WO2016021562A1 - Dérivé de cyanothiophène - Google Patents

Dérivé de cyanothiophène Download PDF

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WO2016021562A1
WO2016021562A1 PCT/JP2015/071993 JP2015071993W WO2016021562A1 WO 2016021562 A1 WO2016021562 A1 WO 2016021562A1 JP 2015071993 W JP2015071993 W JP 2015071993W WO 2016021562 A1 WO2016021562 A1 WO 2016021562A1
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alkyl
mixture
compound
group
room temperature
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PCT/JP2015/071993
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Japanese (ja)
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康徳 上野
孝介 大野
貴史 宮城
清水　和夫
雄介 恩田
皓 鈴木
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キッセイ薬品工業株式会社
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Priority to JP2016540227A priority Critical patent/JP6609253B2/ja
Publication of WO2016021562A1 publication Critical patent/WO2016021562A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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 or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/535—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/535—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
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/54—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C07D409/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the present invention relates to a cyanothiophene derivative useful as a pharmaceutical product.
  • the present invention has a substance P / neurokinin 1 (NK 1 ) receptor antagonistic action, and is useful as a preventive or therapeutic agent for nausea and vomiting (CINV) associated with administration of an antineoplastic agent.
  • CINV nausea and vomiting
  • the present invention relates to a thiophene derivative or a pharmacologically acceptable salt thereof.
  • CINV is expressed by stimulation of the vomiting center present in the lateral medullary medulla.
  • Administration of an antineoplastic agent increases the secretion of serotonin from enterochromophilic (EC) cells present in the gastrointestinal tract, and serotonin vomits via the 5-Hydroxytryptamine 3 (5-HT 3 ) receptor in the gastrointestinal tract. Stimulate the center directly.
  • nausea and vomiting develop when serotonin stimulates the emetic center via a chemoreceptor trigger zone (CTZ) present in the last ventricle of the fourth ventricle.
  • CTZ chemoreceptor trigger zone
  • Substance P like serotonin, is present in EC cells of the gastrointestinal tract, and secretion is promoted by administration of an antineoplastic agent. Recently, substance P, via the NK 1 receptor present CTZ, or is shown to induce vomiting by binding to NK 1 receptors in the central nervous system, NK 1 receptors antiemetic It is attracting attention as a development target (Non-patent Document 1).
  • Aprepitant is the world's first selective NK 1 receptor antagonist approved as a prophylactic against nausea and vomiting associated with antineoplastic agents.
  • the mechanism of action of aprepitant is thought to prevent CINV by selectively inhibiting the binding of substance P, a central nervous system NK 1 receptor, which is one of the induction pathways of CINV.
  • Aprepitant is sold as a preventive for CINV (Non-patent Document 2).
  • Aprepitant is known to be metabolized by cytochrome P450 (CYP) 3A4. Aprepitant is also known to have a dose-dependent inhibitory effect on CYP3A4, an inducing action of CYP3A4, and an inducing action of CYP2C9. Therefore, aprepitant may cause drug-drug interactions with drugs that inhibit or induce CYP3A4, or drugs that are metabolized by CYP3A4 or CYP2C9.
  • CYP3A4 inhibitory action of aprepitant may inhibit dexamethasone metabolism, and dexamethasone has been reported to require dose adjustment when used in combination with aprepitant (Non-patent Document 3). For this reason, the use of aprepitant requires sufficient attention to the drug-drug interaction based on the CYP3A4 inhibitory action of aprepitant.
  • a novel NK 1 receptor antagonist is desired, and preferably a novel NK 1 receptor antagonist with little drug-drug interaction is desired.
  • Non-patent Document 4 Casopitant was in clinical trials in the United States and Europe as a preventive against nausea and vomiting associated with antineoplastic agents, but development was discontinued after application.
  • Netupitant is under development as a prophylactic agent against nausea and vomiting associated with administration of an antineoplastic agent, but has been reported to have an inhibitory effect on CYP3A4 and drug-drug interaction resulting therefrom (Non-patent Document 5).
  • Ezlopitant was in clinical trials in the United States as a prophylactic agent for nausea and vomiting associated with antineoplastic agents, but its development was discontinued.
  • Vofopitant was in clinical trials in Europe as a prophylactic agent against nausea and vomiting associated with the administration of antineoplastic agents, but its development was discontinued. Many of these compounds have been discontinued. None of these are commercially available.
  • An object of the present invention is to provide a novel compound having an NK 1 receptor antagonistic action and useful for preventing or treating nausea and vomiting associated with administration of an antineoplastic agent.
  • An object of the present invention is to provide the above-mentioned compound in which the inhibitory action of CYP3A4 is preferably attenuated compared to aprepitant.
  • the present invention relates to a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof.
  • R 1a is a hydrogen atom, a halogen atom, C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or haloC 1-6 alkyl
  • R 1b is a hydrogen atom, a halogen atom, or C 1-6 alkyl
  • R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or haloC 1-6 alkyl
  • R 3a and R 3b are each independently a hydrogen atom, C 1-6 alkyl, or hydroxy C 1-6 alkyl
  • R 4a , R 4b , and R 4c are each independently a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, or hal
  • m is an integer from 1 to 4;
  • W is a C 1-3 alkylene which may have a single bond or an arbitrary group selected from the substituent group ⁇ ; (However, when R 6 is a hydrogen atom or C 1-6 alkyl, W is a single bond; when R 6 is carboxy, W has an arbitrary group selected from the substituent group ⁇ .
  • Substituent group ⁇ is a group consisting of a halogen atom and C 1-6 alkyl;
  • R 6 represents a hydrogen atom, C 1-6 alkyl, carboxy, C 1-6 alkoxycarbonyl, carbamoyl, mono (di) C 1-6 alkylcarbamoyl, haloC 1-6 alkyl, C 1-6 alkylsulfonyl, mono (Di) C 1-6 alkylsulfamoyl, triazolonyl, tetrazolyl, cyano, carboxycarbonyl, C 1-6 alkoxycarbonylcarbonyl, carbamoylcarbonyl, mono (di) C 1-6 alkylcarbamoylcarbonyl, or substituent group ⁇ C 2-7 acyl optionally having any group selected;
  • Substituent group ⁇ is a group consisting of a halogen atom, hydroxy, C 1-6 alk
  • U 1 and U 2 are groups selected from the group consisting of 1) to 3) below when ring A is any of a) to j): 1) U 1 is a single bond and U 2 is a single bond; 2) U 1 is a single bond and U 2 is methylene which may have any group selected from substituent group ⁇ 2 ; and 3) U 1 is selected from substituent group ⁇ 1 C 1-2 alkylene optionally having any group, and U 2 is methylene optionally having any group selected from the substituent group ⁇ 2 ; U 1 and U 2 are groups selected from the group consisting of 4) to 5) below when ring A is any of k) to r): 4) U 1 is a single bond; U 2 is a single bond; and 5) U 1 is a single bond, and U 2 may have any group selected from the substituent group ⁇ 1.
  • Substituent group ⁇ 1 is a group consisting of a halogen atom, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy
  • Substituent group ⁇ 2 is a group consisting of a halogen atom and C 1-6 alkyl
  • V is a single bond or C 1-3 alkylene which may have any group selected from the substituent group ⁇ ; (However, when R 5 is a halogen atom or C 1-6 alkyl, V is a single bond.);
  • Substituent group ⁇ is a group consisting of a halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and mono (di) C 1-6 alkylamino;
  • R 5 is a halogen atom, C 1-6 alkyl, hydroxy, amino, carboxy, mono (di) C 1-6 alkylamino, C 1-6 alkoxycarbonyl, carbamoyl, mono (di)
  • U 1a and U 2a are groups selected from the group consisting of 1) to 3) below when ring A a is any of a) to j): 1) U 1a is a single bond and U 2a is a single bond; 2) U 1a is a single bond and U 2a is methylene; and 3) U 1a is C 1-2 alkylene and U 2a is methylene; U 1a and U 2a are groups selected from the group consisting of the following 4) to 5) when ring A a is any of m), n), or p) to r): 4) U 1a is a single bond and U 2a is a single bond; and 5) U 1a is a single bond and U 2a is C 1-3 alkylene; V a is a single bond or C 1-3 alkylene which may have any group selected from the substituent group ⁇ a ; (However, when R 5a is a halogen atom or C 1-6 alkyl, V a is a single bond.);
  • a pharmaceutical composition comprising the compound according to any one of [1] to [13] or a pharmacologically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition according to [14] above which is a pharmaceutical composition for preventing nausea and vomiting associated with administration of an antineoplastic agent.
  • the compound of the present invention has an excellent NK 1 receptor antagonistic action. Moreover, the inhibitory action of CYP3A4 of the preferred compound of the present invention is attenuated compared to aprepitant. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof is useful as a preventive or therapeutic agent for nausea and vomiting associated with administration of an antineoplastic agent.
  • Halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. Is mentioned.
  • C 1-2 alkylene refers to a divalent group derived from a linear or branched alkyl group having 1 to 2 carbon atoms.
  • C 1-3 alkylene refers to a divalent group derived from a linear or branched alkyl group having 1 to 3 carbon atoms.
  • C 2-7 acyl refers to a linear or branched acyl group having 2 to 7 carbon atoms, and examples thereof include acetyl, propionyl, butyryl, isobutyryl, pivaloyl and the like.
  • C 1-6 alkoxy refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy and the like.
  • Haldroxy C 1-6 alkyl refers to a linear or branched hydroxyalkyl group having 1 to 6 carbon atoms.
  • Halo C 1-6 alkyl refers to C 1-6 alkyl substituted with one to three same or different halogen atoms, for example, fluoromethyl group, 2-fluoroethyl group, difluoromethyl group, A trifluoromethyl group, 2,2,2-trifluoroethyl group, 3,3,3-trifluoropropyl group, 4,4,4-trifluorobutyl group and the like can be mentioned.
  • C 1-6 alkoxy C 1-6 alkyl refers to C 1-6 alkyl substituted with the above C 1-6 alkoxy.
  • Carboxy C 1-6 alkyl refers to C 1-6 alkyl substituted with 1 to 3 carboxy groups.
  • Halo C 1-6 alkoxy refers to C 1-6 alkoxy substituted with one to three same or different halogen atoms, for example, monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, etc. Is mentioned.
  • Carboxy C 1-6 alkoxy refers to C 1-6 alkoxy substituted with 1 to 3 carboxy groups.
  • C 2-7 acyloxy refers to a group represented by C 2-7 acyl-O—.
  • C 2-7 acylamino refers to a group represented by (C 1-6 alkyl) -C (O) NH—.
  • C 1-6 alkylsulfonyl refers to a group represented by (C 1-6 alkyl) —SO 2 —, and examples thereof include methylsulfonyl, ethylsulfonyl and the like.
  • “Mono (di) C 1-6 alkylsulfamoyl” refers to sulfamoyl mono- or di-substituted with the above C 1-6 alkyl. In the case of disubstitution, each substituent may be different from each other.
  • Mono (di) C 1-6 alkylamino refers to an amino mono- or di-substituted with the above C 1-6 alkyl. In the case of disubstitution, each substituent may be different from each other.
  • Carboxy-C 1-6 alkylamino refers to a C 1-6 alkylamino substituted with 1-3 carboxyl groups.
  • C 2-7 acyl (C 1-6 alkyl) amino refers to a group represented by C 2-7 acyl (C 1-6 alkyl) N—.
  • Carboxy C 1-6 alkyl (C 1-6 alkyl) amino means a group represented by C 1-6 alkyl (C 1-6 alkyl) N— substituted with 1 to 3 carboxy groups.
  • C 1-6 alkylsulfonylamino refers to a group represented by (C 1-6 alkyl) -SO 2 NH—, and examples thereof include methylsulfonylamino, ethylsulfonylamino and the like.
  • the "C 1-6 alkylsulfonyl (C 1-6 alkyl) amino” refers to a C 1-6 alkylsulfonyl (C 1-6 alkyl) N- group represented by.
  • “Mono (di) C 1-6 alkylsulfamoylamino” refers to a group represented by mono (di) C 1-6 alkylsulfamoyl-NH—.
  • “Mono (di) C 1-6 alkylsulfamoyl (C 1-6 alkyl) amino” is represented by mono (di) C 1-6 alkylsulfamoyl (C 1-6 alkyl) N—.
  • “Carboxycarbonyl” refers to a group represented by carboxy-C (O) —.
  • Carbamoylcarbonyl refers to a group represented by carbamoyl-C (O) —.
  • “C 1-6 alkoxycarbonyl” refers to a group represented by C 1-6 alkoxy-C (O) —.
  • C 1-6 alkoxycarbonylcarbonyl refers to a group represented by C 1-6 alkoxycarbonyl-C (O) —.
  • C 1-6 alkylsulfonylaminocarbonyl refers to a group represented by C 1-6 alkylsulfonyl-NH—C (O) —.
  • Mono (di) C 1-6 alkylcarbamoyl refers to carbamoyl mono- or di-substituted with the above C 1-6 alkyl. In the case of disubstitution, each substituent may be different from each other.
  • “Mono (di) C 1-6 alkylcarbamoylcarbonyl” refers to a group represented by mono (di) C 1-6 alkylcarbamoyl-C (O) —.
  • “C 1-6 alkoxycarbonyl C 1-6 alkoxy” refers to C 1-6 alkoxy-C (O) —C 1-6 alkoxy.
  • “C 1-6 alkylsulfonyloxy” refers to a group represented by (C 1-6 alkyl) —SO 2 —O—.
  • “Mono (di) C 1-6 alkylaminocarbonyloxy” refers to a group represented by mono (di) C 1-6 alkyl-NH—C (O) —O—.
  • C 1-6 alkoxycarbonylamino refers to a group represented by C 1-6 alkoxy-C (O) —NH—.
  • C 1-6 alkoxycarbonyl C 1-6 alkylamino refers to a group represented by C 1-6 alkoxy-C (O) —C 1-6 alkyl-NH—.
  • C 1-6 alkoxycarbonyl (C 1-6 alkyl) amino refers to a group represented by C 1-6 alkoxy-C (O) — (C 1-6 alkyl) N—.
  • C 1-6 alkoxycarbonylC 1-6 alkyl (C 1-6 alkyl) amino means C 1-6 alkoxy-C (O) —C 1-6 alkyl- (C 1-6 alkyl) N— The group represented by these.
  • “Mono (di) C 1-6 alkylcarbamoylamino” refers to a group represented by mono (di) C 1-6 alkylcarbamoyl-NH—. It refers to (C 1-6 alkyl) N-, a group represented by - The "mono (di) C 1-6 alkylcarbamoyl (C 1-6 alkyl) amino", mono (di) C 1-6 alkylcarbamoyl .
  • C 3-6 cycloalkyl refers to a 3- to 6-membered saturated cyclic hydrocarbon group, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl and the like.
  • C 3-6 cycloalkylcarbonylamino refers to a group represented by C 3-6 cycloalkyl-C (O) —NH—.
  • “It may have an arbitrary group selected from substituent group ⁇ 1 ” means that it may have 1 to 3 identical or different groups selected from substituent group ⁇ 1. Good, unsubstituted or preferably having one. “It may have an arbitrary group selected from substituent group ⁇ 2 ” means that it may have one or two identical or different groups selected from substituent group ⁇ 2. Good, unsubstituted or preferably having one. “It may have any group selected from substituent group ⁇ ” means that it may have 1 to 3 identical or different groups selected from substituent group ⁇ , It is preferably unsubstituted or one.
  • “Have any group selected from substituent group beta a may also be” A, that the same or different groups selected from substituent group beta a may have 1 to 3 Good, unsubstituted or preferably having one. “May have any group selected from substituent group ⁇ ” means that it may have 1 to 3 identical or different groups selected from substituent group ⁇ , It is preferably unsubstituted or one. "Have any group selected from substituent group gamma a may also be” A, that the same or different groups selected from substituent group gamma a may have 1 to 3 Good, unsubstituted or preferably having one.
  • “It may have an arbitrary group selected from substituent group ⁇ ” means that it may have 1 to 3 identical or different groups selected from substituent group ⁇ , It is preferably unsubstituted or one. “It may have any group selected from the substituent group ⁇ ” means that it may have 1 to 3 identical or different groups selected from the substituent group ⁇ , It is preferably unsubstituted or one.
  • the “may have C 1-6 alkoxy” means that it may have 1 to 3 of the above C 1-6 alkoxy, preferably unsubstituted or having one.
  • (R 5 -V) n- represents a substituent on the ring of ring A.
  • ring A is a bicyclic group represented by f), g), h), i) or j) above,
  • (R 5 -V) n - is a substituent on any ring, Also good.
  • the present invention relates to a compound in which each asymmetric carbon atom is in R configuration, a compound in S configuration, and Compounds of any combination thereof are also included. Also included within the scope of the invention are those racemates, racemic mixtures, single enantiomers and diastereomeric mixtures.
  • the present invention includes any of the cis-trans isomers.
  • the determination of stereochemistry can also be performed by a method well known in the art (for example, see “Special Lecture NMR Stereochemistry” (Kodansha), issued in 2012, page 59).
  • the compound represented by the formula (I) of the present invention can be converted into a pharmacologically acceptable salt thereof according to a conventional method as necessary.
  • salts include acid addition salts and salts with bases.
  • Acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, organic acids such as p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid and aspartic acid
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, organic acids such as p-tolu
  • salts with bases include salts with inorganic bases such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, N-methyl-D-glucamine, N, N′-dibenzylethylenediamine, triethylamine, piperidine, Mention may be made of salts with organic bases such as morpholine, pyrrolidine, arginine, lysine and choline.
  • inorganic bases such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, N-methyl-D-glucamine, N, N′-dibenzylethylenediamine, triethylamine, piperidine
  • organic bases such as morpholine, pyrrolidine, arginine, lysine and choline.
  • the pharmacologically acceptable salt includes a solvate with a pharmaceutically acceptable solvent such as water or ethanol.
  • X is O, S, or SO 2 .
  • ring A is a
  • X is O, S, or SO 2 .
  • ring A is f), j), or m
  • X is O.
  • l is 1 or 2, and m is 1, 2, 3, or 4.
  • ring A is a), d), f), g), h), i), j), m), or n), preferably, l is 1.
  • ring A is b), preferably l is 1 or 2.
  • ring A is c), preferably m is 1, 2, 3 or 4.
  • ring A is e
  • m is 2 or 3.
  • ring A is q) or r)
  • m is 3.
  • R 6 is C 1-6 alkyl, carboxy, triazolonyl, carboxycarbonyl, carbamoylcarbonyl, or C 2-7 acyl.
  • W is a single bond or C 1-3 alkylene.
  • R 6 is C 1-6 alkyl, carboxy, carboxycarbonyl, carbamoylcarbonyl, or C 2-7 acyl, and W is a single bond or C 1 -3 alkylene.
  • ring A is n
  • R 6 is C 1-6 alkyl, carboxy, triazolonyl, or C 2-7 acyl
  • W is a single bond or C 1-3 alkylene.
  • R 5 is a halogen atom, C 1-6 alkyl, hydroxy, carboxy, mono (di) C 1-6 alkylamino, Carbamoyl, mono (di) C 1-6 alkylcarbamoyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 2-7 acyloxy, C 1-6 alkylsulfonyl, cyano, carboxy C 1-6 alkylamino, carboxy C 1-6 alkyl (C 1-6 alkyl) amino, carboxy C 1-6 alkoxy, C 1-6 alkylsulfonylamino, mono (di) C 1-6 alkylaminocarbonyloxy, C 1-6 alkylsulfonylaminocarbonyl , C 3-6 cycloalkyl carbonyl amino, have an optional group selected from substituent group ⁇ C 2-7 acylamino, or C 2-7 acyl
  • R 5 is carboxy and V is a single bond. More preferably, when ring A is b), R 5 is hydroxy, carboxy, or C 2-7 acyloxy, and V is a single bond or C 1-3 alkylene.
  • R 5 is a halogen atom, C 1-6 alkyl, hydroxy, carboxy, mono (di) C 1-6 alkylamino, carbamoyl, mono (di) C 1-6 Alkylcarbamoyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, cyano, carboxy C 1-6 alkylamino, carboxy C 1-6 alkyl (C 1-6 alkyl) amino, carboxy C Selected from 1-6 alkoxy, C 1-6 alkylsulfonylamino, mono (di) C 1-6 alkylaminocarbonyloxy, C 1-6 alkylsulfonylaminocarbonyl, C 3-6 cycloalkylcarbonylamino, substituent group ⁇ any good C 2-7 acylamino optionally having a group, or C 2-7 acyl (C 1-6 Al Le) is amino, V is a halogen atom, C
  • R 5 is carboxy and V is C 1-3 alkylene. More preferably, when ring A is m) or q), R 5 is hydroxy or carboxy, and V is a single bond or C 1-3 alkylene. When ring A is n), more preferably R 5 is hydroxy or carboxy and V is a single bond.
  • n is an integer of 0-3.
  • n is 0 or 1.
  • ring A is c)
  • more preferably n is 0, 1, 2 or 3.
  • n is 0 when ring A is f), h), or j).
  • More preferably, n is 1 when ring A is g), i), m), q), or r).
  • the compound represented by the formula (I) of the present invention can be synthesized, for example, according to the method shown in Scheme 1 to 7 (Scheme 1 to 7) or a method equivalent thereto, or the method described in the literature or a method equivalent thereto. ) To (IE).
  • the compound represented by the formula (IA) can be produced, for example, according to the process 1-1 to 1-8 or 1-9 described in Scheme 1.
  • L 1 in the formula is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom.
  • R 1a , R 1b , R 2 , R 3a , R 3b , R 4a , R 4b , R 4c , V, R 5 , and n have the same meaning as described above.
  • Ring A is a group selected from the group consisting of a), b), c), d), e), f), g), h), i), and j).
  • U 1 is a single bond and U 2 is a single bond.
  • Process 1-1 Compound (IA) can also be produced by subjecting compound (1) to a coupling reaction with an amine compound or an amide compound in an inert solvent in the presence or absence of a base and a palladium catalyst.
  • the inert solvent include N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, and mixed solvents thereof.
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, pyridine, N, N-diisopropylethylamine, 2,6-lutidine, 1,8-diazabicyclo [5, 4,0] -7-undecene and the like.
  • Examples of the palladium catalyst include tris (dibenzylideneacetone) dipalladium (0).
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • the reaction can also be performed using a microwave reactor (Biotage).
  • Examples of the compound that can be synthesized by Step 1-1 include Examples A-1-1 and A-1-16.
  • a tert-butoxycarbonylamine derivative can also be produced by subjecting compound (1) to a coupling reaction with an amine compound in the same manner as in Step 1-1.
  • An amine derivative can also be produced by reacting a tert-butoxycarbonylamine derivative in an inert solvent under acidic conditions.
  • the inert solvent include dichloromethane, tetrahydrofuran, ethyl acetate, 1,4-dioxane and the like.
  • Examples of the acid include trifluoroacetic acid and hydrogen chloride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IA) can be produced by subjecting an amine derivative to a condensation reaction with an acid chloride or an acid anhydride in the presence of a base in an inert solvent.
  • the inert solvent include dichloromethane
  • examples of the base include triethylamine, N, N-diisopropylethylamine, and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • compound (IA) can also be produced by condensing an amine derivative with a carboxylic acid compound in the presence of a condensing agent in an inert solvent.
  • Examples of the inert solvent include N, N-dimethylformamide, tetrahydrofuran, dichloromethane and the like.
  • Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like. If necessary, additives such as 1-hydroxybenzotriazole and N, N-dimethyl-4-aminopyridine may be used.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. Examples of the compound that can be synthesized by Step 1-2 include Example A-2-1.
  • An alkoxycarbonyl derivative can also be produced by subjecting compound (1) to a coupling reaction with an amine compound in the same manner as in Step 1-1.
  • Compound (IA) can also be produced by subjecting an alkoxycarbonyl derivative to alkaline hydrolysis in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkaline hydrolysis and can also manufacture a compound (IA) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 1-3 include Example A-3-1.
  • An acylamine derivative can also be produced by subjecting compound (1) to a coupling reaction with an amine compound in the same manner as in Step 1-1.
  • Compound (IA) can also be produced by performing an alkylation reaction of an acylamine derivative with an alkyl halide in the presence of a base in an inert solvent.
  • the inert solvent include N, N-dimethylformamide, tetrahydrofuran and the like.
  • Examples of the base include sodium hydride and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. Examples of the compound that can be synthesized by Step 1-4 include Example A-4-1.
  • Process 1-5 A hydroxy derivative can also be produced by subjecting compound (1) to a coupling reaction with an amine compound in the same manner as in Step 1-1.
  • An alkoxycarbonylalkyloxy derivative can also be produced by subjecting the hydroxy derivative to an alkylation reaction with an alkyl halide or an acrylate ester in the presence of a base in an inert solvent.
  • the inert solvent include toluene, water, 1,4-dioxane, a mixed solvent thereof and the like.
  • the base include sodium hydroxide and potassium tert-butoxide.
  • An additive such as tetrabutylammonium hydrogen sulfate may be used as necessary.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IA) can also be produced by reacting an alkoxycarbonylalkyloxy derivative in an inert solvent under acidic conditions.
  • the inert solvent include dichloromethane, tetrahydrofuran, ethyl acetate, 1,4-dioxane and the like.
  • Examples of the acid include trifluoroacetic acid and hydrogen chloride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. In addition, it can change into reaction on acidic conditions, and can also manufacture compound (IA) by the method by alkaline hydrolysis or hydrogenolysis. Examples of the compound that can be synthesized by Step 1-5 include Example A-5-1.
  • Process 1-6 A hydroxy derivative can also be produced by subjecting compound (1) to a coupling reaction with an amine compound in the same manner as in Step 1-1.
  • Compound (IA) can also be produced by reacting a hydroxy derivative with an isocyanate compound in an inert solvent.
  • the inert solvent include dichloromethane.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Examples of the compound that can be synthesized by Step 1-6 include Example A-6-1.
  • Carboxy derivatives can also be produced by reacting compound (1) in the same manner as in Step 1-3.
  • Compound (IA) can also be produced by condensing a carboxy derivative with an amine compound in an inert solvent in the presence of a condensing agent.
  • the inert solvent include N, N-dimethylformamide, tetrahydrofuran, dichloromethane and the like.
  • the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like.
  • reaction temperature is usually from 0 ° C. to reflux temperature.
  • reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. Examples of the compound that can be synthesized by Step 1-7 include Example A-7-1.
  • a hydroxy derivative can also be produced by subjecting compound (1) to a coupling reaction with an amine compound in the same manner as in Step 1-1.
  • a sulfonyloxy derivative can also be produced by reacting a hydroxy derivative with a sulfonic acid chloride in the presence of a base in an inert solvent.
  • the inert solvent include dichloromethane.
  • the base include triethylamine, N, N-diisopropylethylamine and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IA) can also be produced by cyanating a sulfonyloxy derivative with an cyanating agent in an inert solvent.
  • the inert solvent include dimethyl sulfoxide, N, N-dimethylformamide and the like.
  • the cyanating agent include potassium cyanide and sodium cyanide.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. Examples of the compound that can be synthesized by Step 1-8 include Example A-8-1.
  • An alkoxycarbonyl-tert-butoxycarbonylamine derivative can also be produced by subjecting compound (1) to a coupling reaction with an amine compound in the same manner as in Step 1-1.
  • An alkoxycarbonyl-amine derivative can also be produced by reacting an alkoxycarbonyl-tert-butoxycarbonylamine derivative in an inert solvent under acidic conditions.
  • the inert solvent include dichloromethane, tetrahydrofuran, ethyl acetate, 1,4-dioxane and the like.
  • the acid include trifluoroacetic acid and hydrogen chloride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • An alkoxycarbonyl-alkylamine derivative can also be produced by reacting an alkoxycarbonyl-amine derivative with a carbonyl compound in an inert solvent in the presence of a reducing agent.
  • the inert solvent include dichloromethane and tetrahydrofuran.
  • the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like.
  • acids such as an acetic acid, hydrochloric acid, and tetrachloro titanium, as needed.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IA) can also be produced by subjecting an alkoxycarbonyl-alkylamine derivative to alkaline hydrolysis in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkaline hydrolysis and can also manufacture a compound (IA) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 1-9 include Example A-9-1.
  • the compound represented by the formula (IB) can be produced, for example, according to the method of Process 2-1 to 2-8 or 2-9 described in Scheme 2.
  • L 1 in the formula is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom.
  • R 1a , R 1b , R 2 , R 3a , R 3b , R 4a , R 4b , R 4c , V, R 5 , and n have the same meaning as described above.
  • Ring A is a group selected from the group consisting of k), l), m), n), o), p), q), and r).
  • U 1 is a single bond and U 2 is a single bond.
  • Process 2-1 Compound (IB) can also be produced by reacting compound (1) with a carbonyl compound after lithiation with alkyllithium in an inert solvent.
  • the inert solvent include tetrahydrofuran, 1,4-dioxane, diethyl ether and the like.
  • the alkyl lithium include n-butyl lithium, sec-butyl lithium, tert-butyl lithium and the like.
  • the reaction temperature is usually from ⁇ 78 ° C. to the reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Examples of the compound that can be synthesized by the step 2-1 include Example B-1-1.
  • a tert-butoxycarbonylamine derivative can also be produced by reacting compound (1) with a carbonyl compound in the same manner as in Step 2-1.
  • An amine derivative can also be produced by reacting a tert-butoxycarbonylamine derivative in an inert solvent under acidic conditions.
  • the inert solvent include dichloromethane, tetrahydrofuran, ethyl acetate, 1,4-dioxane and the like.
  • Examples of the acid include trifluoroacetic acid and hydrogen chloride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • An alkoxycarbonylalkylamine derivative can also be produced by subjecting the amine derivative to an alkylation reaction with an alkyl halide or the like in the presence of a base in an inert solvent.
  • the inert solvent include tetrahydrofuran.
  • the base include potassium carbonate, sodium carbonate, cesium carbonate and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IB) can also be produced by subjecting an alkoxycarbonylalkylamine derivative to alkaline hydrolysis in an inert solvent.
  • Examples of the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. In addition, it can change to alkali hydrolysis and can also manufacture a compound (IB) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 2-2 include Example B-2-1.
  • a tert-butoxycarbonylamine derivative can also be produced by reacting compound (1) with a carbonyl compound in the same manner as in Step 2-2.
  • an amine derivative can also be produced by reacting a tert-butoxycarbonylamine derivative under acidic conditions.
  • Compound (IB) can also be produced by subjecting an amine derivative to an alkylation reaction with an alkyl halide in the presence of a base in an inert solvent.
  • the inert solvent include acetonitrile and ethanol.
  • Examples of the base include N, N-diisopropylethylamine.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. Examples of the compound that can be synthesized by Step 2-3 include Example B-3-1.
  • An olefin-alkoxycarbonyl derivative can also be produced by performing a coupling reaction of compound (1) with a boronic acid compound in the presence of a base and a palladium catalyst in an inert solvent.
  • the inert solvent include N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol, ethanol, water, these Examples thereof include mixed solvents.
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, pyridine, N, N-diisopropylethylamine, 2,6-lutidine, 1,8-diazabicyclo [5, 4,0] -7-undecene and the like.
  • Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium (0).
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • the reaction can also be performed using a microwave reactor (Biotage).
  • Compound (IB) can also be produced by subjecting an olefin-alkoxycarbonyl derivative to alkaline hydrolysis in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkali hydrolysis and can also manufacture a compound (IB) by the method by acid hydrolysis or hydrogenolysis.
  • the compound that can be synthesized by Step 2-4 include Example B-4-1.
  • Process 2-5 An olefin-carboxy derivative can also be produced by reacting compound (1) in the same manner as in Step 2-4.
  • Compound (IB) can also be produced by reducing an olefin from an olefin-carboxy derivative by a catalytic reduction method or the like.
  • the catalytic reduction method can be performed by using a catalyst in an inert solvent of an olefin derivative in a hydrogen atmosphere.
  • the inert solvent include methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, and mixed solvents thereof.
  • Examples of the catalyst include palladium carbon powder, rhodium carbon powder, platinum carbon powder, and platinum carbon powder doped with vanadium.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Examples of the compound that can be synthesized by Step 2-5 include Example B-5-1.
  • Process 2-6 An olefin-tert-butoxycarbonylamine derivative can also be produced by subjecting compound (1) to a boronic acid compound in the same manner as in Step 2-4.
  • a tert-butoxycarbonylamine derivative can also be produced by reducing an olefin by a catalytic reduction method or the like in the same manner as in Step 2-5, with the olefin-tert-butoxycarbonylamine derivative.
  • An amine derivative can also be produced by reacting a tert-butoxycarbonylamine derivative in an inert solvent under acidic conditions.
  • Examples of the inert solvent include dichloromethane, tetrahydrofuran, ethyl acetate, 1,4-dioxane and the like.
  • Examples of the acid include trifluoroacetic acid and hydrogen chloride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • An alkoxycarbonylalkylamine derivative can also be produced by subjecting the amine derivative to an alkylation reaction with an alkyl halide or the like in the presence of a base in an inert solvent.
  • Examples of the inert solvent include tetrahydrofuran and dichloromethane.
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IB) can also be produced by subjecting an alkoxycarbonylalkylamine derivative to alkaline hydrolysis in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkali hydrolysis and can also manufacture a compound (IB) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 2-6 include Example B-6-1.
  • Process 2-7 An olefin-alkoxycarbonyl derivative can also be produced by subjecting compound (1) to a boronic acid compound in the same manner as in Step 2-4.
  • An alkoxycarbonyl derivative can also be produced by reducing an olefin with an olefin-alkoxycarbonyl derivative in the same manner as in Step 2-5 by a catalytic reduction method or the like.
  • Compound (IB) can also be produced by subjecting an alkoxycarbonyl derivative to alkaline hydrolysis in an inert solvent. Examples of the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • the base examples include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. In addition, it can change to alkali hydrolysis and can also manufacture a compound (IB) by the method by acid hydrolysis or hydrogenolysis. Examples of the compound that can be synthesized by Step 2-7 include Example B-7-1.
  • Process 2-8 An olefin-ketal derivative can also be produced by subjecting compound (1) to a coupling reaction with a boronic acid compound in the same manner as in Step 2-4.
  • a ketal derivative can also be produced by reducing an olefin by a catalytic reduction method or the like in the same manner as in Step 2-5.
  • a ketone derivative can also be produced by reacting a ketal derivative under acidic conditions in an inert solvent.
  • the inert solvent include dichloromethane, tetrahydrofuran, ethyl acetate, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • the acid include trifluoroacetic acid and hydrogen chloride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IB) can also be produced by performing a reduction reaction of a ketone derivative in an inert solvent in the presence of a reducing agent.
  • the inert solvent include tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, a mixed solvent thereof and the like.
  • the reducing agent include lithium borohydride and sodium borohydride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Examples of the compound that can be synthesized by Step 2-8 include Example B-8-1.
  • Process 2-9 An olefin-alkoxycarbonyl derivative can also be produced by subjecting compound (1) to a boronic acid compound in the same manner as in Step 2-7. In the same manner as in Step 2-7, an olefin-alkoxycarbonyl derivative can also be produced by reducing the olefin by a catalytic reduction method or the like.
  • Compound (IB) can also be produced by subjecting an alkoxycarbonyl derivative to a reduction reaction in the presence of a reducing agent in an inert solvent. Examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, a mixed solvent thereof and the like.
  • Examples of the reducing agent include lithium borohydride and sodium borohydride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Examples of the compound that can be synthesized by Step 2-9 include Example B-9-1.
  • the compound represented by the formula (IC) can be produced, for example, according to the method of Process 3-1 to 3-9 or 3-10 described in Scheme 3.
  • L 2 in the formula is a leaving group such as a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group.
  • R 1a , R 1b , R 2 , R 3a , R 3b , R 4a , R 4b , R 4c , V, R 5 , and n have the same meaning as described above.
  • Ring A is a group selected from the group consisting of a), b), c), d), e), f), g), h), i), and j).
  • U 1 is a single bond
  • U 2 is methylene which may have an arbitrary group selected from the substituent group ⁇ 2 .
  • ⁇ 2 has the same meaning as described above.
  • Process 3-1 Compound (IC) can be produced by reacting compound (2) with an amine compound in the presence of a reducing agent in an inert solvent.
  • a reducing agent examples include dichloromethane and tetrahydrofuran.
  • the reducing agent examples include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like.
  • acids such as an acetic acid, hydrochloric acid, and tetrachloro titanium, as needed.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • compound (IC) can also be produced by reacting compound (3) with an amine compound in the presence of a base in an inert solvent.
  • the inert solvent include acetonitrile, dichloromethane, 1,2-dichloroethane and the like.
  • the base include N, N-diisopropylethylamine and triethylamine.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Examples of the compound that can be synthesized by Step 3-1 include Examples C-1-1 and C-1-4.
  • a tert-butoxycarbonylamine derivative can also be produced by subjecting compound (2) or (3) to an amination reaction in the same manner as in Step 3-1.
  • An amine derivative can also be produced by reacting a tert-butoxycarbonylamine derivative in an inert solvent under acidic conditions.
  • the inert solvent include dichloromethane, tetrahydrofuran, ethyl acetate, 1,4-dioxane and the like.
  • Examples of the acid include trifluoroacetic acid and hydrogen chloride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IC) can be produced by subjecting an amine derivative to a condensation reaction with an acid chloride or acid anhydride in the presence of a base in an inert solvent.
  • the inert solvent include dichloromethane.
  • the base include triethylamine, N, N-diisopropylethylamine and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • the compound (IC) can also be produced by condensing an amine derivative with a carboxylic acid compound in the presence of a condensing agent in an inert solvent.
  • Examples of the inert solvent include N, N-dimethylformamide, tetrahydrofuran, dichloromethane and the like.
  • Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like. If necessary, additives such as 1-hydroxybenzotriazole and N, N-dimethyl-4-aminopyridine may be used.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. Examples of the compound that can be synthesized by Step 3-2 include Examples C-2-1 and C-2-5.
  • An alkoxycarbonyl-acyl derivative can also be produced by reacting compound (2) or (3) in the same manner as in Step 3-2.
  • Compound (IC) can also be produced by alkali hydrolysis of an alkoxycarbonyl-acyl derivative in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkaline hydrolysis and can also manufacture a compound (IC) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 3-3 include Example C-3-1.
  • An alkoxycarbonyl derivative can be produced by subjecting compound (2) or (3) to an amination reaction with an amine compound in the same manner as in Step 3-1. Moreover, an alkoxycarbonyl derivative can also be produced by reacting compound (3) with an amide compound in the presence of a base in an inert solvent.
  • the inert solvent include acetonitrile, tetrahydrofuran, N, N-dimethylformamide and the like.
  • Examples of the base include sodium hydride and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IC) can also be produced by subjecting an alkoxycarbonyl derivative to alkaline hydrolysis in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkaline hydrolysis and can also manufacture a compound (IC) by the method by acid hydrolysis or hydrogenolysis.
  • the compound that can be synthesized by Step 3-4 include Examples C-4-1 and C-4-23.
  • Process 3-5 An acyl-acyloxy derivative can also be produced by reacting compound (2) or (3) in the same manner as in Step 3-2.
  • Compound (IC) can also be produced by reacting an acyl-acyloxy derivative in an inert solvent under basic conditions.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, and the like.
  • Examples of the base include sodium methoxide.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Examples of the compound that can be synthesized by Step 3-5 include Examples C-5-1 and C-5-2.
  • a tert-butoxycarbonylamine derivative can also be produced by subjecting compound (2) or (3) to an amination reaction with an amine compound in the same manner as in Step 3-2.
  • an amine derivative can also be produced by reacting a tert-butoxycarbonylamine derivative under acidic conditions.
  • An alkoxycarbonylcarbonyl derivative can also be produced by reacting an amine derivative with an alkoxycarbonylcarbonyl chloride compound in the presence of a base in an inert solvent. Examples of the inert solvent include dichloromethane. Examples of the base include triethylamine, N, N-diisopropylethylamine and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IC) can also be produced by subjecting an alkoxycarbonylcarbonyl derivative to alkaline hydrolysis in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkaline hydrolysis and can also manufacture a compound (IC) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 3-6 include Example C-6-1.
  • Carboxycarbonyl derivatives can also be produced by reacting compound (2) or (3) in the same manner as in Step 3-6.
  • Compound (IC) can also be produced by condensing a carboxycarbonyl derivative with an amine compound in an inert solvent in the presence of a condensing agent.
  • the inert solvent include N, N-dimethylformamide, tetrahydrofuran, dichloromethane and the like.
  • the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like.
  • reaction temperature is usually from 0 ° C. to reflux temperature.
  • reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. Examples of the compound that can be synthesized by Step 3-7 include Example C-7-1.
  • a hydroxy derivative can also be produced by subjecting compound (2) or (3) to an amination reaction with an amine compound in the same manner as in Step 3-1.
  • a ketone derivative can also be produced by reacting a hydroxy derivative in an inert solvent in the presence of an oxidizing agent.
  • the inert solvent include dichloromethane, acetonitrile, dimethyl sulfoxide and the like.
  • the oxidizing agent include Dess-Martin periodinane, sulfur trioxide pyridine complex-dimethyl sulfoxide, 4-methylmorpholine-N-oxide, and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • An alkoxycarbonylalkylamine derivative can also be produced by reacting a ketone derivative with an amine compound in an inert solvent in the presence of a reducing agent.
  • the inert solvent include dichloromethane and tetrahydrofuran.
  • the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like.
  • acids such as an acetic acid, hydrochloric acid, and tetrachloro titanium, as needed.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IC) can also be produced by subjecting an alkoxycarbonylalkylamine derivative to alkaline hydrolysis in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkaline hydrolysis and can also manufacture a compound (IC) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 3-8 include Example C-8-1.
  • a tert-butoxycarbonylamine derivative can also be produced by subjecting compound (2) or (3) to an amination reaction with an amine compound in the same manner as in Step 3-2.
  • an amine derivative can also be produced by reacting a tert-butoxycarbonylamine derivative under acidic conditions.
  • An alkoxycarbonylalkylamine derivative can also be produced by reacting an amine derivative with a carbonyl compound in an inert solvent in the presence of a reducing agent. Examples of the inert solvent include dichloromethane and tetrahydrofuran.
  • Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like.
  • acids such as an acetic acid, hydrochloric acid, and tetrachloro titanium, as needed.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IC) can also be produced by subjecting an alkoxycarbonylalkylamine derivative to alkaline hydrolysis in an inert solvent.
  • Examples of the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. In addition, it can change to alkaline hydrolysis and can also manufacture a compound (IC) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 3-9 include Example C-9-1.
  • Carboxy derivatives can also be produced by reacting compound (2) or (3) in the same manner as in step 3-4.
  • Compound (IC) can also be produced by condensing a carboxy derivative with an amine compound in an inert solvent in the presence of a condensing agent.
  • the inert solvent include N, N-dimethylformamide, tetrahydrofuran, dichloromethane and the like.
  • the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like.
  • reaction temperature is usually from 0 ° C. to reflux temperature.
  • reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. Examples of the compound that can be synthesized by Step 3-10 include Example C-10-1.
  • the compound represented by the formula (ID) can be produced, for example, according to the process 4-1 to 4-4 or 4-5 described in Scheme 4.
  • L 2 in the formula is a leaving group such as a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group.
  • R 1a , R 1b , R 2 , R 3a , R 3b , R 4a , R 4b , R 4c , V, R 5 , and n have the same meaning as described above.
  • Ring A is a group selected from the group consisting of k), l), m), n), o), p), q), and r).
  • U 1 is a single bond
  • U 2 is methylene which may have an arbitrary group selected from the substituent group ⁇ 1 .
  • ⁇ 1 has the same meaning as described above.
  • a phosphate ester derivative can also be produced by reacting compound (3) with a phosphite.
  • the phosphite include triethyl phosphite.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • An olefin-t-butoxycarbonylamine derivative can also be produced by subjecting a phosphate ester derivative to an olefination reaction with a carbonyl compound in an inert solvent in the presence of a base.
  • the inert solvent include tetrahydrofuran.
  • the base include sodium hydride and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • a tert-butoxycarbonylamine derivative can also be produced by reducing an olefin with an olefin-t-butoxycarbonylamine derivative by a catalytic reduction method or the like.
  • the catalytic reduction method can be performed by using a catalyst in an inert solvent of an olefin derivative in a hydrogen atmosphere.
  • the inert solvent include methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, and mixed solvents thereof.
  • the catalyst examples include palladium carbon powder, rhodium carbon powder, platinum carbon powder, and platinum carbon powder doped with vanadium.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • An amine derivative can also be produced by reacting a tert-butoxycarbonylamine derivative in an inert solvent under acidic conditions.
  • the inert solvent include dichloromethane, tetrahydrofuran, ethyl acetate, 1,4-dioxane, and examples of the acid include trifluoroacetic acid and hydrogen chloride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • a compound (ID) can be produced by subjecting an amine derivative to a condensation reaction with an acid chloride or an acid anhydride in the presence of a base in an inert solvent.
  • the inert solvent include dichloromethane.
  • the base include triethylamine, N, N-diisopropylethylamine and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • a compound (ID) can also be produced by condensing an amine derivative with a carboxylic acid compound in the presence of a condensing agent in an inert solvent.
  • a condensing agent examples include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like.
  • additives such as 1-hydroxybenzotriazole and N, N-dimethyl-4-aminopyridine may be used.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. Examples of the compound that can be synthesized by Step 4-1 include Example D-1-1.
  • a tert-butoxycarbonylamine-alkoxycarbonyl derivative can also be produced by reacting compound (3) with an ester compound in the presence of a base in an inert solvent.
  • the inert solvent include tetrahydrofuran, 1,4-dioxane, diethyl ether and the like.
  • the base include lithium diisopropylamide.
  • the reaction temperature is usually from ⁇ 78 ° C. to the reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • An amine-alkoxycarbonyl derivative can also be produced by reacting a tert-butoxycarbonylamine-alkoxycarbonyl derivative in an inert solvent under acidic conditions.
  • the inert solvent include dichloromethane, tetrahydrofuran, ethyl acetate, 1,4-dioxane and the like.
  • the acid include trifluoroacetic acid and hydrogen chloride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • An acylamine-alkoxycarbonyl derivative can be produced by a condensation reaction of an amine-alkoxycarbonyl derivative with an acid chloride or acid anhydride in the presence of a base in an inert solvent.
  • the inert solvent include dichloromethane.
  • the base include triethylamine, N, N-diisopropylethylamine and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • An acylamine-alkoxycarbonyl derivative can also be produced by condensing an amine-alkoxycarbonyl derivative with a carboxylic acid compound in an inert solvent in the presence of a condensing agent.
  • a condensing agent examples include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like. If necessary, additives such as 1-hydroxybenzotriazole and N, N-dimethyl-4-aminopyridine may be used.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (ID) can also be produced by subjecting an acylamine-alkoxycarbonyl derivative to alkaline hydrolysis in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkali hydrolysis and can also manufacture a compound (ID) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 4-2 include Example D-2-1.
  • Process 4-3 An alkoxycarbonyl derivative can also be produced by reacting compound (3) with an ester compound in the same manner as in Step 4-2.
  • a compound (ID) can also be produced by subjecting an alkoxycarbonyl derivative to alkaline hydrolysis in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkali hydrolysis and can also manufacture a compound (ID) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 4-3 include Example D-3-1.
  • An alkoxycarbonyl derivative can also be produced by reacting compound (3) with an ester compound in the same manner as in Step 4-2.
  • a compound (ID) can also be produced by subjecting an alkoxycarbonyl derivative to a reduction reaction in the presence of a reducing agent in an inert solvent.
  • the inert solvent include tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, a mixed solvent thereof and the like.
  • the reducing agent include lithium borohydride and sodium borohydride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Examples of the compound that can be synthesized by Step 4-4 include Example D-4-1.
  • a phosphate ester derivative can also be produced by reacting compound (3) with a phosphite in the same manner as in Step 4-1.
  • An olefin-alkoxycarbonyl derivative can also be produced by subjecting the phosphate ester derivative to an olefination reaction with a carbonyl compound in the same manner as in Step 4-1.
  • An alkoxycarbonyl derivative can also be produced by reducing an olefin-alkoxycarbonyl derivative by catalytic reduction or the like in the same manner as in Step 4-1.
  • a compound (ID) can also be produced by subjecting an alkoxycarbonyl derivative to alkaline hydrolysis in an inert solvent.
  • Examples of the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. In addition, it can change to alkali hydrolysis and can also manufacture a compound (ID) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 4-5 include Example D-5-1.
  • the compound represented by the formula (IE) can be produced, for example, according to the process 5-1 or 5-2 described in Scheme-5.
  • L 1 in the formula is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom.
  • R 1a , R 1b , R 2 , R 3a , R 3b , R 4a , R 4b , R 4c , V, R 5 , and n have the same meaning as described above.
  • Ring A is a group selected from the group consisting of a), b), c), d), e), f), g), h), i), and j).
  • U 1 is C 1-2 alkylene which may have an arbitrary group selected from the substituent group ⁇ 1
  • U 2 has an arbitrary group selected from the substituent group ⁇ 2 It may be methylene.
  • ⁇ 1 and ⁇ 2 have the same meaning as described above.
  • An alkyne derivative can also be produced by subjecting compound (1) to a coupling reaction with an alkyne compound in the presence of a base, palladium and a copper catalyst in an inert solvent.
  • a base include acetonitrile.
  • the base include triethylamine.
  • the palladium catalyst include dichlorobis (triphenylphosphine) palladium (II).
  • the copper catalyst include copper (I) iodide.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (IE) can also be produced by reducing an alkyne with an alkyne derivative by a catalytic reduction method or the like.
  • the catalytic reduction method can be carried out by using the alkyne derivative in a hydrogen atmosphere in an inert solvent and using a catalyst.
  • the inert solvent include methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, and mixed solvents thereof.
  • the catalyst include palladium carbon powder, rhodium carbon powder, platinum carbon powder, and platinum carbon powder doped with vanadium.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Examples of the compound that can be synthesized by Step 5-1 include Example E-1-1.
  • An alkoxycarbonyl derivative can also be produced by reacting compound (1) in the same manner as in Step 5-1.
  • Compound (IE) can also be produced by subjecting an alkoxycarbonyl derivative to alkaline hydrolysis in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkaline hydrolysis and can also manufacture a compound (IE) by the method by acid hydrolysis or hydrogenolysis.
  • Examples of the compound that can be synthesized by Step 5-2 include Example E-2-1.
  • Compound (1) can be produced, for example, according to the method of Process 6 to 14 described in Scheme 6.
  • L 1 , L 3 and L 4 in the formula are leaving groups such as chlorine atom, bromine atom and iodine atom.
  • PG 1 and PG 2 are protecting groups.
  • R 1a , R 1b , R 2 , R 3a , R 3b , R 4a , R 4b , and R 4c have the same meaning as described above.
  • Process 6 Compound (6) can also be produced by cyclizing compound (4) and compound (5) in an inert solvent.
  • the inert solvent include acetic acid, pyridine, and a mixed solvent thereof.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Process 7 Compound (7) can also be produced by brominating compound (6) in the presence of a brominating reagent such as N-bromosuccinimide in an inert solvent.
  • a brominating reagent such as N-bromosuccinimide
  • the inert solvent include dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, acetic acid, acetonitrile, methanol, dimethylformamide, and mixed solvents thereof.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Process 8 Compound (9) can also be produced by subjecting compound (7) and compound (8) to a coupling reaction in an inert solvent in the presence of a base and a palladium catalyst.
  • the inert solvent include N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol, ethanol, water, these Examples thereof include mixed solvents.
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, pyridine, N, N-diisopropylethylamine, 2,6-lutidine, 1,8-diazabicyclo [5, 4,0] -7-undecene and the like.
  • Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium (0).
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Process 9 Compound (10) can also be produced by halogenating compound (9) in the presence of copper halide and nitrite in an inert solvent.
  • the inert solvent include acetonitrile.
  • the copper halide include copper (II) bromide, copper (II) chloride, and copper (I) iodide.
  • the nitrite ester include isoamyl nitrite and tert-butyl nitrite.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (11) can also be produced by subjecting compound (10) to alkaline hydrolysis in an inert solvent.
  • the inert solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • it can change to alkaline hydrolysis and can also manufacture a compound (11) by the method by acid hydrolysis or hydrogenolysis.
  • Compound (12) can also be produced by reacting compound (11) with an alcohol in the presence of diphenylphosphoryl azide (DPPA) and a base in an inert solvent or without a solvent.
  • DPPA diphenylphosphoryl azide
  • the inert solvent include toluene.
  • the base include triethylamine, N, N-diisopropylethylamine and the like.
  • the alcohol include tert-butyl alcohol and benzyl alcohol.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (13) can also be produced by reacting compound (12) in an inert solvent under acidic conditions.
  • the inert solvent include dichloromethane, tetrahydrofuran, ethyl acetate, 1,4-dioxane and the like.
  • the acid include trifluoroacetic acid and hydrogen chloride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days. In addition, it can change to reaction on acidic conditions, and can also manufacture a compound (13) by the method by alkaline hydrolysis or hydrogenolysis.
  • Process 13 Compound (15) can also be produced by subjecting compound (13) and compound (14) to a condensation reaction in the presence of a base in an inert solvent.
  • a base examples include pyridine.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (1) can also be produced by reacting compound (15) and compound (16) in an inert solvent in the presence of a base.
  • the inert solvent include N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran and the like.
  • the base include sodium hydride and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (2) can be produced, for example, according to Process 15 and 16, or Process 17 described in Scheme 7.
  • Compound (3) can be produced, for example, according to the method of Process 15, 16, 18 and 19 or Process 17, 18 and 19 described in Scheme 7.
  • L 1 is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom
  • L 2 is a leaving group such as a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group.
  • R 1a , R 1b , R 2 , R 3a , R 3b , R 4a , R 4b , and R 4c have the same meaning as described above.
  • U 1 is a single bond
  • U 2 is methylene which may have an arbitrary group selected from the substituent group ⁇ 1 .
  • ⁇ 1 has the same meaning as described above.
  • Process 15 Compound (17) can also be produced by subjecting compound (1) to a coupling reaction with a tin compound in the presence of a palladium catalyst in an inert solvent.
  • inert solvents include N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol, ethanol, and mixed solvents thereof.
  • Etc examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium (0).
  • the tin compound include tributyl vinyl tin.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (2) can also be produced by reacting compound (17) in the presence of an oxidizing agent and a reoxidizing agent in an inert solvent.
  • the inert solvent include 1,4-dioxane, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, water, tert-butyl alcohol, and a mixed solvent thereof.
  • the oxidizing agent and the reoxidizing agent include osmium oxide (VIII) and sodium periodate. If necessary, a base such as 2,6-lutidine may be used.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (2) can also be produced by reacting compound (1) with N, N-dimethylformamide after lithiation with alkyllithium in an inert solvent.
  • the inert solvent include tetrahydrofuran, 1,4-dioxane, diethyl ether and the like.
  • the alkyl lithium include n-butyl lithium, sec-butyl lithium, tert-butyl lithium and the like.
  • the reaction temperature is usually from ⁇ 78 ° C. to the reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Process 18 Compound (18) can also be produced by subjecting compound (2) to a reduction reaction in the presence of a reducing agent in an inert solvent.
  • a reducing agent examples include lithium borohydride and sodium borohydride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • Compound (3) can be produced by reacting compound (18) in the presence of a halogenating agent in an inert solvent.
  • a halogenating agent examples include thionyl chloride.
  • the reaction temperature is usually from 0 ° C. to reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • compound (3) can also be produced by reacting compound (18) with sulfonyl chloride in an inert solvent in the presence of a base. Examples of the inert solvent include dichloromethane.
  • the base examples include triethylamine, N, N-diisopropylethylamine and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 7 days.
  • the scheme shown above is an example of a method for producing the compound represented by the formula (I) of the present invention or a production intermediate thereof.
  • the above scheme can be modified in various ways as can be easily understood by those skilled in the art.
  • the compound represented by the formula (I) of the present invention and its production intermediate are, as necessary, solvent extraction, crystallization, recrystallization, isolation and purification means well known to those skilled in the art. It can also be isolated and purified by chromatography, preparative high performance liquid chromatography or the like.
  • the compound of the present invention has an excellent NK 1 receptor antagonistic action, it can also be used as a preventive or therapeutic agent for various diseases mediated by the NK 1 receptor.
  • the compound of the present invention is useful as an antiemetic agent, and particularly useful as a prophylactic agent for gastrointestinal symptoms (eg, nausea and vomiting) associated with administration of an antineoplastic agent (eg, cisplatin).
  • antineoplastic agent eg, cisplatin
  • Preferred compounds of the present invention are useful not only for acute nausea and vomiting associated with administration of antineoplastic agents, but also for late-stage nausea and vomiting associated with administration of antineoplastic agents.
  • the compounds of the present invention have excellent NK 1 receptor antagonism, such as postoperative nausea and vomiting (PONV), nausea and vomiting associated with radiation therapy, morphine-induced vomiting, Or prevention drugs for motion sickness, or schizophrenia, social anxiety disorder, anxiety and depression, alcoholism, irritable bowel syndrome, ulcerative colitis, cough, asthma, atopic dermatitis, psoriasis, pruritus, pain It can also be used as a treatment for migraine, tinnitus, benign prostatic hyperplasia, overactive bladder, or urinary incontinence.
  • PONV postoperative nausea and vomiting
  • nausea and vomiting associated with radiation therapy nausea and vomiting associated with radiation therapy
  • morphine-induced vomiting Or prevention drugs for motion sickness
  • schizophrenia social anxiety disorder, anxiety and depression, alcoholism, irritable bowel syndrome, ulcerative colitis, cough, asthma, atopic dermatitis, psoriasis, pruritus, pain It can also be used as a treatment for migraine, tinnitus, benign
  • the pharmaceutical composition of the present invention may be used in various dosage forms depending on the usage.
  • dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, and oral or parenteral. Administered.
  • the pharmaceutical composition of the present invention is prepared using a compound represented by the formula (I) or a pharmacologically acceptable salt thereof and at least one pharmaceutical additive.
  • These pharmaceutical compositions are prepared according to pharmacologically known techniques depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, It can also be prepared by appropriately mixing, diluting or dissolving with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents.
  • the dose of the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof as the active ingredient is determined by the age of the patient, It is determined appropriately according to gender, weight, disease, degree of treatment, and the like.
  • the dose for adults should be determined in the range of, for example, 0.1 to 1000 mg / day, 0.1 to 500 mg / day, 0.1 to 100 mg / day, or 0.1 to 50 mg / day.
  • the daily dose may be divided into 1, 2, 3 or 4 divided doses.
  • parenteral administration for example, it can be set in the range of 0.1 to 1000 mg / day, 0.1 to 500 mg / day, 0.1 to 100 mg / day, or 0.1 to 50 mg / day,
  • the daily dose may be divided into 1, 2, 3, or 4 divided doses.
  • the pharmaceutical composition of the present invention when used as a pharmaceutical composition for the prevention of nausea and vomiting associated with administration of an antineoplastic agent, it can be administered after the administration of the antineoplastic agent.
  • romiplostim can be administered immediately before administration of an antineoplastic agent to 1 hour 30 minutes before administration and administered in the morning after the second day.
  • the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof can be used in combination with other drugs other than the NK 1 receptor antagonist.
  • other drugs that can be used in combination include corticosteroids and 5-HT 3 receptor antagonist antiemetic drugs.
  • the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof, and another drug are used in combination, a preparation containing these active ingredients together, or these effective
  • a preparation containing these active ingredients together, or these effective Each of the components can be administered as a separately formulated formulation.
  • the formulations can be administered separately or simultaneously.
  • the dose of the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof may be appropriately reduced depending on the dose of other drugs used in combination. .
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (0.600 g).
  • Trifluoroacetic acid (4.36 mL) was added to a solution of the obtained compound (1.59 g) in dichloromethane (30 mL) under ice cooling, and the mixture was stirred at room temperature for 12 hours.
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.390 g).
  • Reference Example 1-6 3-Methoxymethylpiperidine-3-carboxylic acid ethyl monohydrochloride
  • piperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl was obtained.
  • Lithium diisopropylamide (1.1 mol / L tetrahydrofuran-n-hexane solution, 8.47 mL) was added dropwise at ⁇ 78 ° C. to a solution of the obtained compound (2.00 g) in tetrahydrofuran (20 mL) at ⁇ 78 ° C. Stir for 30 minutes.
  • Reference Example 1-7 (4-Hydroxypiperidin-4-yl) ethyl acetate Lithium diisopropylamide (1.09 mol / L tetrahydrofuran-n-hexane) at ⁇ 78 ° C. in a solution of ethyl acetate (0.815 g) in tetrahydrofuran (20 mL) under an argon gas atmosphere. Solution, 5.6 mL) was added dropwise, and the mixture was stirred at ⁇ 78 ° C. for 30 minutes.
  • ethanol 6 mL
  • 10% palladium-carbon 100 mg, wet
  • the reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (0.221 g).
  • ethyl acetate 10 mL
  • 4 mol / L hydrogen chloride-ethyl acetate solution 5 mL
  • the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (0.155 g).
  • Reference Example 1-12 Azepan-4-yl ethyl acetate A suspension of azepan-4-one monohydrochloride (1.00 g) in dichloromethane (30 mL) at room temperature with triethylamine (1.02 g) and di-tert-butyl dicarbonate (2.20 g). ) And stirred at room temperature for 65 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • n-hexane / ethyl acetate 90/10 to 50/50
  • tert-butyl 4-oxoazepan-1-carboxylate (1.33 g).
  • the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • 6-tert-butyl 1-ethyl (0.252 g) was obtained.
  • To a solution of the obtained compound (0.252 g) in ethyl acetate (4 mL) was added 4 mol / L hydrogen chloride-ethyl acetate solution (4 mL) at room temperature, and the mixture was stirred at room temperature for 15 hours.
  • the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Reference Example 1-20 (3-Methoxypiperidin-4-yl) ethyl acetate
  • the compound of Reference Example 1-20 was synthesized using the corresponding starting materials.
  • Reference Example 1-21 1- (4-prop-2-ynylpiperazin-1-yl) ethanone
  • the compound of Reference Example 1-21 was synthesized using the corresponding starting materials.
  • the reaction mixture was concentrated under reduced pressure, and a hexane-ethyl acetate mixed solvent was added.
  • Benzyl-(tert-butoxycarbonylaminomethoxycarbonylmethylene) piperidine-1-carboxylate (0.450 g) was obtained.
  • Butyl (1.10 g) was obtained. Under an argon gas atmosphere, ethyl diazoacetate (0.721 g) was added at 40 ° C. to a solution of the obtained compound (1.10 g) and rhodium (II) acetate dimer dihydrate (0.0532 g) in dichloromethane (15 mL). ) In dichloromethane (15 mL) was added dropwise and stirred at 40 ° C.
  • Reference Example 1-24 Methyl 4-methoxypiperidine-4-carboxylate The compound of Reference Example 1-24 was synthesized in the same manner as in Reference Example 1-18, using the corresponding starting materials.
  • Reference Example 1-25 (3,3-Dimethylpiperidin-4-yl) ethyl acetate
  • the compound of Reference Example 1-25 was synthesized in the same manner as in Reference Example 1-19, using the corresponding starting materials.
  • Reference Example 1-28 (4-Oxocyclohexyl) ethyl acetate
  • the compound of Reference Example 1-28 was synthesized from the corresponding starting material by a method similar to the method of obtaining methyl (4-oxocyclohexyl) acetate in Reference Example 1-26.
  • Triethylamine (1.63 g) and methanesulfonyl chloride (1.48 g) were added to a dichloromethane (55 mL) solution of the obtained compound (2.00 g) at room temperature, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2- (1,4-dioxaspiro [4.5] dec-8-yl) ethyl methanesulfonate (2.82 g).
  • Reference example 3 Ethyl 5-amino-2-bromo-4-cyanothiophene-3-carboxylate To a solution of Reference Example 2 (9.12 g) in acetonitrile (186 mL) was added N-bromosuccinimide (9.92 g) at room temperature. And stirred for 1 hour. A saturated aqueous sodium hydrogen sulfite solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (12.8 g).
  • Reference example 4 Ethyl 5-amino-4-cyano-2- (4-fluoro-2-methylphenyl) thiophene-3-carboxylate 1,2-dimethoxyethane (174 mL) of Reference Example 3 (12.8 g) under an argon gas atmosphere -A mixture of water (58 mL) at room temperature with 4-fluoro-2-methylphenylboronic acid (12.9 g), sodium carbonate (14.8 g) and tetrakis (triphenylphosphine) palladium (0) (4.30 g) And stirred at 80 ° C. for 16 hours.
  • Reference Example 6 5-Bromo-4-cyano-2- (4-fluoro-2-methylphenyl) thiophene-3-carboxylic acid To a mixture of Reference Example 5 (3.99 g) in methanol (10 mL) -tetrahydrofuran (30 mL) at room temperature A 2 mol / L aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid (21 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.65 g).
  • Reference Example 8 4-amino-2-bromo-5- (4-fluoro-2-methylphenyl) thiophene-3-carbonitrile 4 mol / L hydrogen chloride in a solution of Reference Example 7 (3.61 g) in ethyl acetate (80 mL) at room temperature -An ethyl acetate solution (40 mL) was added, and the mixture was stirred at room temperature for 21 hours. A 20% aqueous potassium carbonate solution (115 g) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (2.73 g).
  • Reference Example 10 2- (3,5-bistrifluoromethylphenyl) -N- [5-bromo-4-cyano-2- (4-fluoro-2-methylphenyl) thiophen-3-yl] -N-methylisobutyramide Argon gas Under an atmosphere, sodium hydride (content 60%, 0.453 g) was added to a solution of Reference Example 9 (5.16 g) in N, N-dimethylformamide (58 mL) under ice-cooling, and 15% under ice-cooling. Stir for minutes. Methyl iodide (2.22 g) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours.
  • Reference Example 11 2- (3,5-bistrifluoromethylphenyl) -N- [4-cyano-2- (4-fluoro-2-methylphenyl) -5-vinylthiophen-3-yl] -N-methylisobutyramide Argon gas Under an atmosphere, tributylvinyltin (1.57 g) and tetrakis (triphenylphosphine) palladium (0) (0.380 g) were added to a toluene (16 mL) solution of Reference Example 10 (2.00 g) at room temperature, and 120 ° C. For 5 hours.
  • the reaction mixture was cooled to room temperature, 0.5 mol / L aqueous potassium fluoride solution and ethyl acetate were added, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Reference Example 12 3- (3,5-Bistrifluoromethylphenyl) -N- [4-cyano-2- (4-fluoro-2-methylphenyl) -5-formylthiophen-3-yl] -N-methylisobutyramide
  • Reference Example 11 (1.60 g) in 1,4-dioxane (39 mL) -water (13 mL) mixed solution at room temperature with sodium periodate (2.47 g), osmium (VIII) -tert-butyl alcohol solution (content ratio) 2.5%, 0.588 g) and 2,6-lutidine (0.618 g) were added and stirred at room temperature for 12 hours.
  • Example 13 2- (3,5-Bistrifluoromethylphenyl) -N- [4-cyano-2- (4-fluoro-2-methylphenyl) -5-hydroxymethylthiophen-3-yl] -N-methylisobutyramide Reference To a mixed solution of Example 12 (0.614 g) in methanol (11.3 mL) -tetrahydrofuran (5.6 mL) was added sodium borohydride (0.0418 g) at room temperature, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 15 2- (3,5-Bistrifluoromethylphenyl) -N- [5-chloromethyl-4-cyano-2- (4-fluoro-2-methylphenyl) thiophen-3-yl] -N-methylisobutyramide Reference To a solution of Example 13 (0.140 g) in tetrahydrofuran (2.5 mL) was added thionyl chloride (0.0357 g) under ice cooling, and the mixture was stirred at 50 ° C. for 2 hours.
  • Reference Example 16 Ethyl 5-amino-4-cyano-2-ortho-tolylthiophene-3-carboxylate The compound of Reference Example 16 was synthesized in the same manner as in Reference Example 4 using the corresponding starting materials.
  • Reference Example 17 Ethyl 5-bromo-4-cyano-2-ortho-tolylthiophene-3-carboxylate The compound of Reference Example 17 was synthesized in the same manner as in Reference Example 5 using the corresponding starting materials.
  • Reference Example 18 5-Bromo-4-cyano-2-ortho-tolylthiophene-3-carboxylic acid
  • the compound of Reference Example 18 was synthesized in the same manner as in Reference Example 6 using the corresponding starting materials.
  • Reference Example 19 Tert-butyl (5-bromo-4-cyano-2-ortho-tolylthiophen-3-yl) carbamate
  • the compound of Reference Example 19 was synthesized in the same manner as in Reference Example 7 using the corresponding starting materials.
  • Reference Example 20 4-Amino-2-bromo-5-ortho-tolylthiophene-3-carbonitrile In the same manner as in Reference Example 8, the compound of Reference Example 20 was synthesized using the corresponding starting materials.
  • Reference Example 21 2- (3,5-bistrifluoromethylphenyl) -N- (5-bromo-4-cyano-2-ortho-tolylthiophen-3-yl) isobutyramide The corresponding starting material was prepared in the same manner as in Reference Example 9. The compound of Reference Example 21 was synthesized.
  • Reference Example 22 2- (3,5-bistrifluoromethylphenyl) -N- (5-bromo-4-cyano-2-ortho-tolylthiophen-3-yl) -N-methylisobutyramide In the same manner as in Reference Example 10, The compound of Reference Example 22 was synthesized using corresponding raw materials.
  • Reference Example 23 2- (3,5-bistrifluoromethylphenyl) -N- (4-cyano-2-ortho-tolyl-5-vinylthiophen-3-yl) -N-methylisobutyramide In the same manner as in Reference Example 11, The compound of Reference Example 23 was synthesized using corresponding raw materials.
  • Reference Example 24 2- (3,5-bistrifluoromethylphenyl) -N- (4-cyano-5-formyl-2-ortho-tolylthiophen-3-yl) -N-methylisobutyramide In the same manner as in Reference Example 12, The compound of Reference Example 24 was synthesized using corresponding raw materials.
  • Reference Example 10 (0.0930 g), 1-acetylpiperazine (0.0785 g) and cesium carbonate (0.0997 g) in toluene (2 mL) at room temperature under an argon gas atmosphere.
  • Tris (dibenzylideneacetone) dipalladium (0) (0.0140 g) and ( ⁇ ) -BINAP (0.0028 g) were added, and the mixture was stirred at 100 ° C. for 42 hours.
  • the reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred for a while and filtered through celite. Saturated brine was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Reference Example 10 (0.100 g), (R) -N-pyrrolidin-3-ylacetamide (0.103 g) and cesium carbonate (at room temperature under an argon gas atmosphere) Tris (dibenzylideneacetone) dipalladium (0) (0.0301 g) and ( ⁇ ) -BINAP (0.0061 g) were added to a suspension of 0.107 g) in toluene (2 mL), and the mixture was stirred at 100 ° C.
  • Example A-1-1 and Example A-1-2 The same method as in Example A-1-1 and Example A-1-2, using the corresponding amine or amide compound instead of 1-acetylpiperazine or (R) -N-pyrrolidin-3-ylacetamide Thus, Example A-1-3 to Example A-1-24 were synthesized.
  • Example A-2-1 Cyclopropanecarboxylic acid ⁇ (R) -1- [4- ⁇ [2- (3,5-bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2 -Methylphenyl) thiophen-2-yl] pyrrolidin-3-yl ⁇ amide
  • Reference Example 10 (0.100 g) under argon gas atmosphere, tert-butyl (R) -pyrrolidin-3-ylcarbamate (0.123 g) And tris (dibenzylideneacetone) dipalladium (0) (0.0151 g) and ( ⁇ ) -BINAP (0.0031 g) to a suspension of toluene (1 mL) in cesium carbonate (0.107 g) at room temperature, The mixture was stirred at 100 ° C.
  • Example A-2-3 2- (3,5-bistrifluoromethylphenyl) -N- ⁇ 4-cyano-2- (4-fluoro-2-methylphenyl) -5-[(R) -3- (3-methoxypropionylamino) pyrrolidine -1-yl] thiophen-3-yl ⁇ -N-methylisobutyramide
  • N- [5-((R) -3-aminopyrrolidin-1-yl)- 4-Cyano-2- (4-fluoro-2-methylphenyl) thiophen-3-yl] -2- (3,5-bistrifluoromethylphenyl) -N-methylisobutyramide hydrochloride was obtained.
  • Example A-2-2 was synthesized in the same manner as Example A-2-1 using the corresponding acid chloride instead of cyclopropanecarbonyl chloride.
  • Example A-2-5 Using the corresponding amine compound instead of tert-butyl (R) -pyrrolidin-3-ylcarbamate, the corresponding acid anhydride instead of cyclopropanecarbonyl chloride, and the same method as in Example A-2-1, Example A-2-4 to Example A-2-5 were synthesized.
  • Example A-3-1 1- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophen-2-yl Piperidine-4-carboxylic acid To a suspension of Reference Example 10 (0.100 g), ethyl piperidine-4-carboxylate (0.104 g) and cesium carbonate (0.107 g) in toluene (2 mL) under an argon gas atmosphere.
  • Tris (dibenzylideneacetone) dipalladium (0) (0.0301 g) and ( ⁇ ) -BINAP (0.0061 g) were added at room temperature, and the mixture was stirred at 100 ° C. for 42 hours.
  • the reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred for a while and filtered through celite. Saturated brine was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example A-3-4 ⁇ 1- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- [Il] piperidin-4-yl ⁇ acetic acid
  • toluene (1 mL) was suspended in Reference Example 10 (0.150 g), piperidin-4-ylethyl acetate (0.169 g), and cesium carbonate (0.161 g).
  • Tris (dibenzylideneacetone) dipalladium (0) (0.0227 g) and ( ⁇ ) -BINAP (0.0047 g) were added to the solution at room temperature, and the mixture was stirred at 100 ° C. for 49 hours.
  • the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example A-3-24 ⁇ 1- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- Yl] -3-methylpiperidin-4-yl ⁇ acetic acid under argon gas atmosphere, Reference Example 10 (0.100 g), Reference Example 1-19 (0.122 g) and cesium carbonate (0.107 g) in toluene (1 mL) Tris (dibenzylideneacetone) dipalladium (0) (0.0151 g) and ( ⁇ ) -BINAP (0.0031 g) were added to the suspension at room temperature, and the mixture was stirred at 100 ° C.
  • Example A-3-25 ⁇ 1- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- Yl] -3-methoxypiperidin-4-yl ⁇ acetic acid under argon gas atmosphere, Reference Example 10 (0.100 g), Reference Example 1-20 (0.133 g) and cesium carbonate (0.107 g) in toluene (1 mL) Tris (dibenzylideneacetone) dipalladium (0) (0.0151 g) and ( ⁇ ) -BINAP (0.0031 g) were added to the suspension at room temperature, and the mixture was stirred at 100 ° C.
  • Example A-3-28 ⁇ 1- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- Yl] -3,3-dimethylpiperidin-4-yl ⁇ acetic acid Under an argon gas atmosphere, toluene of Reference Example 10 (0.100 g), Reference Example 1-25 (0.131 g) and cesium carbonate (0.107 g) To the suspension was added tris (dibenzylideneacetone) dipalladium (0) (0.0151 g) and ( ⁇ ) -BINAP (0.0031 g) at room temperature, and the mixture was stirred at 100 ° C.
  • Example A-3- 1 In place of ethyl piperidine-4-carboxylate, ethyl piperidin-4-yl acetate, Reference Example 1-19, Reference Example 1-20, or Reference Example 1-25, Example A-3- 1.
  • Example A-3-4 Example A-3-24, Example A-3-25, and Example A-3-28, Example A-3-2 to Example A-3-3, Example A-3-5 to Example A-3-23, and Example A-3-26 to Example A-3-27 were synthesized.
  • Example A-4-1 N- [5- [4- (Acetylmethylamino) piperidin-1-yl] -4-cyano-2- (4-fluoro-2-methylphenyl) thiophen-3-yl] -2- (3,5- Bistrifluoromethylphenyl) -N-methylisobutyramide
  • Example A-1-5 (0.0200 g) and sodium hydride (content 55%, 0.0030 g) in N, N-dimethylformamide (1 mL) in ice Methyl iodide (0.0127 g) was added under cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example A-5-1 ⁇ 1- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- [Il] piperidin-4-yloxy ⁇ acetic acid
  • Example A-1-7 (0.0400 g), tert-butyl bromoacetate (0.0186 g) and tetrabutylammonium hydrogensulfate (0.0010 g) in toluene (0.800 mL) )
  • a 5 mol / L aqueous sodium hydroxide solution (0.400 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 136 hours.
  • Example A-5-2 3- ⁇ 1- [4- ⁇ [2- (3,5-bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene- 2-yl] piperidin-4-yloxy ⁇ propionic acid
  • tert-butyl acrylate 0.0511 g
  • potassium tert-butoxide 0.0010 g
  • Example A-6-1 [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-ethylcarbamate 2-Iyl] piperidin-4-yl
  • Ethyl isocyanate (0.0045 g) was added to a solution of Example A-1-7 (0.0200 g) in dichloromethane (1 mL), and the mixture was stirred at 35 ° C. overnight. The reaction mixture was concentrated under reduced pressure.
  • the obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol) to obtain the title compound (0.0030 g).
  • Example A-7-1 2- (3,5-bistrifluoromethylphenyl) -N- [5- (4-carbamoylmethylpiperidin-1-yl) -4-cyano-2- (4-fluoro-2-methylphenyl) thiophene-3- Yl] -N-methylisobutyramide N, N′-carbonyldiimidazole (0.0145 g) was added to a solution of Example A-3-4 (0.0300 g) in tetrahydrofuran (1 mL) at room temperature, and 2% at room temperature. Stir for hours. Aqueous ammonia (content 28%, 0.050 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid and water were added to the reaction mixture. The precipitated solid was collected by filtration and dried overnight at 50 ° C. under reduced pressure to obtain the title compound (0.0300 g).
  • Example A-7-2 2- (3,5-bistrifluoromethylphenyl) -N- ⁇ 4-cyano-2- (4-fluoro-2-methylphenyl) -5- [4- (2-methanesulfonylamino-2-oxoethyl) piperidine -1-yl] thiophen-3-yl ⁇ -N-methylisobutyramide
  • Example A-3-4 (0.0400 g), methanesulfonamide (0.0062 g) and N, N-dimethyl-4-aminopyridine ( To a suspension of 0.0160 g) in dichloromethane (1 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.0229 g) at room temperature, and the mixture was stirred overnight at room temperature.
  • Example A-7-3 to Example A-7-4 were synthesized in the same manner as in Example A-7-1 using the corresponding amine compound instead of ammonia water.
  • Example A-8-1 2- (3,5-bistrifluoromethylphenyl) -N- [4-cyano-5- (4-cyanomethylpiperidin-1-yl) -2- (4-fluoro-2-methylphenyl) thiophene-3- Yl] -N-methylisobutyramide Methanesulfonyl chloride (0.0734 g) was added to a solution of Example A-1-20 (0.205 g) and triethylamine (0.0970 g) in dichloromethane (3 mL) under ice cooling. The mixture was stirred for 30 minutes under ice cooling. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example A-9-1 ⁇ 1- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- [Il] piperidin-4-yl ⁇ dimethylaminoacetic acid
  • Reference Example 10 (0.100 g), Reference Example 1-22 (0.179 g) and cesium carbonate (0.107 g) in toluene (1 mL) under an argon gas atmosphere
  • Tris (dibenzylideneacetone) dipalladium (0) (0.0151 g) and ( ⁇ ) -BINAP (0.0031 g) were added to the solution at room temperature, and the mixture was stirred at 100 ° C.
  • Example B-1-1 2- (3,5-bistrifluoromethylphenyl) -N- [4-cyano-2- (4-fluoro-2-methylphenyl) -5- (4-hydroxy-1-methylpiperidin-4-yl) thiophene -3-yl] -N-methylisobutyramide
  • Reference Example 10 (0.100 g) in tetrahydrofuran (1.7 mL) at ⁇ 78 ° C. in an argon gas atmosphere at ⁇ 78 ° C. (2.65 mol / Ln—)
  • a hexane solution (0.075 mL) was added dropwise, and the mixture was stirred at ⁇ 78 ° C. for 30 minutes.
  • Example B-2-1 ⁇ 4- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- Yl] -4-hydroxypiperidin-1-yl ⁇ acetic acid
  • a solution of Reference Example 10 (0.200 g) in tetrahydrofuran (3.3 mL) at ⁇ 78 ° C. at n-butyllithium solution (2.65 mol / Ln-hexane solution, 0.150 mL) was added dropwise, and the mixture was stirred at ⁇ 78 ° C. for 30 minutes.
  • tert-butyl 4-oxopiperidine-1-carboxylate (0.328 g) was added dropwise at ⁇ 78 ° C., and the mixture was stirred at ⁇ 78 ° C. for 10 minutes and at room temperature for 30 minutes.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Trifluoroacetic acid (0.375 mL) was added to a solution of the obtained compound (0.119 g) in dichloromethane (5 mL) under ice cooling, and the mixture was stirred for 10 minutes under ice cooling and 3 hours at room temperature.
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Lithium hydroxide monohydrate (0.0094 g) was added to a mixture of the obtained compound (0.0400 g) in tetrahydrofuran (1 mL) -ethanol (0.500 mL) -water (0.500 mL) at room temperature. For 2 hours. 2 mol / L hydrochloric acid (0.112 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (0.0290 g).
  • Example B-3-1 2- (3,5-bistrifluoromethylphenyl) -N- ⁇ 4-cyano-2- (4-fluoro-2-methylphenyl) -5- [4-hydroxy-1- (5-oxo-4,5 -Dihydro-1H- [1,2,4] triazol-3-ylmethyl) piperidin-4-yl] thiophen-3-yl ⁇ -N-methylisobutyramide
  • -(3,5-bistrifluoromethylphenyl) -N- [4-cyano-2- (4-fluoro-2-methylphenyl) -5- (4-hydroxypiperidin-4-yl) thiophen-3-yl] -N-methylisobutyramide was obtained.
  • N, N-diisopropylethylamine (0.0474 g) and 5-chloromethyl-2,4-dihydro- [1,2,4] triazole were added to an acetonitrile-ethanol mixed solution of the obtained compound (0.0460 g) at room temperature.
  • -3-one (0.0147 g) was added and stirred at 50 ° C. for 4 hours.
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example B-4-1 ⁇ 4- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- Yl] cyclohex-3-enyl ⁇ acetic acid
  • Reference Example 10 (0.100 g) in 1,2-dimethoxyethane (1.25 mL) -ethanol (0.247 mL) at room temperature under an argon gas atmosphere, Reference Example 1 -26 (0.0692 g), tetrakis (triphenylphosphine) palladium (0) (0.0095 g) and 2 mol / L sodium carbonate aqueous solution (0.247 mL) were added, and the mixture was stirred at 120 ° C.
  • Lithium hydroxide monohydrate (0.0145 g) was added to a mixture of the obtained compound (0.0680 g) in tetrahydrofuran (1 mL) -methanol (0.500 mL) -water (0.500 mL) at room temperature. For 2 hours. 2 mol / L hydrochloric acid (0.173 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (0.0620 g).
  • Example B-5-1 ⁇ 4- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- Yl] cyclohexyl ⁇ acetic acid
  • methanol 3 mL
  • 10% palladium-carbon 5 mg, wet
  • the reaction mixture was filtered through celite and concentrated under reduced pressure to obtain the title compound (0.0410 g).
  • Example B-6-1 ⁇ 4- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- [Il] piperidin-1-yl ⁇ acetic acid Under an argon gas atmosphere, a mixture of Reference Example 10 (0.200 g) in 1,2-dimethoxyethane (2.35 mL) -ethanol (0.470 mL) at room temperature was added 4- ( 4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylate tert-butyl (0.153 g), tetrakis ( Triphenylphosphine) palladium (0) (0.0190 g) and 2 mol / L aqueous sodium carbonate solution (0.470 mL) were added, and the
  • Lithium hydroxide monohydrate (0.0075 g) was added to a mixture of the obtained compound (0.0310 g) in tetrahydrofuran (1 mL) -ethanol (0.500 mL) -water (0.500 mL) at room temperature. At rt overnight. 2 mol / L hydrochloric acid (0.178 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (0.0200 g).
  • Example B-7-1 4- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophen-2-yl Cyclohexanecarboxylic acid Reference Example 1 in a mixture of 1,2-dimethoxyethane (1 mL) -ethanol (0.200 mL) -water (0.200 mL) of Reference Example 10 (0.0500 g) in an argon gas atmosphere at room temperature -27 (0.0461 g), tetrakis (triphenylphosphine) palladium (0) (0.0094 g) and sodium carbonate (0.0262 g) were added, and the mixture was stirred at 120 ° C.
  • Example B-7-2 was synthesized in the same manner as in Example B-7-1 using the corresponding boronic acid compound instead of Reference Example 1-27.
  • Example B-8-1 2- (3,5-bistrifluoromethylphenyl) -N- [4-cyano-2- (4-fluoro-2-methylphenyl) -5- (4-hydroxycyclohexyl) thiophen-3-yl] -N- Methyl isobutyramide
  • Reference Example 1 (0.100 g) in a mixture of 1,2-dimethoxyethane (1 mL) -ethanol (0.200 mL) -water (0.200 mL) at room temperature was used.
  • Trifluoroacetic acid (1 mL) and water (0.050 mL) were added to the obtained compound (0.0393 g) under ice cooling, and the mixture was stirred for 15 minutes under ice cooling and at room temperature for 5 hours.
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example B-9-1 2- (3,5-bistrifluoromethylphenyl) -N- ⁇ 4-cyano-2- (4-fluoro-2-methylphenyl) -5- [4- (2-hydroxyethyl) cyclohexyl] thiophene-3- Yl ⁇ -N-methylisobutyramide ⁇ 4- [4- ⁇ [2- (3,5-bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ by a method similar to that in Example B-4-1 -3-Cyano-5- (4-fluoro-2-methylphenyl) thiophen-2-yl] cyclohex-3-enyl ⁇ methyl acetate was obtained.
  • acetic acid 0.0098 g
  • the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example C-1-20 2- (3,5-bistrifluoromethylphenyl) -N- [4-cyano-2- (4-fluoro-2-methylphenyl) -5- (6-oxohexahydropyrrolo [1,2-a] pyrazine -2-ylmethyl) thiophen-3-yl] -N-methylisobutyramide Reference Example 12 (0.0500 g), hexahydropyrrolo [1,2-a] pyrazin-6-one hydrochloride (0.0252 g), acetic acid And sodium triacetoxyborohydride (0.0381 g) was added to a mixture of dichloromethane (2 mL) at room temperature and stirred at room temperature for 18 hours.
  • Example C-1-2 to Example C-1-3 and Example C-1-5 were carried out in the same manner as in Example C-1-1 using the corresponding amine compound instead of 1-acetylpiperazine.
  • Example C-1-7 and Example C-1-14 to Example C-1-18 were synthesized.
  • Example C-1-8 to C-1-13 and Example C-1-19 were prepared in the same manner as in Example C-1-4 using the corresponding amine compound instead of 4-hydroxypiperidine. Synthesized.
  • Example C-2-1 4-acetyl-1- [4- ⁇ [2- (3,5-bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) acetate Thiophen-2-ylmethyl] piperazin-2-ylmethyl Reference Example 12 (0.0800 g) and tert-butyl 3-hydroxymethylpiperazine-1-carboxylate (0.0621 g) in dichloromethane (1 mL) at room temperature with acetic acid ( 0.0173 g) was added and stirred at room temperature for 50 minutes.
  • Triethylamine (0.0450 g) and acetic anhydride (0.0227 g) were added to a solution of the obtained compound (0.0616 g) in dichloromethane (2 mL) at room temperature, and the mixture was stirred at room temperature for 14 hours.
  • Triethylamine (0.0225 g) and acetic anhydride (0.0113 g) were added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 8 hours.
  • Acetic anhydride (0.0113 g) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example C-2-5 N- [5- [4- (Acetylaminomethyl) piperidin-1-ylmethyl] -4-cyano-2- (4-fluoro-2-methylphenyl) thiophen-3-yl] -2- (3,5- Bistrifluoromethylphenyl) -N-methylisobutyramide
  • a solution of Reference Example 14 (0.109 g) in acetonitrile (1.6 mL) at room temperature with piperidin-4-ylmethylcarbamate tert-butyl (0.0550 g), N, N Add diisopropylethylamine (0.0664 g) and sodium iodide (0.0051 g) and stir at 60 ° C. overnight.
  • the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example C-2-2 was synthesized.
  • Example C-2-5 Using the corresponding amine compound instead of tert-butyl piperidin-4-ylmethylcarbamate and the corresponding acid chloride instead of acetyl chloride, the same procedure as in Example C-2-5 was carried out to give Example C-2- 3 to Example C-2-4 and Example C-2-6 to Example C-2-7 were synthesized.
  • Example C-3-2 was prepared in the same manner as in Example C-3-1 except that the corresponding amine compound was used instead of (R) -piperazine-1,2-dicarboxylic acid 1-tert-butyl-2-methyl.
  • Example C-3-4 was synthesized.
  • Example C-4-1 (R) -1- [4- ⁇ [2- (3,5-bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene -2-ylmethyl] piperidine-3-carboxylic acid
  • Acetic acid (0 .015 mL) and sodium triacetoxyborohydride (0.0920 g) were added and stirred at room temperature for 1 hour.
  • Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example C-4-11 ⁇ 1- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2-
  • acetic acid 0.0129 g
  • sodium triacetoxyborohydride 0.457 g
  • Example C-4-23 1- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophen-2-ylmethyl ] -5-Oxopyrrolidine-3-carboxylic acid
  • Sodium hydride was added to a solution of Reference Example 14 (0.0620 g) and ethyl 5-oxopyrrolidine-3-carboxylate (0.0305 g) in acetonitrile (1 mL) under ice-cooling. (Content 55%, 0.0063 g) was added and stirred overnight at room temperature.
  • Example C-4-24 ⁇ 1- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- [Ilmethyl] -3-methylpiperidin-4-yl ⁇ acetic acid
  • acetic acid 0.0108 g
  • sodium triacetoxyborohydride 0.0381 g
  • Example C-4-16 was synthesized in the same manner as in Example C-4-1 using the corresponding aldehyde compound instead of Reference Example 12.
  • Example C-5-1 N- [5- (4-Acetyl-2-hydroxymethylpiperazin-1-ylmethyl) -4-cyano-2- (4-fluoro-2-methylphenyl) thiophen-3-yl] -2- (3,5 -Bistrifluoromethylphenyl) -N-methylisobutyramide
  • Acetic acid (0.0511 g) was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • Example C-5-2 was synthesized in the same manner as in Example C-5-1 using the corresponding acyloxy compound instead of Example C-2-1.
  • Example C-6-1 ⁇ 4- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- [Ilmethyl] piperazin-1-yl ⁇ oxoacetic acid
  • acetic acid 0.0129 g
  • Example C-7-1 N- [5- (4-Aminooxalylpiperazin-1-ylmethyl) -4-cyano-2- (4-fluoro-2-methylphenyl) thiophen-3-yl] -2- (3,5-bistrifluoromethyl Phenyl) -N-methylisobutyramide N, N′-carbonyldiimidazole (0.0066 g) was added to a solution of Example C-6-1 (0.0189 g) in tetrahydrofuran (1 mL) under ice-cooling, and the mixture was brought to room temperature. And stirred for 1 hour.
  • Example C-8-1 ⁇ 1- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- [Ilmethyl] piperidin-4-ylamino ⁇ acetic acid
  • Dess-Martin periodinane (0.0986 g) was added to a solution of Example C-1-4 (0.142 g) in dichloromethane (2.2 mL) under ice-cooling. For 10 hours. A 1 mol / L aqueous sodium hydroxide solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Triethylamine (0.0235 g) and 1 mol / L tetrachlorotitanium-dichloromethane were added to a suspension of the obtained compound (0.0707 g) and ethyl aminoacetate monohydrochloride (0.0308 g) in tetrahydrofuran (1.5 mL) at room temperature.
  • the solution (0.166 mL) was added and stirred at room temperature for 30 minutes.
  • sodium triacetoxyborohydride (0.0468 g) was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example C-8-2 was synthesized in the same manner as in Example C-8-1, using the corresponding amine compound instead of aminoacetic acid ethyl monohydrochloride.
  • Example C-9-1 4- ⁇ 4- [4- ⁇ [2- (3,5-bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene- 2-ylmethyl] piperazin-1-yl ⁇ butyric acid
  • 2- (3,5-bistrifluoromethylphenyl) -N- [4-cyano-2- (4-fluoro -2-Methylphenyl) -5-piperazin-1-ylmethylthiophen-3-yl] -N-methylisobutyramide hydrochloride was obtained.
  • Triethylamine (0.0113 g) was added to a solution of the obtained compound (0.0617 g) in dichloromethane (2 mL) at room temperature, and the mixture was stirred at room temperature for 20 minutes.
  • methyl 4-oxobutyrate (0.0216 g) and acetic acid (0.0112 g) at room temperature, and the mixture was stirred at room temperature for 30 minutes.
  • sodium triacetoxyborohydride 0.0394 g
  • Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example C-10-1 2- (3,5-bistrifluoromethylphenyl) -N- [5- (4-carbamoylmethylpiperidin-1-ylmethyl) -4-cyano-2- (4-fluoro-2-methylphenyl) thiophene-3- Yl] -N-methylisobutyramide
  • N, N′-carbonyldiimidazole 0.0237 g
  • Aqueous ammonia content 28%, 0.100 mL
  • 1 mol / L hydrochloric acid and water were added to the reaction mixture.
  • the precipitated solid was collected by filtration and dried overnight at 50 ° C. under reduced pressure to obtain the title compound (0.0480 g).
  • Example C-10-2 2- (3,5-bistrifluoromethylphenyl) -N- ⁇ 4-cyano-2- (4-fluoro-2-methylphenyl) -5- [4- (2-methanesulfonylamino-2-oxoethyl) piperidine -1-ylmethyl] thiophen-3-yl ⁇ -N-methylisobutyramide
  • Example C-4-11 (0.0500 g), methanesulfonamide (0.0076 g), N, N-dimethyl-4-aminopyridine ( 0.0196 g) and dichloromethane (1 mL) were added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.0280 g) at room temperature and stirred overnight at room temperature.
  • Example D-1-1 N- [5- (1-Acetylpiperidin-4-ylmethyl) -4-cyano-2- (4-fluoro-2-methylphenyl) thiophen-3-yl] -2- (3,5-bistrifluoromethylphenyl ) -N-methylisobutyramide Triethyl phosphite (1 mL) was added to Reference Example 15 (0.133 g) at room temperature, and the mixture was stirred at an external temperature of 150 ° C. for 5 hours.
  • Sodium hydride (content 55%, 0.0302 g) was added to a tetrahydrofuran (3 mL) solution of the obtained residue under ice cooling, and the mixture was stirred for 30 minutes under ice cooling.
  • tert-butyl 4-oxopiperidine-1-carboxylate 0.0550 g
  • Example D-2-1 1-acetyl-4- [4- ⁇ [2- (3,5-bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene -2-ylmethyl] piperidine-4-carboxylic acid
  • tetrahydrofuran (0.700 mL) at ⁇ 78 ° C.
  • lithium diisopropylamide (1.09 mol / L tetrahydrofuran-n-hexane solution). , 0.100 mL was added dropwise, and the mixture was stirred at ⁇ 78 ° C. for 45 minutes.
  • the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate.
  • the diluted solution was washed successively with 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained crude product was purified by aminopropylated silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol) to give 4- [4- ⁇ [2- (3,5-bistrifluoromethylphenyl)].
  • Lithium hydroxide monohydrate (0.0024 g) was added to a mixed solution of the obtained compound (0.0101 g) in tetrahydrofuran (0.300 mL) -methanol (0.150 mL) -water (0.150 mL) at room temperature. And stirred at room temperature overnight. A 1 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was washed with diethyl ether. 1 mol / L hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (0.0047 g).
  • Example D-3-1 [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophen-2-ylmethyl ] Cyclohexanecarboxylic acid Lithium diisopropylamide (1.09 mol / L tetrahydrofuran-n-hexane solution, 0.120 mL) was added dropwise to a solution of methyl cyclohexanecarboxylate (0.0094 g) in tetrahydrofuran (0.700 mL) at -78 ° C. , And stirred at ⁇ 78 ° C. for 45 minutes.
  • Methylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophen-2-ylmethyl] cyclohexanecarboxylate (0.0336 g) was obtained.
  • Lithium hydroxide monohydrate (0.0080 g) was added to a mixture of the obtained compound (0.0310 g) in tetrahydrofuran (0.250 mL) -methanol (0.125 mL) -water (0.125 mL) at room temperature. And stirred at room temperature overnight. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example D-3-2 was synthesized in the same manner as in Example D-3-1 using the corresponding ester compound instead of methylcyclohexanecarboxylate.
  • Example D-4-1 2- (3,5-bistrifluoromethylphenyl) -N- [4-cyano-2- (4-fluoro-2-methylphenyl) -5- (1-hydroxymethylcyclohexylmethyl) thiophen-3-yl]- N-methylisobutyramide 1- [4- ⁇ [2- (3,5-bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano was prepared in the same manner as in Example D-3-1. A methyl -5- (4-fluoro-2-methylphenyl) thiophen-2-ylmethyl] cyclohexanecarboxylate was obtained.
  • Example D-4-2 was synthesized by the same method as in Example D-4-1 using the corresponding ester compound instead of methylcyclohexanecarboxylate.
  • Example D-5-1 ⁇ 4- [4- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene-2- [Ilmethyl] cyclohexyl ⁇ acetic acid
  • Triethyl phosphite (1 mL) was added to Reference Example 15 (0.0559 g) at room temperature, and the mixture was stirred at 150 ° C. for 5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • Example E-1-1 N- [5- [3- (4-Acetylpiperazin-1-yl) propyl] -4-cyano-2- (4-fluoro-2-methylphenyl) thiophen-3-yl] -2- (3,5 -Bistrifluoromethylphenyl) -N-methylisobutyramide
  • Reference Example 10 0.0500 g
  • Reference Example 1-21 0.0205 g
  • Triethylamine 0.0416 g
  • Example E-2-1 1- ⁇ 3- [4- ⁇ [2- (3,5-bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -3-cyano-5- (4-fluoro-2-methylphenyl) thiophene- 2-yl] propyl ⁇ piperidine-4-carboxylic acid
  • Reference Example 10 0.0500 g
  • Reference Example 1-17 0.0241 g
  • triethylamine 0.0416 g
  • Reference Example 1-32 methyl trans-4-methylaminocyclohexanecarboxylate In the same manner as in Reference Example 1-31, the compound of Reference Example 1-32 was synthesized using the corresponding starting materials.
  • the reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Triethylamine (0.587 g) and methanesulfonyl chloride (0.532 g) were added to a solution of the obtained compound (0.942 g) in dichloromethane (20 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4- (tert-butoxycarbonylmethylamino) cyclohexylmethyl cis-methanesulfonate (1.23 g).
  • N-dimethylformamide (12 mL) was added sodium iodide (0.0286 g) and potassium cyanide (0.994 g) at room temperature, and the mixture was stirred at 140 ° C. for 17 hours. .
  • Water was added to the reaction mixture at room temperature, and the mixture was extracted with a mixed solvent of n-hexane-ethyl acetate (n-hexane: ethyl acetate 1: 4). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • a solution of the obtained compound (0.606 g) in ethanol (5 mL) was added 5 mol / L aqueous sodium hydroxide solution (5 mL) at room temperature, and the mixture was stirred at 90 ° C. for 45 hours.
  • Reference Example 1-34 trans- (4-Methylaminocyclohexyl) ethyl acetate
  • the compound of Reference Example 1-34 was synthesized in the same manner as in Reference Example 1-33 using the corresponding starting materials.
  • the filtrate was extracted with ethyl acetate.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • N-iodosuccinimide (1.31 g) was added to a solution of the obtained compound (1.94 g) in acetonitrile (30 mL) at room temperature, and the mixture was stirred at an external temperature of 60 ° C. for 16 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate.
  • Reference Example 26 to Reference Example 29 were synthesized by the same method as Example A-3-1 using the corresponding amine compound instead of ethyl piperidine-4-carboxylate.
  • the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Reference Example 31 ⁇ 4- [3- ⁇ [2- (3,5-Bistrifluoromethylphenyl) -2-methylpropionyl] methylamino ⁇ -2- (4-fluoro-2-methylphenyl) thieno [2,3-c] Pyridin-7-yl] cyclohexyl ⁇ acetic acid Reference Example 25 instead of Reference Example 10 and [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane instead of Reference Example 1-27
  • Reference Example 31 was synthesized in the same manner as in Example B-7-1 using ethyl -2-yl) cyclohex-3-enyl] acetate.
  • Test example 1 Affinity for human NK 1 receptor (1) Preparation of human NK 1 receptor expression vector Forward primer shown in SEQ ID NO: 1, using human adult normal tissue-derived brain cDNA (biochain) as a template, shown in SEQ ID NO: 2 PCR was performed with the PCR enzyme PrimeSTAR Max DNA Polymerase or PrimeSTAR GXL DNA Polymerase (registered trademark, Takara Bio) using the reverse primer. The amplified product was incorporated into a plasmid (pCR-BluntII-TOPO (registered trademark), Life Technologies) using Zero Blunt PCR Cloning Kit (registered trademark, Life Technologies). E.
  • coli (One-shot TOP10 competent cell, Life Technologies) was transformed by a conventional method using a plasmid in which the amplification product was incorporated.
  • This Escherichia coli was cultured on an LB agar medium containing 50 ⁇ g / mL kanamycin for 1 day. After culture, colonies were selected and cultured in LB medium containing 50 ⁇ g / mL kanamycin. After the culture, the plasmid was purified using Quantum Prep Plasmid Miniprep Kit (BioRad).
  • This plasmid was double-digested with restriction enzymes XhoI and HindIII (New England Biolabs) for about 2 hours, followed by 1% agarose electrophoresis, and the cleaved fragment was recovered and purified using TaKaRa RICOCHIP (Takara Bio).
  • the plasmid was also purified from E. coli transformed with a vector (pcDNA3.1 ( ⁇ ) (registered trademark), Life Technologies), double digested with restriction enzymes XhoI and HindIII (New England Biolabs) for about 2 hours, 1% agarose electrophoresis was performed, and the cleaved vector was recovered and purified using TaKaRa RICOCHIP (Takara Bio).
  • a fragment cleaved from pCR-Blunt-II and a pcDNA3.1 ( ⁇ ) vector treated with a restriction enzyme were subjected to a ligation reaction using DNA Ligation Kit ⁇ Mighty Mix> (Takara Bio).
  • Escherichia coli one-shot TOP10 competent cell, Life Technologies
  • the base sequence (SEQ ID NO: 3) encoding the protein of the obtained plasmid is the base sequence (NM_001058.3) of human tachykinin receptor 1 (TACR1, NK 1 R) registered in a known database (NCBI). A perfect match. Therefore, it was confirmed that the cloned gene sequence was the base sequence of human NK 1 receptor, and the translated amino acid sequence was human NK 1 receptor.
  • PcDNA3.1 ( ⁇ ) (registered trademark) into which the nucleotide sequence shown in SEQ ID NO: 3 was inserted was used as a human NK 1 receptor expression plasmid.
  • 293T cells are antibiotic penicillin-streptomycin solution (Rice Technologies, final concentration: 100 U / mL as penicillin, 100 ⁇ g streptomycin) / ML) and fetal bovine serum (final concentration: 10%) using a D-MEM (Dulbecco's Modified Eagle Medium) liquid medium (containing low glucose, L-glutamine, Wako Pure Chemical Industries), 5% The cells were cultured at 37 ° C. in an incubator under CO 2 gas conditions.
  • D-MEM Dulbecco's Modified Eagle Medium
  • the suspended cells are diluted with the above liquid medium, and the number of cells is 5 ⁇ 10 4 cells / well in a 96-well microplate (BD Biocoat (registered trademark), Nippon Becton Dickinson) coated with poly D-lysine. was prepared to be 100 ⁇ L / well and seeded. After seeding, the cells were cultured at 37 ° C. for about 4 to 5 hours in an incubator under 5% CO 2 gas conditions to obtain human NK 1 receptor expression plasmid introduction cells. (2-4) was used for the introduction human NK 1 receptor expression plasmid introduced into 293T cells of the human NK 1 receptor expression plasmid, Lipofectamine 2000 (TM, Life Technologies) was.
  • TM Lipofectamine 2000
  • the human NK 1 receptor expression plasmid was diluted with Opti-MEM (registered trademark) I Reduced-Serum Medium (Life Technologies) to a concentration of 0.2 ⁇ g / 25 ⁇ L / well.
  • Lipofectamine 2000 (registered trademark, Life Technologies) was diluted with Opti-MEM (registered trademark) I Reduced-Serum Medium (Life Technologies) to 0.4 ⁇ L / 25 ⁇ L / well and incubated at room temperature for 5 minutes. . After 5 minutes, the diluted human NK 1 receptor expression plasmid and diluted Lipofectamine 2000 were mixed and incubated at room temperature for 20-25 minutes for complex formation of human NK 1 receptor expression plasmid / Lipofectamine 2000.
  • Human NK 1 receptor-expressing cells were prepared by preparing a membrane fraction buffer (50 mM Tris (Wako Pure Chemical Industries), 120 mM sodium chloride (Wako Pure Chemical Industries), 5 mM potassium chloride (Wako Pure Chemical Industries), 1 mM ethylenediaminetetraacetic acid ( Sigma), 0.002 mg / mL chymostatin (Peptide Laboratories), 0.04 mg / basidacrine (Wako Pure Chemical Industries), 0.005 mg / mL phosphoramidon (Peptide Laboratories), 0.5 mM phenylmethylsulfonyl fluoride (Wako Pure) And collected at pH 7.4), centrifuged at 1,880 g for 10 minutes, and the cell sediment was suspended in a buffer for membrane fraction preparation.
  • a membrane fraction buffer 50 mM Tris (Wako Pure Chemical Industries), 120 mM sodium chloride (Wako Pure Chemical Industries), 5 mM potassium chloride (Wako Pure Chemical
  • the cells were disrupted using a Dounce type homogenizer (under ice cooling, 1000 rpm, 20 times). The disrupted cell suspension was centrifuged at 20,000 rpm for 10 minutes, and the supernatant was discarded to obtain a cell precipitate. The cell pellet was resuspended in the membrane fraction preparation buffer and then disrupted using a Dounce type homogenizer (under ice cooling, 1000 rpm, 30 times), and the cell suspension was centrifuged at 20,000 rpm for 10 minutes, The supernatant was discarded and cell sedimentation was obtained. Similar disruption and centrifugation were repeated again to obtain final cell sedimentation.
  • a Dounce type homogenizer under ice cooling, 1000 rpm, 20 times.
  • the disrupted cell suspension was centrifuged at 20,000 rpm for 10 minutes, and the supernatant was discarded to obtain a cell precipitate.
  • the cell pellet was resuspended in the membrane fraction preparation buffer and then disrupted using a Dounce type
  • Receptor binding test A test prepared by dispensing 22.5 ⁇ L / well of the above-mentioned receptor binding test buffer to a 96-well assay plate (Gleiner) and preparing 100% dimethyl sulfoxide (DMSO) at an 80-fold concentration. Compound DMSO solution was added in 2.5 ⁇ L / well (final concentration: 1 nM to 100 nM) and mixed.
  • Radiolabeled ligand 125 I- Substance P (Substance P, [125 I ] Tyr 8 -, Perkin Elmer) was used.
  • 125 I-Substance P was diluted with receptor binding test buffer to 125 pmol / 25 ⁇ L / well, added to a 96-well assay plate, and mixed.
  • the membrane fraction prepared from human NK 1 receptor-expressing cells is diluted with a receptor binding test buffer so as to be 8-10 ⁇ g protein / well, and is uniformly suspended until it can pass smoothly through a 27 G injection needle.
  • 150 ⁇ L / well was added to a 96-well assay plate and incubated at room temperature for 60 minutes with shaking.
  • the reaction solution is suction filtered through a multi-screen 96-well filter plate (Millipore) pretreated with 0.3% polyethyleneimine, and washed four times with a washing solution (50 mM Tris, 0.04% bovine serum albumin, pH 7.4). The reaction was terminated. After the bottom of the microplate was dried at 60 ° C., microcinch 20 (Perkin Elmer) was dispensed at 100 ⁇ L / well, and the top of the plate was sealed with top seal A (Perkin Elmer) and shaken for 5 to 10 minutes. The radioactivity was measured with TopCount NXT (registered trademark) (Perkin Elmer).
  • the radioactivity in each well was calculated by subtracting the radioactivity (nonspecific binding) when aprepitant was added at 10 ⁇ M.
  • 125 I-Substance P binding rate% (Radioactivity of test compound added group) / (Radioactivity of vehicle added group) ⁇ 100 was calculated, and% of binding was calculated using Microsoft Excel (registered trademark) (Microsoft Corporation).
  • a 50% inhibitory concentration IC 50 was calculated by linearly approximating a plot against the test compound concentration.
  • Table 27 shows the chemical structural formulas, physical property values, and affinity for human NK 1 receptor of Reference Examples 26 to 31. Abbreviations in the table are Ref. No. Are reference example numbers, Ex. No. Is an example number, Str. Represents a chemical structural formula, Physical data represents a physical property value, 1 H-NMR represents a hydrogen nuclear magnetic resonance spectrum, DMSO-d6 represents dimethyl sulfoxide-d6, and CDCl 3 represents chloroform-d1. MS indicates mass spectrometry, and ESI_APCI indicates that measurement was performed by a multi ionization method of electrospray ionization method-atmospheric pressure chemical ionization method. NK 1 pIC 50 represents the inverse logarithm of 50% inhibitory concentration.
  • Table 27 shows the compounds of Reference Examples 26 to 31.
  • Test example 2 Inhibitory action on human NK 1 receptor (1) Preparation of human NK 1 receptor-expressing cells The cells were prepared in the same manner as 2-3 and 2-4 in Test Example 1.
  • a test compound DMSO solution prepared with 100% dimethyl sulfoxide (DMSO) at an 80-fold concentration was added by 2.5 ⁇ L / well (final concentrations: 0.1, 1, 10 ⁇ M), mixed, and further at 37 ° C. Incubated for 30 minutes in incubator. The intracellular calcium concentration was measured immediately after 30 minutes. The intracellular calcium concentration was measured as a fluorescence signal using FDSS (registered trademark) 7000 (Hamamatsu Photonics). The fluorescence signal was substance P (prepared to 0.4 ⁇ M or 4 ⁇ M in assay buffer (containing 20 mM HEPES / Hank's Balanced Salt Solution (HBSS) pH 7.3, 0.1% bovine serum albumin) 10 seconds after the start of reading).
  • FDSS registered trademark
  • 7000 Haamamatsu Photonics
  • Intracellular calcium concentration% (fluorescence signal in the test compound addition group) / (fluorescence signal in the medium addition group) ⁇ 100
  • This intracellular calcium concentration% was defined as the substance P agonist activity residual activity (Substance P-Response Remaining: SPRR).
  • Test example 3 Inhibitory effect on CYP3A4
  • DMSO dimethyl sulfoxide
  • test compound having a concentration 1000 times the evaluation concentration
  • the enzyme reaction was carried out by incubation at 37 ° C. for 10 minutes in potassium buffer (pH 7.4).
  • the reaction volume was 50 ⁇ L / well.
  • Table 29 shows the results of measurement of IC 50 values in the 30-minute preincubation group of the test compound by the above measurement method.
  • Ex. No. Indicates an example number
  • IC 50 ( ⁇ M) indicates a 50% inhibitory concentration.
  • Table 29 it was revealed that the CYP3A4 inhibitory activity of the compounds of the present invention was attenuated compared to aprepitant. Therefore, the compound of the present invention is expected to have less drug-drug interaction based on CYP3A4 inhibitory action than aprepitant.
  • the compound of the present invention or a pharmacologically acceptable salt thereof has an excellent NK 1 receptor antagonistic action, it is useful as a preventive or therapeutic agent for nausea and vomiting associated with administration of an antineoplastic agent.
  • SEQ ID NO: 1 is the sequence of the forward primer used for amplifying the DNA of SEQ ID NO: 3.
  • SEQ ID NO: 2 is the sequence of the reverse primer used to amplify the DNA of SEQ ID NO: 3.

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Abstract

La présente invention concerne : un dérivé de cyanothiophène représenté par la formule (I), présentant une activité d'antagoniste des récepteurs NK1 et utile dans la prévention ou le traitement de la nausée et des vomissements qui accompagnent l'administration d'agents anti-néoplasiques, ou un sel de qualité pharmaceutique de celui-ci. Dans la formule, R1a représente un groupe alkyle ou autre, R1b représente un atome d'halogène ou autre, R2 représente un groupe alkyle ou autre, R3a et R3b représentent chacun un groupe alkyle ou autre, R4a, R4b et R4c représentent chacun un atome d'hydrogène ou un groupe halogénoalkyle ou autre, le noyau A représente un groupe hétérocycloalkyle ou autre, U1 et U2 représentent chacun une liaison simple ou un groupe alkylène ou autre, V représente une liaison simple ou un groupe alkylène ou autre et R5 représente un groupe carboxy ou un groupe acyle ou autre.
PCT/JP2015/071993 2014-08-06 2015-08-03 Dérivé de cyanothiophène WO2016021562A1 (fr)

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WO2017099049A1 (fr) * 2015-12-07 2017-06-15 キッセイ薬品工業株式会社 Antagoniste du récepteur nk1
CN107011216A (zh) * 2017-03-31 2017-08-04 泰州新威生物科技有限公司 一种反式‑4‑Boc‑氨基环己烷乙酸的制备方法

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WO2011054773A1 (fr) * 2009-11-03 2011-05-12 Glaxosmithkline Llc Nouveaux composes lactame
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WO2015024203A1 (fr) * 2013-08-20 2015-02-26 Leo Pharma A/S Nouveaux composés ii antagonistes du récepteur de la neurokinine 1
WO2015068744A1 (fr) * 2013-11-08 2015-05-14 キッセイ薬品工業株式会社 Dérivé de carboxyméthylpipéridine

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WO2000073278A2 (fr) * 1999-05-31 2000-12-07 F. Hoffmann-La Roche Ag Derives de 5-phenyle-pyrimidine
WO2006060390A1 (fr) * 2004-12-03 2006-06-08 Merck & Co., Inc. Antagonistes de récepteurs de tachykinine de type quinoline
WO2007028654A1 (fr) * 2005-09-09 2007-03-15 Smithkline Beecham Corporation Dérivés de pyridine et utilisation de ceux-ci dans le traitement de troubles psychotiques
JP2007277231A (ja) * 2006-03-16 2007-10-25 Tanabe Seiyaku Co Ltd 医薬組成物
WO2008128891A1 (fr) * 2007-04-20 2008-10-30 F. Hoffmann-La Roche Ag Dérivés de pyrrolidine comme antagonistes du récepteur nk1/nk3 double
WO2009138393A1 (fr) * 2008-05-14 2009-11-19 Glaxo Wellcome Manufacturing Pte Ltd 5- [5- [2- (3, 5-bis (trifluorométhyl) phényl) -2-méthylpropanoylméthylamino] -4- (4-fluoro-2-méthylphényl) ] -2-pyridinyl-2-alkyl-prolinamide, antagonistes du récepteur nk1
WO2011054773A1 (fr) * 2009-11-03 2011-05-12 Glaxosmithkline Llc Nouveaux composes lactame
WO2011131571A1 (fr) * 2010-04-20 2011-10-27 F. Hoffmann-La Roche Ag Dérivés de pyrazolopyridine
WO2011138916A1 (fr) * 2010-05-07 2011-11-10 第一三共株式会社 Composé polycyclique
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CN107011216A (zh) * 2017-03-31 2017-08-04 泰州新威生物科技有限公司 一种反式‑4‑Boc‑氨基环己烷乙酸的制备方法

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