.
  • 2,2,2-Trifluoroethanol (0.10 ml) was dissolved in anhydrous THF (3 ml) under a nitrogen atmosphere and sodium hydride (about 55% oil) (60 mg) was added under ice-cooling. The reaction mixture was stirred at room temperature for 30 min under a nitrogen atmosphere.

Abstract

Provided is a superior, novel heterocyclic compound with improved solubility in oil such as sesame oil and benzyl benzoate, which has a broader treatment spectrum, causes less side effects, and is superior in tolerability and safety, and use thereof. A heterocyclic compound represented by the formula (I) wherein each symbol is as defined in the specification, or a salt thereof.
Figure US20190167672A1-20190606-C00001

Description

    TECHNICAL FIELD OF THE INVENTION
  • The present invention relates to a novel heterocyclic compound and use thereof.
    • BACKGROUND OF THE INVENTION
  • As a compound having a broad treatment spectrum for central neurological diseases such as schizophrenia and the like, for example, a compound represented by the following formula (1) (hereinafter compound (1)) has been reported (patent document 1).
  • Figure US20190167672A1-20190606-C00002
  • wherein each symbol is as defined in patent document 1.
  • The above-mentioned compound (1) is an antipsychotic agent having a broader treatment spectrum as compared to conventional typical antipsychotic agents and atypical antipsychotic agents, causing less side effects, and superior in tolerability and safety. However, this compound is associated with problems in that its application to oil injections is limited and the like, since it is poorly soluble in oil such as sesame oil and benzyl benzoate. Oil injections are useful as compared to aqueous suspensions from the aspects of imparted blood concentration sustainability (control of diffusion in administration site by oily base), shortened liquid preparation time when in use (unnecessitated mixing and shaking), secured sterilization by filtration (oily base filtration), avoidance of physical stimulation at administration site (oily base stability), improved accuracy of filling into injection container (container filled with oily base) and the like.
    • DOCUMENT LIST Patent Document
    • patent document 1: WO2006/112464
    SUMMARY OF THE INVENTION Problems to be Solved by the Invention
  • The problem of the present invention is to provide a superior, novel heterocyclic compound with improved solubility in oil such as sesame oil and benzyl benzoate and use thereof.
    • Means of Solving the Problems
  • The present inventors have conducted various studies in an attempt to solve the aforementioned problems and found that the liposolubility of compound (1) can be markedly improved by introducing a substituent into a particular position on ring Q. The present invention has been completed based on such finding.
  • The present invention preferably provides a heterocyclic compound or a salt thereof shown in the following Items 1-4, a pharmaceutical composition shown in the Item 5, a prophylactic and/or therapeutic agent shown in the Items 6 and 7, use shown in the Item 8, a prophylactic and/or treatment method shown in the Items 9 and 10, and a production method shown in the Item 11.
  • Item 1. A heterocyclic compound represented by the formula (I)
  • Figure US20190167672A1-20190606-C00003
  • wherein
    A is a lower alkylene group;
  • Figure US20190167672A1-20190606-C00004
  • in the monocyclic heterocycle containing Q is
  • Figure US20190167672A1-20190606-C00005
  • wherein
    R2′ is the following group
  • Figure US20190167672A1-20190606-C00006
  • wherein
    Y1′ is a lower alkylene group,
    • R3′ is
  • (1) an alkyl group,
    (2) a cycloalkyl group optionally substituted by a lower alkyl group,
    (3) a phenyl group,
    (4) a phenyl lower alkyl group
    (5) a lower alkoxy group,
    (6) a cycloalkyloxy group,
    (7) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a phenyl lower alkyl group, or
    (8) a piperidyl group optionally having a piperidyl group;
  • Figure US20190167672A1-20190606-C00007
  • at the 3-position and the 4-position of the bicyclic heterocycle skeleton containing Z and W is —CH═CH— or
  • Figure US20190167672A1-20190606-C00008
  • wherein R6 and R7 are the same or different and each is a hydrogen or a lower alkyl group;
  • Figure US20190167672A1-20190606-C00009
  • is
  • Figure US20190167672A1-20190606-C00010
  • wherein
    • R1 is
  • a lower alkoxy lower alkoxy group,
    a phosphonooxy lower alkoxy group,
    a phenyl lower alkoxy lower alkoxy group,
    a phosphonooxy group optionally having 1 or 2 lower alkyl groups,
    the following group
  • Figure US20190167672A1-20190606-C00011
  • wherein
    • R8 is
  • (1) an alkyl group,
    (2) a hydroxy-substituted lower alkyl group,
    (3) a cycloalkyl group,
    (4) a phenyl group,
    (5) a phenyl lower alkyl group,
    (6) an alkenyl group,
    (7) a lower alkoxy group,
    (8) a cycloalkyloxy group,
    (9) a lower alkoxy lower alkoxy group,
    (10) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group,
    (11) a piperidyl group optionally having a piperidyl group,
    (12) a piperazinyl group optionally having a lower alkyl group, or
    (13) the following group
  • Figure US20190167672A1-20190606-C00012
  • wherein Aa is an alkylene group, and other symbols are as defined above, or
    the following group
  • Figure US20190167672A1-20190606-C00013
  • wherein
    • R9 is
  • (1) an alkyl group,
    (2) a hydroxy-substituted lower alkyl group,
    (3) a cycloalkyl group,
    (4) a phenyl group,
    (5) a phenyl lower alkyl group,
    (6) an alkenyl group,
    (7) a lower alkoxy group,
    (8) a cycloalkyloxy group,
    (9) a lower alkoxy lower alkoxy group,
    (10) a phenyloxy group,
    (11) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group,
    (12) a piperidyl group optionally having a piperidyl group,
    (13) a piperazinyl group optionally having a lower alkyl group, or
    (14) the following group
  • Figure US20190167672A1-20190606-C00014
  • wherein Ab is an alkylene group, and other symbols are as defined above;
    R2 is a hydrogen or
    the following group
  • Figure US20190167672A1-20190606-C00015
  • wherein
    Y1 is a lower alkylene group optionally substituted by
    (1) a lower alkoxycarbonyl group or
    (2) a lower alkyl group,
    Y2 is a lower alkylene group,
    Y3 is a single bond or a lower alkylene group optionally substituted by a lower alkyl group,
    • R3 is
  • (1) an alkyl group,
    (2) a halogen-substituted lower alkyl group,
    (3) an alkenyl group,
    (4) an amino lower alkyl group,
    (5) a cycloalkyl group,
    (6) a phenyl group,
    (7) a phenyl lower alkyl group,
    (8) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group and a piperidyl group,
    (9) a halogen-substituted piperidyl group,
    (10) a morpholinyl group,
    (11) a pyrrolidinyl group,
    (12) a tetrahydropyranyl group,
    (13) a furyl group,
    (14) a thienyl group,
    (15) a pyridyl group,
    (16) a pyrimidinyl group,
    (17) a pyridazinyl group,
    (18) a benzofuryl group,
    (19) a quinolyl group,
    (20) a lower alkoxycarbonyl lower alkyl group,
    (21) a lower alkoxy lower alkoxy lower alkyl group,
    (22) a lower alkoxy lower alkoxy lower alkoxy lower alkyl group,
    (23) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a lower alkenyl group, a halogen-substituted lower alkyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a phenyl lower alkyl group, a phenyl lower alkoxy group, a furyl lower alkyl group, a pyridyl lower alkyl group, a hydroxy-substituted lower alkyl group,
    (24) an amino lower alkyl group optionally having a lower alkylcarbonyl group,
    (25) a piperazinyl group optionally having a lower alkyl group, or
    (26) the following group
  • Figure US20190167672A1-20190606-C00016
  • wherein Ac is an alkylene group, and other symbols are as defined above,
    • R4 is
  • (1) an alkyl group,
    (2) a phenyl group,
    (3) a phenyl lower alkyl group,
    (4) a halogen-substituted lower alkyl group, or
    (5) a cycloalkyl group,
    • R5 is
  • (1) a hydrogen,
    (2) a lower alkyl group,
    (3) a halogen-substituted lower alkyl group,
    (4) a phenyl lower alkyl group,
    (5) a phenyl lower alkoxy lower alkyl group,
    (6) a tri-lower alkylsilyl group,
    (7) a tetrahydropyranyl group, or
    (8) a phosphono group,
    • R10 is
  • (1) an alkyl group,
    (2) an alkenyl group,
    (3) a phenyl group,
    (4) a phenyl lower alkyl group,
    (5) a hydroxy-substituted lower alkyl group,
    (6) a cycloalkyl group,
    (7) an amino lower alkyl group optionally having 1 or 2 substituents selected from the group consisting of an amino lower alkylcarbonyl group and a lower alkylcarbonyl group,
    (8) a pyrrolidinyl group optionally having an amino lower alkylcarbonyl group,
    (9) an alkoxy group,
    (10) a lower alkoxy lower alkoxy lower alkyl group,
    (11) a lower alkoxy lower alkoxy lower alkoxy lower alkyl group,
    (12) a phenyl lower alkoxy group,
    (13) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group, a hydroxy-substituted lower alkyl group and a phenyl lower alkyl group,
    (14) a morpholino group,
    (15) a piperazinyl group optionally having a lower alkyl group,
    (16) a piperidyl group optionally having a piperidyl group, or
    (17) a cycloalkyloxy group;
    provided when
  • Figure US20190167672A1-20190606-C00017
  • is
  • Figure US20190167672A1-20190606-C00018
  • then
    R2 is not a hydrogen,
    or a salt thereof.
    Item 2. The heterocyclic compound according to Item 1, which is represented by the formula (II)
  • Figure US20190167672A1-20190606-C00019
  • wherein each symbol is as defined in Item 1, or a salt thereof.
    Item 3. The heterocyclic compound according to Item 1, which is represented by the formula (III)
  • Figure US20190167672A1-20190606-C00020
  • wherein
  • Figure US20190167672A1-20190606-C00021
  • is
  • Figure US20190167672A1-20190606-C00022
  • wherein
    R1a is the following group
  • Figure US20190167672A1-20190606-C00023
  • wherein
    • R8a is
  • (1) an alkyl group,
    (2) a cycloalkyl group,
    (3) a lower alkoxy group,
    (4) a cycloalkyloxy group,
    (5) a lower alkoxy lower alkoxy group,
    (6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or
    (7) the following group
  • Figure US20190167672A1-20190606-C00024
  • wherein Aa′ is an alkylene group, and other symbol is as defined in Item 1, or
    the following group
  • Figure US20190167672A1-20190606-C00025
  • wherein
    • R9a is
  • (1) an alkyl group,
    (2) a hydroxy-substituted lower alkyl group,
    (3) a cycloalkyl group,
    (4) a lower alkoxy group,
    (5) a cycloalkyloxy group,
    (6) a lower alkoxy lower alkoxy group,
    (7) a phenyloxy group,
    (8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group,
    (9) a piperidyl group optionally having a piperidyl group,
    (10) a piperazinyl group optionally having a lower alkyl group, or
    (11) the following group
  • Figure US20190167672A1-20190606-C00026
  • wherein Ab′ is an alkylene group, and other symbol is as defined in Item 1;
    • R2a is
  • the following group
  • Figure US20190167672A1-20190606-C00027
  • wherein
    Y1a is a lower alkylene group,
    Y2a is a lower alkylene group,
    • R3a is
  • (1) an alkyl group,
    (2) a cycloalkyl group,
    (3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group,
    (4) a tetrahydropyranyl group,
    (5) a lower alkoxycarbonyl lower alkyl group,
    (6) a lower alkoxy lower alkoxy lower alkyl group
    (7) an amino lower alkyl group optionally having a lower alkylcarbonyl group, or
    (8) the following group
  • Figure US20190167672A1-20190606-C00028
  • wherein Ac′ is an alkylene group, Y1a is a lower alkylene group and other symbols are as defined in Item 1,
    • R4a is
  • (1) an alkyl group, or
    (2) a cycloalkyl group; and
    A is a lower alkylene group,
    or a salt thereof.
    Item 4. The heterocyclic compound according to Item 2, wherein
    • R1 is
  • the following group
  • Figure US20190167672A1-20190606-C00029
  • wherein
    • R8a′ is
  • (1) an alkyl group,
    (2) a cycloalkyl group,
    (3) a lower alkoxy group,
    (4) a cycloalkyloxy group,
    (5) a lower alkoxy lower alkoxy group, or
    (6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or the following group
  • Figure US20190167672A1-20190606-C00030
  • wherein
    • R9a′ is
  • (1) an alkyl group,
    (2) a hydroxy-substituted lower alkyl group,
    (3) a cycloalkyl group,
    (4) a lower alkoxy group,
    (5) a cycloalkyloxy group,
    (6) a lower alkoxy lower alkoxy group,
    (7) a phenyloxy group,
    (8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group,
    (9) a piperidyl group optionally having a piperidyl group, or
    (10) a piperazinyl group optionally having a lower alkyl group;
    • R2 is
  • the following group
  • Figure US20190167672A1-20190606-C00031
  • wherein
    Y1a is a lower alkylene group,
    Y2a is a lower alkylene group,
    • R3a′ is
  • (1) an alkyl group,
    (2) a cycloalkyl group
    (3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group,
    (4) a tetrahydropyranyl group,
    (5) a lower alkoxycarbonyl lower alkyl group,
    (6) a lower alkoxy lower alkoxy lower alkyl group
    (7) an amino lower alkyl group optionally having a lower alkylcarbonyl group,
    • R4a is
  • (1) an alkyl group, or
    (2) a cycloalkyl group;
    or a salt thereof.
    Item 5. A pharmaceutical composition comprising the heterocyclic compound according to Item 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and/or a carrier.
    Item 6. A prophylactic and/or therapeutic agent for a central neurological disease, comprising the heterocyclic compound according to Item 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
    Item 7. The agent according to Item 6, wherein the central neurological disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, emotional disturbance, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, Alzheimer's disease, Parkinson disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder, Tourette's disorder, tic disorder, attention deficit hyperactivity disorder, conduct disorder and Down's syndrome.
    Item 8. Use of the heterocyclic compound according to Item 1 or a pharmaceutically acceptable salt thereof as a medicament.
    Item 9. A method of preventing and/or treating a central neurological disease, comprising administering the heterocyclic compound according to Item 1 or a pharmaceutically acceptable salt thereof to a human or an so animal.
    Item 10. The method according to Item 9, wherein the central neurological disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, emotional disturbance, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, Alzheimer's disease, Parkinson disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder, Tourette's disorder, tic disorder, attention deficit hyperactivity disorder, conduct disorder and Down's syndrome.
    Item 11. A method of producing a heterocyclic compound represented by the formula (I)
  • Figure US20190167672A1-20190606-C00032
  • wherein each symbol is as defined in Item 1,
    or a salt thereof, comprising reacting a compound represented by the formula
  • Figure US20190167672A1-20190606-C00033
  • wherein X1 is a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined in Item 1, or a salt thereof, with a compound represented by
  • Figure US20190167672A1-20190606-C00034
  • wherein Q is as defined in Item 1, or a salt thereof.
    • BRIEF DESCRIPTION OF DRAWINGS
  • FIG. 1 is a graph showing the transition of blood concentration of test preparations 1, 2 and 3 after administration.
    •  DESCRIPTION OF EMBODIMENTS
  • Each group shown in the aforementioned formula (I) is specifically as follows.
  • Lower means, unless otherwise specified, a group having 1 to 6 (preferably 1-4) carbon atoms.
  • As the halogen atom, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom can be mentioned.
  • As the alkyl group, a straight chain or branched chain alkyl group having a carbon number of 1-30 (preferably 1-20) can be mentioned. More specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, l-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 1,1-dimethylpentyl, 4,4-dimethylpentyl, 1-pentylhexyl, n-octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1,1-dimethylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, n-nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, n-decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, n-undecyl, 1,1-dimethylundecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, icosyl, 3,7,11,15-tetramethylhexadecyl, henicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, triacontyl group and the like.
  • As the lower alkyl group, a linear or branched chain alkyl group having a carbon number of 1-6 can be mentioned. More specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl group and the like.
  • As the alkenyl group, a straight chain or branched chain alkenyl group having 1-10 double bonds and a carbon number of 2-30 can be mentioned, including both a trans form and a cis form. More specific examples thereof include ethenyl(vinyl), 1-propenyl, 2-propenyl, l-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-pentene-4-ynyl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl, 1,4-hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icocenyl group and the like.
  • As the lower alkenyl group, a straight chain or branched chain alkenyl group having 1-3 double bonds and a carbon number of 2-6 can be mentioned, including both a trans form and a cis form. More specific examples thereof include vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-pentene-4-ynyl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl, 1,4-hexadienyl group and the like.
  • As the cycloalkyl group, cyclo C3-C20 alkyl group having 3-20 carbon atoms can be mentioned. More specific examples thereof include monocycloalkyl such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclodecyl group, cyclododecyl group and the like, bicycloalkyl, tricycloalkyl, polycycloalkyl and the like. As the bicycloalkyl, norbornyl, pinanyl, bicyclo[2,2,2]octyl group and the like can be mentioned, and as the tricycloalkyl and polycycloalkyl, adamantyl group and the like can be mentioned.
  • As the cycloalkyloxy group, a cyclo C3-C20 alkyl having 3-20 carbon atoms—oxy group can be mentioned. More specific examples thereof include monocycloalkyloxy such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclooctyloxy group, cyclodecyloxy group, cyclododecyloxy group and the like, bicycloalkyloxy, tricycloalkyloxy, polycycloalkyloxy and the like. As the cycloalkyloxy, norbornyloxy, pinanyloxy, bicyclo[2,2,2]octyloxy group and the like can be mentioned, and as the tricycloalkyloxy and polycycloalkyloxy, adamantyloxy group and the like can be mentioned.
  • As the lower alkoxy group, a straight chain or branched chain alkoxy group having a carbon number of 1-6 can be mentioned. More specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy group and the like.
  • As the halogen-substituted lower alkyl group, the aforementioned lower alkyl group, which is substituted by 1-7, more preferably 1-3, halogen atoms can be mentioned. More specific examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2-chloroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5,5-trifluoropentyl, 5-chloropentyl, 6,6,6-trifluorohexyl, 6-chlorohexyl, perfluorohexyl group and the like.
  • As the hydroxy-substituted lower alkyl group, the aforementioned lower alkyl group, which is substituted by 1-7, more preferably 1-3, hydroxy groups can be mentioned. More specific examples thereof include hydroxymethyl, 2-hydroxyethyl, 1,1-dimethyl-2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxybutyl, 5-hydroxypentyl, 1-hydroxypentyl, 6-hydroxyhexyl and the like.
  • As the cycloalkyl lower alkyl group, the aforementioned lower alkyl group (preferably a straight chain or branched chain alkyl group having a carbon number of 1-6), which has 1-3, preferably 1, cycloalkyl group mentioned above can be mentioned. It may be substituted with a lower alkyl group on the cycloalkyl group. Specific examples of the cycloalkyl lower alkyl group include cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, cyclopentylmethyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 5-cycloheptylpentyl, 6-cyclooctylhexyl, 1,1-dimethyl-2-cyclohexylethyl, 2-methyl-3-cyclopropylpropyl group and the like.
  • As the amino lower alkyl group, the aforementioned lower alkyl group (preferably a straight chain or branched chain alkyl group having a carbon number of 1-6), which has 1-5, preferably 1-3, amino group can be mentioned. Specific examples of the amino lower alkyl group include aminomethyl, diaminomethyl, triaminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1-amino-2-methylethyl, 1-aminobutyl, 1-amino-2-methylpropyl, l-amino-2,2-dimethylethyl, 1-amino-2-methylbutyl, 1-amino-3-methylbutyl, 1-aminohexyl, 1-amino-2-methylpentyl group and the like.
  • As the phenyl lower alkyl group, the aforementioned lower alkyl group, which has 1-3, preferably 1, phenyl group can be mentioned. It may be substituted with a lower alkyl group on the phenyl group. Specific examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, diphenylmethyl, 2,2-diphenylethyl group and the like.
  • As the furyl lower alkyl group, the aforementioned lower alkyl group, which has 1-3, preferably 1, furyl group can be mentioned. It may be substituted with a lower alkyl group on the furyl group. Specific examples of the furyl lower alkyl group include (2-furyl)methyl, 2-(3-furyl)ethyl, l-(2-furyl)ethyl, 3-(3-furyl)propyl, 4-(2-furyl)butyl, 5-(3-furyl)pentyl, 6-(2-furyl)hexyl, 1,1-dimethyl-2-(3-furyl)ethyl, 2-methyl-3-(2-furyl)propyl group and the like.
  • As the pyridyl lower alkyl group, the aforementioned lower alkyl group, which has 1-3, preferably 1, pyridyl group can be mentioned. It may be substituted with a lower alkyl group on the pyridyl group. Specific examples of the pyridyl lower alkyl group include (4-pyridyl)methyl, 1-(3-pyridyl)ethyl, 2-(2-pyridyl)ethyl, 3-(2-pyridyl)propyl, 4-(3-pyridyl)butyl, 5-(4-pyridyl)pentyl, 6-(2-pyridyl)hexyl, 1,1-dimethyl-2-(3-pyridyl)ethyl, 2-methyl-3-(4-pyridyl)propyl group and the like.
  • As the lower alkoxy lower alkyl group, the aforementioned lower alkyl group (preferably a straight chain or branched chain alkyl group having a carbon number of 1-6), which has 1-3, preferably 1, lower alkoxy group (preferably a straight chain or branched chain alkoxy group having a carbon number of 1-6) mentioned above can be mentioned. Specific examples of the lower alkoxy lower alkyl group include methoxymethyl, ethoxymethyl, propoxymethyl, hexyloxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxymethyl, butoxy methyl, tert-butoxy methyl, pentyloxymethyl, hexyloxymethyl group and the like.
  • As the lower alkoxycarbonyl group, a straight chain or branched chain alkoxycarbonyl group having a carbon number of 1-6, wherein the lower alkoxy moiety is the aforementioned lower alkoxy group can be mentioned. More specific examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxy, n-hexyloxycarbonyl, isohexyloxycarbonyl, 3-methylpentyloxycarbonyl group and the like.
  • As the lower alkylcarbonyl group, a straight chain or branched chain alkylcarbonyl group having a carbon number of 1-6, wherein the lower alkyl moiety is the aforementioned lower alkyl group can be mentioned. More specific examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like.
  • As the amino lower alkylcarbonyl group, the aforementioned lower alkylcarbonyl group having 1-5, preferably 1 or 2, amino groups, can be mentioned. More specific examples thereof include aminomethylcarbonyl, 2-aminoethylcarbonyl, 1-aminoethylcarbonyl, 3-aminopropylcarbonyl, 4-aminobutylcarbonyl, 5-aminopentylcarbonyl, 6-aminohexylcarbonyl, 1,1-dimethyl-2-aminoethylcarbonyl, 2-methyl-3-aminopropylcarbonyl group and the like.
  • As the lower alkoxycarbonyl lower alkyl group, the aforementioned lower alkyl group (preferably straight chain or branched chain alkyl group having a carbon number of 1-6), which has 1-3, preferably 1, lower alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxy, n-hexyloxycarbonyl, isohexyloxycarbonyl, 3-methylpentyloxycarbonyl group etc.) can be mentioned. Specific examples of the lower alkoxycarbonyl lower alkyl group include methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, isopropoxycarbonylmethyl group, butoxycarbonylmethyl group, isobutoxycarbonylmethyl group, sec-butoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group, 2-propoxycarbonylethyl group, 3-methoxycarbonylpropyl group, 3-ethoxycarbonylpropyl group, 4-methoxycarbonylbutyl group, 4-ethoxycarbonylbutyl group and the like.
  • As the lower alkoxy lower alkoxy group, the aforementioned lower alkoxy group (preferably straight chain or branched chain alkoxy group having a carbon number of 1-6), which has 1-3, preferably 1, lower alkoxy group (preferably straight chain or branched chain alkoxy group having a carbon number of 1-6) mentioned above can be mentioned. Specific examples of the lower alkoxy lower alkoxy group include methoxymethoxy, ethoxymethoxy, propoxymethoxy, hexyloxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, isopropoxymethoxy, butoxymethoxy, tert-butoxymethoxy, pentyloxymethoxy, hexyloxymethoxy group and the like.
  • As the phenyl lower alkoxy lower alkoxy group, the aforementioned lower alkoxy lower alkoxy group having 1-3, preferably 1, phenyl group can be mentioned. Specific examples of the phenyl lower alkoxy lower alkoxy group include benzyloxymethoxy, 2-phenylethoxymethoxy, 1-phenylethoxymethoxymethoxy, 3-phenylpropoxymethoxy, 4-phenylbutoxymethoxy, 1,1-dimethyl-2-phenylethoxymethoxy, 5-phenylpentyloxymethoxy, 6-phenylhexyloxymethoxy, 2-benzyloxyethoxy, 3-benzyloxypropoxy, 4-benzyloxybutoxy, 1,1-dimethyl-2-benzyloxyethoxy, 5-benzyloxypentoxy, 6-benzyloxyhexyloxy, 2-methyl-3-benzyloxypropoxy group and the like.
  • As the lower alkoxy lower alkoxy lower alkyl group, the aforementioned lower alkyl group (preferably straight chain or branched chain alkyl group having a carbon number of 1-6), which has 1-3, preferably 1, lower alkoxy lower alkoxy group mentioned above can be mentioned. Specific examples of the lower alkoxy lower alkoxy lower alkyl group include methoxymethoxymethyl, 3-(3-methoxypropoxy)propyl, ethoxymethoxymethyl, 3-(3-ethoxypropoxy)propyl, 4-(4-ethoxybutoxy)butyl, 5-(5-isopropoxypentyloxy)pentyl, 6-(6-propoxyhexyloxy)hexyl, 1,1-dimethyl-2-(2-butoxyethoxy)ethyl, 2-methyl-3-(3-tert-butoxypropoxy)propyl, 2-(2-pentyloxyethoxy)ethyl, hexyloxymethoxymethyl group and the like.
  • As the lower alkoxy lower alkoxy lower alkoxy lower alkyl group, the aforementioned lower alkoxy lower alkyl group having 1-3, preferably 1, lower alkoxy lower alkoxy group mentioned above can be mentioned. Specific examples of the lower alkoxy lower alkoxy lower alkoxy lower alkyl group include methoxyethoxyethoxyethyl, ethoxyethoxyethoxyethyl group and the like.
  • As the phenyl lower alkoxy group, the aforementioned lower alkoxy group having 1-3, preferably 1, phenyl group can be mentioned. Specific examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1,1-dimethyl-2-phenylethoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 2-benzyloxy, 3-benzyloxy, 4-benzyloxy, 1,1-dimethyl-2-benzyloxy, 5-benzyloxy, 6-benzyloxy, 2-methyl-3-benzyloxy group and the like.
  • As the phosphono lower alkoxy group, the aforementioned lower alkoxy group (preferably straight chain or branched chain alkoxy group having a carbon number of 1-6), which has 1-3, preferably 1, phosphono group can be mentioned. Specific examples of the phosphono lower alkoxy group include phosphonomethoxy, phosphonoethoxy, phosphonopropoxy, phosphonobutoxy, phosphonopentyloxy, phosphonohexyloxy group and the like.
  • As the piperidyl group optionally having a lower alkyl group, a piperidyl group optionally having 1-3, preferably 1, lower alkyl group mentioned above can be mentioned. Specific examples of the piperidyl group optionally having a lower alkyl group include piperidyl, 2-methylpiperidyl, 3-methylpiperidyl, 2-ethylpiperidyl, 3-ethylpiperidyl group and the like.
  • As the halogen-substituted piperidyl group, a piperidyl group substituted by 1-7, more preferably 1-3, halogen atoms can be mentioned. More specific examples thereof include fluoropiperidyl, difluoropiperidyl, chloropiperidyl, dichloropiperidyl, bromopiperidyl, dibromopiperidyl group and the like.
  • The tri-lower alkylsilyl group is a silyl group substituted by 3 lower alkyl groups mentioned above. Specific examples thereof include trimethylsilyl, ethyldimethylsilyl, n-propyldimethylsilyl, tert-butyldimethylsilyl, triethylsilyl, methyldiethylsilyl, dimethylethylsilyl, triisopropylsilyl group and the like.
  • As the lower alkylene group, a straight chain or branched chain alkylene group having a carbon number of 1-6 can be mentioned. More specific examples thereof include methylene, ethylene, trimethylene, 2-methyltrimethylene, 3-methyltetramethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene group and the like.
  • As the alkylene group, a straight chain or branched chain alkylene group having a carbon number of 1-30 can be mentioned. More specific examples thereof include methylene, ethylene, trimethylene, tetramethylene, hexamethylene, heptamethylene, octamethylene, decamethylene, undecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene, hexadecamethylene, octadecamethylene, tricosamethylene, hexacosamethylene, triacontamethylene, 1-methylethylene, 2-ethyltrimethylene, 1-methylheptamethylene, 2-methylheptamethylene, 1-butylhexamethylene, 2-methyl-5-ethylheptamethylene, 2,3,6-trimethylheptamethylene, 6-ethyldecamethylene, 7-methyltetradecamethylene, 7-ethylhexadecamethylene, 7,12-dimethyloctadecamethylene, 8,11-dimethyloctadecamethylene, 7,10-dimethyl-7-ethylhexadecamethylene, 1-octadecylethylene, 9,10-dioctyloctadecamethylene, 8,9-dinonylhexadecamethylene, ethenylene, 1-octadecenylethylene, 7,11-octadecadienylene, 7-ethenyl-9-hexadecamethylene, 7,12-dimethyl-7,11-octadecadienylene, 8,11-dimethyl-7,11-octadecadienylene, 9,10-dioctyl-7,11-octadecadienylene, 8,9-dinonyl-6,10-hexadecadienylene group and the like.
  • When the heterocyclic compound represented by the formula (I) is a cation, it is preferably present as a salt together with anion. The anion includes a halogen ion (e.g., Cl—, I—) and the like.
  • In the formula (I),
  • Figure US20190167672A1-20190606-C00035
  • Figure US20190167672A1-20190606-C00036
  • R1 is preferably the following group
  • Figure US20190167672A1-20190606-C00037
  • wherein
    • R8a is
  • (1) an alkyl group,
    (2) a cycloalkyl group,
    (3) a lower alkoxy group,
    (4) a cycloalkyloxy group,
    (5) a lower alkoxy lower alkoxy group,
    (6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or
    (7) the following group
  • Figure US20190167672A1-20190606-C00038
  • wherein Aa′ is an alkylene group and A is a lower alkylene group, or
    the following group
  • Figure US20190167672A1-20190606-C00039
  • wherein
    • R9a is
  • (1) an alkyl group,
    (2) a hydroxy-substituted lower alkyl group,
    (3) a cycloalkyl group,
    (4) a lower alkoxy group,
    (5) a cycloalkyloxy group,
    (6) a lower alkoxy lower alkoxy group,
    (7) a phenyloxy group,
    (8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group,
    (9) a piperidyl group optionally having a piperidyl group,
    (10) a piperazinyl group optionally having a lower alkyl group, or
    (11) the following group
  • Figure US20190167672A1-20190606-C00040
  • wherein Ab′ is an alkylene group and A is a lower alkylene group,
    more preferably,
    the following group
  • Figure US20190167672A1-20190606-C00041
  • wherein
    • R8a′ is
  • (1) an alkyl group,
    (2) a cycloalkyl group,
    (3) a lower alkoxy group,
    (4) a cycloalkyloxy group,
    (5) a lower alkoxy lower alkoxy group, or
    (6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or
    the following group
  • Figure US20190167672A1-20190606-C00042
  • wherein
    • R9a′ is
  • (1) an alkyl group,
    (2) a hydroxy-substituted lower alkyl group,
    (3) a cycloalkyl group,
    (4) a lower alkoxy group,
    (5) a cycloalkyloxy group,
    (6) a lower alkoxy lower alkoxy group,
    (7) a phenyloxy group,
    (8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group,
    (9) a piperidyl group optionally having a piperidyl group, or
    (10) a piperazinyl group optionally having a lower alkyl group.
  • As R2,
  • the following group
  • Figure US20190167672A1-20190606-C00043
  • wherein
    Y1a is a lower alkylene group,
    Y2a is a lower alkylene group,
    • R3a is
  • (1) an alkyl group,
    (2) a cycloalkyl group,
    (3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group,
    (4) a tetrahydropyranyl group,
    (5) a lower alkoxycarbonyl lower alkyl group,
    (6) a lower alkoxy lower alkoxy lower alkyl group,
    (7) an amino lower alkyl group optionally having a lower alkylcarbonyl group, or
    (8) the following group
  • Figure US20190167672A1-20190606-C00044
  • wherein Ac′ is an alkylene group, Y1a is a lower alkylene group and A is a lower alkylene group,
    • R4a is
  • (1) an alkyl group, or
    (2) a cycloalkyl group is preferable, more preferably, R2 is the following group
  • Figure US20190167672A1-20190606-C00045
  • wherein
    Y1a is a lower alkylene group,
    Y2a is a lower alkylene group,
    • R3a′ is
  • (1) an alkyl group,
    (2) a cycloalkyl group,
    (3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group,
    (4) a tetrahydropyranyl group,
    (5) a lower alkoxycarbonyl lower alkyl group,
    (6) a lower alkoxy lower alkoxy lower alkyl group, or
    (7) an amino lower alkyl group optionally having a lower alkylcarbonyl group,
    • R4a is
  • (1) an alkyl group, or
    (2) a cycloalkyl group.
  • The heterocyclic compound represented by the formula (I) is preferably a heterocyclic compound represented by the following formula (II)
  • Figure US20190167672A1-20190606-C00046
  • wherein each symbol is as defined in the present specification.
  • More preferably, it is a heterocyclic compound represented by the following formula (III)
  • Figure US20190167672A1-20190606-C00047
  • wherein each symbol is as defined In the present specification.
  • That is, in the formula (I),
  • Figure US20190167672A1-20190606-C00048
  • shown at the 3-position and the 4-position of the bicyclic heterocycle skeleton containing Z and W is preferably —CH═CH—, and
  • Figure US20190167672A1-20190606-C00049
  • in the monocyclic heterocycle containing Q is preferably
  • Figure US20190167672A1-20190606-C00050
  • A heterocyclic compound represented by the above-mentioned formula (I) (hereinafter sometimes to be referred to as compound (I)) can be produced by various methods. For example, it can be produced by a method shown by the following reaction scheme.
  • Figure US20190167672A1-20190606-C00051
  • wherein each symbol is as defined above.
  • In the formula (I-a), the halogen atom for X1 is as defined above.
  • Examples of the group that causes a substitution reaction similar to that by a halogen atom include a lower alkanesulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group and the like.
  • Specific examples of the lower alkanesulfonyloxy group for X1 include a straight chain or branched chain alkanesulfonyloxy group having a carbon number of 1-6 such as methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy, isopropanesulfonyloxy, n-butanesulfonyloxy, tert-butanesulfonyloxy, n-pentanesulfonyloxy, n-hexanesulfonyloxy group and the like.
  • Examples of the arylsulfonyloxy group for X1 include phenylsulfonyloxy, naphthylsulfonyloxy group and the like, which optionally have, as a substituent on the phenyl ring, 1-3 groups selected from the group consisting of a straight chain or branched chain alkyl group having a carbon number of 1-6, a straight chain or branched chain alkoxy group having a carbon number of 1-6, a nitro group and a halogen atom. Specific examples of the above-mentioned phenylsulfonyloxy group optionally having substituent(s) include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy group and the like. Specific examples of the naphthylsulfonyloxy group include α-naphthylsulfonyloxy, β-naphthylsulfonyloxy group and the like.
  • Examples of the aralkylsulfonyloxy group for X1 include a straight chain or branched chain alkanesulfonyloxy group having a carbon number of 1-6 and substituted by a phenyl group, which optionally have, as a substituent on the phenyl ring, 1-3 groups selected from the group consisting of a straight chain or branched chain alkyl group having a carbon number of 1-6, a straight chain or branched chain alkoxy group having a carbon number of 1-6, a nitro group and a halogen atom, a straight chain or branched chain alkanesulfonyloxy group having a carbon number of 1-6 and substituted by a naphthyl group and the like. Specific examples of the above-mentioned alkanesulfonyloxy group substituted by a phenyl group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy group and the like. Specific examples of the above-mentioned alkanesulfonyloxy group substituted by a naphthyl group include α-naphthylmethylsulfonyloxy, β-naphthylmethylsulfonyloxy group and the like.
  • The reaction of a compound represented by the formula (I-a) and a compound represented by the formula (I-b) is performed without solvent or in an inert solvent, in the presence or absence of a basic compound.
  • Examples of the inert solvent include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethylether, ethylene glycol dimethylether and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; lower alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methylethyl ketone and the like; polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric acid triamide, acetonitrile and the like.
  • As the basic compound, known ones can be widely used and, for example, alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide and the like; alkali metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate and the like; alkali metal hydrogen carbonate such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; alkali metal such as sodium, potassium and the like; inorganic base such as sodium amide, sodium hydride, potassium hydride and the like, and alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and the like; organic base such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5(DBN), 1,8-diazabicyclo[5.4.0]undecene-7(DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO) and the like.
  • One kind alone from these basic compounds is used, or two or more kinds thereof are mixed and used.
  • The amount of the basic compound to be used is generally 0.5-10-fold mol, preferably 0.5-6-fold mol, relative to the compound of the formula (I-a).
  • The above-mentioned reaction can be performed by adding, as necessary, an alkali metal iodide such as potassium iodide, sodium iodide and the like as a reaction promoter.
  • The proportion of the compound of the formula (I-a) and the compound of the formula (I-b) to be used in the above-mentioned reaction scheme-1 is generally at least 0.5-fold mol, preferably about 0.5- to 5-fold mol, of the latter relative to the former.
  • The above-mentioned reaction is performed generally at room temperature-200° C., preferably room temperature-150° C., and completes in about 1-30 hr.
  • Figure US20190167672A1-20190606-C00052
  • wherein X2 is a hydroxyl group, a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined above.
  • The halogen atom or group that causes a substitution reaction similar to that by a halogen atom for X2 is as defined above.
  • The reaction of a compound represented by the formula (I-c) and a compound represented by the formula (I-d) is performed under the reaction conditions similar to those of the reaction of a compound represented by the formula (I-a) and a compound represented by the formula (I-b) in the aforementioned reaction scheme-1.
  • When compound (I-d) wherein X2 is a hydroxyl group is used, the reaction of compound (I-c) and compound (I-d) can also be performed in a suitable solvent, in the presence of a condensing agent.
  • Specific examples of the solvent to be used here include water; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate and the like; alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve, methylcellosolve and the like; aprotic polar solvent such as acetonitrile, pyridine, acetone, DMF, DMSO, hexamethylphosphoric acid triamide and the like, and a mixed solvent thereof and the like.
  • As the condensing agent, a mixture of azocarboxylate such as diethylazodicarboxylate and the like and phosphorus compound such as triphenylphosphine and the like, and the like can be mentioned.
  • The amount of the condensing agent to be used is generally at least an equimolar amount, preferably equimole to 2-fold molar amount, relative to compound (I-c).
  • The amount of compound (I-d) to be used is generally at least an equimolar amount, preferably equimole to 2-fold molar amount, relative to compound (I-c).
  • This reaction preferably proceeds generally at 0-200° C., preferably about 0-150° C., and generally completes in about 1-10 hr.
  • The compound of the formula (I-a) to be used as a starting material is produced, for example, by of the method shown in the following reaction scheme-3, and the compound represented by the formula (I-d) is produced, for example, by of the method shown in the following reaction scheme-4.
  • Figure US20190167672A1-20190606-C00053
  • wherein X3 is a hydroxyl group, a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined above.
  • The halogen atom or group that causes a substitution reaction similar to that by a halogen atom for X3 is as defined above.
  • The reaction of a compound represented by the formula (I-c) and a compound represented by X3-A-X1 is performed under the reaction conditions similar to those of the reaction of a compound represented by the formula (I-c) and a compound represented by the formula (I-d) in the aforementioned reaction scheme-2.
  • Figure US20190167672A1-20190606-C00054
  • wherein X4 is a hydroxyl group, a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined above.
  • The halogen atom or group that causes a substitution reaction similar to that by a halogen atom for X4 is as defined above.
  • The reaction of a compound represented by the formula (I-b) and a compound represented by X2-A-X4 is performed under the reaction conditions similar to those of the reaction of a compound represented by the formula (I-a) and a compound represented by the formula (I-b) in the aforementioned reaction scheme-1. Both the compound of the formula (I-b) and a compound represented by X2-A-X4 are easily-available known compounds.
  • Figure US20190167672A1-20190606-C00055
  • wherein X5 is a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined above.
  • The halogen atom or group that causes a substitution reaction similar to that by a halogen atom for X5 is as defined above.
  • The reaction of a compound represented by the formula (I-e) and a compound represented by R2—X5 is performed under the reaction conditions similar to those of the reaction of a compound represented by the formula (I-a) and a compound represented by the formula (I-b) in the aforementioned reaction scheme-1.
  • When
  • Figure US20190167672A1-20190606-C00056
  • in the monocyclic heterocycle containing Q is
  • Figure US20190167672A1-20190606-C00057
  • wherein R2′ is as defined above, the compound can be synthesized in the same manner as in the below-mentioned Example 383.
  • A compound wherein R8 is
  • Figure US20190167672A1-20190606-C00058
  • wherein each symbol is as defined above,
    a compound wherein R9 is
  • Figure US20190167672A1-20190606-C00059
  • wherein each symbol is as defined above, and
    a compound wherein R3 is
  • Figure US20190167672A1-20190606-C00060
  • wherein each symbol is as defined above,
    can be synthesized by a combination of the methods described in the below-mentioned Example 14 and Example 22.
  • A compound (I) having a hydroxyl group on the bicyclic heterocycle skeleton containing Z and W is produced by treating a compound (I) having a methoxy group on the skeleton in a suitable solvent or without solvent, in the presence of an acid.
  • Examples of the solvent used here include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; fatty acid such as acetic acid and the like; esters such as ethyl acetate, methyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; acetonitrile, pyridine, DMF, DMSO, hexamethylphosphoric acid triamide and a mixed solvent thereof and the like.
  • Examples of the acid include mineral acid such as hydrobromic acid, hydrochloric acid, conc. sulfuric acid and the like, fatty acid such as formic acid, acetic acid and the like, organic acid such as p-toluenesulfonic acid and the like, Lewis acid such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron trifluoride, boron tribromide and the like, iodide such as sodium iodide, potassium iodide and the like, a mixture of the above-mentioned Lewis acid and iodide and the like.
  • Such acid is preferably used in an amount of generally 0.1- to 15-fold molar amount, preferably 0.5- to 10-fold molar amount, relative to compound (I). When the reaction is performed without solvent, an acid is generally used in an excess amount.
  • This reaction is performed generally at 0-150° C., preferably about 0-100° C., and generally completes in about 0.5-75 hr.
  • The starting compound used for each of the above-mentioned reaction schemes may be a preferable salt, and the object compound obtained in each reaction may form a preferable salt. The preferable salt thereof may be similar to the preferable salts of compound (I) shown below.
  • The preferable salt of compound (I) is a pharmaceutically acceptable salt and, for example, metal salts such as alkali metal salt (e.g., sodium salt, potassium salt etc.), alkaline earth metal salt (e.g., calcium salt, magnesium salt etc.) and the like; salts with inorganic bases such as ammonium salt, alkali metal carbonate (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate etc.), alkali metal hydrogen carbonate (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate etc.), alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide etc.) and the like; salts with organic bases such as tri(lower)alkylamine (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-morpholine (e.g., N-methylmorpholine etc.), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and the like; salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate and the like; salts with organic acids such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, glutamate, pamoate and the like; and the like can be mentioned.
  • In the following, compound (I) and a salt thereof are sometimes to be generically referred to as the compound of the present invention.
  • In addition, a compound wherein a solvate (e.g., hydrate, ethanolate etc.) is added to a starting material or object compound shown in each reaction scheme is also encompassed in each formula. As a preferable solvate, hydrate can be mentioned.
  • Each object compound obtained in each of the above-mentioned reaction schemes can be isolated and purified from the reaction mixture by for example, cooling the reaction mixture, applying an isolation operation of filtration, concentration, extraction and the like to separate a crude reaction product, and applying a general purification operation such as column chromatography, recrystallization and the like.
  • Compound (I) naturally encompasses isomers such as a geometric isomer, a stereoisomer, an optical isomer and the like.
  • Compound (I) usable in the present invention is also encompasses same compounds labeled with the isotope, wherein one or plural atoms is(are) replaced by one or plural atoms having a particular atomic mass or mass number. Examples of the isotope that can be incorporated into compound (I) include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine isotopes such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 36Cl and the like. Compound (I) labeled with particular isotope, which contains the above-mentioned isotope and/or other isotope of other atom, for example, compound (I) incorporating a radioactive isotope such as 3H, 14C and the like, is useful for drug tissue distribution assay and/or substrate tissue distribution assay. Tritiated (i.e., 3H) or carbon-14 (i.e., 14C) isotope are particularly preferred because of easiness of preparation and detectability. Furthermore, substitution with a heavier isotope such as deuterium (i.e., 2H) and the like is expected to provide improved metabolic stability and particular therapeutic advantage attributable to increased in vivo half-time or decreased amount of necessary administration. An isotope-labeled compound of compound (I) can be generally prepared according to the method disclosed in WO2006/112464, by substituting a non-isotope-labeled reagent with an easily available isotope-labeled reagent.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or a cocrystal salt. Here, the cocrystal or cocrystal salt means a crystalline substance, which is constituted from two or more kinds of specific solids each having different physical properties (e.g., structure, melting point, heat of fusion and the like) at room temperature. The cocrystal and cocrystal salt can be produced by applying a cocrystallization method known per se.
  • Compound (I) and a salt thereof are used in the form of a general pharmaceutical preparation. Such preparation is prepared using a diluent or excipient generally used such as filler, extender, binder, humidifying agent, disintegrant, surface activating agent, lubricant and the like. The pharmaceutical preparation can have various forms depending on the treatment object, and representative examples include tablet, pill, powder, liquid, suspension, emulsion, granule, capsule, suppository, injection (liquid, suspension etc.) and the like.
  • For formulation of a tablet, various ones conventionally known as a carrier in this field can be widely used. Examples thereof include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like, binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and the like, disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and the like, disintegration inhibitors such as sucrose, stearin, cacao butter, hydrogenation oil and the like, absorption promoters such as quaternary ammonium base, sodium lauryl sulfate and the like, moisturizers such as glycerol, starch and the like, adsorbent such as starch, lactose, kaolin, bentonite, colloidal silicic acid and the like, lubricants such as purified talc, stearate, boric acid powder, polyethylene glycol and the like; and the like. Where necessary, the tablet can take the form of a tablet having a general coating, for example, sugar-coated tablet, gelatin-coated tablet, enteric tablet, film-coated tablet or double-compressed tablet, or multi-layer tablet.
  • For formulation of a pill, various ones conventionally known as a carrier in this field can be widely used. Examples thereof include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc and the like, binders such as gum arabic powder, tragacanth powder, gelatin, ethanol and the like, disintegrants such as laminaran, agar and the like; and the like.
  • For formulation of a suppository, various ones conventionally known as a carrier in this field can be widely used. Examples thereof include polyethylene glycol, cacao butter, higher alcohol, higher alcohol esters, gelatin, semisynthetic glyceride and the like.
  • A capsule is prepared by a conventional method by generally mixing an active ingredient compound with various carriers mentioned above and filling the mixture in a hard gelatin capsule, a soft capsule and the like.
  • For formulation of an injection, a liquid, an emulsion and a suspension are preferably sterilized and isotonic with blood. For formulation into such form, various ones conventionally known as a diluent in this field can be widely used. Examples thereof include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like.
  • In this case, sodium chloride, glucose or glycerol in an amount sufficient for the preparation of an isotonic solution may be contained in a pharmaceutical preparation, or general solubilizing agent, buffering agent, soothing agent and the like may be further added. Where necessary, colorant, preservative, fragrant material, flavor, sweetening agent and the like and other pharmaceutical products may be further contained in the pharmaceutical preparation.
  • The amount of compound (I) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range. It is generally about 1-70 wt %, preferably about 1-30 wt %, of the preparation composition.
  • The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and a method suitable for various dosage forms, age, sex and other conditions of patients, level of disease and the like is employed for administration. For example, tablet, pill, liquid, suspension, emulsion, granule and capsule are orally administered. An injection is intravenously administered singly or as a mixture with a general fluid replacement such as glucose, amino acid and the like. Where necessary, it is administered singly by intramuscular, intradermal, subcutaneous or intraperitoneal administration. A suppository is intrarectally administered.
  • While the dose of the pharmaceutical preparation of the present invention is appropriately selected according to use, age, sex and other conditions of patients, level of disease and the like, the amount of the active ingredient compound is generally about 0.1-10 mg per day and per 1 kg body weight. The active ingredient compound in the range of about 1-200 mg is desirably contained in a unit administration form of preparation.
    • Effect of the Invention
  • The compound of the present invention has a D2 receptor partial agonist effect, a 5-HT2A receptor antagonist effect and a serotonin uptake inhibitory effect (or serotonin reuptake inhibitory effect).
  • The D2 receptor partial agonist effect suppresses dopaminergic (DA) neurotransmission when it is enhanced, and accelerates the DAergic neurotransmission when it is lowered and thus has a function to stabilize the DA neurotransmission to a normal state (dopamine system stabilizer). According to this function, excellent clinically improving effect on the abnormal DA neurotransmission (enhancement and lowering), for example, improving effect on positive and negative symptoms, improving effect on cognitive impairment, improving effect on depressive symptom etc. are developed without causing side effects (see Michio Toru: Clinical Psychiatry, vol. 46, pages 855-864 (2004), Tetsuro Kikuchi and Tsuyoshi Hirose: Brain Science, vol. 25, pages 579-583 (2004), and Harrison, T. S. and Perry, C. M.: Drugs 64: 1715-1736, 2004).
  • 5-HT2A receptor antagonist effect reduces extrapyramidal side effects, develops superior clinical effects, and is effective, for example, for improvement of negative symptoms, improvement of cognitive impairment, improvement of depressive symptom, improvement of insomnia and the like (see Jun Ishigooka and Ken Inada: Japanese Journal of Clinical Psychopharmacology, vol. 4, pages 1653-1664 (2001), Mitsukuni Murasaki: Japanese Journal of Clinical Psychopharmacology, vol. 1, pages 5-22 (1998), Pullar, I. A. et al.: Eur. J. Pharmacol., 407: 39-46, 2000, and Meltzer, H. Y. et al.: Prog. Neuro-psychopharmacol. Biol. Psychiatry 27: 1159-1172, 2003).
  • Serotonin uptake inhibitory effect (or serotonin reuptake inhibitory effect) is effective, for example, for improvement of depressive symptom (see Mitsukuni Murasaki: Japanese Journal of Clinical Psychopharmacology, vol. 1, pages 5-22 (1998)).
  • The compound of the present invention is excellent in all of these three effects, or remarkably excellent in one or two of these effects.
  • In addition, some of the compounds of the present invention have α1 receptor antagonist effect in addition to the above-mentioned effects. The α1 receptor antagonist effect is effective for improving positive symptoms of schizophrenia (see Svensson, T. H.: Prog. Neuro-psychopharmacol. Biol. Psychiatry 27: 1145-1158, 2003).
  • Therefore, the compound of the present invention has a wide treatment spectrum for and excellent clinical effect on schizophrenia and other central nervous system diseases.
  • Accordingly, the compound, the medicament, and pharmaceutical composition of the present invention are extremely effective for the improvement of various central nervous system disorders including schizophrenia, treatment-resistant, refractory or chronic schizophrenia, emotional disturbance, psychotic disorder, mood disorder, bipolar disorder (e.g., bipolar disorder type I and bipolar disorder type II), mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder (e.g., panic attack, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.), somatoform disorder (e.g., hysteria, somatization disorder, conversion disorder, pain disorder, hypochondriasis, etc.), factitious disorder, dissociative disorder, sexual disorder (e.g., sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction, etc.), eating disorder (e.g., anorexia nervosa, bulimia nervosa, etc.), sleep disorder, adjustment disorder, substance-related disorder (e.g., alcohol abuse, alcohol intoxication and drug addiction, stimulant intoxication, narcotism, etc.), anhedonia (e.g., anhedonia, anhedonia, iatrogenic anhedonia, anhedonia of a psychic or mental cause, anhedonia associated with depression, anhedonia associated with schizophrenia, etc.), delirium, cognitive impairment, cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases, cognitive impairment caused by Alzheimer's disease, Parkinson's disease and associated neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder (autism), Tourette's disorder, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down's syndrome and the like.
  • Moreover, the compound of the present invention scarcely shows side effects and is superior in the tolerability and safety.
  • Furthermore, the compound of the present invention is markedly superior in the solubility in oil such as sesame oil and benzyl benzoate, and can be applied to an oil injection. An oil preparation of the compound of the present invention shows superior blood concentration sustainability. Since the compound of the present invention changes, in blood, to a compound (compound (1)) disclosed in patent document 1, the compound of the present invention is also superior in the long-term maintenance of the blood concentration of compound (1) having desired efficacy.
  • In addition, the compound of the present invention is easily crystallized, superior in the operability, and also superior in the chemical stability.
  • In addition, the compound (I) of the present invention can exert effects such as decreasing the amount of administration, improving side effects, enhancing therapeutic efficacy or the like which could not attained by conventional treatment by administering with at least one clinically used drug(s) selected from the group consisting of (1) mood stabilizers, (2) serotonin reuptake inhibitors, (3) norepinephrine reuptake inhibitors, (4) serotonin and norepinephrine reuptake inhibitors and (5) antidepressants.
  • The present invention is explained in more detail in the following by referring to Reference Example, Example and Experimental Example, which are not to be construed as limitative.
    • Reference Example 1 Synthesis of 7-(tert-butyldimethylsilanyloxy)-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00061
  • 7-(tert-Butyl-dimethylsilanyloxy)-3,4-dihydro-1H-quinolin-2-one (830 mg) was suspended in DMF (13 ml), formaldehyde (4.3 ml) and triethylamine (0.083 ml) were added, and the mixture was stirred at 80° C. overnight. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound (36 mg) as white crystals.
    • Reference Example 2 Synthesis of acetic acid 7-(tert-butyldimethylsilanyioxy)-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00062
  • To a solution of 7-(tert-butyldimethylsilanyloxy)-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (37 mg) obtained in Reference Example 1 in dichloromethane were added pyridine (0.049 ml) and acetyl chloride (0.022 ml) and the mixture was stirred at room temperature overnight, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound (26 mg) as a colorless oil.
  • 1H-NMR (CDCl3) δ: 0.20 (s, 6H), 0.99 (s, 9H), 2.10 (s, 3H), 2.65-2.72 (m, 2H), 2.83-2.89 (m, 2H), 5.89 (brs, 2H), 6.51-6.56 (m, 2H), 6.99-7.04 (m, 1H)
    • Reference Example 3 Synthesis of 7-(4-chlorobutoxy)-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00063
  • The compound was synthesized in the same manner as in Reference Example 1.
    • Reference Example 4 Synthesis of acetic acid 7-(4-chlorobutoxy)-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00064
  • The compound was synthesized in the same manner as in Reference Example 2.
  • 1H-NMR (CDCl3) δ: 1.90-2.03 (m, 4H), 2.12 (s, 3H), 2.64-2.72 (m, as 2H), 2.84-2.90 (m, 2H), 3.63 (t, J=6.2 Hz, 2H), 3.99 (t, J=5.7 Hz, 2H), 5.91 (brs, 2H), 6.58 (dd, J=2.3, 8.2 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H)
    • Reference Example 5 Synthesis of 7-benzyloxy-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00065
  • The compound was synthesized in the same manner as in Reference Example 1.
    • Reference Example 6 Synthesis of tetradecanoic acid 7-benzyloxy-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00066
  • The compound was synthesized in the same manner as in Reference Example 2.
    • Reference Example 7 Synthesis of tetradecanoic acid 7-hydroxy-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00067
  • To a solution of tetradecanoic acid 7-benzyloxy-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester (528 mg) obtained in Reference Example 6 in ethanol (10 ml) was added 10% palladium carbon (53 mg), and the mixture was substituted with hydrogen and stirred at room temperature for 2.5 hr. The catalyst was filtered off, and the residue was concentrated under reduced pressure and purified by moderate-pressure silica gel column chromatography (ethyl acetate). After concentration under reduced pressure, the residue was recrystallized from hexane-ethyl acetate to give the title compound (209 mg) as a white powder.
  • 1H-NMR (CDCl3) δ: 0.88 (t, J=6.8 Hz, 3H), 1.20-1.35 (m, 20H), 1.58-1.68 (m, 2H), 2.35 (t, J=7.6 Hz, 2H), 2.65-2.71 (m, 2H), 2.82-2.88 (m, 2H), 5.05 (brs, 1H), 5.90 (brs, 2H), 6.53 (dd, J=2.4, 8.1 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H)
    • Reference Example 8 Synthesis of acetic acid 7-(4-chlorobutoxy)-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00068
  • Acetic acid 7-(4-chlorobutoxy)-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester (339 mg) obtained in Reference Example 4 was dissolved in tetrahydrofuran (10 ml), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (709 mg) was added, and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added aqueous sodium hydrogen carbonate solution and the mixture was stirred, filtered, and the filtrate was extracted with methylene chloride, dried over sodium sulfate, and concentrated under reduced pressure, and the residue was purified by moderate-pressure silica gel column chromatography (ethyl acetate) and concentrated under reduced pressure to give the title compound (299 mg) as a colorless oil.
  • 1H-NMR (CDCl3) δ: 1.94-2.04 (m, 4H), 2.13 (s, 3H), 3.60-3.68 (m, 2H), 4.05-4.12 (m, 2H), 6.32 (brs, 2H), 6.53 (d, J=9.5 Hz, 1H), 6.83 (dd, J=2.2, 8.6 Hz, 1H), 6.89 (d, J=2.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)
    • Reference Example 9 Synthesis of tetradecanoic acid 7-hydroxy-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00069
  • The compound was synthesized in the same manner as in Reference Example 8.
  • 1H-NMR (CDCl3) δ: 0.88 (t, J=6.8 Hz, 3H), 1.17-1.32 (m, 20H), 1.55-1.70 (m, 2H), 2.35 (t, J=7.6 Hz, 2H), 6.31 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.55-6.68 (m, 1H), 6.78-6.82 (m, 1H), 6.84-6.87 (m, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)
    • Reference Example 10 Synthesis of (2-butoxy ethoxy)-acetic acid 7-benzyloxy-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00070
  • To a solution (20 ml) of 7-benzyloxy-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (760 mg) obtained in Reference Example 5, (2-butoxy ethoxy)acetic acid (473 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (771 mg) in methylene chloride was added 4-dimethylaminopyridine (65.5 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. This was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1), and concentrated under reduced pressure to give the title compound (765 mg) as a colorless oil.
  • 1H-NMR (CDCl3) δ: 0.90 (t, J=7.4 Hz, 3H), 1.29-1.40 (m, 2H), 1.50-1.59 (m, 2H), 2.64-2.71 (m, 2H), 2.82-2.90 (m, 2H), 3.44 (t, J=6.7 Hz, 2H), 3.57-3.63 (m, 2H), 3.70-3.75 (m, 2H), 4.18 (s, 2H), 5.06 (s, 2H), 5.95 (brs, 2H), 6.64-6.70 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 7.30-7.45 (m, 5H)
    • Reference Example 11 Synthesis of (2-butoxy ethoxy)-acetic acid 7-hydroxy-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00071
  • The compound was synthesized in the same manner as in Reference Example 7.
  • 1H-NMR (CDCl3) δ: 0.90 (t, J=7.4 Hz, 3H), 1.29-1.40 (m, 2H), 1.52-1.61 (m, 2H), 2.64-2.72 (m, 2H), 2.81-2.88 (m, 2H), 3.49 (t, J=6.8 Hz, 2H), 3.62-3.67 (m, 2H), 3.71-3.76 (m, 2H), 4.19 (s, 2H), 5.98 (brs, 2H), 6.42-6.53 (m, 1H), 6.57 (dd, J=2.3, 8.1 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H)
    • Reference Example 12 Synthesis of undec-10-enoic acid 7-(4-chlorobutoxy)-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00072
  • The compound was synthesized in the same manner as in Reference Example 10.
  • 1H-NMR (CDCl3) δ: 1.23-1.40 (m, 10H), 1.57-1.68 (m, 2H), 1.90-2.07 (m, 6H), 2.35 (t, J=7.5 Hz, 2H), 2.65-2.71 (m, 2H), 2.83-2.89 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.98 (t, J=6.8 Hz, 2H), 4.90-4.95 (m, 1H), 4.95-5.02 (m, 1H), 5.74-5.86 (m, 1H), 5.91 (brs, 2H), 6.58 (dd, J=2.3, 8.1 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H)
    • Reference Example 13 Synthesis of tetradecanoic acid 7-(4-chlorobutoxy)-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00073
  • To a solution (5 ml) of tetradecanoic acid 7-hydroxy-2-oxo-2H-quinolin-1-ylmethyl ester (208 mg) obtained in Reference Example 9 in dimethylformamide were added 1-bromo-4-chlorobutane (0.358 ml) and potassium carbonate (107 mg) and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. This was dried over sodium sulfate, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:0 to 2:1) to give the title compound (216 mg) as a white powder.
  • 1H-NMR (CDCl3) δ: 0.88 (t, J=6.9 Hz, 3H), 1.18-1.33 (m, 20H), 1.56-1.67 (m, 2H), 1.94-2.04 (m, 4H), 2.36 (t, J=8.5 Hz, 2H), 3.61-3.66 (m, 2H), 4.04-4.10 (m, 2H), 6.33 (brs, 2H), 6.53 (d, J=9.4 Hz, 1H), 6.82 (dd, J=2.2, 8.6 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.63 (d, J=9.4 Hz, 1H)
    • Reference Example 14 Synthesis of (2-butoxy-ethoxy)-acetic acid 7-hydroxy-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00074
  • The compound was synthesized in the same manner as in Reference Example 8.
  • 1H-NMR (CDCl3) δ: 0.88 (t, J=7.3 Hz, 3H), 1.22-1.38 (m, 2H), 1.48-1.59 (m, 2H), 3.40-3.50 (m, 2H), 3.58-3.64 (m, 2H), 3.67-3.73 (m, 2H), 4.18 (s, 2H), 6.39 (brs, 2H), 6.50 (d, J=9.4 Hz, 1H), 6.81-6.87 (m, 1H), 6.90-6.94 (m, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H)
    • Reference Example 15 Synthesis of docosanoic acid 7-(4-chlorobutoxy)-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00075
  • The compound was synthesized in the same manner as in Reference Example 12.
  • 1H-NMR (CDCl3) δ: 0.88 (t, J=6.8 Hz, 3H), 1.19-1.35 (m, 36H), 1.58-1.68 (m, 2H), 1.89-2.03 (m, 4H), 2.35 (t, J=7.6 Hz, 2H), 2.64-2.72 (m, 2H), 2.82-2.90 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.98 (t, J=5.6 Hz, 2H), 5.91 (brs, 2H), 6.58 (dd, J=2.3, 8.2 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H)
    • Reference Example 16 Synthesis of undec-10-enoic acid 7-(4-chlorobutoxy)-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00076
  • The compound was synthesized in the same manner as in Reference Example 8.
  • 1H-NMR (CDCl3) δ: 1.20-1.39 (m, 10H), 1.57-1.67 (m, 2H), 1.95-2.05 (m, 6H), 2.36 (t, J=7.5 Hz, 2H), 3.61-3.66 (m, 2H), 4.04-4.10 (m, 2H), 4.90-4.95 (m, 1H), 4.95-5.01 (m, 1H), 5.74-5.85 (m, 1H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.83 (dd, J=2.2, 8.6 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Reference Example 17 Synthesis of 7-(4-bromobutoxy)-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00077
  • To a solution (20 ml) of 7-hydroxy-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.4 g) in DMF were added 1,4-dibromobutane (0.75 ml) and potassium carbonate (0.35 g) and the mixture was stirred at 60° C. for 6 hr. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1-50:1) to give the title compound (0.6 g) as a colorless solid.
  • 1H-NMR (CDCl3) δ: 1.30 (6H, s), 1.88-1.98 (2H, m), 2.02-2.10 (2H, m), 2.47 (2H, s), 3.48 (2H, t, J=6.6 Hz), 3.97 (2H, t, J=6.0 Hz), 6.32 (1H, d, J=2.5 Hz), 6.57 (1H, dd, J=8.5, 2.5 Hz), 7.18 (1H, d, J=8.5 Hz), 8.11 (1H, brs)
    • Reference Example 18 Synthesis of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00078
  • To a solution (20 ml) of 7-(4-bromobutoxy)-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.6 g) obtained in Reference Example 17 in DMF were added 1-benzo[b]thiophen-4-ylpiperazine hydrochloride (0.52 g) and potassium carbonate (0.64 g) and the mixture was stirred at 60° C. for 6 hr. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1-50:1) and crystallized from ethanol to give the title compound (0.33 g) as a white powder.
  • 1H-NMR (CDCl3) δ: 1.30 (6H, s), 1.68-1.78 (2H, m), 1.80-1.90 (2H, m), 2.46 (2H, s), 2.52 (2H, t, J=7.4 Hz), 2.72 (4H, m), 3.19 (4H, m), 3.98 (2H, t, J=6.2 Hz), 6.30 (1H, d, J=2.5 Hz), 6.59 (1H, dd, J=8.5, 2.5 Hz), 6.90 (1H, d, J=7.2 Hz), 7.18 (1H, d, J=8.5 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.1 Hz), 7.69 (1H, brs)
    • Reference Example 19 Synthesis of Iodomethyldodecanoate
  • Figure US20190167672A1-20190606-C00079
  • To a solution of chloromethyl dodecanoate[61413-67-0] (800 mg) in dichloromethane (10 ml) and acetonitrile (10 ml) was added sodium iodide (1.45 g), and the mixture was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with dichloromethane, and dried over Na2SO4. The solvent was evaporated under reduced pressure to give iodomethyldodecanoate (1.05 g).
  • Oil: Brown
  • 1H-NMR (CDCl3) δ ppm: 0.88 (3H, t, J=7.0 Hz), 1.20-1.40 (16H, m), 1.50-1.70 (2H, m), 2.30-2.40 (2H, m), 5.91 (2H, s)
    • Example 1 Synthesis of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00080
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one (1 g) synthesized in the same manner as in WO2006/112464 (Example 11) in DMF (10 ml) were added 37% aqueous formalin solution (3.7 ml) and triethylamine (0.05 ml), and the mixture was heated at 80° C. for hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give a mixture (1 g, 3:2) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one and 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one.
  • 1H-NMR (CDCl3) δ: 1.68-1.80 (2H, m), 1.80-1.90 (2H, m), 2.48-2.55 (2H, m), 2.58-2.66 (2H, m), 2.66-2.78 (4H, m), 2.78-2.85 (1.2H, m), 2.86-2.92 (0.8H, m), 3.14-3.25 (4H, m), 3.94-4.40 (2H, m), 5.36 (1.2H, s), 6.31 (0.4H, d, J=2.3 Hz), 6.53 (0.4H, dd, J=2.4, 8.3 Hz), 6.58 (0.6H, dd, J=2.4, 8.2 Hz), 6.86 (0.6H, d, J=2.4 Hz), 6.89 (1H, d, J=7.2 Hz), 7.20-7.80 (1H, m), 7.27 (1H, t, J=8.4 Hz), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz), 7.74-7.80 (0.4H, br)
    • Example 2 Synthesis of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-benzyloxymethyl-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00081
    • Example 3 Synthesis of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-benzyloxymethoxy-quinoline
  • Figure US20190167672A1-20190606-C00082
  • 7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one (1.0 g, 2.31 mmol) synthesized in the same manner as in WO2006/112464 (Example 1) was suspended in tetrahydrofuran (THF) (20 ml) and, under a nitrogen atmosphere, sodium hydride (55% oil) (0.15 g, 3.44 mmol) was added and the mixture was stirred with heating under reflux for 30 min. The mixture was ice-cooled, benzylchloromethylether (0.48 ml, 3.46 mmol) was added, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added ice water to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=100:0 to 0:100). The first fraction was concentrated under reduced pressure to give 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-benzyloxymethoxy-quinoline (0.15 g) as a colorless oil.
  • 1H-NMR (CDCl3) δ: 1.73-1.83 (2H, m), 1.88-1.97 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.79 (4H, m), 3.15-3.25 (4H, m), 4.14 (2H, t, J=6.5 Hz), 4.83 (2H, s), 5.78 (2H, s), 6.80 (1H, d, J=8.5 Hz), 6.89 (1H, dd, J=0.5 Hz, J=7.5 Hz), 7.04 (1H, dd, J=2.5 Hz, J=9.0 Hz), 7.21 (1H, d, J=2.5 Hz), 7.24-7.43 (8H, m), 7.54 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=8.0 Hz), 7.94 (1H, d, J=8.5 Hz)
  • The second fraction was concentrated to dryness under reduced pressure to give 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-benzyloxymethyl-1H-quinolin-2-one (0.86 g) as a white amorphous solid.
  • 1H-NMR (CDCl3) δ: 1.71-1.81 (2H, m), 1.85-1.94 (2H, m), 2.52 (2H, t, J=7.5 Hz), 2.64-2.78 (4H, m), 3.13-3.25 (4H, m), 4.09 (2H, t, J=6.0 Hz), 4.67 (2H, s), 5.84 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.89 (1H, dd, J=0.5 Hz, J=7.5 Hz), 7.10 (1H, d, J=2.0 Hz), 7.22-7.46 (9H, m), 7.55 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=9.5 Hz)
    • Example 4 Synthesis of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-benzyloxymethyl-3,4-dihydro-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00083
  • 7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one (1.0 g, 2.30 mmol) synthesized in the same manner as in WO2006/112464 (Example 11) was suspended in tetrahydrofuran (THF) (20 ml) and, under a nitrogen atmosphere, sodium hydride (55% oil) (0.15 g, 3.44 mmol) was added, and the mixture was stirred with heating under reflux for 30 min. The mixture was ice-cooled, benzylchloromethylether (0.48 ml, 3.46 mmol) was added, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added ice water to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=100:0 to 0:100) and concentrated under reduced pressure to give the title compound (yield 0.95 g, 74%) as a pale-yellow oil.
  • 1H-NMR (CDCl3) δ: 1.68-1.90 (4H, m), 2.51 (2H, t, J=7.5 Hz), 2.59-2.76 (6H, m), 2.78-2.85 (2H, m), 3.13-3.24 (4H, m), 3.98 (2H, t, J=6.0 Hz), 4.66 (2H, s), 5.44 (2H, s), 6.08 (1H, dd, J=2.5 Hz, J=8.0 Hz), 6.89 (1H, dd, J=0.5 Hz, J=7.5 Hz), 7.00 (1H, d, J=2.5 Hz), 7.03 (1H, d, J=8.0 Hz), 7.23-7.43 (8H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 5 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester
  • Figure US20190167672A1-20190606-C00084
  • 7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one (1.0 g, 2.30 mmol) synthesized in the same manner as in WO2006/112464 (Example 11) was suspended in tetrahydrofuran (THF) (20 ml) and, under a nitrogen atmosphere, sodium hydride (55% oil) (0.11 g, 2.52 mmol) was added, and the mixture was stirred with heating under reflux for 30 min. The mixture was cooled to −70° C., chloromethylphenylcarbonate (0.64 g, 3.43 mmol) was added, and the mixture was stirred at −70° C. for 3 hr. Water was added to the reaction mixture to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=100:0 to 0:100) and concentrated under reduced pressure to give the title compound (yield 0.95 g, 74%) as a colorless oil.
  • 1H-NMR (CDCl3) δ: 1.69-1.91 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.64-2.77 (6H, m), 2.85-2.92 (2H, m), 3.14-3.24 (4H, m), 4.01 (2H, t, J=6.5 Hz), 6.06 (2H, s), 6.62 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.75 (1H, d, J=2.5 Hz), 6.86-6.91 (1H, m), 7.09 (1H, d, J=8.5 Hz), 7.19-7.29 (5H, m), 7.34-7.44 (3H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 6 Synthesis of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-(tert-butyldimethylsilanyloxymethyl)-3,4-dihydro-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00085
  • To a solution (15 ml) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one (1.5 g) synthesized in the same manner as in WO2006/112464 (Example 11) in dimethylformamide (DMF) were added 37% aqueous formalin solution (5.5 ml) and a catalytic amount of triethylamine (0.08 ml) and the mixture was stirred at 80° C. for 20 hr. After cooling to room temperature, and water was added to the reaction mixture. The obtained insoluble material was collected by filtration, dried, and dissolved in dichloromethane (15 ml). Imidazole (0.313 g) and tert-butylchlorodimethylsilane (0.519 g) were added, and the mixture was stirred at room temperature for 1.5 hr. Methanol was added, and the mixture was concentrated. This was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 2:1) to give the title compound (yield 550 mg, 41.3%) as a colorless amorphous solid.
  • 1H-NMR (CDCl3) δ: 0.14 (6H, s), 0.90 (9H, s), 1.70-1.80 (2H, m), 1.80-1.92 (2H, m), 2.42 (2H, t, J=7.5 Hz), 2.58-2.64 (2H, m), 2.68-2.76 (4H, m), 2.78-2.84 (2H, m), 3.14-3.24 (4H, m), 4.00 (2H, t, J=6.3 Hz), 5.45 (2H, s), 6.58 (1H, dd, J=8.2 Hz, 2.5 Hz), 6.76 (1H, dd, J=7.6 Hz, 0.6 Hz), 7.00-7.04 (2H, m), 7.27 (1H, t, J=7.8 Hz), 7.36-7.42 (2H, m), 7.54 (1H, d, J=8.1 Hz)
    • Example 7 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester
  • Figure US20190167672A1-20190606-C00086
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one synthesized in the same manner as in WO2006/112464 (Example 1) and in the same manner as in Example 5, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.71-1.80 (2H, m), 1.85-1.95 (2H, m), 2.53 (2H, t, J=7.5 Hz), 2.65-2.76 (4H, m), 3.14-3.23 (4H, m), 4.08-4.14 (2H, m), 6.46 (2H, brs), 6.53 (1H, d, J=9.5 Hz), 6.84-6.91 (2H, m), 6.97 (1H, d, J=2.0 Hz), 7.18-7.30 (4H, m), 7.35-7.43 (4H, m), 7.47 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.0 Hz), 7.64 (1H, d, J=9.5 Hz)
    • Example 8 Synthesis of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-(tetrahydropyran-2-yloxymethyl)-3,4-dihydro-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00087
  • A solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (0.26 g), which is a mixture with 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one, was suspended in dichloromethane (10 ml), 3,4-dihydro-2H-pyran (0.08 ml) was added, p-toluenesulfonic acid hydrate (0.11 g) was added with stirring under ice-cooling, and the mixture was stirred at room temperature overnight. With stirring under ice-cooling, aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol-60:1) to give 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-(tetrahydro-2H-pyran-2-yloxy)methyl-3,4-dihydro-1H-quinolin-2-one (180 mg).
  • 1H-NMR (CDCl3) δ:1.50-1.80 (10H, m), 2.40-2.90 (6H, m), 2.72 (4H, brs), 3.20 (4H, brs), 3.40-4.00 (2H, m), 4.01 (2H, t, J=6.2 Hz), 4.90-5.30 (3H, m), 6.58 (1H, dd, J=8.2 Hz, 2.4 Hz), 6.90 (1H, d, J=7.6 Hz), 6.95 (1H, d, J=2.4 Hz), 7.04 (1H, d, J=8.2 Hz), 7.27 (1H, t, J=7.9 Hz), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.1 Hz)
    • Example 9 Synthesis of piperidine-1-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00088
  • To a solution (3 ml) of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester (0.29 g) synthesized in the same manner as in Example 5 in THF were added piperidine (0.5 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.05 ml), and the mixture was stirred at room temperature for 16 hr. Water was added and the reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:1) to remove phenol, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) to give the title compound (yield 0.21 g, 74%) as a colorless oil.
  • 1H-NMR (CDCl3) δ: 1.40-1.62 (6H, m), 1.69-1.90 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.62-2.79 (6H, m), 2.81-2.90 (2H, m), 3.13-3.26 (4H, m), 3.31-3.51 (4H, m), 3.99 (2H, t, J=6.0 Hz), 5.93 (2H, s), 6.59 (1H, dd, J=2.5 Hz, 8.0 Hz), 6.78 (1H, d, J=2.5 Hz), 6.86-6.92 (1H, m), 7.05 (1H, d, J=8.5 Hz), 7.23-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, dd, J=0.5 Hz, 5.5 Hz), 7.54 (1H, d, J=8.0 Hz)
    • Example 10 Synthesis of piperidine-1-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00089
  • To a solution (5 ml) of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester (0.44 g) synthesized in the same manner as in Example 7 in THF was added piperidine (0.76 ml), and the mixture was stirred at room temperature for 3.5 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:1) to give the title compound (0.44 g, yield quantitative) as a colorless amorphous solid.
  • 1H-NMR (CDCl3) δ: 1.38-1.61 (6H, m), 1.72-1.82 (2H, m), 1.85-1.96 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.80 (4H, m), 3.14-3.25 (4H, m), 3.29-3.52 (4H, m), 4.10 (2H, t, J=6.0 Hz), 6.36 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, 8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.12 (1H, t, J=2.0 Hz), 7.23-7.31 (1H, m), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 11 Synthesis of benzoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00090
  • Sodium hydride (55% oil) (0.15 g, 2.52 mmol) was suspended in tetrahydrofuran (THF) (20 ml) and, under a nitrogen atmosphere, 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one (1.0 g, 2.30 mmol) synthesized in the same manner as in WO2006/112464 (Example 11) was added, and the mixture was stirred with heating under reflux for 25 min. The mixture was cooled to 0° C., chloromethyl benzoate (0.627 g, 3.67 mmol) was added, and the mixture was stirred at room temperature for 2.5 hr. Under ice-cooling, aqueous ammonium chloride was added to the reaction mixture to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 2:3) and concentrated under so reduced pressure to give the title compound (yield 1.132 g, 86.55%) as a colorless amorphous solid.
  • 1H-NMR (CDCl3) δ: 1.64-1.75 (m, 2H), 1.77-1.86 (m, 2H), 2.44-2.51 (m, 2H), 2.61-2.77 (m, 6H), 2.87-2.93 (m, 2H), 3.11-3.22 (m, 4H), 3.97 (t, J=6.3 Hz, 2H), 6.17 (brs, 2H), 6.61 (dd, J=2.4, 8.3 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.84-6.91 (m, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.27 (dd, =7.7, 7.7 Hz, 1H), 7.37-7.46 (m, 4H), 7.51-7.58 (m, 2H), 8.00-8.07 (m, 2H)
    • Example 12 Synthesis of benzoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00091
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one synthesized in the same manner as in WO2006/112464 (Example 1) and in the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.67-1.78 (m, 2H), 1.81-1.91 (m, 2H), 2.45-2.53 (m, 2H), 2.63-2.75 (m, 4H), 3.11-3.22 (m, 4H), 4.07 (t, J=6.3 Hz, 2H), 6.56 (d, J=9.5 Hz, 1H), 6.59 (brs, 2H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.86-6.90 (m, 1H), 6.98 (d, J=2.2 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.44 (m, 4H), 7.46 (d, J=8.6 Hz, 1H), 7.51-7.59 (m, 2H), 7.65 (d, J=9.5 Hz, 1H), 8.02-8.07 (m, 2H)
    • Example 13 Synthesis of cyclopentanecarboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00092
  • To a solution (20 ml) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (962 mg, 2.066 mmol) synthesized in the same manner as in Example 1, cyclopentanecarboxylic acid (0.448 ml, 4.13 mmol), 2-chloro-1,3-dimethylimidazolium chloride (768 mg, 4.55 mmol) in methylene chloride was added triethylamine (1.267 ml, 9.09 mmol), and the mixture was stirred at room temperature for 1 hr. 2-Chloro-1,3-dimethylimidazolium chloride (768 mg, 4.55 mmol) was added, and the mixture was heated under reflux for 1 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. This was purified by moderate-pressure basic silica gel column (hexane:ethyl acetate=1:3) and concentrated under reduced pressure to give the title compound (yield 261 mg, 22.49%) as a colorless oil.
  • 1H-NMR (CDCl3) δ: 1.50-1.63 (m, 2H), 1.63-1.79 (m, 4H), 1.79-1.95 (m, 6H), 2.52 (t, J=7.4 Hz, 2H), 2.64-2.83 (m, 7H), 2.83-2.89 (m, 2H), 3.13-3.25 (m, 4H), 3.98 (d, J=6.2 Hz, 2H), 5.91 (brs, 2H), 6.57-6.61 (m, 2H), 6.89 (d, J=7.6 Hz, 1H), 7.04-7.09 (m, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.36-7.43 (m, 2H), 7.54 (d, J=8.0 Hz, 1H)
    • Example 14 Synthesis of cyclohexanecarboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00093
  • To a solution (15 ml) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (550 mg) synthesized in the same manner as in Example 1 in dichloromethane was added pyridine (0.287 ml), cyclohexanecarbonyl chloride (0.158 ml) with stirring under ice-cooling and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:3), and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography, and concentrated to dryness under reduced pressure to give the title compound (yield 172 mg, 25.3%) as a colorless amorphous solid.
  • 1H-NMR (CDCl3) δ:1.15-1.32 (m, 3H), 1.40-1.53 (m, 2H), 1.57-1.65 (m, 1H), 1.68-1.79 (m, 4H), 1.81-1.96 (m, 4H), 2.36 (tt, J=3.6, 11.2 Hz, 1H), 2.52 (t, J=7.5 Hz, 2H), 2.65-2.76 (m, 6H), 2.83-2.90 (m, 2H), 3.15-3.24 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.91 (brs, 2H), 6.56-6.63 (m, 2H), 6.87-6.92 (m, 1H), 7.05-7.09 (m, 1H), 7.27 (dd, J=7.7, 7.7 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 15 Synthesis of 2,2-dimethylpropionic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00094
  • In the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.22 (s, 9H), 1.68-1.90 (m, 4H), 2.48-2.55 (m, 2H), 2.65-2.76 (m, 6H), 2.82-2.89 (m, 2H), 3.13-3.24 (m, 4H), 3.97 (t, J=6.2 Hz, 2H), 5.90 (s, 2H), 6.57-6.62 (m, 2H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.7, 7.7 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.1 Hz, 1H)
    • Example 16 Synthesis of N-butyl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00095
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: {0.82 (t, J=7.0 Hz), 0.94 (t, J=7.0 Hz) total 3H (1:1)}, 1.14-1.58 (4H, m), 1.64-1.91 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.63-2.78 (6H, m), 2.81-2.96 (5H, m), 3.13-3.33 (6H, m), 3.99 (2H, t, J=6.0 Hz), 5.92 (2H, s), 6.59 (1H, dd, J=2.0 Hz, 8.0 Hz), 6.77 (1H, d, J=6.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.0 Hz), 7.27 (1H, dd, J=8.0 Hz, 8.0 Hz), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=7.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 17 Synthesis of N-decylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00096
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=7.0 Hz), 1.16-1.34 (14H, m), 1.42-1.53 (2H, m), 1.69-1.89 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.62-2.77 (6H, m), 2.80-2.88 (2H, m), 3.12-3.25 (6H, m), 4.00 (2H, t, J=6.0 Hz), 4.85 (1H, t, J=5.5 Hz), 5.91 (2H, s), 6.59 (1H, dd, J=2.0 Hz, 8.0 Hz), 6.79 (1H, d, J=2.0 Hz), 6.86-6.91 (1H, m), 7.05 (1H, d, J=8.0 Hz), 7.27 (1H, dd, J=8.0 Hz, 8.0 Hz), 7.36-7.44 (2H, m), 7.54 (1H, d, J=8.0 Hz)
    • Example 18 Synthesis of 2,2-dimethylpropionic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00097
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one synthesized in the same manner as in WO2006/112464 (Example 1) and in the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.20 (s, 9H), 1.71-1.81 (m, 2H), 1.85-1.95 (m, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.67-2.78 (m, 4H), 3.15-3.24 (m, 4H), 4.06 (t, J=6.2 Hz, 2H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.88-6.91 (m, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)
    • Example 19 Synthesis of butyric acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00098
  • In the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.96 (t, J=7.4 Hz, 3H), 1.63-1.79 (m, 4H), 1.80-1.90 (m, 2H), 2.35 (t, J=7.4 Hz, 2H), 2.52 (t, J=7.4 Hz, 2H), 2.64-2.77 (m, 6H), 2.82-2.90 (m, 2H), 3.14-3.25 (m, 4H), 3.99 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.57-6.63 (m, 2H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.44 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 20 Synthesis of butyric acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00099
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one synthesized in the same manner as in WO2006/112464 (Example 1) and in the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.94 (t, J=7.4 Hz, 3H), 1.62-1.72 (m, 2H), 1.72-1.82 (m, 2H), 1.86-1.96 (m, 2H), 2.35 (t, J=7.4 Hz, 2H), 2.54 (t, J=7.4 Hz, 2H), 2.65-2.78 (m, 4H), 3.13-3.25 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.86-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)
    • Example 21 Synthesis of dodecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00100
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=6.8 Hz), 1.20-1.36 (16H, m), 1.58-1.69 (2H, m), 1.69-1.80 (2H, m), 1.80-1.90 (2H, m), 2.36 (2H, t, J=7.6 Hz), 2.52 (2H, t, J=7.4 Hz), 2.64-2.76 (6H, m), 2.82-2.90 (2H, m), 3.14-3.26 (4H, br), 3.98 (2H, t, J=6.2 Hz), 5.92 (2H, brs), 6.56-6.64 (2H, m), 6.89 (1H, d, J=7.6 Hz), 7.07 (1H, d, J=8.1 Hz), 7.27 (1H, t, J=7.8 Hz), 7.40 (2H, dd, J=5.6, 12.6 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 22 Synthesis of dodecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00101
  • To a solution (5 ml) of dodecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester (150 mg) synthesized in the same manner as in Example 21 in THF was added trifluoroacetic acid (TFA) (0.11 ml), then to a solution (3 ml) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.27 g) in THE was added, and the mixture was stirred at room temperature for 3 days. To the reaction mixture were added water and sodium carbonate, and the mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate) to give the title compound (yield 50 mg, 33.4%) as a brown oil.
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=6.9 Hz), 1.20-1.34 (16H, m), 1.55-1.68 (2H, m), 1.72-1.82 (2H, m), 1.85-1.94 (2H, m), 2.36 (2H, t, J=7.5 Hz), 2.50-2.60 (2H, m), 2.73 (4H, m), 3.20 (4H, m), 4.08 (2H, t, J=5.3 Hz), 6.34 (2H, brs), 6.52 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.5 Hz), 6.86-6.92 (2H, m), 7.24-7.30 (1H, m), 7.40 (2H, dd, J=5.6, 10.9 Hz), 7.45 (1H, d, J=8.6 Hz), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 23 Synthesis of hexadecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00102
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (t, J=6.8, 3H), 1.18-1.34 (m, 26H), 1.57-1.80 (m, 4H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.53 (t, J=7.5 Hz, 2H), 2.63-2.77 (m, 6H), 2.83-2.89 (m, 2H), 3.15-3.25 (m, 2H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.59 (dd, J=2.3, 8.1 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 24 Synthesis of octanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00103
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.86 (t, J=6.9 Hz, 3H), 1.19-1.35 (m, 8H), 1.59-1.68 (m, 2H), 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.53 (t, J=7.5 Hz, 2H), 2.65-2.78 (m, 6H), 2.83-2.89 (m, 2H), 3.14-3.24 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.2, 8.1 Hz, 1H), 6.62 (d, J=2.2, 1H), 6.88-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.1 Hz, 1H)
    • Example 25 Synthesis of phenylacetic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00104
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.62-1.86 (m, 4H), 2.52 (t, J=7.4 Hz, 2H), 2.65-2.77 (m, 6H), 2.82-2.88 (m, 2H), 3.14-3.25 (m, 4H), 3.68 (s, 2H), 3.85 (t, J=6.2 Hz, 2H), 5.94 (brs, 2H), 6.51 (d, J=2.3 Hz, 1H), 6.58 (dd, J=2.3, 8.2 Hz, 1H), 6.88-6.92 (m, 1H), 7.06 (d, J=8.2 Hz, 1H), 7.23-7.34 (m, 6H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.1 Hz, 1H)
    • Example 26 Synthesis of phenylacetic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00105
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one synthesized in the same manner as in WO2006/112464 (Example 1) and in the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.65-1.88 (m, 4H), 2.52 (t, J=7.4 Hz, 2H), 2.64-2.78 (m, 4H), 3.14-3.25 (m, 4H), 3.67 (s, 2H), 3.87 (t, J=6.2 Hz, 2H), 6.35 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.72 (d, J=2.1 Hz, 1H), 6.82 (dd, J=2.1, 8.6 Hz, 1H), 6.84-6.92 (m, 1H), 7.22-7.31 (m, 6H), 7.37-7.46 (m, 3H), 7.55 (d, J=8.0 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)
    • Example 27 Synthesis of N-butylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00106
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.92 (3H, t, J=7.5 Hz), 1.24-1.40 (2H, m), 1.43-1.53 (2H, m), 1.69-1.80 (2H, m), 1.81-1.91 (2H, m), 2.53 (2H, t, J=7.5 Hz), 2.64-2.77 (6H, m), 2.82-2.89 (2H, m), 3.13-3.27 (6H, m), 4.00 (2H, t, J=6.0 Hz), 4.74-4.82 (1H, m), 5.92 (2H, s), 6.59 (1H, dd, J=2.0 Hz, 8.0 Hz), 6.79 (1H, d, J=6.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.05 (1H, d, J=8.0 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 28 Synthesis of N,N-dibutylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00107
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.80 (3H, t, J=7.0 Hz), 0.93 (3H, t, J=7.0 Hz), 1.13-1.58 (8H, m), 1.68-1.90 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.62-2.78 (6H, m), 2.80-2.89 (2H, m), 3.09-3.30 (8H, m), 3.98 (2H, t, J=6.0 Hz), 5.93 (2H, s), 6.59 (1H, dd, J=2.5 Hz, 8.5 Hz), 6.76 (1H, d, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 29 Synthesis of N-cyclohexylmethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00108
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.81-0.98 (2H, m), 1.07-1.30 (3H, m), 1.36-1.50 (1H, m), 1.59-1.80 (7H, m), 1.81-1.91 (2H, m), 2.53 (2H, t, J=7.5 Hz), 2.63-2.78 (6H, m), 2.81-2.89 (2H, m), 3.05 (2H, J=6.5 Hz), 3.14-3.24 (4H, m), 4.00 (2H, t, J=6.0 Hz), 4.84 (1H, t, J=5.5 Hz), 5.92 (2H, s), 6.59 (1H, dd, J=2.5 Hz, 8.5 Hz), 6.80 (1H, d, J=2.0 Hz), 6.87-6.92 (1H, m), 7.05 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.37-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 30 Synthesis of octanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00109
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.85 (t, J=6.9 Hz, 3H), 1.16-1.33 (m, 8H), 1.57-1.68 (m, 2H), 1.74-1.96 (m, 4H), 2.36 (t, J=7.5 Hz, 2H), 2.52-2.63 (m, 2H), 2.69-2.85 (m, 4H), 3.15-3.29 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.1, 8.6 Hz, 1H), 6.86-6.92 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.42 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 31 Synthesis of icosanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00110
  • To a solution (6 ml) of arachidic acid (1048 mg, 3.35 mmol) in 1,2-dichloroethane was added thionyl chloride (1.217 ml, 16.77 mmol), and the mixture was heated under reflux, and concentrated under reduced pressure to give acid chloride. To a solution (15 ml) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (781 mg, 1.677 mmol) synthesized in the same manner as in Example 1 in dichloromethane were added pyridine (1.357 ml, 16.77 mmol) and the above-mentioned acid chloride, and the mixture was stirred at room temperature for 3 hr. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:1), and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:1), and concentrated to dryness under reduced pressure to give the title compound (yield 856 mg, 67%) as a colorless oil.
  • 1H-NMR (CDCl3) δ: 0.88 (t, J=6.8 Hz, 3H), 1.19-1.35 (m, 32H), 1.57-1.68 (m, 2H), 1.69-1.79 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.6 Hz, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.64-2.77 (m, 6H), 2.83-2.89 (m, 2H), 3.14-3.25 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.3, 8.1 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.1 Hz, 1H)
    • Example 32 Synthesis of cyclohexanecarboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00111
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one synthesized in the same manner as in WO2006/112464 (Example 1) and in the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.14-1.31 (m, 3H), 1.39-1.52 (m, 2H), 1.54-1.65 (m, 1H), 1.67-1.82 (m, 4H), 1.84-1.95 (m, 4H), 2.31-2.41 (m, 1H), 2.54 (t, J=7.6 Hz, 2H), 2.65-2.79 (m, 4H), 3.13-3.25 (m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.81-6.86 (m, 2H), 6.89 (d, J=7.6 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.47 (m, 3H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H).
    • Example 33 Synthesis of (Z)-octadec-9-enoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00112
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ:0.87 (t, J=6.8 Hz, 3H), 1.20-1.36 (m, 20H), 1.58-1.68 (m, 2H), 1.69-1.79 (m, 2H), 1.80-1.90 (m, 2H), 1.93-2.07 (m, 4H), 2.36 (t, J=7.5 Hz, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.64-2.79 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.25 (m, 4H), 3.99 (t, J=6.3 Hz, 2H), 5.28-5.40 (m, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.3, 8.1 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 34 Synthesis of N-decylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00113
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=7.0 Hz), 1.16-1.35 (12H, m), 1.42-1.53 (4H, m), 1.72-1.83 (2H, m), 1.86-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.67-2.80 (4H, m), 3.13-3.28 (6H, m), 4.11 (2H, t, J=6.0 Hz), 4.87 (1H, t, J=5.5 Hz), 6.33 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.87-6.92 (1H, m), 7.16 (1H, d, J=1.5 Hz), 7.24-7.30 (1H, m), 7.36-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 35 Synthesis of N-butylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00114
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.91 (3H, t, J=7.5 Hz), 1.28-1.39 (2H, m), 1.43-1.53 (2H, m), 1.73-1.82 (2H, m), 1.87-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.67-2.78 (4H, m), 3.15-3.24 (6H, m), 4.11 (2H, t, J=6.0 Hz), 4.88 (1H, t, J=5.5 Hz), 6.32 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.15 (1H, d, J=1.5 Hz), 7.24-7.30 (1H, m), 7.37-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 36 Synthesis of N-butyl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00115
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: {0.87 (t, J=7.5 Hz), 0.94 (t, J=7.5 Hz) total 3H (1:1)}, 1.08-1.19 (1H, m), 1.26-1.43 (2H, m), 1.47-1.57 (1H, m), 1.72-1.83 (2H, m), 1.85-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.79 (4H, m), {2.82 (s), 2.92 (s) total 3H (1:1)}, 3.12-3.25 (5H, m), 3.30 (1H, t, J=7.5 Hz), 4.10 (2H, t, J=6.0 Hz), 6.35 (2H, s), 6.52 (1H, dd, J=1.5 Hz, J=9.5 Hz), 6.83 (1H, dd, J=1.5 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.10 (1H, d, J=16.5 Hz), 7.25-7.30 (1H, m), 7.37-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 37 Synthesis of cyclopentanecarboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00116
  • To a solution (10 ml) of cyclopentanecarboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester (252 mg) synthesized in the same manner as in Example 13 in THF was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (509 mg), and the mixture was stirred at room temperature stirred for 2 days. To the reaction mixture were added water and sodium carbonate, and the mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) and further by NH silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) to give the title compound (yield 38 mg, 15%) as a colorless amorphous solid.
  • 1H-NMR (CDCl3) δ:1.50-1.62 (m, 2H), 1.62-1.95 (m, 10H), 2.54 (t, J=7.5 Hz, 2H), 2.67-2.83 (m, 5H), 3.14-3.25 (m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.81-6.86 (m, 2H), 6.89 (d, J=7.4 Hz, 1H), 7.27 (t, J=7.9, 7.9 Hz, 1H), 7.37-7.47 (m, 3H), 7.55 (d, J=7.9 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 38 Synthesis of N-octadecylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00117
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (3H, t, J=7.0 Hz), 1.13-1.34 (30H, m), 1.43-1.53 (2H, m), 1.73-1.83 (2H, m), 1.85-1.965 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.79 (4H, m), 3.13-3.25 (6H, m), 4.12 (2H, t, J=6.0 Hz), 4.85 (1H, t, J=5.5 Hz), 6.33 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.16 (1H, d, J=1.5 Hz), 7.24-7.30 (1H, m), 7.36-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 39 Synthesis of (Z)-octadec-9-enoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00118
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one synthesized in the same manner as in WO2006/112464 (Example 1) and in the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (t, J=6.8 Hz, 3H), 1.18-1.35 (m, 20H), 1.57-1.68 (m, 2H), 1.72-1.82 (m, 2H), 1.86-2.04 (m, 6H), 2.36 (t, J=7.4 Hz, 2H), 2.52 (t, J=7.4 Hz, 2H), 2.67-2.79 (m, 4H), 3.14-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 5.26-5.39 (m, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.86-6.91 (m, 2H), 7.27 (t, J=7.9 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 40 Synthesis of 2-pentylheptanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00119
  • In the same manner as in Example 31, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.85 (t, 6H), 1.17-1.31 (m, 12H), 1.37-1.49 (m, 2H), 1.55-1.78 (m, 4H), 1.79-1.89 (m, 2H), 2.32-2.41 (m, 1H), 2.52 (t, J=7.4 Hz, 2H), 2.64-2.77 (m, 6H), 2.82-2.89 (m, 2H), 3.13-3.24 (m, 4H), 3.97 (t, J=6.2 Hz, 2H), 5.94 (brs, 2H), 6.59 (dd, J=2.3, 8.2 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 6.87-6.92 (m, 1H), 7.06 (d, J=8.2 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H),
    • Example 41 Synthesis of icosanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00120
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ:0.88 (t, J=6.8 Hz, 3H), 1.18-1.33 (m, 32H), 1.58-1.67 (m, 2H), 1.72-1.82 (m, 2H), 1.86-1.96 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.67-2.77 (m, 4H), 3.14-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.1, 8.6 Hz, 1H), 6.86-6.91 (m, 2H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.36-7.43 (m, 2H), 7.44 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 42 Synthesis of hexadecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00121
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (t, J=6.8 Hz, 3H), 1.18-1.32 (m, 24H), 1.58-1.67 (m, 2H), 1.72-1.95 (m, 4H), 2.36 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.66-2.78 (m, 4H), 3.14-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.86-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.36-7.43 (m, 2H), 7.44 (d, J=9.5 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 43 Synthesis of N-pentadecylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00122
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (3H, t, J=7.0 Hz), 1.16-1.33 (24H, m), 1.42-1.53 (2H, m), 1.72-1.83 (2H, m), 1.86-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.67-2.78 (4H, m), 3.14-3.24 (6H, m), 4.11 (2H, t, J=6.0 Hz), 4.86 (1H, t, J=5.5 Hz), 6.33 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.39 (1H, d, J=−1.5 Hz), 7.24-7.29 (1H, m), 7.37-7.44 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 44 Synthesis of N-methyl-N-octadecylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00123
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (3H, t, J=7.0 Hz), 1.01-1.32 (30H, m), 1.33-1.43 (1H, m), 1.47-1.58 (1H, m), 1.72-1.83 (2H, m), 1.85-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.78 (4H, m), {2.82 (s), 2.93 (s) total 3H (1:1)}, 3.12-3.24 (5H, m), 3.25-3.32 (1H, m), 4.09 (2H, t, J=5.5 Hz), 6.36 (2H, s), 6.52 (1H, dd, J=2.0 Hz, J=9.5 Hz), 6.83 (1H, d, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.10 (1H, d, J=17.5 Hz), 7.24-7.30 (1H, m), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.66 (1H, dd, J=4.0 Hz, J=9.5 Hz)
    • Example 45 Synthesis of N,N-dibutylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00124
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.72 (3H, t, J=7.5 Hz), 0.93 (3H, t, J=7.5 Hz), 1.06-1.19 (2H, m), 1.24-1.42 (4H, m), 1.48-1.59 (2H, m), 1.72-1.83 (2H, m), 1.85-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.65-2.83 (4H, m), 3.12 (2H, t, J=7.5 Hz), 3.15-3.23 (4H, m), 3.26 (2H, J=7.5 Hz), 4.09 (2H, t, J=6.0 Hz), 6.36 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.07 (1H, d, J=2.0 Hz), 7.25-7.31 (1H, m), 7.37-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 46 Synthesis of N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00125
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.70-1.80 (2H, m), 1.81-1.91 (2H, m), 2.53 (2H, t, J=7.5 Hz), 2.63-2.77 (6H, m), 2.79-2.89 (5H, m), 3.14-3.24 (4H, m), 4.00 (2H, t, J=6.0 Hz), 4.75 (1H, d, J=4.0 Hz), 5.92 (2H, s), 6.59 (1H, dd, J=2.5 Hz, 8.5 Hz), 6.78 (1H, d, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 47 Synthesis of N,N-dimethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00126
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.79 (2H, m), 1.81-1.90 (2H, m), 2.52 (2H, t, J=7.5 Hz), 2.64-2.77 (6H, m), 2.83-2.91 (2H, m), 2.88 (3H, s), 2.95 (3H, s), 3.14-3.24 (4H, m), 4.00 (2H, t, J=6.5 Hz), 5.92 (2H, s), 6.59 (1H, dd, J=2.5 Hz, 8.5 Hz), 6.78 (1H, d, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.42 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 48 Synthesis of octadecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00127
  • To a solution (20 ml) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (640 mg, 2.066 mmol) synthesized in the same manner as in Example 1, stearic acid (587 mg, 2.062 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (395 mg, 2.062 mmol) in methylene chloride was added 4-dimethylaminopyridine (33.6 mg, 0.275 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. This was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) and further by basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) and concentrated under reduced pressure to give the title compound (yield 649 mg, 64.5%) as a colorless oil.
  • 1H-NMR (CDCl3) δ:0.88 (t, J=6.9 Hz, 3H), 1.18-1.35 (m, 28H), 1.59-1.68 (m, 2H), 1.69-1.79 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.52 (t, J=7.4 Hz, 2H), 2.65-2.76 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.24 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.2, 8.1 Hz, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 49 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester ethyl ester
  • Figure US20190167672A1-20190606-C00128
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.32 (3H, t, J=7.2 Hz), 1.70-1.80 (2H, m), 1.80-1.90 (2H, m), 2.52 (2H, t, J=7.4 Hz), 2.65-2.73 (2H, m), 2.72 (4H, m), 2.86 (2H, t, J=7.2 Hz), 3.14-3.24 (4H, br), 4.00 (2H, t, J=6.2 Hz), 4.25 (2H, q, J=7.2 Hz), 5.94 (2H, brs), 6.59 (1H, dd, J=2.3, 8.3 Hz), 6.69 (1H, d, J=2.3 Hz), 6.90 (1H, d, J=7.6 Hz), 7.06 (1H, d, J=8.1 Hz), 7.27 (1H, t, J=7.8 Hz), 7.37-7.43 (2H, m), 7.55 (1H, d, J=8.1 Hz)
    • Example 50 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester ethyl ester
  • Figure US20190167672A1-20190606-C00129
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.31 (3H, t, J=7.1 Hz), 1.72-1.84 (2H, m), 1.84-1.96 (2H, m), 2.56 (2H, t, J=7.4 Hz), 2.70-2.80 (4H, m), 3.16-3.26 (4H, m), 4.10 (2H, t, J=6.2 Hz), 4.26 (2H, q, J=7.1 Hz), 6.35 (2H, brs), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.88-6.95 (2H, m), 7.27 (1H, t, J=7.8 Hz), 7.37-7.41 (2H, m), 7.44 (1H, d, J=8.6 Hz), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 51 Synthesis of N-ethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00130
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.14 (3H, t, J=7.0 Hz), 1.69-1.80 (2H, m), 1.81-1.90 (2H, m), 2.52 (2H, t, J=7.5 Hz), 2.61-2.79 (6H, m), 2.81-2.90 (2H, m), 3.09-3.31 (6H, m), 4.00 (2H, t, J=6.0 Hz), 4.73-4.84 (1H, m), 5.92 (2H, s), 6.59 (1H, dd, J=2.5 Hz, 8.5 Hz), 6.79 (1H, d, J=2.0 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.37-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 52 Synthesis of N,N-diethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00131
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.00-1.19 (6H, m), 1.66-1.79 (2H, m), 1.80-1.91 (2H, m), 2.52 (2H, t, J=7.5 Hz), 2.63-2.78 (6H, m), 2.82-2.90 (2H, m), 3.14-3.38 (8H, m), 3.99 (2H, t, J=6.0 Hz), 5.93 (2H, s), 6.59 (1H, dd, J=2.5 Hz, 8.5 Hz), 6.77 (1H, d, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 53 Synthesis of N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00132
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.73-1.84 (2H, m), 1.85-1.96 (2H, m), 2.55 (2H, t, J=7.5 Hz), 2.66-2.78 (4H, m), {2.82 (s), 2.84 (s) total 3H (1:1)}, 3.13-3.26 (4H, m), 4.12 (2H, t, J=6.0 Hz), 4.76-4.86 (1H, m), 6.33 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.15 (1H, d, J=2.0 Hz), 7.24-7.31 (1H, m), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 54 Synthesis of 2-pentylheptanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00133
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ:0.80 (t, J=6.5 Hz, 6H), 1.13-1.24 (m, 12H), 1.37-1.48 (m, 2H), 1.54-1.66 (m, 2H), 1.71-1.81 (m, 2H), 1.85-1.95 (m, 2H), 2.33-2.43 (m, 1H), 2.54 (t, J=7.4 Hz, 2H), 2.64-2.79 (m, 4H), 3.13-3.26 (m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.36 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.83 (dd, J=2.1, 8.6 Hz, 1H), 6.87-6.93 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.44 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 55 Synthesis of N-ethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00134
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.14 (3H, t, J=7.0 Hz), 1.72-1.82 (2H, m), 1.85-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.78 (4H, m), 3.13-3.30 (6H, m), 4.12 (2H, t, J=6.0 Hz), 4.80-4.89 (1H, m), 6.33 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.87-6.92 (1H, m), 7.13-7.17 (1H, m), 7.24-7.30 (1H, m), 7.37-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 56 Synthesis of N,N-dimethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00135
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.72-1.82 (2H, m), 1.86-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.67-2.78 (4H, m), 2.86 (3H, s), 2.96 (3H, s), 3.15-3.24 (4H, m), 4.10 (2H, t, J=6.0 Hz), 6.35 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.12 (1H, d, J=2.0 Hz), 7.24-7.31 (1H, m), 7.37-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 57 Synthesis of N,N-diethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00136
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.01 (3H, t, J=7.0 Hz), 1.15 (3H, t, J=7.0 Hz), 1.72-1.82 (2H, m), 1.84-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.64-2.808 (4H, m), 3.11-3.26 (6H, m), 3.34 (2H, q, J=7.0 Hz), 4.09 (2H, t, J=6.0 Hz), 6.36 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.87-6.92 (1H, m), 7.09 (1H, d, J=2.0 Hz), 7.24-7.31 (1H, m), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 58 Synthesis of hexanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00137
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one synthesized in the same manner as in WO2006/112464 (Example 1) and in the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ:0.85 (t, J=6.8 Hz, 3H), 1.25-1.33 (m, 4H), 1.58-1.69 (m, 2H), 1.70-1.85 (m, 2H), 1.85-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.4 Hz, 2H), 2.67-2.78 (m, 4H), 3.15-3.25 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.84-6.92 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 59 Synthesis of decanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00138
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one synthesized in the same manner as in WO2006/112464 (Example 1) and in the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ:0.86 (t, J=6.8 Hz, 3H), 1.17-1.32 (m, 12H), 1.57-1.68 (m, 2H), 1.72-1.82 (m, 2H), 1.85-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.65-2.78 (m, 4H), 3.13-3.25 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (d, J=2.2, 8.6 Hz, 1H), 6.86-6.92 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 60 Synthesis of octadecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00139
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ:0.88 (t, J=6.8 Hz, 3H), 1.18-1.33 (m, 28H), 1.58-1.67 (m, 2H), 1.72-1.82 (m, 2H), 1.85-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.66-2.79 (m, 4H), 3.14-3.25 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.87-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 61 Synthesis of acetic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00140
  • Acetic acid 7-(4-chlorobutoxy)-2-oxo-2H-quinolin-1-ylmethyl ester (299 mg), 1-benzo[b]thiophen-4-ylpiperazine hydrochloride (235 mg), potassium carbonate (319 mg) and sodium iodide (152 mg) were suspended in DMF (5 ml), and this was stirred at 70° C. for 3 hr and further at 80° C. for 4 hr. After cooling to room temperature, to the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:9) and further by basic silica gel column chromatography, and concentrated under reduced pressure to give the title compound (132 mg) as a colorless amorphous solid.
  • 1H-NMR (CDCl3) δ: 1.73-1.83 (m, 2H), 1.84-1.95 (m, 2H), 2.13 (s, 3H), 2.54 (t, J=7.4 Hz, 2H), 2.68-2.77 (m, 4H), 3.15-3.24 (m, 4H), 4.09 (t, J=6.3 Hz, 2H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.85 (dd, J=2.2, 8.6 Hz, 1H), 6.87-6.92 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)
    • Example 62 Synthesis of N-benzylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00141
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.80 (2H, m), 1.82-1.92 (2H, m), 2.52 (2H, t, J=7.5 Hz), 2.64-2.77 (4H, m), 3.11-3.24 (4H, m), 4.07 (2H, t, J=6.0 Hz), 4.41 (2H, t, J=6.0 Hz), 5.26 (1H, t, J=6.0 Hz), 6.37 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.88 (1H, d, J=7.0 Hz), 7.15 (1H, d, J=1.5 Hz), 7.23-7.34 (6H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.43 (1H, J=8.5 Hz), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 63 Synthesis of N-cyclohexylmethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00142
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.83-0.97 (2H, m), 1.02-1.28 (3H, m), 1.36-1.50 (1H, m), 1.54-1.84 (7H, m), 1.86-1.96 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.65-2.81 (4H, m), 3.05 (2H, t, J=6.5 Hz), 3.13-3.27 (4H, m), 4.11 (2H, t, J=6.0 Hz), 4.90 (1H, t, J=6.0 Hz), 6.33 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.16 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.37-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 64 Synthesis of (7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethoxycarbonylamino acetic acid methyl ester
  • Figure US20190167672A1-20190606-C00143
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.73-1.84 (2H, m), 1.86-1.94 (2H, m), 2.54 (21-1, t, J=7.5 Hz), 2.66-2.81 (4H, m), 3.12-3.27 (4H, m), 3.74 (3H, s), 4.00 (2H, d, J=5.5 Hz), 4.11 (2H, t, J=6.0 Hz), 5.34-5.44 (1H, m), 6.36 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.87-6.92 (1H, m), 7.09 (1H, d, J=2.0 Hz), 7.25-7.30 (1H, m), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 65 Synthesis of tetradecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00144
  • In the same manner as in Example 61, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (t, J=6.8 Hz, 3H), 1.18-1.33 (m, 20H), 1.58-1.68 (m, 2H), 1.72-1.82 (m, 2H), 1.84-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.66-2.79 (m, 4H), 3.13-3.25 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.87-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 66 Synthesis of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-(2,2,2-trifluoroethoxymethyl)-3,4-dihydro-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00145
  • 2,2,2-Trifluoroethanol (0.10 ml) was dissolved in anhydrous THF (3 ml) under a nitrogen atmosphere and sodium hydride (about 55% oil) (60 mg) was added under ice-cooling. The reaction mixture was stirred at room temperature for 30 min under a nitrogen atmosphere. The obtained solution was ice-cooled again and, under a nitrogen atmosphere, a solution (3 ml) of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester (0.25 g) obtained in Example 5 in anhydrous THF was added using a cannula. The reaction mixture was stirred at room temperature for 18 hr under a nitrogen atmosphere. To the reaction mixture was added ice water to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated by filtration. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (90 mg) as a colorless oil.
  • 1H-NMR (CDCl3) δ: 1.69-1.93 (4H, m), 2.47-2.56 (2H, m), 2.64-2.76 (6H, m), 2.80-2.87 (2H, m), 3.13-3.25 (4H, m), 3.93-4.14 (4H, m), 5.42 (2H, s), 6.61 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.86-6.91 (2H, m), 7.05 (1H, d, J=8.5 Hz), 7.24-7.28 (1H, m), 7.37 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.54 (1H, d, J=8.0 Hz)
    • Example 67 Synthesis of morpholine-4-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00146
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.72-1.82 (2H, m), 1.87-1.96 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.80 (4H, m), 3.16-3.34 (4H, m), 3.37-3.73 (8H, m), 4.10 (2H, d, J=6.0 Hz), 6.37 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.09 (1H, d, J=2.5 Hz), 7.24-7.30 (1H, m), 7.37-7.43 (2H, m), 7.45 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=9.5 Hz)
    • Example 68 Synthesis of decanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00147
  • In the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (t, J=6.8 Hz, 3H), 1.20-1.34 (m, 12H), 1.58-1.68 (m, 2H), 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.6 Hz, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.64-2.77 (m, 6H), 2.83-2.89 (m, 2H), 3.13-3.24 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.2, 8.1 Hz, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 69 Synthesis of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl benzyloxycarbamate
  • Figure US20190167672A1-20190606-C00148
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.67-1.79 (2H, m), 1.81-1.92 (2H, m), 2.49 (2H, t, J=7.5 Hz), 2.60-2.74 (4H, m), 3.07-3.21 (4H, m), 4.05 (2H, d, J=6.0 Hz), 4.85 (2H, s), 6.37 (2H, s), 6.46 (1H, d, J=9.5 Hz), 6.80-6.88 (2H, m), 7.03 (1H, d, J=2.0 Hz), 7.23-7.45 (9H, m), 7.54 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=9.5 Hz), 8.11 (1H, s)
    • Example 70 Synthesis of hexanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00149
  • In the same manner as in Example 11, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (t, J=6.9 Hz, 3H), 1.26-1.34 (m, 4H), 1.59-1.69 (m, 2H), 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.53 (t, J=7.4 Hz, 2H), 2.64-2.77 (m, 6H), 2.83-2.89 (m, 2H), 3.14-3.24 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.2, 8.1 Hz, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.88-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 71 Synthesis of N-cyclohexylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00150
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.02-1.22 (3H, m), 1.24-1.41 (2H, m), 1.52-1.97 (9H, m), 2.54 (2H, t, J=7.5 Hz), 2.64-2.82 (4H, m), 3.11-3.28 (4H, m), 3.45-3.59 (1H, m), 4.11 (2H, t, J=6.0 Hz), 4.83 (1H, d, J=8.0 Hz), 6.31 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.14 (1H, brs), 7.24-7.30 (1H, m), 7.36-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=9.5 Hz)
    • Example 72 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester methyl ester
  • Figure US20190167672A1-20190606-C00151
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.68-1.80 (2H, m), 1.80-1.90 (2H, m), 2.52 (2H, t, J=7.4 Hz), 2.64-2.78 (6H, m), 2.86 (2H, t, J=7.0 Hz), 3.14-3.24 (4H, br), 3.83 (3H, s), 4.00 (2H, t, J=6.2 Hz), 5.95 (2H, brs), 6.59 (1H, dd, J=2.4, 8.2 Hz), 6.69 (1H, d, J=2.2 Hz), 6.90 (1H, d, J=7.4 Hz), 7.06 (1H, d, J=8.2 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 73 Synthesis of ((7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethoxycarbonyl)methylamino)acetic acid methyl ester
  • Figure US20190167672A1-20190606-C00152
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.72-1.83 (2H, m), 1.85-1.97 (2H, m), 2.50-2.60 (2H, m), 2.66-2.81 (4H, m), {2.92 (s), 3.02 (s) total 3H (1:1)}, 3.14-3.27 (4H, m), 43.53 (s), 3.74 (s) total 3H (1:1)), 3.91 (1H, s), 4.06 (1H, s), 4.07-4.17 (2H, m), 6.33 (1H, s), 6.38 (1H, s), {6.50 (d, J=9.5 Hz), 6.52 (d, J=9.5 Hz total 1H (1:1)}, 6.80-6.86 (1H, m), {6.88 (brs), 6.90 (brs) total 1H (1:1)}, {6.98 (d, J=2.0 Hz), 7.06 (d, J=2.0 Hz) total 1H (1:1)}, 7.24-7.30 (1H, m), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), {7.61 (d, J=9.5 Hz), 7.63 (d, J=9.0 Hz) total 1H (1:1)}
    • Example 74 Synthesis of undec-10-enoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00153
  • In the same manner as in Example 61, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.19-1.38 (m, 10H), 1.58-1.67 (m, 2H), 1.72-1.82 (m, 2H), 1.86-1.95 (m, 2H), 1.97-2.06 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.66-2.79 (m, 4H), 3.15-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 4.88-4.94 (m, 1H), 4.94-5.02 (m, 1H), 5.73-5.85 (m, 1H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.87-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 75 Synthesis of N-octadecylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00154
  • In the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (3H, t, J=7.0 Hz), 1.16-1.35 (30H, m), 1.42-1.54 (2H, m), 1.70-1.80 (2H, m), 1.81-1.90 (2H, m), 2.52 (2H, t, J=7.5 Hz), 2.62-2.78 (6H, m), 2.81-2.90 (2H, m), 3.12-3.27 (6H, m), 4.00 (2H, t, J=6.0 Hz), 4.79 (1H, t, J=5.5 Hz), 5.92 (2H, s), 6.59 (1H, dd, J=2.5 Hz, 8.0 Hz), 6.80 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.05 (1H, d, J=8.0 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 76 Synthesis of N-pentadecylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00155
  • In the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (3H, t, J=7.0 Hz), 1.16-1.35 (24H, m), 1.43-1.53 (2H, m), 1.69-1.80 (2H, m), 1.81-1.90 (2H, m), 2.53 (2H, t, J=7.5 Hz), 2.63-2.77 (6H, m), 2.81-2.90 (2H, m), 3.14-3.25 (6H, m), 4.00 (2H, t, J=6.0 Hz), 4.80 (1H, t, J=5.5 Hz), 5.92 (2H, s), 6.59 (1H, dd, J=2.5 Hz, 8.0 Hz), 6.80 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.05 (1H, d, J=8.0 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, dd, J=0.5 Hz, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 77 Synthesis of 2-methylbutyric acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00156
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.91 (t, J=7.4 Hz, 3H), 1.17 (d, J=7.0 Hz, 3H), 1.42-1.55 (m, 1H), 1.64-1.92 (m, 5H), 2.43 (m, 1H), 2.52 (t, J=7.5 Hz, 2H), 2.64-2.79 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.25 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.57-6.63 (m, 2H), 6.90 (d, J=7.4 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.27 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 78 Synthesis of 2-methylhexanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00157
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.86 (t, J=6.9 Hz, 3H), 1.16 (d, J=7.0 Hz, 3H), 1.23-1.32 (m, 4H), 1.36-1.48 (m, 1H), 1.58-1.79 (m, 3H), 1.79-1.89 (m, 2H), 2.43-2.56 (m, 3H), 2.64-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.25 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.57-6.62 (m, 2H), 6.90 (d, J=7.5 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.41 (d, J=5.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 79 Synthesis of N-methyl-N-octadecylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00158
  • In the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (3H, t, J=7.0 Hz), 1.10-1.34 (30H, m), 1.38-1.57 (2H, m), 1.68-1.90 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.63-2.79 (6H, m), 2.81-2.95 (5H, m), 3.13-3.31 (6H, m), 3.99 (2H, t, J=5.5 Hz), 5.93 (2H, s), 6.59 (1H, d, J=8.0 Hz), 6.77 (1H, d, J=8.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.0 Hz), 7.24-7.31 (1H, m), 7.36-7.43 (2H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 80 Synthesis of N-benzylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00159
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.89 (4H, m), 2.51 (2H, t, J=7.5 Hz), 2.63-2.77 (6H, m), 2.86 (2H, t, J=7.5 Hz), 3.13-3.25 (4H, m), 3.98 (2H, t, J=6.0 Hz), 4.40 (2H, t, J=6.0 Hz), 5.10-5.18 (1H, m), 5.97 (2H, s), 6.59 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.80 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.23-7.35 (6H, m), 7.37-7.43 (2H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 81 Synthesis of 2-methylpentanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00160
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (t, J=7.2 Hz, 3H), 1.16 (d, J=7.0 Hz, 3H), 1.28-1.46 (m, 3H), 1.61-1.68 (m, 1H), 1.68-1.79 (m, 2H), 1.79-1.90 (m, 2H), 2.45-2.56 (m, 3H), 2.64-2.78 (m, 6H), 2.82-2.90 (m, 2H), 3.12-3.25 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.56-6.62 (m, 2H), 6.90 (d, J=7.6 Hz, 1H), 7.04-7.10 (m, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.38 (d, J 5=5.5 Hz, 1H), 7.41 (d, J=5.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 82 Synthesis of tetradecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00161
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (t, J=6.8 Hz, 3H), 1.20-1.33 (m, 20H), 1.57-1.68 (m, 2H), 1.69-1.79 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.6 Hz, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.65-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.24 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.2, 8.1 Hz, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.24-7.30 (m, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.41 (d, J=5.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 83 Synthesis of N-cyclohexylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00162
  • In the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.05-1.21 (4H, m), 1.25-1.43 (2H, m), 1.63-1.93 (8H, m), 2.52 (2H, t, J=7.5 Hz), 2.63-2.78 (6H, m), 2.81-2.90 (2H, m), 3.14-3.26 (4H, m), 3.46-3.58 (1H, m), 4.00 (2H, t, J=6.0 Hz), 4.71 (1H, d, J=8.0 Hz), 5.91 (2H, s), 6.59 (1H, dd, J=2.0 Hz, J=8.0 Hz), 6.79 (1H, d, J=2.0 Hz), 6.90 (1H, dd, J=0.5 Hz, J=7.5 Hz), 7.05 (1H, d, J=8.0 Hz), 7.24-7.31 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, dd, J=0.5 Hz, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 84 Synthesis of 2,2-dimethylhexanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00163
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.84 (t, J=6.9 Hz, 3H), 1.14-1.29 (m, 4H), 1.17 (s, 6H), 1.47-1.54 (m, 2H), 1.68-1.78 (m, 2H), 1.79-1.89 (m, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.65-2.76 (m, 6H), 2.83-2.89 (m, 2H), 3.15-3.23 (m, 4H), 3.97 (d, J=6.3 Hz, 2H), 5.91 (brs, 2H), 6.57-6.62 (m, 2H), 6.88-6.92 (m, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.27 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 85 Synthesis of acetic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00164
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.64-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.12 (s, 3H), 2.53 (t, J=7.3 Hz, 2H), 2.65-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.13-3.24 (m, 4H), 3.99 (t, J=6.2 Hz, 2H), 5.91 (brs, 2H), 6.60 (dd, J=2.3, 8.2 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.24-7.30 (m, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.41 (d, J=5.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 86 Synthesis of morpholine-4-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00165
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.79 (2H, m), 1.81-1.90 (2H, m), 2.53 (2H, t, J=7.5 Hz), 2.64-2.78 (6H, m), 2.83-2.90 (2H, m), 3.13-3.25 (4H, m), 3.38-3.55 (4H, m), 3.56-3.74 (4H, m), 4.00 (2H, t, J=6.5 Hz), 5.94 (2H, s), 6.60 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.74 (1H, d, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.07 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.39 (1H, d, J=5.5 Hz), 7.41 (1H, dd, J=0.5 Hz, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 87 Synthesis of 2-methylbutyric acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00166
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.89 (t, J=7.5 Hz, 3H), 1.16 (d, J=7.0 Hz, 3H), 1.42-1.54 (m, 1H), 1.60-1.81 (m, 3H), 1.85-1.95 (m, 2H), 2.44 (dt, J=7.0, 7.0 Hz, 1H), 2.54 (t, J=7.5 Hz, 2H), 2.64-2.79 (m, 4H), 3.15-3.25 (m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.81-6.87 (m, 2H), 6.87-6.92 (m, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.3 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)
    • Example 88 Synthesis of 2-methylhexanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00167
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.81 (t, J=7.0 Hz, 3H), 1.15 (d, J=7.0 Hz, 3H), 1.18-1.29 (m, 4H), 1.35-1.47 (m, 1H), 1.59-1.81 (m, 3H), 1.85-1.94 (m, 2H), 2.44-2.58 (m, 3H), 2.65-2.80 (m, 4H), 3.13-3.25 (m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.81-6.87 (m, 2H), 6.87-6.92 (m, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 89 Synthesis of (7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethoxycarbonylamino)acetic acid methyl ester
  • Figure US20190167672A1-20190606-C00168
  • In the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.70-1.79 (2H, m), 1.81-1.90 (2H, m), 2.53 (2H, t, J=7.5 Hz), 2.64-2.77 (6H, m), 2.82-2.89 (2H, m), 3.14-3.24 (4H, m), 3.75 (3H, s), 3.97-4.05 (4H, m), 4.34 (1H, t, J=5.0 Hz), 5.95 (2H, s), 6.60 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.77 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.24-7.31 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 90 Synthesis of ((7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethoxycarbonyl)methylamino)acetic acid methyl ester
  • Figure US20190167672A1-20190606-C00169
  • In the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.70-1.79 (2H, m), 1.81-1.91 (2H, m), 2.49-2.57 (2H, m), 2.63-2.78 (6H, m), 2.81-2.90 (2H, m), {3.64 (s), 3.75 (s) total 3H (1:1)}, 3.14-3.25 (4H, m), {3.64 (s), 3.75 (s) total 3H (1:1)}, 3.93 (s, 1H), 3.97-4.04 (2H, m), 4.06 (1H, s), 5.91 (1H, s), 5.96 (1H, s), 6.56-6.63 (1H, m), {6.68 (d, J=2.0 Hz), 6.77 (d, J=2.0 Hz) total 1H (1:1)}, 6.90 (1H, d, J=7.5 Hz), 7.06 (1H, dd, J=8.0 Hz, J=8.0 Hz), 7.24-7.31 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 91 Synthesis of pentadecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00170
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (t, J=6.8 Hz, 3H), 1.17-1.35 (m, 22H), 1.55-1.68 (m, 2H), 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.6 Hz, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.64-2.76 (m, 6H), 2.83-2.89 (m, 2H), 3.13-3.24 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.59 (dd, J=2.3, 8.2 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 92 Synthesis of 2-methylheptanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00171
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.85 (t, J=6.8 Hz, 3H), 1.16 (d, J=7.0 Hz, 3H), 1.19-1.34 (m, 6H), 1.34-1.47 (m, 1H), 1.60-1.79 (m, 3H), 1.79-1.90 (m, 2H), 2.42-2.56 (m, 3H), 2.64-2.78 (m, 6H), 2.82-2.90 (m, 2H), 3.12-3.26 (m, 4H), 3.97 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.57-6.62 (m, 2H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 93 Synthesis of N-(3,3,3-trifluoropropyl)carbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00172
  • In the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.79 (2H, m), 1.80-1.90 (2H, m), 2.29-2.43 (2H, m), 2.52 (2H, t, J=7.5 Hz), 2.61-2.77 (6H, m), 2.79-2.89 (2H, m), 3.13-3.26 (4H, m), 3.46 (2H, dt, J=6.5 Hz, J=6.5 Hz), 3.99 (2H, t, J=6.0 Hz), 5.20 (1H, t, J=6.0 Hz), 5.92 (2H, s), 6.59 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.74 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.05 (1H, d, J=8.5 Hz), 7.23-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.54 (1H, d, J=8.0 Hz)
    • Example 94 Synthesis of 2-methylpentanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00173
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.86 (t, J=7.2 Hz, 3H), 1.15 (d, J=7.0 Hz, 3H), 1.23-1.45 (m, 3H), 1.59-1.82 (m, 3H), 1.85-1.95 (m, 2H), 2.46-2.58 (m, 3H), 2.65-2.79 (m, 4H), 3.14-3.25 (m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.4 Hz, 1H), 6.82-6.87 (m, 2H), 6.90 (d, J=7.6 Hz, 1H), 7.25-7.30 (m, 1H), 7.39 (d, J=5.5 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H), 7.43-7.47 (m, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)
    • Example 95 Synthesis of heptadecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00174
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (t, J=6.9 Hz, 3H), 1.16-1.35 (m, 26H), 1.57-1.68 (m, 2H), 1.68-1.79 (m, 2H), 1.79-1.90 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.52 (d, J=7.4 Hz, 2H), 2.64-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.24 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.57-6.63 (m, 2H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 96 Synthesis of furan-3-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00175
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.64-1.77 (m, 2H), 1.78-1.88 (m, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.63-2.75 (m, 6H), 2.85-2.92 (m, 2H), 3.12-3.23 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 6.09 (brs, 2H), 6.60 (dd, J=2.3, 8.3 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.74-6.77 (m, 1H), 6.87-6.91 (m, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.37-7.43 (m, 3H), 7.55 (d, J=7.9 Hz, 1H), 8.01-8.05 (m, 1H)
    • Example 97 Synthesis of N-(2-methoxyethyl)carbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00176
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.91 (4H, m), 2.53 (2H, t, J=7.5 Hz), 2.62-2.78 (6H, m), 2.81-2.91 (2H, m), 3.13-3.26 (4H, m), 3.33 (3H, s), 3.35-3.48 (4H, m), 4.00 (2H, t, J=6.0 Hz), 5.12-5.21 (1H, m), 5.92 (2H, s), 6.59 (1H, dd, J=2.0 Hz, J=8.0 Hz), 6.78 (1H, d, J=2.0 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.0 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.42 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 98 Synthesis of N-furan-2-yl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00177
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 5 and in the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.90 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.62-2.77 (6H, m), 2.81-2.90 (2H, m), 3.12-3.27 (4H, m), 3.99 (2H, t, J=6.0 Hz), 4.39 (2H, d, J=6.0 Hz), 5.11-5.19 (1H, m), 5.95 (2H, s), 6.23 (1H, brs), 6.30 (1H, brs), 6.59 (1H, dd, J=2.5 Hz, J=8.0 Hz), 6.77 (1H, d, J=2.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.0 Hz), 7.24-7.30 (1H, m), 7.34 (1H, brs), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)
    • Example 99 Synthesis of 3-{7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethoxycarbonylamino}-propionic acid ethyl ester
  • Figure US20190167672A1-20190606-C00178
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.23 (3H, t, J=7.0 Hz), 1.73-1.83 (2H, m), 1.86-1.96 (2H, m), 2.49-2.59 (4H, m), 2.66-2.80 (4H, m), 3.15-3.27 (4H, m), 3.45-3.53 (2H, m), 4.07-4.15 (4H, m), 5.36-5.43 (1H, m), 6.32 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.11 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 100 Synthesis of (2-butoxyethoxy)acetic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00179
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.90 (t, J=7.4 Hz, 3H), 1.29-1.40 (m, 2H), 1.50-1.59 (m, 2H), 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.53 (t, J=7.4 Hz, 2H), 2.64-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.13-3.24 (m, 4H), 3.45 (t, J=7.7 Hz, 2H), 3.58-3.63 (m, 2H), 3.71-3.76 (m, 2H), 3.98 (t, J=6.2 Hz, 2H), 4.22 (s, 2H), 5.99 (brs, 2H), 6.57-6.62 (m, 2H), 6.87-6.92 (m, 1H), 7.07 (d, J=7.8 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.36-7.44 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 101 Synthesis of 4-{7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethoxycarbonylamino}butyric acid methyl ester
  • Figure US20190167672A1-20190606-C00180
  • Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized in the same manner as in Example 7 and in the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.73-1.95 (6H, m), 2.36 (2H, t, J=7.0 Hz), 2.54 (2H, t, J=7.5 Hz), 2.66-2.80 (4H, m), 3.116-3.31 (6H, m), 3.64 (3H, s), 4.11 (2H, t, J=6.0 Hz) 5.06 (1H, t, J=6.0 Hz), 6.32 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.12 (1H, d, J=1.5 Hz), 7.24-7.30 (1H, m), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 102 Synthesis of 1-methylpiperidine-4-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00181
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.58-2.06 (m, 10H), 2.04 (s, 3H), 2.28-2.40 (m, 1H), 2.52 (t, J=7.4 Hz, 2H), 2.63-2.82 (m, 8H), 2.82-2.90 (m, 2H), 3.14-3.25 (m, 4H), 3.97 (t, J=6.3 Hz, 2H), 5.93 (brs, 2H), 6.56-6.62 (m, 2H), 6.88-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 103 Synthesis of 2,2-dimethylhexanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00182
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.77 (t, J=6.8 Hz, 3H), 1.09-1.20 (m, 10H), 1.42-1.52 (m, 2H), 1.68-1.95 (m, 4H), 2.54 (t, J=7.5 Hz, 2H), 2.66-2.78 (m, 4H), 3.14-3.25 (m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.81-6.86 (m, 2H), 6.87-6.92 (m, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.36-7.37 (m, 3H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 104 Synthesis of pentadecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (t, J=6.8 Hz, 3H), 1.16-1.34 (m, 22H), 1.57-1.67 (m, 2H), 1.67-1.82 (m, 2H), 1.85-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.65-2.79 (m, 4H), 3.13-3.25 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.86-6.92 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
  • Figure US20190167672A1-20190606-C00183
    • Example 105 Synthesis of 4-methylpentanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00184
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.89 (d, J=6.3 Hz, 6H), 1.51-1.63 (m, 3H), 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.33-2.40 (m, 2H), 2.52 (t, J=7.4 Hz, 2H), 2.65-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.24 (m, 4H), 3.99 (t, J=6.2 Hz, 2H), 5.91 (brs, 2H), 6.57-6.63 (m, 2H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.1 Hz, 1H)
    • Example 106 Synthesis of cycloheptanecarboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00185
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.40-1.59 (m, 6H), 1.64-1.79 (m, 6H), 1.80-1.90 (m, 2H), 1.90-1.99 (m, 2H), 2.48-2.59 (m, 3H), 2.64-2.78 (m, 6H), 2.82-2.90 (m, 2H), 3.14-3.23 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.91 (brs, 2H), 6.57-6.63 (m, 2H), 6.90 (d, J=7.3 Hz, 1H), 7.05-7.09 (m, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 107 Synthesis of benzyloxycarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00186
  • In the same manner as in Example 9, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.67-1.89 (4H, m), 2.51 (2H, t, J=7.5 Hz), 2.61-2.76 (6H, m), 2.81-2.90 (2H, m), 3.10-3.23 (4H, m), 4.00 (2H, t, J=6.0 Hz), 4.87 (2H, s), 6.00 (2H, s), 6.60 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.73 (1H, d, J=2.5 Hz), 6.86-6.91 (1H, m), 7.07 (1H, d, J=8.5 Hz), 7.24-7.42 (8H, m), 7.55 (1H, d, J=8.0 Hz), 7.59 (1H, brs)
    • Example 108 Synthesis of heptadecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00187
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (t, J=6.9 Hz, 3H), 1.17-1.33 (m, 26H), 1.57-1.67 (m, 2H), 1.69-1.82 (m, 2H), 1.85-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.67-2.77 (m, 4H), 3.14-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.86-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.36-7.43 (m, 2H), 7.44 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 109 Synthesis of N-(2-methoxyethyl)carbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00188
  • In the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.73-1.83 (2H, m), 1.86-1.96 (2H, m), 2.55 (2H, t, J=7.5 Hz), 2.67-2.80 (4H, m), 3.16-3.25 (4H, m), 3.32 (3H, s), 3.36-3.47 (4H, m), 4.11 (2H, d, J=6.0 Hz), 5.17-5.24 (1H, m), 6.33 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.13 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.37-7.47 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 110 Synthesis of N-furan-2-yl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00189
  • In the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.71-1.82 (2H, m), 1.83-1.96 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.65-2.80 (4H, m), 3.13-3.28 (4H, m), 4.10 (2H, t, J=6.0 Hz), 4.39 (2H, d, J=6.0 Hz), 5.19-5.29 (1H, m), 6.21 (1H, d, J=3.0 Hz), 6.30 (1H, d, J=3.0 Hz), 6.36 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.87-6.91 (1H, m), 7.12 (1H, d, J=1.5 Hz), 7.24-7.30 (1H, m), 7.33 (1H, brs), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 111 Synthesis of N-benzyl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00190
  • In the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.79 (2H, m), 1.82-1.92 (2H, m), 2.53 (2H, t, J=7.0 Hz), 2.64-2.76 (4H, m), {2.80 (s), 2.93 (s) total 3H (1:1)}, 3.13-3.25 (4H, m), 4.02 (1H, t, J=6.0 Hz), 4.08 (1H, t, J=6.0 Hz), 4.37 (1H, s), 4.52 (1H, s), 6.41 (1H, s), 6.43 (1H, s), 6.52 (1H, dd, J=8.5 Hz, J=8.5 Hz), 6.80-6.91 (2H, m), 16.99-7.09 (m), 7.14-7.19 (m) total 3H (1:1)), 7.21-7.35 (4H, m), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, dd, J=9.0 Hz, J=9.0 Hz)
    • Example 112 Synthesis of N-allylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00191
  • In the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.73-1.83 (2H, m), 1.85-1.96 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.64-2.80 (4H, m), 3.13-3.26 (4H, m), 3.84 (2H, t, J=5.5 Hz), 4.11 (2H, t, J=6.0 Hz), 4.91-5.01 (1H, m), 5.08-5.24 (2H, m), 5.77-5.90 (1H, m), 6.35 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.14 (1H, brs), 7.24-7.30 (1H, m), 7.37-7.47 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 113 Synthesis of N-pyridin-2-yl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00192
  • In the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.64-1.81 (2H, m), 1.83-1.93 (2H, m), 2.53 (2H, t, J=7.5 Hz), 2.66-2.80 (4H, m), 3.12-3.25 (4H, m), 4.08 (2H, t, J=6.0 Hz), 4.53 (2H, d, J=5.0 Hz), 6.01 (1H, t, J=5.0 Hz), 6.38 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.88 (1H, d, J=7.5 Hz), 7.03-7.19 (2H, m), 7.21-7.30 (2H, m), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.59-7.67 (2H, m), 8.40-8.57 (1H, m)
    • Example 114 Synthesis of undec-10-enoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00193
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.21-1.40 (m, 10H), 1.54-1.68 (m, 2H), 1.68-1.79 (m, 2H), 1.79-1.90 (m, 2H), 1.97-2.06 (m, 2H), 2.36 (t, J=9.5 Hz, 2H), 2.52 (t, J=7.4 Hz, 2H), 2.64-2.76 (m, 6H), 2.83-2.96 (m, 2H), 3.14-3.23 (m, 4H), 3.99 (t, J=6.3 Hz, 2H), 4.89-4.94 (m, 1H), 4.94-5.02 (m, 1H), 5.73-5.86 (m, 1H), 5.92 (brs, 2H), 6.57-6.63 (m, 2H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.36-7.43 (m, 2H), 7.55 (d, J=7.9 Hz, 1H)
    • Example 115 Synthesis of furan-3-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00194
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.67-1.81 (m, 2H), 1.81-1.97 (m, 2H), 2.52 (dd, J=7.5 Hz, 2H), 2.62-2.78 (m, 4H), 3.11-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.51 (brs, 2H), 6.54 (d, J=9.5 Hz, 1H), 6.74-6.77 (m, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.96 (d, J=2.2 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 3H), 7.46 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H), 8.01-8.04 (m, 1H)
    • Example 116 Synthesis of N-phenethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00195
  • In the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.71-1.82 (2H, m), 1.85-1.96 (2H, m), 2.53 (2H, t, J=7.5 Hz), 2.63-2.77 (4H, m), 2.81 (2H, t, J=7.0 Hz), 3.13-3.26 (4H, m), 3.44-3.52 (2H, m), 4.11 (2H, t, J=6.0 Hz), 4.90 (1H, t, J=5.5 Hz), 6.32 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.88 (1H, d, J=7.5 Hz), 7.12-7.34 (7H, m), 7.37-7.47 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 117 Synthesis of N-isopropyl-carbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00196
  • In the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.15 (6H, d, J=6.5 Hz), 1.72-1.82 (2H, m), 1.85-1.94 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.78 (4H, m), 3.12-3.26 (4H, m), 3.78-3.90 (1H, m), 4.10 (2H, d, J=6.0 Hz), 4.93 (1H, d, J=7.5 Hz), 6.29 (2H, s), 6.48 (1H, d, J=9.5 Hz), 6.82 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.88 (1H, d, J=7.5 Hz), 7.13 (1H, brs), 7.26 (1H, dd, J=8.0 Hz, J=8.0 Hz), 7.35-7.44 (3H, m), 7.54 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=9.5 Hz)
    • Example 118 Synthesis of 2-methylheptanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00197
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.81 (d, J=6.8 Hz, 3H), 1.15 (d, J=7.0 Hz, 3H), 1.17-1.30 (m, 6H), 1.35-1.46 (m, 1H), 1.58-1.71 (m, 1H), 1.71-1.82 (m, 2H), 1.82-1.98 (m, 2H), 2.43-2.58 (m, 3H), 2.66-2.79 (m, 4H), 3.14-3.25 (m, 4H), 4.07 (d, J=6.2 Hz, 2H), 6.35 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.5 Hz, 1H), 6.85-6.92 (m, 2H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.37-7.43 (m, 2H), 7.44 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 119 Synthesis of cycloheptanecarboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00198
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.37-1.58 (m, 6H), 1.62-1.81 (m, 6H), 1.84-1.97 (m, 4H), 2.50-2.58 (m, 3H), 2.67-2.79 (m, 4H), 3.15-3.25 (m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.82-6.86 (m, 2H), 6.87-6.92 (m, 1H), 7.27 (dd, J=8.0, 8.0 Hz, 1H), 7.37-7.43 (m, 2H), 7.43-7.47 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 120 Synthesis of tetrahydropyran-4-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00199
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.90 (m, 8H), 2.52 (t, J=7.4 Hz, 2H), 2.56-2.65 (m, 1H), 2.65-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.25 (m, 4H), 3.37-3.45 (m, 2H), 3.90-4.01 (m, 4H), 5.94 (brs, 2H), 6.57 (d, J=2.2 Hz, 1H), 6.60 (d, J=2.2, 8.2 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.24-7.30 (m, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.42 d, J=5.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H)
    • Example 121 Synthesis of malonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester tert-butyl ester
  • Figure US20190167672A1-20190606-C00200
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.44 (s, 9H), 1.69-1.80 (m, 2H), 1.80-1.89 (m, 2H), 2.52 (d, J=7.4 Hz, 2H), 2.64-2.79 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.25 (m, 4H), 3.35 (s, 2H), 4.01 (t, J=6.2 Hz, 2H), 5.96 (brs, 2H), 6.00 (dd, J=2.3, 8.2 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.90 (d, J=7.4 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.25-7.30 (m, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H).
    • Example 122 Synthesis of N-isobutylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00201
  • In the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.86-0.93 (6H, m), 1.69-1.82 (3H, m), 1.84-1.94 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.65-2.78 (4H, m), 3.03 (2H, t, J=6.5 Hz), 3.13-3.25 (4H, m), 4.10 (2H, d, J=6.0 Hz), 5.09 (1H, t, J=6.0 Hz), 6.32 (2H, s), 6.49 (1H, d, J=9.5 Hz), 6.82 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.86-6.91 (1H, m), 7.13 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.36-7.44 (3H, m), 7.54 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=9.5 Hz)
    • Example 123 Synthesis of 4,4-difluoropiperidine-1-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00202
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.72-2.07 (8H, m), 2.54 (2H, t, J=7.5 Hz), 2.64-2.78 (4H, m), 3.13-3.25 (4H, m), 3.48-3.71 (4H, m), 4.10 (2H, d, J=6.0 Hz), 6.36 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.85 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=2.0 Hz), 7.27 (1H, dd, J=8.0 Hz, J=8.0 Hz), 7.39 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.45 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=9.5 Hz)
    • Example 124 Synthesis of 4,4,4-trifluorobutyric acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00203
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.43-2.57 (m, 4H), 2.62-2.77 (m, 8H), 2.83-2.90 (m, 2H), 3.13-3.24 (m, 4H), 3.99 (t, J=6.2 Hz, 2H), 5.95 (brs, 2H), 6.57-6.63 (m, 2H), 6.87-6.92 (m, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.42 (m, 2H), 7.55 (d, J=8.1 Hz, 1H)
    • Example 125 Synthesis of N-furan-2-ylmethyl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00204
  • In the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.82 (2H, m), 1.84-1.94 (2H, m), 2.53 (2H, t, J=7.5 Hz), 2.65-2.78 (4H, m), {2.84 (s), 2.97 (s) total 3H (1:1)}, 3.13-3.26 (4H, m), 4.05 (1H, d, J=6.0 Hz), 4.10 (1H, t, J=6.0 Hz), 4.31 (1H, s), 4.49 (1H, s), {6.02 (d, J=2.5 Hz), 6.24 (d, J=2.5 Hz) total 1H (1:1)}, {6.17 (brs), 6.32 (brs) total 1H (1:1)}, 6.39 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), {7.02 (brs), 7.12 (brs) total 1H (1:1)}, {7.19 (brs), 7.36 (brs) total 1H (1:1)}, 7.24-7.31 (1H, m), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 126 Synthesis of 4-methylpentanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00205
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (d, J=6.3 Hz, 6H), 1.50-1.62 (m, 3H), 1.70-1.82 (m, 2H), 1.86-1.95 (m, 2H), 2.33-2.40 (m, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.66-2.79 (m, 4H), 3.14-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.86-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)
    • Example 127 Synthesis of cyclobutanecarboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00206
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.68-1.79 (m, 2H), 1.80-2.03 (m, 4H), 2.15-2.25 (m, 2H), 2.25-2.37 (m, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.64-2.77 (m, 6H), 2.83-2.89 (m, 2H), 3.13-3.24 (m, 5H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.57-6.62 (m, 2H), 6.90 (d, J=7.5 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.24-7.30 (m, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.41 (d, J=5.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H)
    • Example 128 Synthesis of benzofuran-5-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00207
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.62-1.74 (m, 2H), 1.75-1.86 (m, 2H), 2.46 (t, J=7.5 Hz, 2H), 2.58-2.71 (m, 4H), 2.71-2.79 (m, 2H), 2.82-2.93 (m, 2H), 3.07-3.20 (m, 4H), 3.96 (t, J=6.3 Hz, 2H), 6.19 (brs, 2H), 6.61 (dd, J=2.3, 8.3 Hz, 1H), 6.77 (d, J=2.3 Hz, 1H), 6.79-6.83 (m, 1H), 6.85-6.90 (m, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.36-7.41 (m, 2H), 7.52 (d, J=8.7 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H), 8.03 (dd, J=1.7, 8.7 Hz, 1H), 8.36 (d, J=1.7 Hz, 1H)
    • Example 129 Synthesis of N-methoxycarbamic acid (7-{4-[4-(benzo[b]thiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-2H-quinolin-1-yl)methyl
  • Figure US20190167672A1-20190606-C00208
  • In the same manner as in Example 10, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.72-1.82 (2H, m), 1.84-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.65-2.79 (4H, m), 3.13-3.26 (4H, m), (3.51 (s), 3.73 (s) total 3H (1:3)), 4.07-4.17 (2H, m), {6.33 (s), 6.39 (s) total 2H (1:3)}, 6.48-6.53 (1H, m), 6.80-6.88 (2H, m), (7.05 (d, J=2.0 Hz), 7.13 (d, J=2.0 Hz) total 1H (3:1)), 7.24-7.30 (1H, m), 7.37-7.47 (3H, m), 7.55 (1H, d, J=8.0 Hz), {7.58 (brs), 7.83 (brs) total 1H (1:3)}, 7.62 (1H, d, J=9.5 Hz)
    • Example 130 Synthesis of tetrahydropyran-4-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00209
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.71-1.95 (m, 8H), 2.54 (t, J=7.5 Hz, 2H), 2.57-2.66 (m, 1H), 2.67-2.79 (m, 4H), 3.14-3.25 (m, 4H), 3.34-3.43 (m, 2H), 3.93 (dt, J=3.6, 7.6 Hz, 2H), 4.08 (t, J=6.3 Hz, 2H), 6.35 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.81-6.87 (m, 2H), 6.87-6.92 (m, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)
    • Example 131 Synthesis of thiophene-2-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00210
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.66-1.76 (m, 2H), 1.77-1.89 (m, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.62-2.76 (m, 6H), 2.85-2.92 (m, 2H), 3.10-3.23 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 6.14 (brs, 2H), 6.61 (dd, J=2.3, 8.2 Hz, 1H), 6.75 (d, J=2.3 Hz, 1H), 6.86-6.91 (m, 1H), 7.05-7.11 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.53-7.58 (m, 2H), 7.82 (dd, J=1.2, 3.8 Hz, 1H)
    • Example 132 Synthesis of nicotinic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00211
  • In the same manner as in Example 48, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.64-1.76 (m, 2H), 1.77-1.88 (m, 2H), 2.49 (t, J=7.5 Hz, 2H), 2.61-2.78 (m, 6H), 2.87-2.94 (m, 2H), 3.10-3.24 (m, 4H), 3.98 (t, J=6.3 Hz, 2H), 6.19 (brs, 2H), 6.62 (dd, J=2.3, 8.3 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.35-7.42 (m, 3H), 7.55 (d, J=8.0 Hz, 1H), 8.30 (ddd, J=2.0, 2.0, 8.0 Hz, 1H), 8.77 (dd, J=1.7 Hz, 4.9 Hz, 1H), 9.21-9.25 (m, 1H)
    • Example 133 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester 4-nitrophenyl ester
  • Figure US20190167672A1-20190606-C00212
  • 7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one (2.0 g) was suspended in anhydrous THF (40 ml) under a nitrogen atmosphere, and sodium hydride (about 55% oil) (0.22 g) was added. The mixture was refluxed for 30 min under a nitrogen atmosphere. The obtained solution was cooled to was cooled to −70° C., and a solution (20 ml) of chloromethyl-4-nitrophenyl carbonate (1.50 g) in anhydrous THF with cannula. The reaction mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated by filtration. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the component (Rf value: 0.62, ethyl acetate, 0.67 g) as a pale-yellow amorphous compound. The obtained compound was used for the next reaction step without further purification.
    • Example 134 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester dodecyl ester
  • Figure US20190167672A1-20190606-C00213
  • 1-Dodecanol (0.10 g) was dissolved in anhydrous THF (5 ml) under a nitrogen atmosphere and sodium hydride (about 55% oil) (25 mg) was added under ice-cooling with stirring. The reaction mixture was stirred at room temperature for 30 min under a nitrogen atmosphere, and then the mixture was ice-cooled. To the mixture was added a solution (5 ml) of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester 4-nitrophenyl ester obtained in Example 133 (0.33 g) in anhydrous THF using a cannula. Under a nitrogen atmosphere, the reaction mixture was stirred with ice-cooling for 2 hr, and at room temperature for 1 hr. Water was added to the reaction mixture to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated by filtration. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane 30=1:1) to give the title compound (0.14 g) as a colorless oil.
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=7.0 Hz), 1.17-1.38 (18H, m), 1.59-1.70 (2H, m), 1.73-1.82 (2H, m), 1.86-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.69-2.78 (4H, m), 3.16-3.24 (4H, m), 4.10 (2H, t, J=6.0 Hz), 4.18 (2H, t, J=6.5 Hz), 6.35 (2H, brs), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 6.93 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.42 (1H, d, J=5.5 Hz), 7.44 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 135 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester decyl ester
  • Figure US20190167672A1-20190606-C00214
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one synthesized in the same manner as in WO2006/112464 (Example 1), and in the same manner as in Example 5, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=7.0 Hz), 1.17-1.38 (14H, m), 1.62-1.70 (2H, m), 1.72-1.83 (2H, m), 1.86-1.96 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.64-2.81 (4H, m), 3.12-3.26 (4H, m), 4.07-4.13 (2H, m), 4.18 (2H, t, J=6.5 Hz), 6.35 (2H, brs), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 6.93 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.42 (1H, d, J=5.5 Hz), 7.44 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 136 Synthesis of cyclobutanecarboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00215
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.66-1.84 (m, 2H), 1.84-2.05 (m, 4H), 2.14-2.24 (m, 2H), 2.24-2.36 (m, 2H), 2.55 (t, J=7.5 Hz, 2H), 2.65-2.80 (m, 4H), 3.12-3.26 (m, 5H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.5 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 7.24-7.30 (m, 1H), 7.39 (d, J=5.6 Hz, 1H), 7.41 (d, J=5.6 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)
    • Example 137 Synthesis of benzofuran-5-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00216
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.66-1.78 (m, 2H), 1.78-1.92 (m, 2H), 2.48 (t, J=7.4 Hz, 2H), 2.59-2.74 (m, 4H), 3.10-3.20 (m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.57 (d, J=9.5 Hz, 1H), 6.61 (brs, 2H), 6.76-6.81 (m, 1H), 6.84 (dd, J=2.1, 8.6 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 7.00-7.04 (m, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.37-7.42 (m, 2H), 7.47 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.62-7.69 (m, 2H), 8.03 (dd, J=1.7, 8.7 Hz, 1H), 8.35 (d, J=1.7 Hz, 1H)
    • Example 138 Synthesis of 4,4,4-trifluorobutyric acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00217
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.68-1.82 (m, 2H), 1.86-1.96 (m, 2H), 2.43-2.58 (m, 4H), 2.62-2.69 (m, 2H), 2.69-2.79 (m, 4H), 3.14-3.26 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.36 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.83-6.88 (m, 2H), 6.88-6.92 (m, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.37-7.43 (m, 2H), 7.46 (d, J=8.3 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H)
    • Example 139 Synthesis of N-(3,3,3-trifluoropropyl)carbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00218
  • In the same manner as in Example 134, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.72-1.95 (4H, m), 2.30-2.44 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.65-2.82 (4H, m), 3.13-3.26 (4H, m), 3.48 (2H, dt, J=6.5 Hz, J=6.5 Hz), 4.04-4.14 (2H, m), 5.32-5.39 (1H, m), 6.31 (2H, s), 6.48 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.86-6.91 (1H, m), 7.07 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.37-7.44 (3H, m), 7.54 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=9.5 Hz)
    • Example 140 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester (E)-3-phenyl-allyl ester
  • Figure US20190167672A1-20190606-C00219
  • In the same manner as in Example 134, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.80 (2H, m), 1.82-1.94 (2H, m), 2.51 (2H, t, J=7.5 Hz), 2.63-2.77 (4H, m), 3.12-3.24 (4H, m), 4.05-4.11 (2H, m), 4.34 (1H, dd, J=1.0 Hz, J=6.5 Hz), 4.83 (1H, dd, J=1.0 Hz, J=6.5 Hz), 6.16-6.30 (1H, m), 6.38 (2H, brs), 6.50 (1H, dd, J=2.0 Hz, J=9.5 Hz), 6.57-6.70 (1H, m), 6.80-6.85 (1H, m), 6.87 (1H, brd, J=7.5 Hz), 6.93 (1H, brs), 7.20-7.46 (9H, m), 7.54 (1H, d, J=8.0 Hz), 7.59 (1H, dd, J=3.5 Hz, J=9.5 Hz)
    • Example 141 Synthesis of thiophene-2-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00220
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.66-1.82 (m, 2H), 1.84-1.93 (m, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.64-2.77 (m, 4H), 3.12-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.52-6.60 (m, 3H), 6.84 (dd, J=2.1, 8.6 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 7.07 (dd, J=3.8, 4.9 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.41 (d, J=5.6 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.53-7.59 (m, 2H), 7.64 (d, J=9.5 Hz, 1H), 7.82 (dd, J=1.2, 3.8 Hz, 1H)
    • Example 142 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester decyl ester
  • Figure US20190167672A1-20190606-C00221
  • In the same manner as in Example 5, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=7.0 Hz), 1.19-1.41 (14H, m), 1.62-1.80 (4H, m), 1.82-1.91 (2H, m), 2.52 (2H, t, J=7.5 Hz), 2.64-2.77 (6H, m), 2.82-2.90 (2H, m), 3.14-3.24 (4H, m), 4.00 (2H, t, J=6.0 Hz), 4.17 (2H, t, J=6.5 Hz), 5.94 (2H, s), 6.59 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.69 (1H, dd, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.25-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.40-7.43 (1H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 143 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester hexyl ester
  • Figure US20190167672A1-20190606-C00222
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (3H, t, J=6.9 Hz), 1.20-1.90 (12H, m), 2.52 (2H, t, J=7.4 Hz), 2.60-2.80 (6H, m), 2.83-2.88 (2H, m), 3.20 (4H, br), 4.00 (2H, t, J=6.2 Hz), 4.18 (2H, t, J=6.7 Hz), 5.94 (2H, brs), 6.59 (1H, dd, J=2.4, 8.2 Hz), 6.69 (1H, d, J=2.3 Hz), 6.90 (1H, d, J=7.6 Hz), 7.06 (1H, d, J=8.3 Hz), 7.20-7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 144 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester hexadecyl ester
  • Figure US20190167672A1-20190606-C00223
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.88 (3H, t, J=6.8 Hz), 1.20-1.90 (32H, m), 2.53 (2H, t, J=7.4 Hz), 2.64-2.78 (6H, m), 2.80-2.90 (2H, m), 3.20 (4H, br), 4.00 (2H, t, J=6.2 Hz), 4.17 (2H, t, J=6.8 Hz), 5.94 (2H, brs), 6.59 (1H, dd, J=2.3, 8.3 Hz), 6.69 (1H, d, J=2.3 Hz), 6.89 (1H, d, J=7.6 Hz), 7.06 (1H, d, J=8.3 Hz), 7.27 (1H, t, J=7.8 Hz), 7.35-7.45 (2H, m), 7.54 (1H, d, J=8.0 Hz)
    • Example 145 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester heptyl ester
  • Figure US20190167672A1-20190606-C00224
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=7.0 Hz), 1.22-1.40 (6H, m), 1.52-1.90 (8H, m), 2.53 (2H, t, J=7.4 Hz), 2.64-2.78 (6H, m), 2.86 (2H, t, J=7.2 Hz), 3.20 (4H, br), 4.00 (2H, t, J=6.2 Hz), 4.17 (2H, t, J=6.8 Hz), 5.94 (2H, brs), 6.59 (1H, dd, J=2.4, 8.3 Hz), 6.69 (1H, d, J=2.3 Hz), 6.90 (1H, d, J=7.6 Hz), 7.06 (1H, d, J=8.2 Hz), 7.27 (1H, t, J=7.8 Hz), 7.35-7.45 (2H, m), 7.55 (1H, d, J=8.1 Hz)
    • Example 146 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester cyclohexyl ester
  • Figure US20190167672A1-20190606-C00225
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one synthesized in the same manner as in WO2006/112464 (Example 1), and in the same manner as in Example 5, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.17-1.28 (1H, m), 1.29-1.41 (2H, m), 1.42-1.57 (3H, m), 1.68-1.82 (4H, m), 1.84-1.98 (4H, m), 2.53 (2H, t, J=7.5 Hz), 2.64-2.80 (4H, m), 3.12-3.26 (4H, m), 4.09 (2H, t, J=6.0 Hz), 4.64-4.72 (1H, m), 6.34 (2H, s), 6.49 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, 8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 6.92 (1H, d, J=2.0 Hz), 7.23-7.30 (1H, m), 7.36-7.44 (3H, m), 7.54 (1H, d, J=8.0 Hz), 7.59 (1H, d, J=9.5 Hz)
    • Example 147 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 2,2,2-trifluoro-ethyl ester
  • Figure US20190167672A1-20190606-C00226
  • In the same manner as in Example 5, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.69-1.79 (2H, m), 1.81-1.90 (2H, m), 2.51 (2H, t, J=7.5 Hz), 2.63-2.76 (6H, m), 2.81-2.90 (2H, m), 3.13-3.26 (4H, m), 3.99 (2H, t, J=6.0 Hz), 4.55 (2H, q, J=8.0 Hz), 6.00 (2H, s), 6.61 (1H, dd, J=2.5 Hz, 8.0 Hz), 6.65 (1H, d, J=2.5 Hz), 6.86-6.91 (1H, m), 7.07 (1H, d, J=8.5 Hz), 7.23-7.29 (1H, m), 7.37 (1H, d, J=5.5 Hz), 7.39-7.43 (1H, m), 7.54 (1H, d, J=8.0 Hz)
    • Example 148 Synthesis of malonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester tert-butyl ester
  • Figure US20190167672A1-20190606-C00227
  • In the same manner as in Example 22, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.38 (s, 9H), 1.69-1.83 (m, 2H), 1.85-1.95 (m, 2H), 2.55 (t, J=7.4 Hz, 2H), 2.67-2.79 (m, 4H), 3.14-3.25 (m, 4H), 3.35 (s, 2H), 4.13 (t, J=6.1 Hz, 2H), 6.37 (brs, 2H), 6.51 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.87-6.92 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.44 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)
    • Example 149 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester octyl ester
  • Figure US20190167672A1-20190606-C00228
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=6.8 Hz), 1.20-1.40 (8H, m), 1.60-1.90 (8H, m), 2.53 (2H, t, J=7.4 Hz), 2.64-2.78 (6H, m), 2.86 (2H, t, J=6.8 Hz), 3.20 (4H, br), 4.00 (2H, t, J=6.2 Hz), 4.17 (2H, t, J=6.8 Hz), 5.94 (2H, brs), 6.59 (1H, dd, J=2.3, 8.2 Hz), 6.69 (1H, d, J=2.3 Hz), 6.90 (1H, d, J=7.6 Hz), 7.06 (1H, d, J=8.1 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.54 (1H, d, J=8.0 Hz)
    • Example 150 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester cyclohexyl ester
  • Figure US20190167672A1-20190606-C00229
  • In the same manner as in Example 5, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.17-1.28 (1H, m), 1.29-1.41 (2H, m), 1.43-1.58 (3H, m), 1.68-1.79 (4H, m), 1.80-1.89 (2H, m), 1.90-1.99 (2H, m), 2.52 (2H, t, J=7.5 Hz), 2.64-2.77 (6H, m), 2.82-2.89 (2H, m), 3.14-3.25 (4H, m), 4.00 (2H, t, J=6.0 Hz), 4.62-4.71 (1H, m), 5.94 (2H, s), 6.59 (1H, dd, J=2.5 Hz, 8.5 Hz), 6.69 (1H, d, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.40-7.44 (1H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 151 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester butyl ester
  • Figure US20190167672A1-20190606-C00230
  • In the same manner as in Example 5, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 0.93 (3H, t, J=7.4 Hz), 1.34-1.46 (2H, m), 1.60-1.90 (6H, m), 2.52 (2H, t, J=7.4 Hz), 2.64-2.76 (6H, m), 2.82-2.88 (2H, m), 3.16-3.26 (4H, br), 4.00 (2H, t, J=6.2 Hz), 4.19 (2H, t, J=6.7 Hz), 5.94 (2H, brs), 6.59 (1H, dd, J=2.3, 8.2 Hz), 6.69 (1H, d, J=2.3 Hz), 6.89 (18, d, J=7.6 Hz), 7.06 (1H, d, J=8.0 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.1 Hz)
    • Example 152 Synthesis of N-methyl-N-pyridin-2-ylmethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00231
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.68-1.81 (2H, m), 1.82-1.94 (2H, m), 2.47-2.58 (2H, m), 2.64-2.78 (4H, m), {2.91 (s), 3.06 (s) total 3H (1:1)}, 3.13-3.25 (4H, m), 4.00-4.10 (2H, m), 4.47 (1H, s), 4.65 (1H, s), 6.37 (1H, brs), 6.43 (1H, brs), {6.48 (d, J=9.5 Hz), 6.53 (d, J=9.5 Hz) total 1H (1:1)}, 6.78-6.97 (2H, m), 6.99-7.05 (1H, m), 7.13-7.21 (1H, m), 7.23-7.31 (2H, m), 7.36-7.47 (3H, m), 7.52-7.68 (3H, m), {8.38 (d, J=4.5 Hz), 8.54 (d, J=4.5 Hz) total 1H (1:1)}
    • Example 153 Synthesis of thiomorpholine-4-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00232
  • In the same manner as in Example 14, the title compound was obtained.
  • 1H-NMR (CDCl3) δ: 1.72-1.82 (2H, m), 1.86-1.95 (2H, m), 2.45-2.52 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.58-2.64 (2H, m), 2.68-2.79 (4H, m), 3.15-3.26 (4H, m), 3.63-3.72 (2H, m), 3.73-3.83 (2H, m), 4.10 (2H, d, J=6.5 Hz), 6.36 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.87-6.92 (1H, m), 7.06 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.37-7.47 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=9.5 Hz)
    • Example 154 Synthesis of dodecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00233
  • Using 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 5.
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=6.9 Hz), 1.20-1.32 (22H, m), 1.56-1.68 (2H, m), 1.68-1.80 (2H, m), 1.80-1.90 (2H, m), 2.35 (2H, t, J=7.5 Hz), 2.50-2.56 (4H, m), 2.68-2.76 (4H, m), 3.14-3.24 (4H, m), 3.99 (2H, t, J=6.2 Hz), 5.97 (2H, brs), 6.62-6.68 (2H, m), 6.89 (1H, d, J=7.6 Hz), 7.20 (1H, d, J=8.3 Hz), 7.27 (1H, t, J=7.8 Hz), 7.40 (2H, dd, J=5.6, 12.5 Hz), 7.54 (1H, d, J=8.0 Hz)
    • Example 155 Synthesis of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00234
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.4 g) obtained in Reference Example 18 in DMF (10 ml) were added 37% aqueous formalin solution (1.5 ml) and triethylamine (0.02 ml), and the mixture was heated at 80° C. for 10 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a mixture (0.46 g, 1:3) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one and 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one.
  • Amorphous: Colorless
  • 1H-NMR (CDCl3) δ: 1.26 (3H, t, J=7.2 Hz), 1.27 (1.5H, s), 1.29 (4.5H, s), 1.68-1.78 (2H, m), 1.78-1.90 (2H, m), 2.46 (1.5H, s), 2.48 (0.5H, s), 2.52 (2H, t, J=7.4 Hz), 2.72 (4H, m), 3.19 (4H, m), 3.95-4.05 (2H, m), 5.41 (0.5H, s), 6.36 (0.75H, d, J=2.5 Hz), 6.58 (0.75H, dd, J=2.5, 8.5 Hz), 6.64 (0.25H, dd, J=2.4, 8.5 Hz), 6.87-6.92 (1.25H, m), 7.17 (0.75H, d, J=8.5 Hz), 7.18 (0.25H, d, J=8.5 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.54 (1H, d, J=8.0 Hz), 8.32 (0.75H, brs)
    • Example 156 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester decyl ester
  • Figure US20190167672A1-20190606-C00235
  • 7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (460 mg), which is a mixture with 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one obtained in Example 155, was suspended in methylene chloride (10 ml), pyridine (0.06 ml) and decyl chloroformate (103 mg) were added, and the mixture was stirred under ice-cooling for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane-2:1) to give carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester decyl ester (108 mg).
  • Colorless Oil
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=6.8 Hz), 1.20-1.40 (20H, m), 1.62-1.70 (2H, m), 1.70-1.80 (2H, m), 1.80-1.90 (2H, m), 2.50-2.56 (4H, m), 2.73 (4H, m), 3.20 (4H, m), 4.00 (2H, t, J=6.2 Hz), 4.17 (2H, t, J=6.8 Hz), 5.99 (2H, s), 6.65 (1H, dd, J=2.4, 8.5 Hz), 6.71 (1H, d, J=2.3 Hz), 6.89 (1H, d, J=7.6 Hz), 7.20 (1H, d, J=8.4 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.54 (1H, d, J=8.1 Hz)
    • Example 157 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester
  • Figure US20190167672A1-20190606-C00236
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.38 g) obtained in Reference Example 18 in THF (10 ml) was added 60% sodium hydride (40 mg) with stirring under ice-cooling, and the mixture was heated under reflux for 0.5 hr. Thereafter, with stirring under ice-cooling, a solution of chloromethyl phenylcarbonate (0.23 g) in THF (1 ml) was added dropwise, and the mixture was stirred at room temperature overnight. With stirring under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane-1:1) to give carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester (130 mg).
  • Colorless Oil
  • 1H-NMR (CDCl3) δ: 1.30 (6H, s), 1.68-1.90 (4H, m), 2.46-2.56 (2H, m), 2.57 (2H, s), 2.68-2.78 (4H, br), 3.14-3.24 (4H, br), 4.02 (2H, t, J=6.2 Hz), 6.11 (2H, s), 6.68 (1H, dd, J=2.4, 8.5 Hz), 6.75 (1H, d, J=2.4 Hz), 6.89 (1H, d, J=7.6 Hz), 7.16-7.46 (9H, m), 7.55 (1H, d, J=8.0 Hz).
    • Example 158 Synthesis of N-decylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester
  • Figure US20190167672A1-20190606-C00237
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.21 g) obtained in Reference Example 18 in THF (10 ml) was added with stirring under ice-cooling 60% sodium hydride (27 mg), and the mixture was heated under reflux for 0.5 hr. Thereafter, with stirring under ice-cooling, a solution of chloromethyl phenylcarbonate (0.17 g) in THF (1 ml) was added dropwise, and the mixture was stirred at room temperature overnight. With stirring under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in THF (10 ml) was added decylamine (0.5 ml), and the mixture was stirred at room temperature overnight. With stirring under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1) to give N-decylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester (126 mg).
  • Yellow Oil
  • 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=6.8 Hz), 1.18-1.34 (20H, m), 1.42-1.52 (2H, m), 1.70-1.80 (2H, m), 1.80-1.90 (2H, m), 2.48-2.56 (4H, m), 2.66-2.78 (4H, br), 3.12-3.24 (6H, m), 4.01 (2H, t, J=6.1 Hz), 4.76-4.84 (1H, m), 5.96 (2H, s), 6.64 (1H, dd, J=2.3, 8.5 Hz), 6.81 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=7.6 Hz), 7.19 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 163 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester methyl ester
  • Figure US20190167672A1-20190606-C00238
  • To a solution of n-hexylalcohol (50.5 mg) in tetrahydrofuran (5 ml) was added with stirring under ice-cooling 60% sodium hydride (18 mg) by small portions, and the mixture was stirred at the same temperature for 0.5 hr, to a solution of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester (240 mg) in tetrahydrofuran (1 ml) was added with stirring under ice-cooling sodium methoxide (30 mg), and the mixture was stirred for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester methyl ester (42 mg).
  • Oil: Colorless
  • 1H-NMR (CDCl3) δ ppm: 1.72-1.84 (2H, m), 1.85-1.96 (2H, m), 2.55 (2H, t, J=7.4 Hz), 2.68-2.80 (4H, br), 3.14-3.26 (4H, br), 3.83 (3H, s), 4.10 (2H, t, J=6.2 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.92 (1H, d, J=2.0 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.50 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=9.5 Hz)
    • Example 165 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester propyl ester
  • Figure US20190167672A1-20190606-C00239
  • In the same manner as in Example 175, the compound was obtained (yield 78 mg, 27.5%) as a colorless oil.
  • 1H-NMR (CDCl3) δ ppm: 0.94 (3H, t, J=7.4 Hz), 1.58-1.84 (4H, m), 1.84-1.96 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.80 (4H, br), 3.14-3.28 (4H, br), 4.09 (2H, t, J=6.0 Hz), 4.15 (2H, t, J=6.7 Hz), 6.34 (2H, s), 6.49 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.1, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.93 (1H, d, J=2.0 Hz), 7.26 (1H, t, J=7.8 Hz), 7.36-7.44 (3H, m), 7.54 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)
    • Example 168 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl) butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester butyl ester
  • Figure US20190167672A1-20190606-C00240
  • In the same manner as in Example 175, the compound was obtained (yield 47 mg, 14.3%) as a colorless oil.
  • 1H-NMR (CDCl3) δ ppm: 0.92 (3H, t, J=7.4 Hz), 1.32-1.44 (2H, m), 1.60-1.70 (2H, m), 1.72-1.84 (2H, m), 1.86-1.96 (2H, m), 2.55 (2H, t, J=7.5 Hz), 2.68-2.80 (4H, br), 3.16-3.26 (4H, br), 4.06-4.15 (2H, m), 4.20 (2H, t, J=6.7 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.7 Hz), 6.93 (1H, d, J=2.1 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 170 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester isobutyl ester
  • Figure US20190167672A1-20190606-C00241
  • In the same manner as in Example 175, the compound was obtained (yield 48 mg, 14.6%) as a colorless oil.
  • 1H-NMR (CDCl3) δ ppm: 0.94 (6H, d, J=6.7 Hz), 1.70-2.04 (5H, m), 2.55 (2H, t, J=7.4 Hz), 2.66-2.80 (4H, br), 3.14-3.24 (4H, br), 3.98 (2H, d, J=6.6 Hz), 4.10 (2H, t, J=6.2 Hz), 6.35 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.93 (1H, d, J=2.0 Hz), 7.27 (1H, t, J=7.8 Hz), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.1 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 175 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester hexyl ester
  • Figure US20190167672A1-20190606-C00242
  • To a solution of n-hexylalcohol (50.5 mg) in tetrahydrofuran (5 ml) was added with stirring under ice-cooling 60% sodium hydride (18 mg) by small portions, and the mixture was stirred at the same temperature for 0.5 hr, a solution of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester (240 mg) in tetrahydrofuran (1 ml) was added dropwise, and the mixture was stirred under ice-cooling for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester hexyl ester (30 mg).
  • Oil: Colorless
  • 1H-NMR (CDCl3) δ ppm: 0.87 (3H, t, J=6.9 Hz), 1.20-1.40 (6H, m), 1.60-1.72 (2H, m), 1.72-1.84 (2H, m), 1.84-2.00 (2H, m), 2.55 (2H, t, J=7.4 Hz), 2.65-2.82 (4H, br), 3.10-3.28 (4H, br), 4.10 (2H, t, J=6.2 Hz), 4.19 (2H, t, J=6.7 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.93 (1H, d, J=2.1 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.6 Hz)
    • Example 177 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester nonyl ester
  • Figure US20190167672A1-20190606-C00243
  • In the same manner as in Example 175, the compound was obtained (yield 40 mg, 10.8%) as a colorless oil.
  • 1H-NMR (CDCl3) δ ppm: 0.86 (3H, t, J=6.9 Hz), 1.20-1.40 (12H, m), 1.60-1.70 (2H, m), 1.72-1.82 (2H, m), 1.85-1.95 (2H, m), 2.55 (2H, t, J=7.4 Hz), 2.68-2.78 (4H, br), 3.14-3.28 (4H, br), 4.06-4.14 (2H, m), 4.18 (2H, t, J=6.7 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.1, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.93 (1H, d, J=2.0 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 179 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester tetradecyl ester
  • Figure US20190167672A1-20190606-C00244
  • In the same manner as in Example 175, the colorless amorphous compound was obtained (yield 33 mg, 9.3%).
  • 1H-NMR (CDCl3) δ ppm: 0.87 (3H, t, J=6.9 Hz), 1.20-1.40 (22H, m), 1.55-1.95 (6H, m), 2.56 (2H, t, J=7.4 Hz), 2.68-2.80 (4H, br), 3.15-3.25 (4H, br), 4.10 (2H, t, J=6.2 Hz), 4.18 (2H, t, J=6.7 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.93 (1H, d, J=2.0 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 180 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester hexadecyl ester
  • Figure US20190167672A1-20190606-C00245
  • In the same manner as in Example 175, the colorless amorphous compound was obtained (yield 48 mg, 15%).
  • 1H-NMR (CDCl3) δ ppm: 0.87 (3H, t, J=6.8 Hz), 1.20-1.38 (26H, m), 1.60-1.96 (6H, m), 2.55 (2H, t, J=7.4 Hz), 2.70-2.80 (4H, br), 3.16-3.24 (4H, br), 4.10 (2H, t, J=6.2 Hz), 4.18 (2H, t, J=6.7 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.93 (1H, d, J=2.0 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.1 Hz), 7.61 (1H, d, J=9.5 Hz)
  • In the same manner as in the above-mentioned Examples, the compounds described in the following Table 1 can be synthesized.
  • TABLE 1
    Example Structure Formula
    159
    Figure US20190167672A1-20190606-C00246
         		N-Benzyl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-2- oxo-3,4-dihydro-2H-quinolin-1- ylmethyl ester
    160
    Figure US20190167672A1-20190606-C00247
         		N-Phenethylcarbamic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    161
    Figure US20190167672A1-20190606-C00248
         		(7-{4-[4-(Benzo[b]thiophen-4- yl)piperazin-1-yl]butoxy}-2-oxo- 3,4-dihydro-2H-quinolin-1- yl)methyl N-methoxycarbamate
    162
    Figure US20190167672A1-20190606-C00249
         		N-Allylcarbamic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    163
    Figure US20190167672A1-20190606-C00250
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester methyl ester
    164
    Figure US20190167672A1-20190606-C00251
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester propyl ester
    165
    Figure US20190167672A1-20190606-C00252
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester propyl ester
    166
    Figure US20190167672A1-20190606-C00253
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester isopropyl ester
    167
    Figure US20190167672A1-20190606-C00254
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazsn-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester isopropyl ester
    168
    Figure US20190167672A1-20190606-C00255
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester butyl ester
    169
    Figure US20190167672A1-20190606-C00256
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester isobutyl ester
    170
    Figure US20190167672A1-20190606-C00257
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester isobutyl ester
    171
    Figure US20190167672A1-20190606-C00258
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester pentyl ester
    172
    Figure US20190167672A1-20190606-C00259
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester pentyl ester
    173
    Figure US20190167672A1-20190606-C00260
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester 3-methylbutyl ester
    174
    Figure US20190167672A1-20190606-C00261
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 3- methylbutyl ester
    175
    Figure US20190167672A1-20190606-C00262
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester hexyl ester
    176
    Figure US20190167672A1-20190606-C00263
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester nonyl ester
    177
    Figure US20190167672A1-20190606-C00264
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester nonyl ester
    178
    Figure US20190167672A1-20190606-C00265
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester tetradecyl ester
    179
    Figure US20190167672A1-20190606-C00266
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester tetradecyl ester
    180
    Figure US20190167672A1-20190606-C00267
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester hexadecyl ester
    181
    Figure US20190167672A1-20190606-C00268
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester benzyl ester
    182
    Figure US20190167672A1-20190606-C00269
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester benzyl ester
    183
    Figure US20190167672A1-20190606-C00270
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1- methoxymethyl-3,4-dihydro- 1H-quinolin-2-one
    184
    Figure US20190167672A1-20190606-C00271
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1- methoxymethyl-1H-quinolin-2- one
    185
    Figure US20190167672A1-20190606-C00272
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazsn-1-yl)butoxy]-2- methoxymethoxyquinoline
    186
    Figure US20190167672A1-20190606-C00273
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1- ethoxymethyl-3,4-dihydro-1H- quinolin-2-one
    187
    Figure US20190167672A1-20190606-C00274
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1- ethoxymethyl-1H-quinolin-2- one
    188
    Figure US20190167672A1-20190606-C00275
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1- isopropoxymethyl-3,4-dihydro- 1H-quinolin-2-one
    189
    Figure US20190167672A1-20190606-C00276
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1- isopropoxymethyl-1H-quinolin- 2-one
    190
    Figure US20190167672A1-20190606-C00277
         		Aminoacetic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    191
    Figure US20190167672A1-20190606-C00278
         		Aminoacetic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    192
    Figure US20190167672A1-20190606-C00279
         		2-Aminopropionic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    193
    Figure US20190167672A1-20190606-C00280
         		2-Aminopropionic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxyl-2-oxo- 2H-quinolin-1-ylmethyl ester
    194
    Figure US20190167672A1-20190606-C00281
         		2-Amino-3-methylbutyric acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    195
    Figure US20190167672A1-20190606-C00282
         		2-Amino-3-methylbutyric acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    196
    Figure US20190167672A1-20190606-C00283
         		2-Amino-4-methylpentanoic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-2- oxo-3,4-dihydro-2H-quinolin-1- ylmethyl ester
    197
    Figure US20190167672A1-20190606-C00284
         		2-Amino-4-methylpentanoic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-2- oxo-2H-quinolin-1-ylmethyl ester
    198
    Figure US20190167672A1-20190606-C00285
         		Pyrrolidine-2-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    199
    Figure US20190167672A1-20190606-C00286
         		Pyrrolidine-2-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    200
    Figure US20190167672A1-20190606-C00287
         		Calcium {7-[4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl]butoxy}-2-oxo- 3,4-dihydro-2H-quinolin-1- yl)methyl phosphate
    201
    Figure US20190167672A1-20190606-C00288
         		Calcium {7-[4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl]butoxy}-2-oxo- 2H-quinolin-1-yl)methyl phosphate
    202
    Figure US20190167672A1-20190606-C00289
         		Calcium (7-{4-[4- (benzo[b]thiophen-4- yl)piperazin-1- yl]buloxy}quinolin-2- yloxy)methyl phosphate
    203
    Figure US20190167672A1-20190606-C00290
         		Propionic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    204
    Figure US20190167672A1-20190606-C00291
         		Pentanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    205
    Figure US20190167672A1-20190606-C00292
         		Heptanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    206
    Figure US20190167672A1-20190606-C00293
         		Nonanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    207
    Figure US20190167672A1-20190606-C00294
         		Undecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    208
    Figure US20190167672A1-20190606-C00295
         		Tridecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    209
    Figure US20190167672A1-20190606-C00296
         		Nonadecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    210
    Figure US20190167672A1-20190606-C00297
         		Henicosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    211
    Figure US20190167672A1-20190606-C00298
         		Docosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    212
    Figure US20190167672A1-20190606-C00299
         		Tricosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    213
    Figure US20190167672A1-20190606-C00300
         		Tetracosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    214
    Figure US20190167672A1-20190606-C00301
         		2,2-Dimethylbutyric acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    215
    Figure US20190167672A1-20190606-C00302
         		2,2-Dimethylpentanoic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    216
    Figure US20190167672A1-20190606-C00303
         		2,2-Dimethyldodecanoic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    217
    Figure US20190167672A1-20190606-C00304
         		Isobutyric acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    218
    Figure US20190167672A1-20190606-C00305
         		3-Methylbutyric acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    219
    Figure US20190167672A1-20190606-C00306
         		Decanoicacid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- yl}ethyl ester
    220
    Figure US20190167672A1-20190606-C00307
         		Dodecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- yl}ethyl ester
    221
    Figure US20190167672A1-20190606-C00308
         		Tetradecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- yl}ethyl ester
    222
    Figure US20190167672A1-20190606-C00309
         		Hexadecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- yl}ethyl ester
    223
    Figure US20190167672A1-20190606-C00310
         		(2-Methoxyethoxy)acetic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    224
    Figure US20190167672A1-20190606-C00311
         		[2-(2- Methoxyethoxy)ethoxy]acetic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-2- oxo-3,4-dihydro-2H-quinolin-1- ylmethyl ester
    225
    Figure US20190167672A1-20190606-C00312
         		(9Z,12Z)-Octadeca-9,12- dienoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    226
    Figure US20190167672A1-20190606-C00313
         		(9Z,12Z,15Z)-Octadeca- 9,12,15-trienoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    227
    Figure US20190167672A1-20190606-C00314
         		(4Z,7Z,10Z,13Z,16Z,19Z)- Docosa-4,7,10,13,16,19- hexaenoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    228
    Figure US20190167672A1-20190606-C00315
         		(6Z,9Z,12Z,15Z)-Octadeca- 6,9,12,15-tetraenoic acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    229
    Figure US20190167672A1-20190606-C00316
         		Isonicotinic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    230
    Figure US20190167672A1-20190606-C00317
         		Pyrimidine-5-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    231
    Figure US20190167672A1-20190606-C00318
         		Pyridazine-4-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    232
    Figure US20190167672A1-20190606-C00319
         		Propionic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    233
    Figure US20190167672A1-20190606-C00320
         		Pentanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    234
    Figure US20190167672A1-20190606-C00321
         		Heptanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    235
    Figure US20190167672A1-20190606-C00322
         		Nonanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    236
    Figure US20190167672A1-20190606-C00323
         		Undecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    237
    Figure US20190167672A1-20190606-C00324
         		Tridecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    238
    Figure US20190167672A1-20190606-C00325
         		Nonadecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    239
    Figure US20190167672A1-20190606-C00326
         		Henicosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    240
    Figure US20190167672A1-20190606-C00327
         		Docosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    241
    Figure US20190167672A1-20190606-C00328
         		Tricosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    242
    Figure US20190167672A1-20190606-C00329
         		Tetracosanoic acid 7-[4-(4~ benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    243
    Figure US20190167672A1-20190606-C00330
         		2,2-Dimethylbutyric acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    244
    Figure US20190167672A1-20190606-C00331
         		2,2-Dimethylpentanoic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    245
    Figure US20190167672A1-20190606-C00332
         		2,2-Dimethyldodecanoic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    246
    Figure US20190167672A1-20190606-C00333
         		Isobutyric acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    247
    Figure US20190167672A1-20190606-C00334
         		3-Methylbutyric acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    248
    Figure US20190167672A1-20190606-C00335
         		Decanoic acid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-yl}ethyl ester
    249
    Figure US20190167672A1-20190606-C00336
         		Dodecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-yl}ethyl ester
    250
    Figure US20190167672A1-20190606-C00337
         		Tetradecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-yl}ethyl ester
    251
    Figure US20190167672A1-20190606-C00338
         		Hexadecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-yl}ethyl ester
    252
    Figure US20190167672A1-20190606-C00339
         		1-Methylpiperidine-4-carboxylic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-2- oxo-2H-quinolin-1-ylmethyl ester
    253
    Figure US20190167672A1-20190606-C00340
         		(2-Methoxyethoxy)acetic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    254
    Figure US20190167672A1-20190606-C00341
         		[2-(2- Methoxyethoxy)ethoxy]acetic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-2- oxo-2H-quinolin-1-ylmethyl ester
    255
    Figure US20190167672A1-20190606-C00342
         		(2-Butoxyethoxy)acetic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    256
    Figure US20190167672A1-20190606-C00343
         		(9Z,12Z)-Octadeca-9,12- dienoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    257
    Figure US20190167672A1-20190606-C00344
         		(9Z,12Z,15Z)-Octadeca- 9,12,15-trienoic add 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    258
    Figure US20190167672A1-20190606-C00345
         		(4Z,7Z,10Z,13Z,16Z,19Z)- Decosa-4,7,10,13,16,19- hexaenoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    259
    Figure US20190167672A1-20190606-C00346
         		(6Z,9Z,12Z,15Z)-Octadeca- 6,9,12,15-tetraenoic acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    260
    Figure US20190167672A1-20190606-C00347
         		Isonicotinic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    261
    Figure US20190167672A1-20190606-C00348
         		Nicotinic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    262
    Figure US20190167672A1-20190606-C00349
         		Pyrimidine-5-carboxyfic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    263
    Figure US20190167672A1-20190606-C00350
         		Pyridazine-4-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    264
    Figure US20190167672A1-20190606-C00351
         		Pyridine-2-carboxylic acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    265
    Figure US20190167672A1-20190606-C00352
         		Pyridine-2-carboxylic acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    266
    Figure US20190167672A1-20190606-C00353
         		Furan-2-carboxylic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    267
    Figure US20190167672A1-20190606-C00354
         		Furan-2-carboxylic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    268
    Figure US20190167672A1-20190606-C00355
         		Thiophene-3-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    269
    Figure US20190167672A1-20190606-C00356
         		Thiophene-3-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    270
    Figure US20190167672A1-20190606-C00357
         		Quinoline-6-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethyl ester
    271
    Figure US20190167672A1-20190606-C00358
         		Quinoline-6-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester
    272
    Figure US20190167672A1-20190606-C00359
         		Benzoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    273
    Figure US20190167672A1-20190606-C00360
         		2,2-Dimethylpropionic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    274
    Figure US20190167672A1-20190606-C00361
         		Butyric acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    275
    Figure US20190167672A1-20190606-C00362
         		Phenylacetic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    276
    Figure US20190167672A1-20190606-C00363
         		Octanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    277
    Figure US20190167672A1-20190606-C00364
         		Cyclohexanecarboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    278
    Figure US20190167672A1-20190606-C00365
         		Cyclopentanecarboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    279
    Figure US20190167672A1-20190606-C00366
         		(Z)-Octadec-9-enoic acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    280
    Figure US20190167672A1-20190606-C00367
         		Hexadecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    281
    Figure US20190167672A1-20190606-C00368
         		Icosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    282
    Figure US20190167672A1-20190606-C00369
         		2-Pentyl-heptanoic acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    283
    Figure US20190167672A1-20190606-C00370
         		Decanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    284
    Figure US20190167672A1-20190606-C00371
         		Hexanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    285
    Figure US20190167672A1-20190606-C00372
         		Octadecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    286
    Figure US20190167672A1-20190606-C00373
         		Acetic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    287
    Figure US20190167672A1-20190606-C00374
         		Propionic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    288
    Figure US20190167672A1-20190606-C00375
         		Pentanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    289
    Figure US20190167672A1-20190606-C00376
         		Heptanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    290
    Figure US20190167672A1-20190606-C00377
         		Nonanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    291
    Figure US20190167672A1-20190606-C00378
         		Undecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    292
    Figure US20190167672A1-20190606-C00379
         		Tridecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    293
    Figure US20190167672A1-20190606-C00380
         		Tetradecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    294
    Figure US20190167672A1-20190606-C00381
         		Pentadecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    295
    Figure US20190167672A1-20190606-C00382
         		Heptadecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethy-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    296
    Figure US20190167672A1-20190606-C00383
         		Nonadecanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    297
    Figure US20190167672A1-20190606-C00384
         		Henicosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    298
    Figure US20190167672A1-20190606-C00385
         		Docosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    299
    Figure US20190167672A1-20190606-C00386
         		Tricosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    300
    Figure US20190167672A1-20190606-C00387
         		Tetracosanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    301
    Figure US20190167672A1-20190606-C00388
         		Malonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester tert- butyl ester
    302
    Figure US20190167672A1-20190606-C00389
         		2-Methyl-butyric acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    303
    Figure US20190167672A1-20190606-C00390
         		2-Methyl-pentanoic acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    304
    Figure US20190167672A1-20190606-C00391
         		2-Methyl-hexanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    305
    Figure US20190167672A1-20190606-C00392
         		2,2-Dimethyl-hexanoic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    306
    Figure US20190167672A1-20190606-C00393
         		Isobutyric acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    307
    Figure US20190167672A1-20190606-C00394
         		3-Methyl-butyric acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    308
    Figure US20190167672A1-20190606-C00395
         		4-Methyl-pentanoic acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    309
    Figure US20190167672A1-20190606-C00396
         		Cyclobutanecarboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    310
    Figure US20190167672A1-20190606-C00397
         		Decanoic acid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-yl}-ethyl ester
    311
    Figure US20190167672A1-20190606-C00398
         		Dodecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-yl}-ethyl ester
    312
    Figure US20190167672A1-20190606-C00399
         		Tetradecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-yl}-ethyl ester
    313
    Figure US20190167672A1-20190606-C00400
         		Hexadecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-yl}-ethyl ester
    314
    Figure US20190167672A1-20190606-C00401
         		Tetrahydro-pyran-4-carboxylic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    315
    Figure US20190167672A1-20190606-C00402
         		(2-Methoxy-ethoxy)-acetic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    316
    Figure US20190167672A1-20190606-C00403
         		[2-(2-Methoxy-ethoxy)-ethoxy]- acetic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    317
    Figure US20190167672A1-20190606-C00404
         		(2-Butoxy-ethoxy)-acetic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    318
    Figure US20190167672A1-20190606-C00405
         		Cycloheptanecarboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    319
    Figure US20190167672A1-20190606-C00406
         		4,4,4-Trifluoro-butyric acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    320
    Figure US20190167672A1-20190606-C00407
         		Piperidine-1-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    321
    Figure US20190167672A1-20190606-C00408
         		N-Butyl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    322
    Figure US20190167672A1-20190606-C00409
         		N,N-Dibutylcarbamic acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    323
    Figure US20190167672A1-20190606-C00410
         		N-Cyclohexylmethylcarbamic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    324
    Figure US20190167672A1-20190606-C00411
         		N-Butylcarbamic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    325
    Figure US20190167672A1-20190606-C00412
         		N-Methylcarbamic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    326
    Figure US20190167672A1-20190606-C00413
         		N,N-Dimethylcarbamic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    327
    Figure US20190167672A1-20190606-C00414
         		N-Ethylcarbamic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    328
    Figure US20190167672A1-20190606-C00415
         		N,N-Diethylcarbamic acid 7-[4- (4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    329
    Figure US20190167672A1-20190606-C00416
         		N-Pentadecylcarbamic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    330
    Figure US20190167672A1-20190606-C00417
         		N-Octadecylcarbamic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    331
    Figure US20190167672A1-20190606-C00418
         		N-Methyl-N-octadecylcarbamic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    332
    Figure US20190167672A1-20190606-C00419
         		N-Cyclohexylcarbamic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    333
    Figure US20190167672A1-20190606-C00420
         		N-Benzylcarbamic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    334
    Figure US20190167672A1-20190606-C00421
         		N-Benzyl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    335
    Figure US20190167672A1-20190606-C00422
         		N-Phenethylcarbamic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    336
    Figure US20190167672A1-20190606-C00423
         		Morpholine-4-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    337
    Figure US20190167672A1-20190606-C00424
         		N-(2-Methoxyethyl)carbamic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    338
    Figure US20190167672A1-20190606-C00425
         		{7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1- ylmethoxycarbonylamino}acetic acid methyl ester
    339
    Figure US20190167672A1-20190606-C00426
         		({7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethoxycarbonyl}- methyl-amino)acetic acid methyl ester
    340
    Figure US20190167672A1-20190606-C00427
         		(7-{4-[4-(Benzo[b]thiophen-4- yl)piperazin-1-yl]butoxy}4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-yl)methyl N- methoxycarbamate
    341
    Figure US20190167672A1-20190606-C00428
         		7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl N- benzyloxycarbamate
    342
    Figure US20190167672A1-20190606-C00429
         		N-(3,3,3-Trifluoro- propyl)carbamic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    343
    Figure US20190167672A1-20190606-C00430
         		N-Furan-2-ylmethylcarbamic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    344
    Figure US20190167672A1-20190606-C00431
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester methyl ester
    345
    Figure US20190167672A1-20190606-C00432
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester ethyl ester
    346
    Figure US20190167672A1-20190606-C00433
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester propyl ester
    347
    Figure US20190167672A1-20190606-C00434
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester isopropyl ester
    348
    Figure US20190167672A1-20190606-C00435
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester butyl ester
    349
    Figure US20190167672A1-20190606-C00436
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester isobutyl ester
    350
    Figure US20190167672A1-20190606-C00437
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester pentyl ester
    351
    Figure US20190167672A1-20190606-C00438
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester 3- methyl-butyl ester
    352
    Figure US20190167672A1-20190606-C00439
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester hexyl ester
    353
    Figure US20190167672A1-20190606-C00440
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester nonyl ester
    354
    Figure US20190167672A1-20190606-C00441
         		Carbonic acid 7-[4-(4- benzo[b]-thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester tetradecyl ester
    355
    Figure US20190167672A1-20190606-C00442
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester hexadecyl ester
    356
    Figure US20190167672A1-20190606-C00443
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester benzyl ester
    357
    Figure US20190167672A1-20190606-C00444
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester heptyl ester
    358
    Figure US20190167672A1-20190606-C00445
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester octyl ester
    359
    Figure US20190167672A1-20190606-C00446
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester 2,2,2- trifluoro-ethyl ester
    360
    Figure US20190167672A1-20190606-C00447
         		Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester cyclohexyl ester
    361
    Figure US20190167672A1-20190606-C00448
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1- methoxymethyl-4,4-dimethyl- 3,4-dihydro-1H-quinolin-2-one
    362
    Figure US20190167672A1-20190606-C00449
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1- ethoxymethyl-4,4-dimethyl-3,4- dihydro-1H-quinolin-2-one
    363
    Figure US20190167672A1-20190606-C00450
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1- isopropoxymethyl-4,4-dimethyl- 3,4-dihydro-1H-quinolin-2-one
    364
    Figure US20190167672A1-20190606-C00451
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1- benzyloxymethyl-4,4-dimethyl- 3,4-dihydro-1H-quinolin-2-one
    365
    Figure US20190167672A1-20190606-C00452
         		7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-1-(2,2,2-trifluoro- ethoxymethyl)-3,4-dihydro-1H- quinolin-2-one
    366
    Figure US20190167672A1-20190606-C00453
         		Amino-acetic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    367
    Figure US20190167672A1-20190606-C00454
         		2-Amino-propionic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    368
    Figure US20190167672A1-20190606-C00455
         		2-Amino-3-methyl-butyric acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    369
    Figure US20190167672A1-20190606-C00456
         		2-Amino-4-methyl-pentanoic acid 7-[4-(4-benzo[b]thiophen- 4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    370
    Figure US20190167672A1-20190606-C00457
         		Pyrrolidine-2-carboxylic acid 7- [4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester
    • Example 371 Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyl dodecanoate
  • Figure US20190167672A1-20190606-C00458
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dimethylformamide (30 ml) was added silver carbonate (I) (0.76 g), chloromethyldodecanoate[61413-67-0] (1.15 g) was added, and the mixture was stirred at 60° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane-2:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyl dodecanoate (22 mg).
  • Oil: Colorless
  • 1H-NMR (CDCl3) δ ppm: 0.87 (3H, t, J=7.1 Hz), 1.16-2.10 (18H, m), 2.36 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.5 Hz), 2.76 (4H, br), 3.21 (4H, br), 4.15 (2H, t, J=6.3 Hz), 6.25 (2H, s), 6.80 (1H, d, J=8.7 Hz), 6.90 (1H, d, J=7.4 Hz), 7.06 (1H, dd, J=2.5, 8.8 Hz), 7.22 (1H, d, J=2.3 Hz), Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=8.8 Hz), 7.96 (1H, d, J=8.7 Hz)
    • Example 372 Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyl cyclohexyl carbonate
  • Figure US20190167672A1-20190606-C00459
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (700 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dimethylformamide (20 ml) was added silver carbonate (I) (0.53 g), chloromethyl cyclohexyl carbonate[40510-86-9] (0.68 g) was added, and the mixture was stirred at 60° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane-2:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyl cyclohexyl carbonate (60 mg).
  • Amorphous: Colorless
  • 1H-NMR (CDCl3) δ ppm: 1.10-2.00 (14H, m), 2.56 (2H, t, J=7.5 Hz), 2.75 (4H, br), 3.21 (4H, br), 4.14 (2H, t, J=6.3 Hz), 4.64-4.74 (1H, m), 6.27 (2H, s), 6.82 (1H, d, J=8.7 Hz), 6.90 (1H, d, J=7.2 Hz), 7.06 (1H, dd, J=2.5, 8.8 Hz), 7.20-7.30 (2H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=8.9 Hz), 7.96 (1H, d, J=8.7 Hz)
    • Example 373 Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethylhexyl carbonate
  • Figure US20190167672A1-20190606-C00460
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (730 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dimethylformamide (20 ml) was added silver carbonate (I) (0.56 g), chloromethyl hexyl carbonate[663597-51-1] (0.72 g) was added, and the mixture was stirred at 60° C. for 10 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyl hexyl carbonate (95 mg).
  • Oil: Yellow
  • 1H-NMR (CDCl3) δ ppm: 0.87 (3H, t, J=6.9 Hz), 1.20-1.40 (6H, m), 1.60-1.70 (2H, m), 1.74-1.84 (2H, m), 1.88-1.98 (2H, m), 2.57 (2H, t, J=7.6 Hz), 2.76 (4H, br), 3.21 (4H, br), 4.14 (2H, t, J=6.3 Hz), 4.19 (2H, t, J=6.7 Hz), 6.27 (2H, s), 6.82 (1H, d, J=8.7 Hz), 6.90 (1H, d, J=7.6 Hz), 7.06 (1H, dd, J=2.5, 8.8 Hz), 7.23 (1H, d, J=2.4 Hz), Hz), 7.27 (1H, t, J=7.9 Hz), 7.35-7.45 (2H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, carbonate (I) (08.8 Hz), 7.96 (H, d, J carbonate[663597-51-1]8.7 Hz)
    • Example 374 Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethylphenyl carbonate
  • Figure US20190167672A1-20190606-C00461
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (1.5 g) synthesized in the same manner as in WO2006/112464 (Example 1) in dimethylformamide (50 ml) was added silver carbonate (I) (1.14 g), chloromethyl phenyl carbonate[35180-03-1] (1.42 g) was added, and the mixture was stirred at 60° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyl phenyl carbonate (20 mg).
  • Oil: Colorless
  • 1H-NMR (CDCl3) δ ppm: 1.70-2.10 (4H, m), 2.59 (2H, t, J=7.4 Hz), 2.78 (4H, br), 3.22 (4H, br), 4.10-4.18 (2H, m), 6.38 (2H, s), 6.80-6.95 (4H, m), 7.08 (1H, dd, J=2.4, 8.8 Hz), 7.18-7.45 (7H, m), 7.55 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=8.9 Hz), 8.00 (1H, d, J=8.7 Hz)
    • Example 375 Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyldecyl carbamate
  • Figure US20190167672A1-20190606-C00462
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyl phenyl carbonate (20 mg) synthesized in the same manner as in Example 374 in THF (10 ml) was added decylamine[2016-57-1] (0.1 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyl decyl carbamate (18 mg).
  • Oil: Colorless
  • 1H-NMR (CDCl3) δ ppm: 0.87 (3H, t, J=6.9 Hz), 1.10-2.40 (20H, m), 2.58 (2H, t, J=7.4 Hz), 2.76 (4H, br), 3.16-3.26 (6H, m), 4.15 (2H, t, J=6.3 Hz), 4.83 (1H, t, J=5.4 Hz), 6.23 (2H, s), 6.82 (1H, d, J=8.7 Hz), 6.90 (1H, d, J=7.6 Hz), 7.06 (1H, dd, J=2.5, 8.8 Hz), 7.23 (1H, d, J=2.4 Hz), Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=8.8 Hz), 7.95 (1H, d, J=8.7 Hz)
    • Example 376 Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1-dodecanoyl-3,4-dihydroquinolin-2 (1H)-one
  • Figure US20190167672A1-20190606-C00463
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one (0.3 g) synthesized in the same manner as in WO2006/112464 (Example 11) in methylene chloride (10 ml) was added pyridine (0.11 ml), with stirring under ice-cooling, dodecanoylchloride (0.24 ml) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with methylene chloride, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-dodecanoyl-3,4-dihydro-1H-quinolin-2-one (0.4 g).
  • Oil: Colorless
  • 1H-NMR (CDCl3) δ ppm: 0.88 (3H, t, J=6.8 Hz), 1.20-1.40 (16H, m), 1.68-1.90 (6H, m), 2.54 (2H, t, J=7.4 Hz), 2.65-2.80 (6H, m), 2.80-2.88 (2H, m), 2.97 (2H, t, J=7.6 Hz), 3.16-3.26 (4H, m), 3.97 (2H, t, J=6.2 Hz), 6.67 (1H, dd, J=2.4, 8.3 Hz), 6.83 (1H, dd, J=0.6, 7.7 Hz), 7.08 (1H, d, J=8.3 Hz), 7.27 (1H, t, J=7.8 Hz), 7.37-7.43 (2H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 377 Synthesis of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-1-(cyclohexanecarbonyl)-3,4-dihydroquinolin-2(1H)-one
  • Figure US20190167672A1-20190606-C00464
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-quinolin-2-one (1 g) synthesized in the same manner as in WO2006/112464 (Example 11) in dichloromethane (30 ml) was added pyridine (0.37 ml), with stirring under ice-cooling, cyclohexanecarbonyl chloride (0.46 ml) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=9:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1-(cyclohexanecarbonyl)-3,4-dihydroquinolin-2(1H)-one (1.2 g).
  • Oil: Yellow
  • 1H-NMR (CDCl3) δ ppm: 1.20-2.25 (14H, m), 2.53 (2H, t, J=7.5 Hz), 2.64-2.78 (6H, m), 2.84-2.90 (2H, m), 3.12-3.24 (5H, m), 3.97 (2H, t, J=6.2 Hz), 6.59 (1H, d, J=2.3 Hz), 6.63 (1H, dd, J=2.4, 8.3 Hz), 6.90 (1H, d, J=7.4 Hz), 7.08 (1H, d, J=8.3 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz)
    • Example 378 Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]quinolin-2-yl acetate
  • Figure US20190167672A1-20190606-C00465
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one (3.14 g) synthesized in the same manner as in WO2006/112464 (Example 1) in methylene chloride (32 mL) were added with stirring under ice-cooling triethylamine (4.0 mL) and acetyl chloride (1.5 mL), and the mixture was stirred at room temperature for 39 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=7:3→1:9) to give 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]quinolin-2-yl acetate (1.24 g).
  • Oil: Yellow
  • 1H-NMR (CDCl3) δ ppm: 1.62-1.81 (2H, m), 1.81-2.00 (2H, m), 2.39 (3H, s), 2.54 (2H, t, J=7.5 Hz), 2.67-2.86 (4H, m), 3.10-3.29 (4H, m), 4.15 (2H, t, J=6.3 Hz), 6.90 (1H, d, J=7.5 Hz), 7.05 (1H, d, J=8.5 Hz), 7.10-7.29 (3H, m), 7.29-7.48 (2H, m), 7.55 (1H, d, J=7.8 Hz), 7.72 (1H, d, J=9.0 Hz), 8.15 (1H, d, J=8.5 Hz)
    • Example 379 Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl dodecanoate
  • Figure US20190167672A1-20190606-C00466
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) in dichloromethane (20 ml) synthesized in the same manner as in WO2006/112464 (Example 1) was added triethylamine (0.77 ml), with stirring under ice-cooling, dodecanoylchloride (1.1 ml) was added and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl dodecanoate (1.34 g).
  • Oil: Yellow
  • 1H-NMR (CDCl3) δ ppm: 0.88 (3H, t, J=6.8 Hz), 1.20-1.50 (16H, m), 1.72-1.86 (4H, m), 1.86-1.98 (2H, m), 2.55 (2H, t, J=7.6 Hz), 2.66 (2H, t, J=7.6 Hz), 2.75 (4H, br), 3.20 (4H, br), 4.14 (2H, t, J=6.3 Hz), 6.90 (1H, d, J=7.5 Hz), 7.04 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=2.4, 8.9 Hz), 7.27 (1H, t, J=7.8 Hz), 7.33 (1H, d, J=2.4 Hz), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.1 Hz), 7.71 (1H, d, J=9.0 Hz), 8.14 (1H, d, J=8.6 Hz)
    • Example 380 Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl cyclohexanecarboxylate
  • Figure US20190167672A1-20190606-C00467
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added triethylamine (0.64 ml), with stirring under ice-cooling, cyclohexanecarbonyl chloride (0.49 ml) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=4:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl cyclohexanecarboxylate (1.08 g).
  • Oil: Yellow
  • 1H-NMR (CDCl3) δ ppm: 1.20-2.20 (14H, m), 2.54 (2H, t, J=7.5 Hz), 2.60-2.80 (5H, m), 3.20 (4H, br), 4.08-4.18 (2H, m), 6.89 (1H, d, J=7.6 Hz), 7.01 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=2.5, 8.9 Hz), 7.27 (1H, t, J=7.8 Hz), 7.34 (1H, d, J=2.4 Hz), 7.36-7.44 (2H, m), 7.54 (1H, d, J=8.0 Hz), 7.70 (1H, d, J=8.9 Hz), 8.12 (1H, d, J=8.6 Hz)
    • Example 381 Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl hexyl carbonate
  • Figure US20190167672A1-20190606-C00468
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added triethylamine (0.65 ml), with stirring under ice-cooling, hexylchloroformate (0.6 g) was added at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl hexyl carbonate (1.09 g).
  • Oil: Colorless
  • 1H-NMR (CDCl3) δ ppm: 0.91 (3H, t, J=7.0 Hz), 1.30-1.50 (6H, m), 1.70-1.84 (4H, m), 1.88-1.98 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.72 (4H, br), 3.20 (4H, br), 4.15 (2H, t, J=6.4 Hz), 4.30 (2H, t, J=6.7 Hz), 6.90 (1H, dd, J=0.4, 7.6 Hz), 7.08 (1H, d, J=8.6 Hz), 7.20 (1H, dd, J=2.4, 8.9 Hz), 7.27 (1H, t, J=7.8 Hz), 7.33 (1H, d, J=2.4 Hz), 7.36-7.44 (2H, m), 7.54 (1H, d, J=8.0 Hz), 7.72 (1H, d, J=9.0 Hz), 8.15 (1H, d, J=8.6 Hz)
    • Example 382 Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl diethylcarbamate
  • Figure US20190167672A1-20190606-C00469
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added triethylamine (0.65 ml), with stirring under ice-cooling, diethylcarbamoylchloride (0.5 g) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=20:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl diethylcarbamate (120 mg).
  • Oil: Colorless
  • 1H-NMR (CDCl3) δ ppm: 1.23 (3H, t, J=7.1 Hz), 1.30 (3H, t, J=7.1 Hz), 1.72-1.84 (2H, m), 1.86-1.98 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.73 (4H, br), 3.20 (4H, br), 3.43 (2H, q, J=7.0 Hz), 3.52 (2H, q, J=7.1 Hz), 4.13 (2H, t, J=6.3 Hz), 6.89 (1H, d, J=7.2 Hz), 7.08 (1H, d, J=8.6 Hz), 7.16 (1H, dd, J=2.5, 8.9 Hz), 7.26 (1H, t, J=7.8 Hz), 7.34 (1H, d, J=2.4 Hz), 7.36-7.44 (2H, m), 7.54 (1H, d, J=7.9 Hz), 7.68 (1H, d, J=8.9 Hz), 8.09 (1H, d, J=8.6 Hz)
    • Example 383 Synthesis of 4-(benzo[b]thiophen-4-yl)-1-(dodecanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)piperazin-1-ium iodide
  • Figure US20190167672A1-20190606-C00470
  • To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (0.85 g) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added iodomethyldodecanoate (1 g) synthesized in the same manner as in Reference Example 19, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, ether was added and the mixture was left standing. The obtained crystals were collected by filtration to give 4-(benzo[b]thiophen-4-yl)-1-(dodecanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)piperazin-1-ium iodide (1.07 g).
  • Powder:Yellow
  • 1H-NMR (DMSO-d6) δ ppm: 0.84 (3H, t, J=6.8 Hz), 1.10-2.56 (24H, m), 3.44-3.56 (4H, m), 3.60-3.90 (6H, m), 4.09 (2H, t, J=5.5 Hz), 5.57 (2H, s), 6.31 (1H, d, J=9.4 Hz), 6.80-6.86 (2H, m), 7.05 (1H, d, J=7.6 Hz), 7.35 (1H, t, J=7.9 Hz), 7.54 (1H, d, J=5.5 Hz), 7.56-7.62 (1H, m), 7.68-7.86 (3H, m), 11.63 (1H, s)
    • Example 384 Synthesis of (7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl octyl carbonate
  • Figure US20190167672A1-20190606-C00471
  • In the same manner as in Example 175, the compound was obtained (yield 25 mg, 8.7%) as a colorless oil.
  • 1H-NMR (CDCl3) δ ppm: 0.86 (3H, t, J=6.9 Hz), 1.16-1.40 (10H, m), 1.58-1.72 (2H, m), 1.72-1.84 (2H, m), 1.85-1.95 (2H, m), 2.55 (2H, t, J=7.5 Hz), 2.68-2.80 (4H, br), 3.14-3.26 (4H, br), 4.10 (2H, t, J=6.2 Hz), 4.18 (2H, t, J=6.7 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.93 (1H, d, J=2.1 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)
    • Example 385 Synthesis of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester cyclohexyl ester hydrochloride
  • Figure US20190167672A1-20190606-C00472
  • Sodium hydride (55% oil) (0.962 g, 22.04 mmol) was suspended in tetrahydrofuran (THF) (200 ml), 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (8.31 g, 19.17 mmol) was added and the mixture was stirred at 50° C. for 1 hr. The mixture was cooled to 0° C., chloromethyl cyclohexyl carbonate (4.80 g, 24.92 mmol) was added dropwise and the mixture was stirred at room temperature overnight. After cooling to 0° C., excess 2N hydrochloric acid was added to quench the reaction. The precipitated solid was collected by filtration and dried. In addition, the filtrate was extracted with ethyl acetate. The organic layer was concentrated and purified by moderate-pressure silica gel column chromatography (methylene chloride:methanol=100:0 to 20:1). Likewise, the solid was purified by moderate-pressure silica gel column chromatography. Concentration under reduced pressure gave the title compound (yield, 5.04 g, 42%) as a white solid.
  • 1H-NMR (DMSO-d6) δ ppm: 1.16 (m, 6H), 1.59-1.69 (m, 2H), 1.80 (m, 6H), 3.00-3.60 (m, 10H), 4.19 (t, J=5.9 Hz, 2H), 4.57-4.65 (m, 18), 6.29 (s, 2H), 6.42 (d, J=9.5 Hz, 1H), 6.97 (dd, J=2.3, 8.5 Hz, 1H), 6.98 (dd, J=1.8, 7.7 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 7.31 (dd, J=7.7, 7.7 Hz, 1H), 7.43 (dd, J=1.8, 5.5 Hz, 1H), 7.63-7.71 (m, 3H), 7.86 (d, J=9.5 Hz, 1H).
  • In the same manner as in the above-mentioned Examples, the compounds described in the following Table 2 can be synthesized.
  • TABLE 2
    Example Structure Formula
    386
    Figure US20190167672A1-20190606-C00473
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl dipropylcarbamate
    387
    Figure US20190167672A1-20190606-C00474
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl diisobutylcarbamate
    388
    Figure US20190167672A1-20190606-C00475
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl dihexylcarbamate
    389
    Figure US20190167672A1-20190606-C00476
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl nonadecylcarbonate
    390
    Figure US20190167672A1-20190606-C00477
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl methyl(nonyl)carbamate
    391
    Figure US20190167672A1-20190606-C00478
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl methyl(tetradecyl)carbamate
    392
    Figure US20190167672A1-20190606-C00479
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl ditetradecylcarbamate
    393
    Figure US20190167672A1-20190606-C00480
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl dinonylcarbamate
    394
    Figure US20190167672A1-20190606-C00481
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl 2,2-dimethyldecanoate
    395
    Figure US20190167672A1-20190606-C00482
         		1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)-2- ethoxy-2-oxoethyl decanoate
    396
    Figure US20190167672A1-20190606-C00483
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl 2,2-dimethyloctanoate
    397
    Figure US20190167672A1-20190606-C00484
         		1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)ethyl butyrate
    398
    Figure US20190167672A1-20190606-C00485
         		1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)ethyl 3- methylbutanoate
    399
    Figure US20190167672A1-20190606-C00486
         		1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)ethyl hexanoate
    400
    Figure US20190167672A1-20190606-C00487
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl 2-hydroxyethylcarbamate
    401
    Figure US20190167672A1-20190606-C00488
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl bis(2-hydroxyethyl)carbamate
    402
    Figure US20190167672A1-20190606-C00489
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl 4-methylpiperazine-1- carboxylate
    403
    Figure US20190167672A1-20190606-C00490
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl 1,4′-bipiperidine-1′- carboxylate
    404
    Figure US20190167672A1-20190606-C00491
         		calcium 1-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2 oxoquinolin-1(2H)-yl)-2- methylpropyl phosphate
    405
    Figure US20190167672A1-20190606-C00492
         		1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)ethyl dimethylcarbamate
    406
    Figure US20190167672A1-20190606-C00493
         		1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)ethyl methyl(tetradecyl)carbamate
    407
    Figure US20190167672A1-20190606-C00494
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl 4-acetamidobutanoate
    408
    Figure US20190167672A1-20190606-C00495
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl 4-heptanamidobutanoate
    409
    Figure US20190167672A1-20190606-C00496
         		1-(7-(4-(4-(benzo[b]thiophen-4- 4-yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)ethyl dinonylcarbamate
    410
    Figure US20190167672A1-20190606-C00497
         		1-(7-(4-(4-(benzo[b]thiophen-4- 4-yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)ethyl ditetradecylcarbamate
    411
    Figure US20190167672A1-20190606-C00498
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl 4-heptanamidobutanoate
    412
    Figure US20190167672A1-20190606-C00499
         		(5Z,8Z,11Z,14Z,17Z)-(7-(4- (4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl henicosa-5,8,11,14,17- pentaenoate
    413
    Figure US20190167672A1-20190606-C00500
         		(7Z,10Z,13Z,16Z,19Z)-(7-(4- (4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl pentacosa-7,10,13,16,19- pentaenoate
    414
    Figure US20190167672A1-20190606-C00501
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl acetate
    415
    Figure US20190167672A1-20190606-C00502
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl propionate
    416
    Figure US20190167672A1-20190606-C00503
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl butyrate
    417
    Figure US20190167672A1-20190606-C00504
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl pentanoate
    418
    Figure US20190167672A1-20190606-C00505
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl hexanoate
    419
    Figure US20190167672A1-20190606-C00506
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl heptanoate
    420
    Figure US20190167672A1-20190606-C00507
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl octanoate
    421
    Figure US20190167672A1-20190606-C00508
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl nonanoate
    422
    Figure US20190167672A1-20190606-C00509
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl decanoate
    423
    Figure US20190167672A1-20190606-C00510
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl undecanoate
    424
    Figure US20190167672A1-20190606-C00511
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl tridecanoate
    425
    Figure US20190167672A1-20190606-C00512
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl tetradecanoate
    426
    Figure US20190167672A1-20190606-C00513
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl pentadecanoate
    427
    Figure US20190167672A1-20190606-C00514
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl palmitate
    428
    Figure US20190167672A1-20190606-C00515
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl heptadecanoate
    429
    Figure US20190167672A1-20190606-C00516
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl stearate
    430
    Figure US20190167672A1-20190606-C00517
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl icosanoate
    431
    Figure US20190167672A1-20190606-C00518
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl 2,2- dimethyltetradecanoate
    432
    Figure US20190167672A1-20190606-C00519
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl pivalate
    433
    Figure US20190167672A1-20190606-C00520
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl 2,2- dimethylbutanoate
    434
    Figure US20190167672A1-20190606-C00521
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl isobutyrate
    435
    Figure US20190167672A1-20190606-C00522
         		(7-(4-(4-(benzo[b]thiophen-4- y)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl 2- hydroxyacetate
    436
    Figure US20190167672A1-20190606-C00523
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl cyclopropanecarboxylate
    437
    Figure US20190167672A1-20190606-C00524
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl cyclobutanecarboxylate
    438
    Figure US20190167672A1-20190606-C00525
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl cyclopentanecarboxylate
    439
    Figure US20190167672A1-20190606-C00526
         		(7-(4-(4-(benzo[b]thiophen-4 yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl cyclohexanecarboxylate
    440
    Figure US20190167672A1-20190606-C00527
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl benzoate
    441
    Figure US20190167672A1-20190606-C00528
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl 2-phenylacetate
    442
    Figure US20190167672A1-20190606-C00529
         		(9Z,12Z,15Z)-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl octadeca- 9,12,15-trienoate
    443
    Figure US20190167672A1-20190606-C00530
         		(5Z,8Z,11Z,14Z,17Z)-(7-(4- (4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl henicosa- 5,8,11,14,17-pentaenoate
    444
    Figure US20190167672A1-20190606-C00531
         		(4Z,7Z,10Z,13Z,16Z,19Z)-(7- (4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl docosa- 4,7,10,13,16,19-hexaenoate
    445
    Figure US20190167672A1-20190606-C00532
         		(6Z,9Z,12Z,15Z)-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl octadeca- 6,9,12,15-tetraenoate
    446
    Figure US20190167672A1-20190606-C00533
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl methyl carbonate
    447
    Figure US20190167672A1-20190606-C00534
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl ethyl carbonate
    448
    Figure US20190167672A1-20190606-C00535
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl butyl carbonate
    449
    Figure US20190167672A1-20190606-C00536
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl pentyl carbonate
    450
    Figure US20190167672A1-20190606-C00537
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl 2-methoxyethyl carbonate
    451
    Figure US20190167672A1-20190606-C00538
         		calcium (7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl phosphate
    452
    Figure US20190167672A1-20190606-C00539
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl methylcarbamate
    453
    Figure US20190167672A1-20190606-C00540
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl ethylcarbamate
    454
    Figure US20190167672A1-20190606-C00541
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl propylcarbamate
    455
    Figure US20190167672A1-20190606-C00542
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl butylcarbamate
    456
    Figure US20190167672A1-20190606-C00543
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl pentylcarbamate
    457
    Figure US20190167672A1-20190606-C00544
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl hexylcarbamate
    458
    Figure US20190167672A1-20190606-C00545
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl octylcarbamate
    459
    Figure US20190167672A1-20190606-C00546
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl dodecylcarbamate
    460
    Figure US20190167672A1-20190606-C00547
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl tetradecylcarbamate
    461
    Figure US20190167672A1-20190606-C00548
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl hexadecylcarbamate
    462
    Figure US20190167672A1-20190606-C00549
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl dimethylcarbamate
    463
    Figure US20190167672A1-20190606-C00550
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl diethylcarbamate
    464
    Figure US20190167672A1-20190606-C00551
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl dipropylcarbamate
    465
    Figure US20190167672A1-20190606-C00552
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl diisobutylcarbamate
    466
    Figure US20190167672A1-20190606-C00553
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl dibutylcarbamate
    467
    Figure US20190167672A1-20190606-C00554
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl dihexylcarbamate
    468
    Figure US20190167672A1-20190606-C00555
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl dioctylcarbamate
    469
    Figure US20190167672A1-20190606-C00556
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl didecylcarbamate
    470
    Figure US20190167672A1-20190606-C00557
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl didodecylcarbamate
    471
    Figure US20190167672A1-20190606-C00558
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl ditetradecylcarbamate
    472
    Figure US20190167672A1-20190606-C00559
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl dihexadecylcarbamate
    473
    Figure US20190167672A1-20190606-C00560
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl bis(2- hydroxyethyl)carbamate
    474
    Figure US20190167672A1-20190606-C00561
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl piperidine-1- carboxylate
    475
    Figure US20190167672A1-20190606-C00562
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2 yloxy)methyl 4- methylpiperazine-1- carboxylate
    476
    Figure US20190167672A1-20190606-C00563
         		(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl 1,4′-bipiperidine- 1′-carboxylate
    477
    Figure US20190167672A1-20190606-C00564
         		1-acetyl-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2(1H)-one
    478
    Figure US20190167672A1-20190606-C00565
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- propionylquinolin-2(1H)-one
    479
    Figure US20190167672A1-20190606-C00566
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- butyrylquinolin-2(1H)-one
    480
    Figure US20190167672A1-20190606-C00567
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- pentanoylquinolin-2(1H)-one
    481
    Figure US20190167672A1-20190606-C00568
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(3- methylbutanoyl)quinolin- 2(1H)-one
    482
    Figure US20190167672A1-20190606-C00569
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- hexanoylquinolin-2(1H)-one
    483
    Figure US20190167672A1-20190606-C00570
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- hexanoyl-3,4-dihydroquinolin- 2(1H)-one
    484
    Figure US20190167672A1-20190606-C00571
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-y)butoxy)-1- heptanoylquinolin-2(1H)-one
    485
    Figure US20190167672A1-20190606-C00572
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- octanoylquinolin-2(1H)-one
    486
    Figure US20190167672A1-20190606-C00573
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- octanoyl-3,4-dihydroquinolin- 2(1H)-one
    487
    Figure US20190167672A1-20190606-C00574
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- nonanoylquinolin-2(1H)-one
    488
    Figure US20190167672A1-20190606-C00575
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- decanoylquinolin-2(1H)-one
    489
    Figure US20190167672A1-20190606-C00576
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- undecanoylquinolin-2(1H)- one
    490
    Figure US20190167672A1-20190606-C00577
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- dodecanoylquinolin-2(1H)- one
    491
    Figure US20190167672A1-20190606-C00578
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- tridecanoylquinolin-2(1H)-one
    492
    Figure US20190167672A1-20190606-C00579
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- tetradecanoylquinolin-2(1H)- one
    493
    Figure US20190167672A1-20190606-C00580
         		7-(4-(4-(benzo[b]thiophen-4- y)piperazin-1-yl)butoxy)-1- pentadecanoylquinolin-2(1H)- one
    494
    Figure US20190167672A1-20190606-C00581
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- palmitoylquinolin-2(1H)-one
    495
    Figure US20190167672A1-20190606-C00582
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- heptadecanoylquinolin-2(1H)- one
    496
    Figure US20190167672A1-20190606-C00583
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- stearoylquinolin-2(1H)-one
    497
    Figure US20190167672A1-20190606-C00584
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- nonadecanoylquinolin-2(1H)- one
    498
    Figure US20190167672A1-20190606-C00585
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- icosanoylquinolin-2(1H)-one
    499
    Figure US20190167672A1-20190606-C00586
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- henicosanoylquinolin-2(1H)- one
    500
    Figure US20190167672A1-20190606-C00587
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- docosanoylquinolin-2(1H)- one
    501
    Figure US20190167672A1-20190606-C00588
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- tricosanoylquinolin-2(1H)-one
    502
    Figure US20190167672A1-20190606-C00589
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- tetracosanoylquinolin-2(1H)- one
    503
    Figure US20190167672A1-20190606-C00590
         		7-(4-(4-(benzo[b]thiophen-4- piperazin-1-yl)butoxy)-1-(2- methylbutanoyl)quinolin- 2(1H)-one
    504
    Figure US20190167672A1-20190606-C00591
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- isobutyrylquinolin-2(1H)-one
    505
    Figure US20190167672A1-20190606-C00592
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- isobutyryl-3,4- dihydroquinolin-2(1H)-one
    506
    Figure US20190167672A1-20190606-C00593
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2- methylpentanoyl)quinolin- 2(1H)-one
    507
    Figure US20190167672A1-20190606-C00594
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2- methylhexanoy)quinolin- 2(1H)-one
    508
    Figure US20190167672A1-20190606-C00595
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (2,2- dimethylhexanoyl)quinolin- 2(1H)-one
    509
    Figure US20190167672A1-20190606-C00596
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (2,2- dimethyloctanoyl)quinolin- 2(1H)-one
    510
    Figure US20190167672A1-20190606-C00597
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (2,2-dimethyloctanoyl)-3,4- dihydroquinolin-2(1H)-one
    511
    Figure US20190167672A1-20190606-C00598
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (2,2- dimethyldecanoyl)quinolin- 2(1H)-one
    512
    Figure US20190167672A1-20190606-C00599
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2- phenylacetyl)quinolin-2(1H)- one
    513
    Figure US20190167672A1-20190606-C00600
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- benzoylquinolin-2(1H)-one
    514
    Figure US20190167672A1-20190606-C00601
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- benzoyl-3,4-dihydroquinolin- 2(1H)-one
    515
    Figure US20190167672A1-20190606-C00602
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (cyclobutanecarbonyl)quinolin- 2(1H)-one
    516
    Figure US20190167672A1-20190606-C00603
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (cyclopentanecarbonyl)quinolin- 2(1H)-one
    517
    Figure US20190167672A1-20190606-C00604
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (cyclonexanecarbonyl)quinolin- 2(1H)-one
    518
    Figure US20190167672A1-20190606-C00605
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (cycloheptanecarbonyl)quinolin- 2(1H)-one
    519
    Figure US20190167672A1-20190606-C00606
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- pivaloylquinolin-2(1H)-one
    520
    Figure US20190167672A1-20190606-C00607
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2 hydroxyacetyl)quinolin-2(1H)- one
    521
    Figure US20190167672A1-20190606-C00608
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2- hydroxyacetyl)-3,4- dihydroquinolin-2(1H)-one
    522
    Figure US20190167672A1-20190606-C00609
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (4Z,7Z,10Z,13Z,16Z,19Z)- docosa-4,7,10,13,16,19- hexaenoylquinolin-2(1H)-one
    523
    Figure US20190167672A1-20190606-C00610
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (9Z,12Z,15Z)-octadeca- 9,12,15-trienoylquinolin- 2(1H)-one
    524
    Figure US20190167672A1-20190606-C00611
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (5Z,8Z,11Z,14Z,17Z)- henicosa-5,8,11,14,17- pentaenoylquinolin-2(1H)-one
    525
    Figure US20190167672A1-20190606-C00612
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (6Z,9Z12Z,15Z)-octadeca- 6,9,12,15-tetraenoylquinolin- 2(1H)-one
    526
    Figure US20190167672A1-20190606-C00613
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (7Z,10Z,13Z,16Z,19Z)- docosa-7,10,13,16,19- pentaenoylquinolin-2(1H)-one
    527
    Figure US20190167672A1-20190606-C00614
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (4Z,7Z,10Z,13Z,16Z)- docosa-4,7,10,13,16- pentaenoylquinolin-2(1H)-one
    528
    Figure US20190167672A1-20190606-C00615
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (4Z,7Z,10Z,13Z,16Z,19Z)- docosa-4,7,10,13,16,19- hexaenoylquinolin-2(1H)-one
    529
    Figure US20190167672A1-20190606-C00616
         		2-amino-N-(2-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)-2- oxoethyl)acetamide
    530
    Figure US20190167672A1-20190606-C00617
         		2-amino-N-(2-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)-2- oxoethyl)propanamide
    531
    Figure US20190167672A1-20190606-C00618
         		2-amino-N-(2-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)-2- oxoethyl)-3- methylbutanamide
    532
    Figure US20190167672A1-20190606-C00619
         		2-amino-N-(2-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)-2- oxoethyl)-4- methylpentanamide
    533
    Figure US20190167672A1-20190606-C00620
         		N-(4-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)-4- oxobutyl)acetamide
    534
    Figure US20190167672A1-20190606-C00621
         		N-(4-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)-4 oxobutyl)acetamide
    535
    Figure US20190167672A1-20190606-C00622
         		N-(4-(7-(4-(4- (benzo[b]thiophen-4- piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)-4- oxobutyl)heptanamide
    536
    Figure US20190167672A1-20190606-C00623
         		1-(2-aminoacetyl)-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2(1H)-one
    537
    Figure US20190167672A1-20190606-C00624
         		1-(2-aminopropanoyl)-7-(4- (4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2(1H)-one
    538
    Figure US20190167672A1-20190606-C00625
         		1-(2-amino-4- methylpentanoyl)-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2(1H)-one
    539
    Figure US20190167672A1-20190606-C00626
         		2-amino-N-(2-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)-2- oxoethyl)acetamide
    540
    Figure US20190167672A1-20190606-C00627
         		2-amino-N-(1-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)-3- methyl-1-oxobutan-2- yl)acetamide
    541
    Figure US20190167672A1-20190606-C00628
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (pyrrolidine-2- carbonyl)quinolin-2(1H)-one
    542
    Figure US20190167672A1-20190606-C00629
         		1-(1-(2- aminoacetyl)pyrrolidine-2- carbonyl)-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2(1H)-one
    543
    Figure US20190167672A1-20190606-C00630
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2- (2- methoxyethoxy)acetyl)quinolin- 2(1H)one
    544
    Figure US20190167672A1-20190606-C00631
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2- (2-methoxyethoxy)acetyl)- 3,4-dihydroquinolin-2(1H)- one
    545
    Figure US20190167672A1-20190606-C00632
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2- (2-(2- methoxyethoxy)ethoxy)acetyl) quinolin-2(1H)-one
    546
    Figure US20190167672A1-20190606-C00633
         		methyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    547
    Figure US20190167672A1-20190606-C00634
         		methyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinoline- 1(2H)-carboxylate
    548
    Figure US20190167672A1-20190606-C00635
         		ethyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    549
    Figure US20190167672A1-20190606-C00636
         		propyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    550
    Figure US20190167672A1-20190606-C00637
         		propyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinoline- 1(2H)-carboxylate
    551
    Figure US20190167672A1-20190606-C00638
         		isobutyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    552
    Figure US20190167672A1-20190606-C00639
         		butyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    553
    Figure US20190167672A1-20190606-C00640
         		pentyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    554
    Figure US20190167672A1-20190606-C00641
         		pentyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinoline- 1(2H)-carboxylate
    555
    Figure US20190167672A1-20190606-C00642
         		hexyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    556
    Figure US20190167672A1-20190606-C00643
         		isopentyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    557
    Figure US20190167672A1-20190606-C00644
         		isopropyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    558
    Figure US20190167672A1-20190606-C00645
         		isopropyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinoline- 1(2H)-carboxylate
    559
    Figure US20190167672A1-20190606-C00646
         		cyclohexyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    560
    Figure US20190167672A1-20190606-C00647
         		cyclohexyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinoline- 1(2H)-carboxylate
    561
    Figure US20190167672A1-20190606-C00648
         		heptyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    562
    Figure US20190167672A1-20190606-C00649
         		heptyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinoline- 1(2H)-carboxylate
    563
    Figure US20190167672A1-20190606-C00650
         		octyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    564
    Figure US20190167672A1-20190606-C00651
         		nonyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    565
    Figure US20190167672A1-20190606-C00652
         		decyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    566
    Figure US20190167672A1-20190606-C00653
         		undecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    567
    Figure US20190167672A1-20190606-C00654
         		undecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinoline- 1(2H)-carboxylate
    568
    Figure US20190167672A1-20190606-C00655
         		dodecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    569
    Figure US20190167672A1-20190606-C00656
         		tridecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    570
    Figure US20190167672A1-20190606-C00657
         		tetradecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    571
    Figure US20190167672A1-20190606-C00658
         		pentadecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    572
    Figure US20190167672A1-20190606-C00659
         		hexadecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    573
    Figure US20190167672A1-20190606-C00660
         		heptadecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    574
    Figure US20190167672A1-20190606-C00661
         		octadecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    575
    Figure US20190167672A1-20190606-C00662
         		nonadecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    576
    Figure US20190167672A1-20190606-C00663
         		icosyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    577
    Figure US20190167672A1-20190606-C00664
         		henicosyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    578
    Figure US20190167672A1-20190606-C00665
         		docosyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    579
    Figure US20190167672A1-20190606-C00666
         		benzyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinoline-1(2H)- carboxylate
    580
    Figure US20190167672A1-20190606-C00667
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- benzyl-2-oxoquinoline-1(2H)- carboxamide
    581
    Figure US20190167672A1-20190606-C00668
         		calcium 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl phosphate
    582
    Figure US20190167672A1-20190606-C00669
         		calcium 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl phosphate
    583
    Figure US20190167672A1-20190606-C00670
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- methyl-2-oxoquinoline-1(2H)- carboxamide
    584
    Figure US20190167672A1-20190606-C00671
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- methyl-2-oxo-3,4- dihydroquinoline-1(2H)- carboxamide
    585
    Figure US20190167672A1-20190606-C00672
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- ethyl-2-oxoquinoline-1(2H)- carboxamide
    586
    Figure US20190167672A1-20190606-C00673
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-N-propylquinoline-1(2H)- carboxamide
    587
    Figure US20190167672A1-20190606-C00674
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- butyl-2-oxoquinoline-1(2H)- carboxamide
    588
    Figure US20190167672A1-20190606-C00675
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-N-pentylquinoline-1(2H)- carboxamide
    589
    Figure US20190167672A1-20190606-C00676
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- hexyl-2-oxoquinoline-1(2H)- carboxamide
    590
    Figure US20190167672A1-20190606-C00677
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- heptyl-2-oxoquinoline-1(2H)- carboxamide
    591
    Figure US20190167672A1-20190606-C00678
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- heptyl-2-oxo-3,4- dihydroquinoline-1(2H)- carboxamide
    592
    Figure US20190167672A1-20190606-C00679
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- octyl-2-oxoquinoline-1(2H)- carboxamide
    593
    Figure US20190167672A1-20190606-C00680
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- nonyl-2-oxoquinoline-1(2H)- carboxamide
    594
    Figure US20190167672A1-20190606-C00681
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- decyl-2-oxoquinoline-1(2H)- carboxamide
    595
    Figure US20190167672A1-20190606-C00682
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- (2-hydroxyethyl)-2- oxoquinoline-1(2H)- carboxamide
    596
    Figure US20190167672A1-20190606-C00683
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N- dimethyl-2-oxoquinoline- 1(2H)-carboxamide
    597
    Figure US20190167672A1-20190606-C00684
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N- dimethyl-2-oxo-3,4- dihydroquinoline-1(2H)- carboxamide
    598
    Figure US20190167672A1-20190606-C00685
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N- diethyl-2-oxoquinoline-1(2H)- carboxamide
    599
    Figure US20190167672A1-20190606-C00686
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-N,N-dipropylquinoline- 1(2H)-carboxamide
    600
    Figure US20190167672A1-20190606-C00687
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N- dibutyl-2-oxoquinoline-1(2H)- carboxamide
    601
    Figure US20190167672A1-20190606-C00688
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-N,N-dipentylquinoline- 1(2H)-carboxamide
    602
    Figure US20190167672A1-20190606-C00689
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N- dihexyl-2-oxoquinoline-1(2H)- carboxamide
    603
    Figure US20190167672A1-20190606-C00690
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N- diheptyl-2-oxoquinoline- 1(2H)-carboxamide
    604
    Figure US20190167672A1-20190606-C00691
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N- diheptyl-2-oxo-3,4- dihydroquinoline-1(2H)- carboxamide
    605
    Figure US20190167672A1-20190606-C00692
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N- dinonyl-2-oxoquinoline-1(2H)- carboxamide
    606
    Figure US20190167672A1-20190606-C00693
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-N,N- ditetradecylquinoline-1(2H)- carboxamide
    607
    Figure US20190167672A1-20190606-C00694
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- methyl-2-oxo-N- tetradecylquinoline-1(2H)- carboxamide
    608
    Figure US20190167672A1-20190606-C00695
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N- methyl-N-nonyl-2- oxoquinoline-1(2H)- carboxamide
    609
    Figure US20190167672A1-20190606-C00696
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (morpholine-4-
    610
    Figure US20190167672A1-20190606-C00697
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (morpholine-4-carbonyl)-3,4- dihydroquinolin-2(1H)-one
    611
    Figure US20190167672A1-20190606-C00698
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N- bis(2-hydroxyethyl)-2- oxoquinoline-1(2H)- carboxamide
    612
    Figure US20190167672A1-20190606-C00699
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N- dibenzyl-2-oxoquinoline- 1(2H)-carboxamide
    613
    Figure US20190167672A1-20190606-C00700
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(4- methylpiperazine-1- carbonyl)quinolin-2(1H)-one
    614
    Figure US20190167672A1-20190606-C00701
         		1-(1,4′-bipiperidine-1′- carbonyl)-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2(1H)-one
    615
    Figure US20190167672A1-20190606-C00702
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (cyclopropanecarbonyl)quinolin- 2(1H)-one
    616
    Figure US20190167672A1-20190606-C00703
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl propionate
    617
    Figure US20190167672A1-20190606-C00704
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl butyrate
    618
    Figure US20190167672A1-20190606-C00705
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl pentanoate
    619
    Figure US20190167672A1-20190606-C00706
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl hexanoate
    620
    Figure US20190167672A1-20190606-C00707
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl heptanoate
    621
    Figure US20190167672A1-20190606-C00708
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl octanoate
    622
    Figure US20190167672A1-20190606-C00709
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl nonanoate
    623
    Figure US20190167672A1-20190606-C00710
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl decanoate
    624
    Figure US20190167672A1-20190606-C00711
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl undecanoate
    625
    Figure US20190167672A1-20190606-C00712
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl tridecanoate
    626
    Figure US20190167672A1-20190606-C00713
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl tetradecanoate
    627
    Figure US20190167672A1-20190606-C00714
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl pentadecanoate
    628
    Figure US20190167672A1-20190606-C00715
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl palmitate
    629
    Figure US20190167672A1-20190606-C00716
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl heptadecanoate
    630
    Figure US20190167672A1-20190606-C00717
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl stearate
    631
    Figure US20190167672A1-20190606-C00718
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl icosanoate
    632
    Figure US20190167672A1-20190606-C00719
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl 2,2- dimethyltetradecanoate
    633
    Figure US20190167672A1-20190606-C00720
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl pivalate
    634
    Figure US20190167672A1-20190606-C00721
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl 2,2- dimethylbutanoate
    635
    Figure US20190167672A1-20190606-C00722
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl isobutyrate
    636
    Figure US20190167672A1-20190606-C00723
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl-2- hydroxyacetate
    637
    Figure US20190167672A1-20190606-C00724
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl cyclopropanecarboxylate
    638
    Figure US20190167672A1-20190606-C00725
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl cyclobutanecarboxylate
    639
    Figure US20190167672A1-20190606-C00726
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl cyclopentanecarboxylate
    640
    Figure US20190167672A1-20190606-C00727
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl benzoate
    641
    Figure US20190167672A1-20190606-C00728
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl-2- phenylacetate
    642
    Figure US20190167672A1-20190606-C00729
         		(9Z,12Z,15Z)-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl octadeca-9,12,15-trienoate
    643
    Figure US20190167672A1-20190606-C00730
         		(5Z,8Z,11Z,14Z,17Z)-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl henicosa-5,8,11,14,17- pentaenoate
    644
    Figure US20190167672A1-20190606-C00731
         		(4Z,7Z,10Z,13Z,16Z,19Z)-7- (4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl docosa-4,7,10,13,16,19- hexaenoate
    645
    Figure US20190167672A1-20190606-C00732
         		(6Z,9Z,12Z,15Z)-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl octadeca-6,9,12,15- tetraenoate
    646
    Figure US20190167672A1-20190606-C00733
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl methyl carbonate
    647
    Figure US20190167672A1-20190606-C00734
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl ethyl carbonate
    648
    Figure US20190167672A1-20190606-C00735
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl butyl carbonate
    649
    Figure US20190167672A1-20190606-C00736
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl pentyl carbonate
    650
    Figure US20190167672A1-20190606-C00737
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl cyclohexyl carbonate
    651
    Figure US20190167672A1-20190606-C00738
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl 2- methoxyethyl carbonate
    652
    Figure US20190167672A1-20190606-C00739
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl diethyl phosphate
    653
    Figure US20190167672A1-20190606-C00740
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl methylcarbamate
    654
    Figure US20190167672A1-20190606-C00741
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl ethylcarbamate
    655
    Figure US20190167672A1-20190606-C00742
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl propylcarbamate
    656
    Figure US20190167672A1-20190606-C00743
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl butylcarbamate
    657
    Figure US20190167672A1-20190606-C00744
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl pentylcarbamate
    658
    Figure US20190167672A1-20190606-C00745
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl hexylcarbamate
    659
    Figure US20190167672A1-20190606-C00746
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl octylcarbamate
    660
    Figure US20190167672A1-20190606-C00747
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl decylcarbamate
    661
    Figure US20190167672A1-20190606-C00748
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl dodecylcarbamate
    662
    Figure US20190167672A1-20190606-C00749
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl tetradecylcarbamate
    663
    Figure US20190167672A1-20190606-C00750
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl hexadecylcarbamate
    664
    Figure US20190167672A1-20190606-C00751
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl dimethylcarbamate
    665
    Figure US20190167672A1-20190606-C00752
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl dipropylcarbamate
    666
    Figure US20190167672A1-20190606-C00753
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl diisobutylcarbamate
    667
    Figure US20190167672A1-20190606-C00754
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl dibutylcarbamate
    668
    Figure US20190167672A1-20190606-C00755
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl dihexylcarbamate
    669
    Figure US20190167672A1-20190606-C00756
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl dioctylcarbamate
    670
    Figure US20190167672A1-20190606-C00757
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl didecylcarbamate
    671
    Figure US20190167672A1-20190606-C00758
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl didodecylcarbamate
    672
    Figure US20190167672A1-20190606-C00759
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl ditetradecylcarbamate
    673
    Figure US20190167672A1-20190606-C00760
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl dihexadecylcarbamate
    674
    Figure US20190167672A1-20190606-C00761
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl bis(2- hydroxyethyl)carbamate
    675
    Figure US20190167672A1-20190606-C00762
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl piperidine-1-carboxylate
    676
    Figure US20190167672A1-20190606-C00763
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl 4- methylpiperazine-1- carboxylate
    677
    Figure US20190167672A1-20190606-C00764
         		7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl 1,4′- bipiperidine-1′-carboxylate
    678
    Figure US20190167672A1-20190606-C00765
         		4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1- (propionyloxymethyl)piperazin- 1-ium chloride
    679
    Figure US20190167672A1-20190606-C00766
         		4-(benzo[b]thiophen-4-yl)-1- (butyryloxymethyl)-1-(4-(2- oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride
    680
    Figure US20190167672A1-20190606-C00767
         		4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1- (pentanoyloxymethyl)piperazin- 1-ium chloride
    681
    Figure US20190167672A1-20190606-C00768
         		4-(benzo[b]thiophen-4-yl)-1- (hexanoyloxymethyl)-1-(4-(2- oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride
    682
    Figure US20190167672A1-20190606-C00769
         		4-(benzo[b]thiophen-4-yl)-1- (heptanoyloxymethyl)-1-(4-(2- oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride
    683
    Figure US20190167672A1-20190606-C00770
         		4-(benzo[b]thiophen-4-yl)-1- (octanoyloxymethyl)-1-(4-(2- oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride
    684
    Figure US20190167672A1-20190606-C00771
         		4-(benzo[b]thiophen-4-yl)-1- (nonanoyloxymethyl)-1-(4-(2- oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride
    685
    Figure US20190167672A1-20190606-C00772
         		4-(benzo[b]thiophen-4-yl)- (decanoyloxymethyl)-1-(4-(2- oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride
    686
    Figure US20190167672A1-20190606-C00773
         		4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1- (undecanoyloxymethyl)pipera- zin-1-ium iodide
    687
    Figure US20190167672A1-20190606-C00774
         		4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1- (tetradecanoyloxymethyl) piperazin-1-ium iodide
    688
    Figure US20190167672A1-20190606-C00775
         		4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1- (palmitoyloxymethyl)piperazin- 1-ium iodide
    689
    Figure US20190167672A1-20190606-C00776
         		4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1- (stearoyloxymethyl)piperazin- 1-ium iodide
    690
    Figure US20190167672A1-20190606-C00777
         		4-(benzo[b]thiophen-4-yl)-1- (icosanoyloxymethyl)-1-(4-(2- oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    691
    Figure US20190167672A1-20190606-C00778
         		4-(benzo[b]thiophen-4-yl)-1- (docosanoyloxymethyl)-1-(4- (2-oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    692
    Figure US20190167672A1-20190606-C00779
         		4-(benzo[b]thiophen-4-yl)-1- (cyclopentanecarbonyloxy- methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    693
    Figure US20190167672A1-20190606-C00780
         		4-(benzo[b]thiophen-4-yl)-1- (cyclohexanecarbonyloxy- methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    694
    Figure US20190167672A1-20190606-C00781
         		4-(benzo[b]thiophen-4-yl)-1- isobutyryloxymethyl)-1-(4-(2- oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride
    695
    Figure US20190167672A1-20190606-C00782
         		4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1-((2- propylpentanoyloxy)methyl) piperazin-1-ium iodide
    696
    Figure US20190167672A1-20190606-C00783
         		4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1-((2- pentylheptanoyloxy)methyl) piperazin-1-ium iodide
    697
    Figure US20190167672A1-20190606-C00784
         		4-(benzo[b]thiophen-4-yl)-1- 4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1- (pivaloyloxymethyl)piperazin- 1-ium chloride
    698
    Figure US20190167672A1-20190606-C00785
         		4-(benzo[b]thiophen-4-yl)-1- ((2,2- dimethylbutanoyloxy)methyl)- 1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    699
    Figure US20190167672A1-20190606-C00786
         		4-(benzo[b]thiophen-4-yl)-1 ((2,2- dimethylpentanoyloxy)methyl)- 1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    700
    Figure US20190167672A1-20190606-C00787
         		4-(benzo[b]thiophen-4-yl)-1- ((2,2- dimethylhexanoyloxy)methyl)- 1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    701
    Figure US20190167672A1-20190606-C00788
         		4-(benzo[b]thiophen-4-yl)-1- ((2,2- dimethyltetradecanoyloxy) metthyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    702
    Figure US20190167672A1-20190606-C00789
         		4-(benzo[b]thiophen-4-yl)-1- ((1- methylcyclohexanecarbonyloxy) methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    703
    Figure US20190167672A1-20190606-C00790
         		4-(benzo[b]thiophen-4-yl)-1- ((hexylcarbamoyloxy)methyl)- 1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    704
    Figure US20190167672A1-20190606-C00791
         		4-(benzo[b]thiophen-4-yl)-1- ((diethylcarbamoyloxy)methyl)- 1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    705
    Figure US20190167672A1-20190606-C00792
         		4-(benzo[b]thiophen-4-yl)-1- ((dibenzylcarbamoyloxy)meth- yl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    706
    Figure US20190167672A1-20190606-C00793
         		4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1-((piperidine- 1- carbonyloxy)methyl)piperazin- 1-ium iodide
    707
    Figure US20190167672A1-20190606-C00794
         		4-(benzo[b]thiophen-4-yl)-1- ((ethoxycarbonyloxy)methyl)- 1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride
    708
    Figure US20190167672A1-20190606-C00795
         		4-(benzo[b]thiophen-4-yl)-1- ((cyclohexyloxycarbonyloxy) methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride
    709
    Figure US20190167672A1-20190606-C00796
         		4-(benzo[b]thiophen-4-yl)-1- ((hexyloxycarbonyloxy)methyl)- 1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide
    710
    Figure US20190167672A1-20190606-C00797
         		4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1-(((pentan-3- yloxy)carbonyloxy)methyl) piperazin-1-ium iodide
    711
    Figure US20190167672A1-20190606-C00798
         		4-(benzo[b]thiophen-4-yl)-1- (benzoyloxymethyl)-1-(4-(2- oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride
    712
    Figure US20190167672A1-20190606-C00799
         		4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin- 7-yloxy)butyl)-1-((2- phenylacetoxy)methyl) piperazin-1-ium chloride
    713
    Figure US20190167672A1-20190606-C00800
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) succinate
    714
    Figure US20190167672A1-20190606-C00801
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) succinate
    715
    Figure US20190167672A1-20190606-C00802
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) glutarate
    716
    Figure US20190167672A1-20190606-C00803
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) glutarate
    717
    Figure US20190167672A1-20190606-C00804
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) adipate
    718
    Figure US20190167672A1-20190606-C00805
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) adipate
    719
    Figure US20190167672A1-20190606-C00806
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) heptanedioate
    720
    Figure US20190167672A1-20190606-C00807
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) heptanedioate
    721
    Figure US20190167672A1-20190606-C00808
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) octanedioate
    722
    Figure US20190167672A1-20190606-C00809
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) octanedioate
    723
    Figure US20190167672A1-20190606-C00810
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) decanedioate
    724
    Figure US20190167672A1-20190606-C00811
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) decanedioate
    725
    Figure US20190167672A1-20190606-C00812
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) dodecanedioate
    726
    Figure US20190167672A1-20190606-C00813
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) dodecanedioate
    727
    Figure US20190167672A1-20190606-C00814
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) tetradecanedioate
    728
    Figure US20190167672A1-20190606-C00815
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) tetradecanedioate
    729
    Figure US20190167672A1-20190606-C00816
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) hexadecanedioate
    730
    Figure US20190167672A1-20190606-C00817
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) hexadecanedioate
    731
    Figure US20190167672A1-20190606-C00818
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) octadecanedioate
    732
    Figure US20190167672A1-20190606-C00819
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) octadecanedioate
    733
    Figure US20190167672A1-20190606-C00820
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) icosanedioate
    734
    Figure US20190167672A1-20190606-C00821
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) icosanedioate
    735
    Figure US20190167672A1-20190606-C00822
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methyl) docosanedioate
    736
    Figure US20190167672A1-20190606-C00823
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) docosanedioate
    737
    Figure US20190167672A1-20190606-C00824
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) succinate
    738
    Figure US20190167672A1-20190606-C00825
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) glutarate
    739
    Figure US20190167672A1-20190606-C00826
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) adipate
    740
    Figure US20190167672A1-20190606-C00827
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) heptanedioate
    741
    Figure US20190167672A1-20190606-C00828
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) octanedioate
    742
    Figure US20190167672A1-20190606-C00829
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) decanedioate
    743
    Figure US20190167672A1-20190606-C00830
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) dodecanedioate
    744
    Figure US20190167672A1-20190606-C00831
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) tetradecanedioate
    745
    Figure US20190167672A1-20190606-C00832
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) hexadecanedioate
    746
    Figure US20190167672A1-20190606-C00833
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) octadecanedioate
    747
    Figure US20190167672A1-20190606-C00834
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) icosanedioate
    748
    Figure US20190167672A1-20190606-C00835
         		bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2- yloxy)methyl) docosanedioate
    749
    Figure US20190167672A1-20190606-C00836
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl) succinate
    750
    Figure US20190167672A1-20190606-C00837
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl) glutarate
    751
    Figure US20190167672A1-20190606-C00838
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl) adipate
    752
    Figure US20190167672A1-20190606-C00839
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl) heptanedioate
    753
    Figure US20190167672A1-20190606-C00840
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-y) octanedioate
    754
    Figure US20190167672A1-20190606-C00841
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl) decanedioate
    755
    Figure US20190167672A1-20190606-C00842
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl) dodecanedioate
    756
    Figure US20190167672A1-20190606-C00843
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl) tetradecanedioate
    757
    Figure US20190167672A1-20190606-C00844
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-24) hexadecanedioate
    758
    Figure US20190167672A1-20190606-C00845
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl) octadecanedioate
    759
    Figure US20190167672A1-20190606-C00846
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl) icosanedioate
    760
    Figure US20190167672A1-20190606-C00847
         		bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl) docosanedioate
    • Example A: Synthesis of deuteride of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one A-1: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one Synthesis Method 1 Step 1: Synthesis of 2-benzyloxy-7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)quinoline
  • Figure US20190167672A1-20190606-C00848
  • To a mixture of 2-benzyloxy-7-hydroxy quinoline (2.52 g) and potassium carbonate (1.67 g) in dimethylformamide (25 ml) was added 1,4-dibromobutane-d8 (99.6 atom % D: 2.4 ml), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, ethyl acetate, the insoluble material was filtered off, and the filtrate was partitioned, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:0→9:1) to give 2-benzyloxy-7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)quinoline (3.14 g). 2-benzyloxy-7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)quinoline white powder, 1H-NMR (CDCl3) δ: 5.52 (2H, s), 6.81 (1H, d, J=8.7 Hz), 7.02 (1H, dd, J=8.8, 2.5 Hz), 7.21 (1H, d, J=2.5 Hz), 7.29-7.47 (3H, m), 7.49-7.56 (2H, m), 7.60 (1H, d, J=8.8 Hz), 7.91 (1H, d, J=8.7 Hz)
    • Step 2: Synthesis of 2-benzyloxy-7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]quinoline
  • Figure US20190167672A1-20190606-C00849
  • A mixture of 2-benzyloxy-7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)quinoline (3.14 g), 1-benzothiophene-4-piperazine hydrochloride (2.43 g), sodium iodide (1.31 g) and potassium carbonate (2.64 g) in dimethylformamide (60 ml) was stirred at 80° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3→5:5) to give 2-benzyloxy-7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]quinoline (3.73 g).
  • 2-benzyloxy-7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]quinoline: pale-yellow amorphous solid, 1H-NMR (CDCl3) δ: 2.64-2.83 (4H, m), 3.14-3.25 (4H, m), 5.53 (2H, s), 6.81 (1H, d, J=8.8 Hz), 6.89 (1H, d, J=7.6 Hz), 7.03-7.08 (1H, m), 7.25-7.49 (7H, m), 7.50-7.63 (4H, m), 7.91 (1H, d, J=8.8 Hz)
    • Step 3: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00850
  • A mixture of 2-benzyloxy-7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]quinoline (3.73 g) and 1N hydrochloric acid (35.1 ml) in tetrahydrofuran (60 ml) was stirred at 60° C. for 4 hr, and ice-cooled. Ice water was added, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure. To a mixture of the obtained powder in ethanol (70 ml) was added under ice-cooling 1N sodium hydroxide to basify the mixture. The solvent was evaporated under reduced pressure and the residue was washed with water, and recrystallized from a mixture of ethanol and water to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one (2.29 g). 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one:white powder, 1H-NMR (DMSO-d6) δ: 2.54-2.67 (4H, m), 2.91-3.15 (4H, m), 6.29 (1H, d, J=9.5 Hz), 6.75-6.83 (2H, m), 6.88 (1H, d, J=7.6 Hz), 7.21-7.30 (1H, m), 7.39 (1H, d, J=5.5 Hz), 7.50-7.66 (2H, m), 7.69 (1H, d, J=5.5 Hz), 7.80 (1H, d, J=9.5 Hz), 11.58 (1H, s)
    • Synthesis Method 2 Step 1: Synthesis of 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00851
  • To a mixture of 7-hydroxy-1H-quinolin-2-one [70500-72-0] (0.72 g) and potassium carbonate (0.68 g) in dimethylformamide (20 ml) was added 1,4-dibromobutane-d8 (99.6 atom % D: 3 g), and the mixture was stirred at 50° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1) to give 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d5)-1H-quinolin-2-one (1.1 g). 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)-1H-quinolin-2-one:white powder like, 1H-NMR (CDCl3) δ: 6.56 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 7.45 (1H, d, J=8.6 Hz), 7.74 (1H, d, J=9.4 Hz), 12.33 (1H, brs).
    • Step 2: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00852
  • A mixture of 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)-1H-quinolin-2-one (0.4 g), 1-benzothiophene-4-piperazine hydrochloride (0.37 g), potassium carbonate (0.45 g) and dimethylformamide (20 ml) was stirred at 60° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one (0.3 g).
  • 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one same as that synthesized in synthesis method 1 was obtained.
  • white powder m.p. 177-179° C. (recrystallized from EtOH)
    • A-2: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy-1,1,2,2,3,3,4,4-d]-1H-quinolin-2-one Step 1: Synthesis of tert-butyl 4-(benzo[b]thiophen-4-yl)piperazine-2,2,3,3,5,5,6,6-de-1-carboxylate
  • Figure US20190167672A1-20190606-C00853
  • A mixture of 4-bromo-benzo[b]thiophene [5118-13-8] (0.55 g), tert-butyl 1-piperazine-2,2,3,3,5,5,6,6-de-carboxylate (98.3 atom % D:0.5 g), sodium t-butoxide (0.25 g), (R)-(+)-BINAP (30 mg), tris(dibenzylideneacetone)dipalladium(0) (30 mg) and toluene (20 ml) was heated under reflux under an argon atmosphere for 3 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:100) to give tert-butyl 4-(benzo[b]thiophen-4-yl)piperazine-2,2,3,3,5,5,6,6-de-1-carboxylate (0.41 g).
    • tert-butyl 4-(benzo[b]thiophen-4-yl)piperazine-2,2,3,3,5,5,6,6-de-1-carboxylate
  • Yellow Powder
  • 1H-NMR (CDCl3) δ: 1.50 (9H, s), 3.03-3.09 (0.06H, br), 3.59-3.65 (0.06H, br), 6.87 (1H, dd, J=0.8, 7.7 Hz), 7.28 (1H, t, J=7.8 Hz), 7.41 (2H, s), 7.57 (1H, d, J=8.0 Hz). Confirmed by 1H-NMR (CDCl3): at least 98 atom % D.
    • Step 2: Synthesis of 1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-d8
  • Figure US20190167672A1-20190606-C00854
  • To a solution of tert-butyl 4-(benzo[b]thiophen-4-yl)piperazine-2,2,3,3,5,5,6,6-de-1-carboxylate (0.57 g) in dichloromethane (5 ml) was added trifluoroacetic acid (1 ml) and the mixture was stirred at room temperature for 3 hr. Water was poured into the reaction mixture, alkalified with aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate:methanol=20:1) to give 1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-d8 (0.31 g).
    • 1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-d8: oil brown
  • 1H-NMR (CDCl3) δ: 3.06-3.10 (0.13H, br), 6.88 (1H, dd, J=0.8, 7.6 Hz), 7.27 (1H, t, J=7.8 Hz), 7.38 (1H, d, J=5.4 Hz), 7.42 (1H, dd, J=0.7, 5.5 Hz), 7.54 (1H, d, J=8.1 Hz).
  • Confirmed by 1H-NMR (CDCl3): at least 98 atom % D.
    • Step 3: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00855
  • A mixture of 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d5)-1H-quinolin-2-one (633 mg) obtained in Example A-1, synthesis method 2, step 1, l-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-d8 (471 mg) obtained in this Example, step 2, potassium carbonate (374 mg) and dimethylformamide (20 ml) was stirred at 60° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one (0.45 g). 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one: yellow powder m.p. 176-178° C. (recrystallized from EtOH)
  • 1H-NMR (CDCl3) δ: 2.64-2.72 (0.06H, m), 3.02-3.20 (0.06H, m), 6.55 (1H, d, J=9.4 Hz), 6.79-6.86 (2H, m), 6.89 (1H, dd, J=0.7, 7.6 Hz), 7.26 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.54 (1H, d, J=8.0 Hz), 7.72 (1H, d, J=9.4 Hz), 12.34 (1H, brs).
    • A-3: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy]-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00856
  • A mixture of 7-(4-chlorobutoxy)-1H-quinolin-2-one (340 mg), 1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-d8 (310 mg) obtained in Example A-2, step 2, sodium iodide (220 mg), potassium carbonate (240 mg) and dimethylformamide (10 ml) was stirred at 60° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy]-1H-quinolin-2-one (0.31 g).
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy]-1H-quinolin-2-one: yellow powder m.p. 175.5-177° C. (recrystallized from EtOH)
  • 1H-NMR (CDCl3) δ: 1.70-1.84 (2H, m), 1.84-1.96 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.72 (0.06H, m), 3.14-3.18 (0.06H, m), 4.12 (2H, t, J=6.2 Hz), 6.54 (1H, d, J=9.4 Hz), 6.79-6.86 (2H, m), 6.89 (1H, dd, J=0.6, 7.6 Hz), 7.26 (1H, t, J=7.9 Hz), 7.36-7.48 (3H, m), 7.54 (1H, d, J=8.0 Hz), 7.72 (1H, d, J=9.4 Hz), 12.27 (1H, brs).
    • A-4: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d5 Step 1: Synthesis of 7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d5
  • Figure US20190167672A1-20190606-C00857
  • To a mixture of 7-hydroxy-1H-quinolin-2-one-3,4,5,6,8-d5 (99 atom % D: 3 g) obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485; Bull. Chem. Soc. Jpn. 2008, 81, 278) of 7-hydroxy-1H-quinolin-2-one [70500-72-0] and potassium carbonate (3 g) in dimethylformamide (120 ml) was added 1,4-dibromobutane (6.5 ml), and the mixture was stirred at 50° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1) to give 7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d5 (3.45 g). 7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d8: white powder like
  • 1H-NMR (CDCl3) δ ppm: 1.94-2.05 (2H, m), 2.05-2.15 (2H, m), 3.51 (2H, t, J=6.5 Hz), 4.10 (2H, t, J=6.0 Hz), 6.55 (0.01H, s), 6.79-6.81 (2H, m), 7.52 (0.008H, s), 7.73 (0.008H, s), 11.89 (1H, brs).
    • Step 2: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d5
  • Figure US20190167672A1-20190606-C00858
  • A mixture of 7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d5 (0.6 g), 1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-d8 (0.5 g), potassium carbonate (360 mg) and dimethylformamide (20 ml) was stirred at 60° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d5 (0.45 g).
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d5: white powder m.p. 175.5-177.5° C. (recrystallized from EtOH)
  • 1H-NMR (CDCl3) δ ppm: 1.70-1.84 (2H, m), 1.80-1.96 (2H, m), 2.54 (2H, t, J=7.4 Hz), 2.66-2.72 (<0.07H, br), 3.14-3.20 (<0.06H, br), 4.12 (2H, t, J=6.2 Hz), 6.54 (<0.008H, s), 6.82 (<0.025H, d, J=5.7 Hz), 6.89 (1H, dd, J=0.6, 7.7 Hz), 7.26 (1H, t, J=7.9 Hz), 7.38 (1H, d, J=5.5 Hz), 7.42 (1H, d, J=5.9 Hz), 7.54 (1H, d, J=8.0 Hz), 7.72 (<0.01H, s), 12.10 (1H, brs).
    • A-5: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d5
  • Figure US20190167672A1-20190606-C00859
  • A mixture of 7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d5 (0.6 g) obtained in Example A-4, step 1, 1-benzothiophene-4-piperazine hydrochloride (0.56 g), potassium carbonate (690 mg) and dimethylformamide (20 ml) was stirred at 60° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d5 (0.5 g). 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d5: white powder m.p. 177-179° C. (recrystallized from EtOH)
  • 1H-NMR (CDCl3) δ ppm: 1.70-1.85 (2H, m), 1.85-1.95 (2H, m), 2.54 (2H, t, J=7.4 Hz), 2.66-2.82 (4H, br), 3.14-3.28 (4H, br), 4.08-4.12 (2H, m), 6.54 (<0.01H, s), 6.83 (<0.02H, d, J=10.3 Hz), 6.89 (1H, d, J=7.7 Hz), 7.26 (1H, t, J=7.8 Hz), 7.36 (1H, d, J=5.5 Hz), 7.42 (1H, dd, J=0.6, 5.5 Hz), 7.54 (1H, d, J=8.0 Hz), 7.72 (<0.01H, s), 12.24 (1H, brs).
    • A-6: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d5
  • Figure US20190167672A1-20190606-C00860
  • A mixture of 7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d5 (0.6 g) obtained in Example A-4, step 1, 1-benzo[b]thiophen-4-yl-5,7-d2-piperazine hydrochloride (0.56 g) obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485; Bull. Chem. Soc. Jpn. 2008, 81, 278) of 1-benzothiophene-4-piperazine hydrochloride, potassium carbonate (690 mg) and dimethylformamide (20 ml) was stirred at 60° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d5 (0.42 g). 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d5: white powder m.p. 176.5-178.5° C. (recrystallized from EtOH)
  • 1H-NMR (CDCl3) δ ppm: 1.70-1.98 (4H, m), 2.54 (2H, t, J=7.4 Hz), 2.66-2.80 (4H, br), 3.14-3.26 (4H, br), 4.12 (2H, t, J=6.1 Hz), 6.54 (<0.01H, s), 6.83 (<0.02H, d, J=10.0 Hz), 6.89 (<0.01H, d, J=7.7 Hz), 7.08 (<0.02H, m), 7.25-7.28 (1H, m), 7.38 (0.89H, d, J=5.5 Hz), 7.42 (1H, d, J=5.5 Hz), 7.54 (0.06H, d, J=8.1 Hz), 7.72 (<0.01H, s), 12.23 (1H, brs).
    • A-7: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one-3,4,5,6,8-d5 Step 1: Synthesis of 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)-1H-quinolin-2-one-3,4,5,6,8-d5
  • Figure US20190167672A1-20190606-C00861
  • To a mixture of 7-hydroxy-1H-quinolin-2-one-3,4,5,6,8-d5 (99 atom % D: 1.65 g) obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485; Bull. Chem. Soc. Jpn. 2008, 81, 278) of 7-hydroxy-1H-quinolin-2-one [70500-72-0] and potassium carbonate (1.51 g) in dimethylformamide (40 ml) was added 1,4-dibromobutane-d8 (99.6 atom % D: 5.55 g), and the mixture was stirred at 50° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1) to give 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)-1H-quinolin-2-one-3,4,5,6,8-d5 (1.1 g).
  • 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)-1H-quinolin-2-one-3,4,5,6,8-d5: white powder like, 1H-NMR (CDCl3) δ ppm: 6.55 (0.008H, s), 6.81 (0.021H, d, J=9.6 Hz), 7.45 (0.008H, s), 7.74 (0.008H, s), 12.28 (1H, brs).
    • Step 2: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one-3,4,5,6,8-d5
  • Figure US20190167672A1-20190606-C00862
  • A mixture of 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)-1H-quinolin-2-one-3,4,5,6,8-d5 (0.5 g) obtained in this Example, step 1,1-benzothiophene-4-piperazine hydrochloride (0.45 g), potassium carbonate (0.56 g) and dimethylformamide (20 ml) was stirred at 60° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one-3,4,5,6,8-d5 (0.24 g). 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one-3,4,5,6,8-d5: white powder m.p. 176-177.5° C. (recrystallized from EtOH)
  • 1H-NMR (CDCl3) δ ppm: 2.60-2.84 (4H, br), 3.10-3.28 (4H, br), 6.54 (<0.007H, s), 6.82 (<0.02H, d, J=6.0 Hz), 6.89 (1H, dd, J=0.5, 7.6 Hz), 7.27 (1H, t, J=7.8 Hz), 7.38 (1H, d, J=5.6 Hz), 7.42 (1H, dd, J=0.5, 5.6 Hz), 7.54 (1H, d, J=8.0 Hz), 7.72 (<0.009H, s), 12.13 (1H, brs).
    • A-8: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy]-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00863
  • A mixture of 7-(4-chlorobutoxy)-1H-quinolin-2-one (0.5 g), 1-benzo[b]thiophen-4-yl-5,7-d2-piperazine hydrochloride (0.56 g) obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485; Bull. Chem. Soc. Jpn. 2008, 81, 278) of 1-benzothiophene-4-piperazine hydrochloride, sodium iodide (0.33 g), potassium carbonate (690 mg) and dimethylformamide (20 ml) was stirred at 60° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (0.31 g).
  • 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy]-1H-quinolin-2-one: white powder m.p. 179.5-181.5° C. (recrystallized from EtOH)
  • 1H-NMR (CDCl3) δ ppm: 1.68-1.84 (2H, m), 1.84-1.96 (2H, m), 2.54 (2H, t, J=7.4 Hz), 2.66-2.80 (4H, br), 3.16-3.26 (4H, br), 4.12 (2H, t, J=6.2 Hz), 6.54 (1H, d, J=9.4 Hz), 6.78-6.86 (2H, m), 6.90 (<0.02H, d, J=7.7 Hz), 7.25-7.28 (1H, m), 7.38 (0.82H, d, J=5.6 Hz), 7.40-7.48 (2H, m), 7.54 (0.05H, d, J=8.6 Hz), 7.72 (1H, d, J=9.4 Hz), 12.09 (1H, brs).
    • A-9: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00864
  • A mixture of 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)-1H-quinolin-2-one (0.5 g) obtained in Example A-1, synthesis method 2, step 1,1-benzo[b]thiophen-4-yl-5,7-d2-piperazine hydrochloride (0.46 g) obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485; Bull. Chem. Soc. Jpn. 2008, 81, 278) of l-benzothiophene-4-piperazine hydrochloride, potassium carbonate (0.57 g) and dimethylformamide (20 ml) was stirred at 50° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one (0.35 g).
  • 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one: white powder m.p. 176.5-178.5° C. (recrystallized from EtOH)
  • 1H-NMR (CDCl3) δ ppm: 2.66-2.80 (4H, br), 3.10-3.28 (4H, br), 6.55 (1H, d, J=9.4 Hz), 6.81 (1H, dd, J=2.4, 8.6 Hz), 6.85 (1H, d, J=2.3 Hz), 6.89 (<0.04H, d, J=7.7 Hz), 7.24-7.28 (1H, m), 7.38 (0.85H, d, J=5.6 Hz), 7.40-7.46 (2H, m), 7.54 (0.06H, dd, J=0.5, 8.0 Hz), 7.72 (1H, d, J=9.4 Hz), 12.47 (1H, brs).
    • A-10: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one-3,4,5,6,8-d5
  • Figure US20190167672A1-20190606-C00865
  • A mixture of 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d8)-1H-quinolin-2-one-3,4,5,6,8-d5 (0.6 g) obtained in Example A-7, step 1,1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-d (0.57 g) obtained in Example A-2, step 2, potassium carbonate (380 mg) and dimethylformamide (20 ml) was stirred at 60° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one-3,4,5,6,8-d5 (0.45 g).
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one-3,4,5,6,8-d5: white powder m.p. 175.5-177.5° C. (recrystallized from EtOH)
  • 1H-NMR (CDCl3) δ ppm: 2.64-2.72 (<0.06H, br), 3.14-3.20 (<0.06H, br), 6.54 (<0.01H, s), 6.80-6.86 (<0.04H, m), 6.89 (1H, dd, J=0.8, 7.6 Hz), 7.26 (1H, t, J=7.9 Hz), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, dd, J=0.7, 5.6 Hz), 7.54 (1H, d, J=8.0 Hz), 7.72 (<0.01H, s), 12.35 (1H, brs).
    • A-11: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one-3,4,5,6,8-d5
  • Figure US20190167672A1-20190606-C00866
  • A mixture of 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-do)-1H-quinolin-2-one-3,4,5,6,8-d5 (0.5 g) obtained in Example A-7, step 1,1-benzo[b]thiophen-4-yl-5,7-d2-piperazine hydrochloride (0.46 g) obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485; Bull. Chem. Soc. Jpn. 2008, 81, 278) of 1-benzothiophene-4-piperazine hydrochloride, potassium carbonate (0.56 g) and dimethylformamide (20 ml) was stirred at 50° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinoline-2-one-3,4,5,6,8-d5 (0.34 g). 7-[4-(4-benzo[b]thiophen-4-yl-5,7-d2-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d8]-1H-quinolin-2-one-3,4,5,6,8-d5: white powder m.p. 175.5-177.5° C. (recrystallized from EtOH)
  • 1H-NMR (CDCl3) δ ppm: 2.66-2.80 (4H, br), 3.14-3.26 (4H, br), 6.54 (<0.01H, s), 6.83 (<0.02H, d, J=11.2 Hz), 6.89 (<0.01H, d, J=7.6 Hz), 7.06-7.10 (<0.02H, m), 7.25-7.28 (1H, m), 7.38 (0.86H, d, J=5.6 Hz), 7.42 (1H, d, J=5.6 Hz), 7.54 (<0.05H, dd, J=0.6, 8.0 Hz), 7.72 (<0.01H, s), 12.28 (1H, brs).
    • Example B: Synthesis of salt of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one
  • Figure US20190167672A1-20190606-C00867
    • Phosphate:
  • A suspension of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (15 g) in dichloromethane (100 ml) and methanol (100 ml) was warmed to 60° C., dissolved, and phosphoric acid (4.39 g) was added at room temperature. The precipitated crystals were collected by filtration, and dried to give 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one phosphate (17.9 g).
  • 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one phosphate (17.5 g) was recrystallized from ethanol (550 ml) and water (550 ml) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one phosphate (14.4 g).
  • Figure US20190167672A1-20190606-C00868
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one phosphate:colorless crystals:m.p. 226-228° C. (recrystallized from EtOH—H2O)
  • 1H-NMR (DMSO-d6) δ ppm: 1.66-1.76 (2H, m), 1.76-1.86 (2H, m), 2.63 (2H, t, J=7.0 Hz), 2.76-2.86 (4H, br), 3.08-3.18 (4H, br), 4.07 (2H, t, J=6.2 Hz), 6.30 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 6.90 (1H, d, J=7.4 Hz), 7.28 (1H, t, J=7.8 Hz), 7.42 (1H, d, J=5.5 Hz), 7.56 (1H, d, J=9.4 Hz), 7.63 (1H, d, J=8.0 Hz), 7.71 (1H, d, J=5.5 Hz), 7.81 (1H, d, J=9.5 Hz), 11.2-12.2 (1H, br).
  • DL-Malate:
  • A suspension of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (15 g) in dichloromethane (100 ml) and methanol (100 ml) was warmed to 60° C., dissolved, and DL-malic acid (5.11 g) dissolved in water (10 ml) was added at room temperature. The precipitated crystals were collected by filtration, and dried to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one DL-malate (20 g).
  • 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-H-quinolin-2-one DL-malate (20 g) was recrystallized from ethanol (350 ml) and water (50 ml) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one DL-malate (14.5 g).
  • Figure US20190167672A1-20190606-C00869
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one DL-malate: colorless crystal: m.p. 136-139° C. (recrystallized from EtOH—H2O)
  • 1H-NMR (DMSO-d6) δ ppm: 1.64-1.76 (2H, m), 1.76-1.86 (2H, m), 2.62 (2H, t, J=7.1 Hz), 2.74-2.86 (4H, br), 3.06-3.18 (4H, br), 4.06 (2H, t, J=6.0 Hz), 4.21 (2H, s), 6.30 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 6.90 (1H, d, J=7.4 Hz), 7.28 (1H, t, J=7.8 Hz), 7.42 (1H, d, J=5.5 Hz), 7.56 (1H, d, J=9.3 Hz), 7.63 (1H, d, J=8.0 Hz), 7.71 (1H, d, J=5.5 Hz), 7.81 (1H, d, J=9.5 Hz), 11.59 (1H, brs).
  • L(+)-Tartrate:
  • A suspension of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (15 g) in dichloromethane (100 ml) and methanol (100 ml) was heated to 60° C., dissolved, and L(+)-tartaric acid (5.72 g) dissolved in water (10 ml) was added at room temperature. The precipitated crystals were collected by filtration, and dried to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one L(+)-tartrate (19.3 g).
  • 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one L(+)-tartrate (19.3 g) was recrystallized from ethanol (700 ml) and water (250 ml) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one L(+)-tartrate (16.5 g).
  • Figure US20190167672A1-20190606-C00870
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one L(+)-tartrate: colorless crystal: m.p. 198-203° C. (recrystallized from EtOH—H2O)
  • 1H-NMR (DMSO-d6) δ ppm: 1.64-1.76 (2H, m), 1.76-1.86 (2H, m), 2.41 (1H, dd, J=6.7, 15.6 Hz), 2.59 (1H, dd, J=6.4, 15.6 Hz), 2.66 (2H, t, J=7.2 Hz), 2.78-2.88 (4H, br), 3.06-3.18 (4H, br), 4.07 (2H, t, J=6.2 Hz), 4.16 (1H, t, J=6.5 Hz), 6.30 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 6.90 (1H, d, J=7.2 Hz), 7.29 (1H, t, J=7.8 Hz), 7.43 (1H, dd, J=0.6, 5.5 Hz), 7.56 (1H, d, J=9.3 Hz), 7.63 (1H, d, J=8.0 Hz), 7.71 (1H, d, J=5.5 Hz), 7.81 (1H, d, J=9.5 Hz), 11.59 (1H, brs).
  • Oxalate:
  • A suspension of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (3 g) in dichloromethane (20 ml) and methanol (20 ml) was warmed to 60° C., dissolved, and oxalic acid (0.69 g) dissolved in methanol (5 ml) was added at room temperature. The precipitated crystals were collected by filtration, and dried to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one oxalate (3.3 g).
  • 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-H-quinolin-2-one oxalate (1 g) was recrystallized from ethanol (20 ml) and water (20 ml) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one oxalate (0.8 g).
  • Figure US20190167672A1-20190606-C00871
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one oxalate:colorless crystal: m.p. 126.5-128° C. (recrystallized from EtOH—H2O)
  • 1H-NMR (DMSO-d6) δ ppm: 1.78-1.90 (4H, br), 3.06-3.14 (2H, br), 3.24-3.36 (4H, br), 3.62-4.24 (6H, br), 6.31 (1H, d, J=9.4 Hz), 6.78-6.86 (2H, m), 6.95 (1H, d, J=7.4 Hz), 7.31 (1H, t, J=7.9 Hz), 7.48 (1H, dd, J=0.4, 5.6 Hz), 7.57 (1H, d, J=9.4 Hz), 7.69 (1H, d, J=8.1 Hz), 7.75 (1H, d, J=5.5 Hz), 7.81 (1H, d, J=9.5 Hz), 11.62 (1H, brs).
  • Succinate:
  • A suspension of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (2 g) in dichloromethane (20 ml) and methanol (20 ml) was warmed to 60° C., dissolved, and succinic acid (0.6 g) dissolved in methanol-water was added at room temperature. The precipitated crystals were collected by filtration, and dried to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one succinate (2.4 g).
  • 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one succinate (1 g) was recrystallized from ethanol (20 ml) and water (8 ml) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one succinate (0.74 g).
  • Figure US20190167672A1-20190606-C00872
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one succinate: colorless crystal: m.p. 158.5-160° C. (recrystallized from EtOH—H2O)
  • 1H-NMR (DMSO-d6) δ ppm: 1.60-1.70 (2H, m), 1.76-1.86 (2H, m), 2.41 (4H, s), 2.44-2.50 (2H, m), 2.60-2.70 (4H, br), 3.04-3.10 (4H, br), 4.06 (2H, t, J=6.4 Hz), 6.29 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 6.89 (1H, d, J=7.3 Hz), 7.27 (1H, t, J=7.8 Hz), 7.40 (1H, dd, J=0.4, 5.6 Hz), 7.56 (1H, d, J=9.3 Hz), 7.61 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=5.5 Hz), 7.81 (1H, d, J=9.5 Hz), 11.58 (1H, brs).
  • ½ Succinate:
  • A suspension of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (2 g) in dichloromethane (20 ml) and methanol (20 ml) was warmed to 60° C., dissolved, and succinic acid (0.3 g) dissolved in methanol-water was added at room temperature. The precipitated crystals were collected by filtration, and dried to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one ½ succinate (1.84 g).
  • 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-H-quinolin-2-one ½ succinate (1 g) was recrystallized from ethanol (20 ml) and water (5 ml) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-H-quinolin-2-one ½ succinate (0.69 g).
  • Figure US20190167672A1-20190606-C00873
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one ½ succinate: colorless crystal: m.p. 158-160° C. (recrystallized from EtOH—H2O)
  • 1H-NMR (DMSO-d6) δ ppm: 1.60-1.70 (2H, m), 1.76-1.86 (2H, m), 2.41 (2H, s), 2.47 (2H, t, J=7.2 Hz), 2.60-2.70 (4H, br), 3.02-3.10 (4H, br), 4.06 (2H, t, J=6.4 Hz), 6.30 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 6.88 (1H, d, J=7.3 Hz), 7.28 (1H, t, J=7.8 Hz), 7.40 (1H, dd, J=0.4, 5.5 Hz), 7.56 (1H, d, J=9.4 Hz), 7.61 (1H, d, J=7.6 Hz), 7.69 (1H, d, J=5.5 Hz), 7.80 (1H, d, J=9.5 Hz), 11.59 (1H, brs).
  • Hydrobromide:
  • A suspension of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (2 g) in dichloromethane (20 ml) and methanol (20 ml) was warmed to 60° C., dissolved, and a solution of 47% hydrobromic acid (0.86 g) in methanol was added at room temperature. The precipitated crystals were collected by filtration, and dried to give 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one hydrobromide (2.2 g).
  • 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one hydrobromide (1 g) was recrystallized from ethanol (20 ml) and water (5 ml) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one hydrobromide (0.81 g).
  • Figure US20190167672A1-20190606-C00874
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one hydrobromide: colorless crystal: m.p. 223-228° C. (recrystallized from EtOH—H2O)
  • 1H-NMR (DMSO-d6) δ ppm: 1.80-2.00 (4H, br), 3.06-3.20 (2H, m), 3.26-3.40 (4H, br), 3.50-3.74 (4H, m), 4.09 (2H, t, J=5.4 Hz), 6.31 (1H, d, J=9.4 Hz), 6.80-6.86 (2H, m), 6.99 (1H, d, J=7.6 Hz), 7.33 (1H, t, J=7.9 Hz), 7.51 (1H, d, J=5.5 Hz), 7.59 (1H, d, J=9.2 Hz), 7.72 (1H, d, J=8.0 Hz), 7.78 (1H, d, J=5.5 Hz), 7.82 (1H, d, J=9.5 Hz), 9.65 (1H, brs), 11.62 (1H, s).
  • Malonate:
  • A suspension of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (2 g) in dichloromethane (20 ml) and methanol (20 ml) was warmed to 60° C., dissolved, and malonic acid (0.53 g) dissolved in methanol was added at room temperature. The precipitated crystals were collected by filtration, and dried to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one malonate (2.4 g).
  • 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one malonate (1 g) was recrystallized from ethanol (4 ml) and water (10 ml) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one malonate (0.72 g).
  • Figure US20190167672A1-20190606-C00875
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one malonate: colorless crystal: m.p. 134-136° C. (recrystallized from EtOH—H2O)
  • 1H-NMR (DMSO-d6) δ ppm: 1.68-1.88 (4H, m), 2.82 (2H, brs), 2.92-3.08 (6H, m), 3.12-3.22 (4H, br), 4.07 (2H, t, J=5.8 Hz), 6.30 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 6.93 (1H, d, J=7.6 Hz), 7.30 (1H, t, J=7.8 Hz), 7.45 (1H, d, J=5.5 Hz), 7.57 (1H, d, J=9.4 Hz), 7.66 (1H, d, J=8.1 Hz), 7.73 (1H, d, J=5.5 Hz), 7.81 (1H, d, J=9.5 Hz), 11.60 (1H, brs).
  • ½ Pamoate:
  • A suspension of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (1 g) in dimethylformamide (10 ml) and acetonitrile (10 ml) was warmed to give a solution, and pamoic acid (0.49 g) was added. The mixture was warmed to 60° C., dissolved, and the mixture was stood at room temperature. Water was added, the suspended substances were collected by filtration, and dried to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one ½ pamoate (1.5 g).
  • Figure US20190167672A1-20190606-C00876
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one ½ pamoate: yellow amorphous
  • 1H-NMR (DMSO-d6) δ ppm: 1.78-1.92 (4H, m), 3.4-3.8 (10H, br), 4.05-4.12 (2H, m), 4.71 (1H, s), 6.31 (1H, d, J=9.5 Hz), 6.78-6.84 (2H, m), 6.96 (1H, d, J=7.6 Hz), 7.04 (1H, t, J=7.4 Hz), 7.13-7.19 (1H, m), 7.31 (1H, t, J=7.8 Hz), 7.49 (1H, d, J=5.5 Hz), 7.56 (1H, d, J=8.7 Hz), 7.69 (2H, d, J=8.0 Hz), 7.76 (1H, d, J=5.5 Hz), 7.81 (1H, d, J=9.5 Hz), 8.18 (1H, d, J=8.6 Hz), 8.25 (1H, s), 11.63 (1H, brs).
    • Experimental Example 1
  • Each of the Example compounds was examined for the solubility in oil (sesame oil, benzyl benzoate).
  • For the specific gravity of an oil, the following values were applied.
  • sesame oil (specific gravity: 0.914-0.921)
    benzyl benzoate (specific gravity: 1.123)
    • (Method)
  • Example compound is measured in a microtube and an oil (sesame oil, or, benzyl benzoate) in an amount to make the concentration 10 mg/0.1 ml is added. After stirring, the solubility is evaluated by visual observation. When the compound is not dissolved, the mixture is heated, and the solubility is evaluated after cooling.
  • The results are shown in Table 3 and Table 4. In the Tables, ◯ means soluble.
  • TABLE 3
    Example No. Sesame oil
    Example 17 ◯
    Example 21 ◯
    Example 28 ◯
    Example 44 ◯
    Example 45 ◯
    Example 52 ◯
    Example 57 ◯
    Example 60 ◯
    Example 75 ◯
    Example 76 ◯
    Example 79 ◯
    Example 134 ◯
    Example 135 ◯
    Example 142 ◯
    Example 144 ◯
    Example 149 ◯
    Example 150 ◯
    Example 154 ◯
    Example 156 ◯
    Example 158 ◯
    Example 177 ◯
    Example 179 ◯
    Example 180 ◯
    Example 373 ◯
    Example 379 ◯
    Example 380 ◯
    Example 381 ◯
    Example 384 ◯
  • TABLE 4
    Example No. benzyl benzoate
    Example 9 ◯
    Example 10 ◯
    Example 11 ◯
    Example 12 ◯
    Example 13 ◯
    Example 14 ◯
    Example 15 ◯
    Example 16 ◯
    Example 17 ◯
    Example 18 ◯
    Example 19 ◯
    Example 20 ◯
    Example 21 ◯
    Example 22 ◯
    Example 23 ◯
    Example 24 ◯
    Example 25 ◯
    Example 26 ◯
    Example 27 ◯
    Example 28 ◯
    Example 29 ◯
    Example 30 ◯
    Example 31 ◯
    Example 32 ◯
    Example 33 ◯
    Example 34 ◯
    Example 35 ◯
    Example 36 ◯
    Example 37 ◯
    Example 38 ◯
    Example 39 ◯
    Example 40 ◯
    Example 41 ◯
    Example 42 ◯
    Example 43 ◯
    Example 44 ◯
    Example 45 ◯
    Example 46 ◯
    Example 47 ◯
    Example 48 ◯
    Example 49 ◯
    Example 50 ◯
    Example 51 ◯
    Example 52 ◯
    Example 53 ◯
    Example 54 ◯
    Example 55 ◯
    Example 56 ◯
    Example 57 ◯
    Example 58 ◯
    Example 59 ◯
    Example 60 ◯
    Example 61 ◯
    Example 62 ◯
    Example 63 ◯
    Example 64 ◯
    Example 65 ◯
    Example 67 ◯
    Example 68 ◯
    Example 69 ◯
    Example 70 ◯
    Example 71 ◯
    Example 72 ◯
    Example 73 ◯
    Example 74 ◯
    Example 75 ◯
    Example 76 ◯
    Example 77 ◯
    Example 78 ◯
    Example 79 ◯
    Example 80 ◯
    Example 81 ◯
    Example 82 ◯
    Example 83 ◯
    Example 84 ◯
    Example 85 ◯
    Example 86 ◯
    Example 87 ◯
    Example 88 ◯
    Example 89 ◯
    Example 90 ◯
    Example 91 ◯
    Example 92 ◯
    Example 93 ◯
    Example 94 ◯
    Example 95 ◯
    Example 96 ◯
    Example 97 ◯
    Example 98 ◯
    Example 99 ◯
    Example 100 ◯
    Example 101 ◯
    Example 102 ◯
    Example 103 ◯
    Example 104 ◯
    Example 105 ◯
    Example 106 ◯
    Example 107 ◯
    Example 108 ◯
    Example 109 ◯
    Example 110 ◯
    Example 111 ◯
    Example 112 ◯
    Example 113 ◯
    Example 114 ◯
    Example 115 ◯
    Example 116 ◯
    Example 117 ◯
    Example 118 ◯
    Example 119 ◯
    Example 120 ◯
    Example 121 ◯
    Example 122 ◯
    Example 123 ◯
    Example 124 ◯
    Example 125 ◯
    Example 126 ◯
    Example 127 ◯
    Example 128 ◯
    Example 129 ◯
    Example 130 ◯
    Example 131 ◯
    Example 132 ◯
    Example 134 ◯
    Example 135 ◯
    Example 136 ◯
    Example 137 ◯
    Example 139 ◯
    Example 140 ◯
    Example 141 ◯
    Example 142 ◯
    Example 143 ◯
    Example 144 ◯
    Example 145 ◯
    Example 146 ◯
    Example 147 ◯
    Example 148 ◯
    Example 149 ◯
    Example 150 ◯
    Example 151 ◯
    Example 152 ◯
    Example 153 ◯
    Example 154 ◯
    Example 156 ◯
    Example 158 ◯
    Example 163 ◯
    Example 165 ◯
    Example 168 ◯
    Example 170 ◯
    Example 175 ◯
    Example 177 ◯
    Example 179 ◯
    Example 180 ◯
    Example 371 ◯
    Example 372 ◯
    Example 373 ◯
    Example 379 ◯
    Example 380 ◯
    Example 381 ◯
    Example 382 ◯
    Example 384 ◯
    • Experimental Example 2; Pharmacokinetics of Intramuscular Preparations
  • A suspended fine particle preparation used as a sustainable injection requires re-suspending before administration, and the particle surface area markedly affects the drug release profile. Thus, the particle size after re-suspending needs to be strictly controlled, so that coagulation and the like will not occur.
  • On the other hand, since an oil-soluble preparation contains a drug completely dissolved therein, re-suspending before administration is not necessary and, since the drug is released depending on the oil-water distribution coefficient, control of the particle size is not necessary. Furthermore, since sterilization by filtration, which has been unattainable for suspended fine particle preparations, has become possible, a preparation can be prepared more conveniently.
  • Since the compound disclosed in patent document 1 shows low solubility in an oil base material such as benzyl benzoate and the like, an oil-soluble preparation cannot be produced. When a soluble preparation is produced, an aqueous base material using a solubilizing agent such as Captisol (Sulfobutylether-β-cyclodextrin) and the like needs to be used. In contrast, since the compound of the present invention shows high solubility in an oil base material, an oil-soluble preparation can be produced.
  • Thus, an oil-soluble preparation of the compound of the present invention and an water soluble preparation of the compound disclosed in patent document 1 were prepared, intramuscularly administered to rats and pharmacokinetics of these preparations were evaluated.
    • Animal
  • 7-week-old male rats were purchased from CHARLES RIVER LABORATORIES JAPAN, INC, preliminarily bred and rats weighing 265.2 g-288.6 g were used for the experiment. The experiment was performed under the conditions of no fasting, free access to water and feed, and the following breeding environment. Rats per cage: 4, temperature: 23±2° C., humidity: 60±10%, light-on time: 7:00-19:00
    • Production Method of Preparation
  • As the compound disclosed in patent document 1, used was 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (control compound) disclosed in Example 1 that expresses desired efficacy. A water-soluble preparation was obtained by dissolving the control compound in aqueous 15% Captisol and 0.78% tartaric acid solution to a concentration of 0.5%, and the pH was adjusted to 4.3 with 5N aqueous sodium hydroxide solution.
  • An oil-soluble preparation was obtained by dissolving the compound of the present invention disclosed in Example 146 in benzyl benzoate to a concentration of 15%, and adjusted.
    • Methods of Administration and Blood Sampling
  • Under isoflurane anesthesia, non-fasting male rats were intramuscularly administered at left leg region (about 4 mm depth) using a syringe with 24G needle. The dose is as described below.
  • Test preparation 1: low dose of oil-soluble preparation of the compound of the present invention: 25 mg/kg (based on control compound)
    Test preparation 2: high dose of oil-soluble preparation of the compound of the present invention: 50 mg/kg (based on control compound)
    Test preparation 3: water-soluble preparation of control compound: 0.1 mg/kg
  • The test preparation was administered to the rats. For test preparation 3, about 0.3 mL each of blood samples were collected from the jugular vein 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr and 20 hr later. For test preparations 1 and 2, about 0.3 mL each of blood samples were collected from the jugular vein 6 hr, 1 day, 3 days, 7 days, 14 days, 21 days and 28 days later. For collection of blood samples, a 1 mL syringe treated with EDTA-lithium fluoride-heparin was used. The collected blood was preserved under ice-cooling, the plasma was rapidly separated by centrifugation, and the concentration of the control compound was quantified by LCMS. The pharmacokinetics parameters such as Cmax, Tmax, AUClast, AUCinf, t½ and the like were determined by WinNonlin Professional Version 6.1 (model-independent method, Pharsight corporation).
    • Results
  • The results are shown in FIG. 1 (blood concentration profile of control compound after administration of test preparations 1, 2 and 3) and Table 5 (pharmacokinetics parameters of test preparations 1, 2 and 3).
  • TABLE 5
    Cmax Tmax AUClast AUCinf t½
    (μg/mL) (day) (μg · day/mL) (μg · day/mL) (day)
    Test 0.0258 5.00 0.270 0.473 27.99
    preparation 1
    Test 0.0423 5.31 0.480 0.621 16.99
    preparation 2
    Test 0.0629 0.01 0.003 0.003 0.05
    preparation 3
    Each parameter shows mean value (n = 4)
    • Discussion
  • In test preparation 3, the control compound disappeared immediately after intramuscular administration. On the other hand, in test preparations 1 and 2, the control compound showed a sustained blood concentration profile. Therefrom it was shown that the improved solubility of the compound of the present invention in an oily substrate has enabled the production of a dissolution preparation that shows blood concentration sustainability of the compound of patent document 1.
  • This application is based on application No. 61/532,393 filed in United States of America (filing date; Sep. 8, 2011), the content of which is incorporated hereinto by reference.

Claims (11)

1. A heterocyclic compound represented by the formula (I)
Figure US20190167672A1-20190606-C00877
wherein
A is a lower alkylene group;
Figure US20190167672A1-20190606-C00878
in the monocyclic heterocycle containing Q is
Figure US20190167672A1-20190606-C00879
wherein
R2′ is the following group
Figure US20190167672A1-20190606-C00880
wherein
Y1′ is a lower alkylene group,
R3′ is
(1) an alkyl group,
(2) a cycloalkyl group optionally substituted by a lower alkyl group,
(3) a phenyl group,
(4) a phenyl lower alkyl group
(5) a lower alkoxy group,
(6) a cycloalkyloxy group,
(7) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a phenyl lower alkyl group, or
(8) a piperidyl group optionally having a piperidyl group;
Figure US20190167672A1-20190606-C00881
at the 3-position and the 4-position of the bicyclic heterocycle skeleton containing Z and W is —CH═CH— or
Figure US20190167672A1-20190606-C00882
wherein R6 and R7 are the same or different and each is a hydrogen or a lower alkyl group;
Figure US20190167672A1-20190606-C00883
is
Figure US20190167672A1-20190606-C00884
wherein
R1 is
a lower alkoxy lower alkoxy group,
a phosphonooxy lower alkoxy group,
a phenyl lower alkoxy lower alkoxy group,
a phosphonooxy group optionally having 1 or 2 lower alkyl groups,
the following group
Figure US20190167672A1-20190606-C00885
wherein
R8 is
(1) an alkyl group,
(2) a hydroxy-substituted lower alkyl group,
(3) a cycloalkyl group,
(4) a phenyl group,
(5) a phenyl lower alkyl group,
(6) an alkenyl group,
(7) a lower alkoxy group,
(8) a cycloalkyloxy group,
(9) a lower alkoxy lower alkoxy group,
(10) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group,
(11) a piperidyl group optionally having a piperidyl group,
(12) a piperazinyl group optionally having a lower alkyl group, or
(13) the following group
Figure US20190167672A1-20190606-C00886
wherein Aa is an alkylene group, and other symbols are as defined above, or
the following group
Figure US20190167672A1-20190606-C00887
wherein
R9 is
(1) an alkyl group,
(2) a hydroxy-substituted lower alkyl group,
(3) a cycloalkyl group,
(4) a phenyl group,
(5) a phenyl lower alkyl group,
(6) an alkenyl group,
(7) a lower alkoxy group,
(8) a cycloalkyloxy group,
(9) a lower alkoxy lower alkoxy group,
(10) a phenyloxy group,
(11) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group,
(12) a piperidyl group optionally having a piperidyl group,
(13) a piperazinyl group optionally having a lower alkyl group, or
(14) the following group
Figure US20190167672A1-20190606-C00888
wherein Ab is an alkylene group, and other symbols are as defined above;
R2 is a hydrogen or
the following group
Figure US20190167672A1-20190606-C00889
wherein
Y1 is a lower alkylene group optionally substituted by
(1) a lower alkoxycarbonyl group or
(2) a lower alkyl group,
Y2 is a lower alkylene group,
Y3 is a single bond or a lower alkylene group optionally substituted by a lower alkyl group,
R3 is
(1) an alkyl group,
(2) a halogen-substituted lower alkyl group,
(3) an alkenyl group,
(4) an amino lower alkyl group,
(5) a cycloalkyl group,
(6) a phenyl group,
(7) a phenyl lower alkyl group,
(8) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group and a piperidyl group,
(9) a halogen-substituted piperidyl group,
(10) a morpholinyl group,
(11) a pyrrolidinyl group,
(12) a tetrahydropyranyl group,
(13) a furyl group,
(14) a thienyl group,
(15) a pyridyl group,
(16) a pyrimidinyl group,
(17) a pyridazinyl group,
(18) a benzofuryl group,
(19) a quinolyl group,
(20) a lower alkoxycarbonyl lower alkyl group,
(21) a lower alkoxy lower alkoxy lower alkyl group,
(22) a lower alkoxy lower alkoxy lower alkoxy lower alkyl group,
(23) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a lower alkenyl group, a halogen-substituted lower alkyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a phenyl lower alkyl group, a phenyl lower alkoxy group, a furyl lower alkyl group, a pyridyl lower alkyl group, a hydroxy-substituted lower alkyl group,
(24) an amino lower alkyl group optionally having a lower alkylcarbonyl group,
(25) a piperazinyl group optionally having a lower alkyl group, or
(26) the following group
Figure US20190167672A1-20190606-C00890
wherein Ac is an alkylene group, and other symbols are as defined above,
R4 is
(1) an alkyl group,
(2) a phenyl group,
(3) a phenyl lower alkyl group,
(4) a halogen-substituted lower alkyl group, or
(5) a cycloalkyl group,
R5 is
(1) a hydrogen,
(2) a lower alkyl group,
(3) a halogen-substituted lower alkyl group,
(4) a phenyl lower alkyl group,
(5) a phenyl lower alkoxy lower alkyl group,
(6) a tri-lower alkylsilyl group,
(7) a tetrahydropyranyl group, or
(8) a phosphono group,
R10 is
(1) an alkyl group,
(2) an alkenyl group,
(3) a phenyl group,
(4) a phenyl lower alkyl group,
(5) a hydroxy-substituted lower alkyl group,
(6) a cycloalkyl group,
(7) an amino lower alkyl group optionally having 1 or 2 substituents selected from the group consisting of an amino lower alkylcarbonyl group and a lower alkylcarbonyl group,
(8) a pyrrolidinyl group optionally having an amino lower alkylcarbonyl group,
(9) an alkoxy group,
(10) a lower alkoxy lower alkoxy lower alkyl group,
(11) a lower alkoxy lower alkoxy lower alkoxy lower alkyl group,
(12) a phenyl lower alkoxy group,
(13) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group, a hydroxy-substituted lower alkyl group and a phenyl lower alkyl group,
(14) a morpholino group,
(15) a piperazinyl group optionally having a lower alkyl group,
(16) a piperidyl group optionally having a piperidyl group, or
(17) a cycloalkyloxy group;
provided when
Figure US20190167672A1-20190606-C00891
is
Figure US20190167672A1-20190606-C00892
then
R2 is not a hydrogen,
or a salt thereof.
2. The heterocyclic compound according to claim 1, which is represented by the formula (II)
Figure US20190167672A1-20190606-C00893
wherein each symbol is as defined in claim 1, or a salt thereof.
3. The heterocyclic compound according to claim 1, which is represented by the formula (III)
Figure US20190167672A1-20190606-C00894
wherein
Figure US20190167672A1-20190606-C00895
is
Figure US20190167672A1-20190606-C00896
wherein
R1a is the following group
Figure US20190167672A1-20190606-C00897
wherein
R8a is
(1) an alkyl group,
(2) a cycloalkyl group,
(3) a lower alkoxy group,
(4) a cycloalkyloxy group,
(5) a lower alkoxy lower alkoxy group,
(6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or
(7) the following group
Figure US20190167672A1-20190606-C00898
wherein Aa′ is an alkylene group, and other symbol is as defined in claim 1, or
the following group
Figure US20190167672A1-20190606-C00899
wherein
R9a is
(1) an alkyl group,
(2) a hydroxy-substituted lower alkyl group,
(3) a cycloalkyl group,
(4) a lower alkoxy group,
(5) a cycloalkyloxy group,
(6) a lower alkoxy lower alkoxy group,
(7) a phenyloxy group,
(8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group,
(9) a piperidyl group optionally having a piperidyl group,
(10) a piperazinyl group optionally having a lower alkyl group, or
(11) the following group
Figure US20190167672A1-20190606-C00900
wherein Ab′ is an alkylene group, and other symbol is as defined in claim 1;
R2a is
the following group
Figure US20190167672A1-20190606-C00901
wherein
Y1a is a lower alkylene group,
Y2a is a lower alkylene group,
R3a is
(1) an alkyl group,
(2) a cycloalkyl group,
(3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group,
(4) a tetrahydropyranyl group,
(5) a lower alkoxycarbonyl lower alkyl group,
(6) a lower alkoxy lower alkoxy lower alkyl group
(7) an amino lower alkyl group optionally having a lower alkylcarbonyl group, or
(8) the following group
Figure US20190167672A1-20190606-C00902
wherein Ac′ is an alkylene group, Y1a is a lower alkylene group and other symbols are as defined in claim 1,
R4a is
(1) an alkyl group, or
(2) a cycloalkyl group; and
A is a lower alkylene group,
or a salt thereof.
4. The heterocyclic compound according to claim 2, wherein R1 is
the following group
Figure US20190167672A1-20190606-C00903
wherein
R8a′ is
(1) an alkyl group,
(2) a cycloalkyl group,
(3) a lower alkoxy group,
(4) a cycloalkyloxy group,
(5) a lower alkoxy lower alkoxy group, or
(6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or
the following group
Figure US20190167672A1-20190606-C00904
wherein
R9a′ is
(1) an alkyl group,
(2) a hydroxy-substituted lower alkyl group,
(3) a cycloalkyl group,
(4) a lower alkoxy group,
(5) a cycloalkyloxy group,
(6) a lower alkoxy lower alkoxy group,
(7) a phenyloxy group,
(8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group,
(9) a piperidyl group optionally having a piperidyl group, or
(10) a piperazinyl group optionally having a lower alkyl group;
R2 is
the following group
Figure US20190167672A1-20190606-C00905
wherein
Y1a is a lower alkylene group,
Y2a is a lower alkylene group,
R3a′ is
(1) an alkyl group,
(2) a cycloalkyl group
(3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group,
(4) a tetrahydropyranyl group,
(5) a lower alkoxycarbonyl lower alkyl group,
(6) a lower alkoxy lower alkoxy lower alkyl group
(7) an amino lower alkyl group optionally having a lower alkylcarbonyl group,
R4a is
(1) an alkyl group, or
(2) a cycloalkyl group;
or a salt thereof.
5. A pharmaceutical composition comprising the heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and/or a carrier.
6. A prophylactic and/or therapeutic agent for a central neurological disease, comprising the heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
7. The agent according to claim 6, wherein the central neurological disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, emotional disturbance, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, Alzheimer's disease, Parkinson disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder, Tourette's disorder, tic disorder, attention deficit hyperactivity disorder, conduct disorder and Down's syndrome.
8. Use of the heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof as a medicament.
9. A method of preventing and/or treating a central neurological disease, comprising administering the heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof to a human or an animal.
10. The method according to claim 9, wherein the central neurological disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, emotional disturbance, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, Alzheimer's disease, Parkinson disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder, Tourette's disorder, tic disorder, attention deficit hyperactivity disorder, conduct disorder and Down's syndrome.
11. A method of producing a heterocyclic compound represented by the formula (I)
Figure US20190167672A1-20190606-C00906
wherein each symbol is as defined in claim 1,
or a salt thereof, comprising reacting a compound represented by
the formula
Figure US20190167672A1-20190606-C00907
wherein X1 is a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined in claim 1, or a salt thereof, with a compound represented by
Figure US20190167672A1-20190606-C00908
wherein Q is as defined in claim 1, or a salt thereof.
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