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WO2015125785A1 - Dérivé de pyrazolone portant de mulitples substituants - Google Patents

Dérivé de pyrazolone portant de mulitples substituants Download PDF

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Publication number
WO2015125785A1
WO2015125785A1 PCT/JP2015/054316 JP2015054316W WO2015125785A1 WO 2015125785 A1 WO2015125785 A1 WO 2015125785A1 JP 2015054316 W JP2015054316 W JP 2015054316W WO 2015125785 A1 WO2015125785 A1 WO 2015125785A1
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group
compound
phenyl
chloro
atom
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Japanese (ja)
Inventor
正幸 海老澤
智晴 塚田
杉本　雄一
憲康 萩野谷
亨 谷口
慎平 平野
宮内　理江
知明 浜田
村上　亮
武彦 高田
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to a compound having a specific chemical structure or an pharmacologically acceptable salt thereof, which has an excellent inhibitory action on ATPase activity of TIP48 / TIP49 complex.
  • TIP48 (referred to as CGI-46, ECP51, INO80J, REPTIN, RUVBL2, RUVB-LIKE2, RVB2, TIH2, or TIP49B) and TIP49 (ECP54, INO80H, NMP238, PONTIN, Pontin52, RUVBL1, VUV1, VUV1B, RUVBL1, VUV1B , Or TIP49A) is AAA + (adenosine triphosphatase associated with diverse cellular activites) Walker-type superfamily ATPase, which is classified into the ATPase family, and forms ring-shaped multimers that form a ring-like multimer.
  • AAA + adenosine triphosphatase associated with diverse cellular activites
  • Walker-type superfamily ATPase which is classified into the ATPase family, and forms ring-shaped multimers that form a ring-like multimer.
  • telomerase Protein group, telomerase It forms a complex with tubulin and the like, and is involved in the control of various intracellular molecular mechanisms such as regulation of gene expression by transcription factors, DNA damage repair, and telomerase activity (Non-Patent Document 1 and Non-Patent Document 2). ).
  • c-Myc an oncogene that promotes canceration of cells
  • c-Myc is known as a factor that interacts with the TIP48 / TIP49 complex.
  • c-Myc is a transcription factor that induces the expression of genes involved in cell cycle and cell apoptosis in response to various stresses.
  • c-Myc is considered to promote canceration of cells due to an abnormality in its transcriptional regulatory function.
  • translocation or mutation of c-Myc gene has been observed in human lymphoma.
  • One of the factors involved in the ability of c-Myc to promote canceration is the ATPase activity of the TIP48 / TIP49 complex.
  • Non-patent Document 3 It has been reported that inhibition of ATPase activity of TIP48 / TIP49 complex suppresses the ability of c-Myc to promote canceration.
  • ⁇ -catenin, ATF-2, E2F family and the like have been reported as a group of transcription factors involved in canceration of cells that interact with the TIP48 / TIP49 complex (Non-patent Document 2).
  • TIP48 / TIP49 has been reported to be more highly expressed in tumor tissues such as liver cancer, colon cancer, lymphoma, etc. than normal tissues, suggesting an association with TIP48 / TIP49 canceration. (Non-Patent Documents 4 to 6).
  • the present invention provides a novel low molecular weight compound having a potent TIP48 / TIP49 complex ATPase activity inhibitory action and showing an antitumor effect.
  • the present invention relates to the following (1) to (15).
  • R 1 represents a hydrogen atom or a C 1 -C 6 alkyl group optionally having 1 to 3 substituents independently selected from the following group A;
  • R 2 represents a hetero atom independently selected from the group consisting of a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group, a nitrogen atom, an oxygen atom, and a sulfur atom.
  • a 5-membered or 6-membered aliphatic heterocyclic group which may have 1 to 3, or —CR 21 R 22 — (CR 23 R 24 ) m — (CR 25 R 26 ) n —R 27
  • the phenyl group, the 5-membered or 6-membered aliphatic heterocyclic group, and the C 3 -C 6 cycloalkyl group may have 1 to 3 substituents independently selected from the following group B:
  • m and n each independently represents an integer of 0 or 1, (Here, when m represents 0, n represents 0)
  • R 21 , R 22 , R 23 , R 24 , R 25 , and R 26 each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a C 1 -C 6 alkyl group, or a C 1 -C 6 alkoxy group.
  • R 21 and R 22 , R 23 and R 24 , and R 25 and R 26 may each independently form an oxo group
  • R 27 may have 1 to 3 heteroatoms in the ring independently selected from the group consisting of a halogen atom, a hydroxyl group, a C 1 -C 6 alkoxy group, a nitrogen atom, an oxygen atom, and a sulfur atom.
  • a good 5- or 6-membered aliphatic heterocyclic group, or —NR 271 R 272 may have 1 to 3 C 1 -C 6 alkyl groups, R 271 and R 272 are each independently a hydrogen atom, one to three C 1 may be substituted by a halogen atom ⁇ C 6 alkylcarbonyl group, C 1 ⁇ C 6 alkoxycarbonyl group, C 3 ⁇ C A 6 cycloalkyl group, or a C 1 -C 6 alkyl group optionally having 1 to 3 substituents independently selected from the group consisting of a halogen atom and a hydroxyl group;
  • R 1 and R 2 have 1 to 3 hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in which R 1 and R 2 are combined.
  • the 5- to 7-membered heterocyclic ring may have 1 to 3 substituents independently selected from the following group C;
  • R 3 is a phenyl group optionally having 1 to 5 substituents independently selected from the following group D, or a heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom
  • the 5-membered or 6-membered aromatic heterocyclic ring may have 1 to 4 substituents independently selected from the following group D;
  • R 4 represents a hetero atom independently selected from the group consisting of a phenyl group, a nitrogen atom, an oxygen atom, and a sulfur atom, which may have 1 to 5 substituents independently selected from the following group E: 1 to 3 heteroatoms independently selected from the group consisting of a 5- or 6-membered aromatic heterocyclic group, nitrogen atom,
  • a 6-membered or 6-membered aromatic heterocycle having 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom 5
  • a 6-membered or 6-membered aromatic heterocycle The C 1 -C 6 alkylene group, the C 3 -C 6 cycloalkyl ring, the benzene ring, the 3-membered to 6-membered aliphatic heterocycle, and the 5-membered or 6-membered aromatic heterocycle are: May have 1 to 3 substituents independently selected from group F; (Wherein Z is a 3- to 6-membered aliphatic heterocycle having 1 to 3 heteroatoms in the ring independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, or nitrogen A nitrogen on the Z ring when it represents a 5- or 6-membered aromatic heterocycle having 1 to 3 heteroatoms independently selected from the group consisting of an atom, an oxygen atom and a sulfur atom
  • the benzene ring and the 5-membered or 6-membered aromatic heterocycle may have 1 to 3 substituents independently selected from the following group F.
  • group F 3 to 6-membered fat having 1 to 3 heteroatoms in the ring, wherein y is 0 and Z is independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • W is not bound to a nitrogen atom on the Z ring except when W is an oxadiazole ring and a thiadiazole ring.
  • Group A halogen atom, hydroxyl group, C 1 -C 6 alkoxy group
  • B group halogen atom, hydroxyl group, C 1 -C 6 alkyl group, C 1 -C 6 alkylamino group, di-C 1 -C 6 alkylamino group
  • D group halogen atom, C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 alkoxy group
  • Z is 1 to 3 C 1 ⁇ C 6 alkyl cyclohexane ring which may be substituted with a group, from 1-3 C 1 ⁇ C 6 alkyl optionally piperidine ring optionally substituted with a group or 1 to,
  • R 1 represents a C 1 -C 6 alkyl group
  • R 2 has 1 to 3 heteroatoms in the ring independently selected from the group consisting of a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a nitrogen atom, an oxygen atom, and a sulfur atom.
  • An optionally substituted 5- or 6-membered aliphatic heterocyclic group or —CR 21a R 22a — (CR 23a R 24a ) ma — (CR 25a R 26a ) na —R 27a ,
  • the 5-membered or 6-membered aliphatic heterocyclic group and the C 3 -C 6 cycloalkyl group have 1 to 3 substituents independently selected from a hydroxyl group and a C 1 -C 6 alkyl group.
  • R 21a , R 22a , R 23a , R 24a , R 25a , and R 26a each independently represent a hydrogen atom or a C 1 -C 6 alkyl group
  • R 27a represents a hydroxyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylamino group, or a di C 1 -C 6 alkylamino group
  • R 1 and R 2 have 1 to 3 heteroatoms in the ring, wherein R 1 and R 2 are combined and are independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom May form a 5- to 7-membered heterocyclic ring
  • the compound according to any one of (1) to (3), wherein the 5- to 7-membered heterocyclic ring may have 1 to 3 substituents independently selected from Group G below: Or a
  • Group G C 1 -C 6 alkyl group, C 1 -C 6 alkylamino group, di-C 1 -C 6 alkylamino group (5)
  • R 3 indicates a one to three C 1 ⁇ C 6 alkyl phenyl group which may be substituted with a group or 1 to 3 C 1 ⁇ C 6 alkyl pyridyl group which may be substituted with a group, , The compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof.
  • R 4 represents the following formula (II) or the following formula (III)
  • R 41 represents a halogen atom
  • R 42 represents a hydrogen atom or a halogen atom
  • R 43 represents a C 1 -C 6 alkoxy group which may be substituted with 1 to 3 halogen atoms, or a C 1 -C 6 alkoxy C 1 -C 6 alkoxy group
  • R 44 represents a C 1 -C 4 alkyl group
  • V represents a nitrogen atom or CH
  • a pharmacologically acceptable salt thereof according to any one of (1) to (5).
  • R 5 represents a methyl group or an ethyl group
  • R 6 represents an N-methylpyrrolidyl group, or —CR 61 R 62 — (CH 2 ) p —R 63
  • p represents an integer of 0 or 1
  • R 61 and R 62 each independently represent a hydrogen atom or a methyl group
  • R 63 represents a hydrogen atom, a methoxy group, a methylamino group, or a dimethylamino group
  • R 5 and R 6 may form a ring of any of the following formulas (V) to (IX) by combining R 5 and R 6 ,
  • R 51 represents a hydrogen atom or a methyl group
  • R 52 represents a hydrogen atom, a methylamino group, or a dimethylamino group.
  • R 7 represents an ethoxy group or an isopropoxy group
  • T represents a nitrogen atom or CH
  • V represents a nitrogen atom or CH.
  • a pharmacologically acceptable salt thereof Any one compound selected from the following group or a pharmacologically acceptable salt thereof.
  • An ATPase activity inhibitor of a TIP48 / TIP49 complex comprising the compound according to any one of (1) to (9) or a pharmacologically acceptable salt thereof as an active ingredient.
  • An antitumor agent comprising the compound according to any one of (1) to (9) or a pharmacologically acceptable salt thereof as an active ingredient.
  • Tumor is bladder cancer, breast cancer, brain tumor, colon cancer, ovarian cancer, stomach cancer, head and neck cancer, kidney cancer, leukemia, multiple myeloma, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate cancer, skin cancer
  • the antitumor agent according to (12) which is a bone soft tissue tumor.
  • a therapeutic agent for a tumor in which the expression level of TIP48 / TIP49 complex is increased comprising the compound according to any one of (1) to (9) or a pharmacologically acceptable salt thereof as an active ingredient .
  • Treatment can be carried out by inhibiting the ATPase activity of the TIP48 / TIP49 complex comprising the compound according to any one of (1) to (9) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the “C 1 -C 6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms.
  • the “C 3 -C 6 cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • “C 1 -C 6 alkoxy group” means a C 1 -C 6 alkoxy group formed from the above C 1 -C 6 alkyl group.
  • methoxy group, ethoxy group, n-propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentoxy group, isopentoxy group, 2-methylbutoxy group, hexyloxy, or iso A hexyloxy group etc. are mentioned.
  • C 3 -C 6 cycloalkoxy group means a C 3 -C 6 cycloalkoxy group formed from the above C 3 -C 6 cycloalkyl group. Examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
  • C 1 -C 6 alkylamino group means a group in which one of the above C 1 -C 6 alkyl groups is substituted with an amino group.
  • Examples thereof include a butylamino group, a neopentylamino group, a 1-ethylpropylamino group, a hexylamino group, and an isohexylamino group.
  • the “di-C 1 -C 6 alkylamino group” means a group in which two identical or different C 1 -C 6 alkyl groups are substituted with amino groups.
  • the “C 1 -C 6 alkylcarbonyl group” means a group in which one C 1 -C 6 alkyl group is substituted with a carbonyl group.
  • a carbonyl group for example, an acetyl group, an ethylcarbonyl group, a propylcarbonyl group, an isopropylcarbonyl group, or the like can be given.
  • the “C 1 -C 6 alkoxycarbonyl group” means a group in which one of the above C 1 -C 6 alkoxy groups is substituted with a carbonyl group. Examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, and a tert-butoxycarbonyl group.
  • the “C 1 -C 6 alkoxy C 1 -C 6 alkyl group” means a group in which one C 1 -C 6 alkoxy group is substituted with the C 1 -C 6 alkyl group.
  • Examples thereof include a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, an isopropoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, and an isopropoxyethyl group.
  • C 1 ⁇ C 6 alkoxy C 1 ⁇ C 6 alkoxy group one of the C 1 ⁇ C 6 alkoxy group means a group substituted in the C 1 ⁇ C 6 alkoxy group. Examples thereof include a methoxymethoxy group, an ethoxymethoxy group, a propoxymethoxy group, an isopropoxymethoxy group, a methoxyethoxy group, an ethoxyethoxy group, a propoxyethoxy group, and an isopropoxyethoxy group.
  • the “aromatic heterocyclic group” means a group derived from a monocyclic aromatic compound containing a hetero atom as a ring constituting atom.
  • a monocyclic aromatic compound containing a hetero atom as a ring constituting atom.
  • the “aliphatic heterocyclic group” means a group derived from a monocyclic aliphatic cyclic compound containing a hetero atom as a ring constituent atom.
  • oxiranyl group aziridinyl group, tyranyl group, oxetanyl group, azetidyl group, thietanyl group, tetrahydrofuranyl group, pyrrolidinyl group, tetrahydrothiophenyl group, tetrahydropyranyl group, piperazinyl group, tetrahydrothiopyranyl group, morpholino group, morpholinyl Group, piperidinyl group and the like.
  • the “bicyclic aromatic heterocyclic group” means a group derived from a condensed aromatic cyclic compound containing a hetero atom as a ring constituent atom.
  • indolyl group isoindolyl group, benzofuryl group, benzothienyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzo [b] pyridyl group, imidazopyridyl group, benzo [c] pyridyl group, and the like can be given.
  • the “aliphatic heterocyclic group in which a part of the bicyclic ring is unsaturated” means a condensed aliphatic group having an unsaturated bond in a part of the ring and containing a hetero atom in the ring constituent atom. This means a group derived from a cyclic compound.
  • indolyl group 2,3-dihydrobenzofuryl group, 2,3-dihydrobenzothienyl group, 1,3-benzodioxolyl group, benzopyranyl group, 1,2,3,4-tetrahydroquinolyl group, 3 , 4-dihydro-2H-1,4-benzoxazyl group, 2,3-dihydro-1,4-benzodioxy group, 4H-1,4-benzoxazyl group, and the like.
  • the “C 1 -C 6 alkylene group” is a divalent substituent obtained by removing one hydrogen atom from the above C 1 -C 6 alkyl group, and is a straight chain having 1 to 6 carbon atoms. Or a branched chain alkylene group.
  • methylene group ethylene group, propane-1,3-diyl group, butane-1,4-diyl group, hexane-1,6-diyl group, methylmethylene group, dimethylmethylene group, or 1-methylethylene group Is mentioned.
  • the “C 3 -C 6 cycloalkyl ring” is a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring.
  • aromatic heterocycle means a ring of an aromatic cyclic compound containing a heteroatom as a constituent atom of the ring.
  • aromatic heterocycle means a ring of an aromatic cyclic compound containing a heteroatom as a constituent atom of the ring.
  • aliphatic heterocycle means a ring of an aliphatic cyclic compound containing a hetero atom as a constituent atom of the ring.
  • heterocycle means the above aromatic heterocycle and the above aliphatic heterocycle.
  • a pyrrolidine ring, a piperidine ring, a piperazine ring, a diazepan ring, an oxazepan ring, and the like can be given.
  • the “tumor” is not limited to a malignant tumor and includes all kinds of tumors, for example, a carcinoma, a sarcoma, a benign tumor, and the like.
  • a malignant tumor may be expressed as “cancer”.
  • “enhanced expression of TIP48 / TIP49 complex” means that TIP48 gene or TIP49 gene mRNA expression level and protein expression level increase gene transcriptional activity, promote translation, suppress protein degradation, It means that it has increased due to improvements in stabilization.
  • ATPase activity of TIP48 / TIP49 complex refers to an enzyme activity that catalyzes the hydrolysis of ATP in the presence of TIP48 protein and TIP49 protein.
  • R 1 is preferably a methyl group or an ethyl group. More preferably, it is a methyl group.
  • R 2 is preferably a methyl group, ethyl group, methoxymethyl group, 2- (dimethylamino) ethyl group, 2- (dimethylamino) -1-methyl-ethyl group, 3-hydroxycyclobutyl group, 3- A hydroxy-3-cyclobutyl group, a 2-hydroxypropyl group, a 1- (methylamino) ethyl group, a 1-methylpyrrolidin-3-yl group, or a 1,3-dimethylpyrrolidin-3-yl group; More preferably, it is a methyl group.
  • R 1 and R 2 have 1 to 3 heteroatoms in the ring, wherein R 1 and R 2 are taken together and are independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom
  • suitable rings are R 2A to R 2I below. * Is bonded to a nitrogen atom on the pyrazolone ring.
  • R 3 is preferably a pyridyl group or a phenyl group. More preferably, it is a phenyl group.
  • R 4 is preferably any of the following R 4A to R 4K .
  • R 4D or R 4H is more preferable.
  • Y is preferably 0.
  • Z is preferably is any of the following Z A to Z H. * Is bonded to a carbonyl group.
  • W is preferably either below W A to W K. * It is attached to R 4.
  • the compound represented by the general formula (I) of the present invention can be converted into a pharmaceutically acceptable salt if desired.
  • a pharmaceutically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicament.
  • the compound represented by the general formula (I) of the present invention has a basic group, it can be converted into a salt by reacting with an acid.
  • Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C 1 -C 6 alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
  • Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, adipate, maleate;
  • amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.
  • the compound represented by the general formula (I) of the present invention or a salt thereof may be left in the atmosphere or recrystallized to take in water molecules and become a hydrate. Such hydrates are also encompassed by the salts of the present invention.
  • the compound represented by the general formula (I) of the present invention or a salt thereof may be allowed to stand in a solvent or recrystallize to absorb a certain solvent and become a solvate. Such solvates are also encompassed by the salts of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof includes all isomers (diastereoisomers, optical isomers, geometric isomers, rotational isomers, etc.). .
  • these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound can also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the ATPase activity of the TIP48 / TIP49 complex can be measured using the ATPase assay described in Test Example 1 or 2 below.
  • the ATPase activity of the TIP48 / TIP49 complex is determined by recombinant human TIP48 and TIP49 proteins (hereinafter referred to as rTIP48 and rTIP49) in the presence or absence of a test compound, as described in the following test examples.
  • rTIP48 and rTIP49 recombinant human TIP48 and TIP49 proteins
  • ATP can be detected by measuring the amount of ADP hydrolyzed by the ATPase activity of the TIP48 / TIP49 complex using ADP-Glo.
  • the ATPase activity of the TIP48 / TIP49 complex is described, for example, in J. Org. Mol. Biol. 366, 172-179 (2007).
  • the cell growth inhibitory activity of the compound of the present invention can be examined using a growth inhibition test method commonly used by those skilled in the art.
  • Cell growth inhibitory activity can be carried out, for example, by comparing the degree of cell proliferation in the presence or absence of a test compound, as described in Test Example 3 below.
  • the degree of proliferation can be examined, for example, using a test system that measures live cells. Examples of the method for measuring living cells include [ 3 H] -thymidine incorporation test, BrdU method, MTT assay and the like.
  • the antitumor activity in vivo can be examined using an antitumor test method usually used by those skilled in the art. For example, after transplanting various tumor cells into mice, rats, etc., and confirming the engraftment of the transplanted cells, the compound of the present invention is administered orally, intravenously, etc. The in vivo antitumor activity of the present invention can be confirmed by comparing the tumor growth in the group and the tumor growth in the compound administration group.
  • the compound of the present invention is a tumor such as bladder cancer, breast cancer, brain tumor, colon cancer, ovarian cancer, gastric cancer, head and neck cancer, kidney cancer, leukemia, multiple myeloma, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate For use in the treatment of cancer, skin cancer, or bone and soft tissue tumors.
  • a tumor such as bladder cancer, breast cancer, brain tumor, colon cancer, ovarian cancer, gastric cancer, head and neck cancer, kidney cancer, leukemia, multiple myeloma, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate
  • a tumor such as bladder cancer, breast cancer, brain tumor, colon cancer, ovarian cancer, gastric cancer, head and neck cancer, kidney cancer, leukemia, multiple myeloma, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate
  • the compound of the present invention can be used for tumors in which TIP48 / TIP49 expression is enhanced.
  • Known tumors with enhanced expression of TIP48 / TIP49 include liver cancer, colon cancer, lymphoma, and the like.
  • Whether TIP48 / TIP49 expression is increased is determined by determining whether TIP48 / TIP49 in a patient's test tissue (eg, collected by blood sampling, biopsy, etc.) is Southern blot, Northern blot, Western blot, ELISA, DNA chip, FISH Assays, tissue immunostaining, and other known gene analysis methods (for example, PCR, LCR (Ligase chain reaction), SDA (Strand displacement an amplification), NASBA (Nucleic acid sequence-based amplification, ICAN (Issential-indication)) amplification), LAMP method (Loop-mediated isoth) Analysis using rnal amplification), etc. ⁇ and the like can be confirmed by using a pathological techniques such known methods.
  • the compound of the present invention may be used in combination with other antitumor agents.
  • antitumor antibiotics for example, antitumor antibiotics, antitumor plant components, BRM (biological response control substances), hormones, vitamins, antitumor antibodies, molecular targeted drugs, other antitumor agents and the like can be mentioned.
  • BRM biological response control substances
  • hormones for example, vitamins, antitumor antibodies, molecular targeted drugs, other antitumor agents and the like can be mentioned.
  • examples of the alkylating agent include an alkylating agent such as nitrogen mustard, nitrogen mustard N-sodium oxide or chlorambutyl, an aziridine alkylating agent such as carbocone or thiotepa, dibromomannitol or dibromodarsi
  • alkylating agent such as nitrogen mustard, nitrogen mustard N-sodium oxide or chlorambutyl
  • an aziridine alkylating agent such as carbocone or thiotepa, dibromomannitol or dibromodarsi
  • examples thereof include epoxide-based alkylating agents such as Toll, carmustine, lomustine, semustine, nimustine hydrochloride, nitrosourea-based alkylating agents such as streptozocin, chlorozotocin or ranimustine, busulfan, improsulfan tosylate or dacarbazine.
  • antimetabolites for example, purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine, pyrimidine antimetabolites such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine And antifolate inhibitors such as methotrexate or trimethrexate.
  • purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine
  • pyrimidine antimetabolites such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine
  • antifolate inhibitors such as methotrexate or trimethrexate.
  • Antitumor antibiotics include, for example, anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin or epirubicin, chromomycin A Examples include 3 or actinomycin D.
  • anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin or epirubicin, chromomycin A
  • anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pir
  • antineoplastic plant component examples include vinca alkaloids such as vindesine, vincristine and vinblastine, taxanes such as paclitaxel and docetaxel, and epipodophyllotoxins such as etoposide and teniposide.
  • BRM examples include tumor necrosis factor or indomethacin.
  • hormones include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, phosfestol, ethinyl estradiol, chlormadinone, or medroxyprogesterone.
  • vitamins examples include vitamin C and vitamin A.
  • Antitumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, sorafenib, etc.
  • antitumor agents include, for example, cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, acecraton, schizophyllan, picibanil, procarbazine, pipobroman, neocartinostatin, Examples include hydroxyurea, ubenimex, and krestin.
  • the compound of the present invention can be produced by various production methods, and the production methods shown below are merely examples, and the present invention should not be construed as being limited thereto.
  • the compound represented by the general formula (I) and its production intermediate can be produced by utilizing various known reactions described below.
  • the functional group may be protected with a suitable protecting group at the stage of the raw material or intermediate. Examples of such a functional group include a hydroxyl group, a carboxy group, an amino group, and the like.
  • the types of protecting groups and the conditions for introducing and removing these protecting groups are, for example, Protective Groups in Organic Synthesis (T. W.
  • General formula (I) can be expressed as general formula (V) by defining linker site L, and can be divided into site A, site B, site C, and site D.
  • first, (A) and (B) are first combined, and a site C is constructed between the complex and (D), or first, (B) and (D) Examples include a method of constructing site C between them and binding the complex to (A), or a method of sequentially binding other sites to site C that has already been constructed, but is not particularly limited.
  • R 10 represents a hydrogen atom or a carboxylic acid protecting group.
  • R 11 represents a hydrogen atom, a carboxy group or a protected carboxy group.
  • R 12 is a substituent necessary for constructing the site C. Depending on the structure of the site C, R 12 represents, for example, a halogen atom, a carboxy group, a cyano group, an amino group, or a derivative thereof.
  • the protecting group for carboxylic acid include a methyl group, an ethyl group, a tert-butyl group, and a benzyl group.
  • R 13 is a protecting group for a carboxy group, and is preferably a lower alkyl group such as a methyl group or an ethyl group.
  • R 13 is a protecting group for a carboxy group, and is preferably a lower alkyl group such as a methyl group or an ethyl group.
  • Examples of the method for activating the carboxylic acid include a method using 1,1′-carbonyldiimidazole and a method via an acid chloride.
  • a base can be added as necessary, and examples of the base include triethylamine.
  • Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, toluene, and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • compound (3) can be obtained by introducing the protecting group to the amino group and then subjecting it to the above conditions.
  • the conditions for introducing a protecting group vary depending on the protecting group.
  • the protecting group is a tert-butoxycarbonyl group or a trifluoroacetyl group
  • the reaction is introduced by reacting the corresponding acid anhydride with an amino group in the presence or absence of a base. can do.
  • a base is used, triethylamine, pyridine and the like can be mentioned.
  • Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • the protecting group is a benzoyl group, a tosyl group or the like, it can be introduced by reacting the corresponding acid chloride with an amino group in the presence of a base. When a base is used, triethylamine, pyridine and the like can be mentioned.
  • Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Compound (3) can be obtained by reacting compound (3) with an appropriate hydrazine derivative in the presence or absence of a base.
  • An appropriate hydrazine derivative can be purchased from, for example, Tokyo Chemical Industry Co., Ltd.
  • the solvent used in the reaction include ethanol, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, toluene, acetic acid, and the like, or a mixed solvent thereof, and is not particularly limited.
  • examples of the base used include potassium carbonate and potassium tert-butoxide.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 180 ° C.
  • Synthesis of Compound (5) It can be obtained by reacting Compound (4) with an alkyl halide or dialkyl sulfuric acid, alkyl trifluoromethanesulfonate, or the like.
  • the solvent used in the reaction include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 180 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 150 ° C.
  • Compound (5) can be obtained by reacting compound (4) with the corresponding alcohol in the presence of phosphine and azodicarboxylic acid ester or azodicarboxylic acid amide.
  • phosphine include triphenylphosphine and tri-n-butylphosphine.
  • azodicarboxylic acid ester or azodicarboxylic acid amide used include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1 ′-(azodicarbonyl) dipiperidine, and the like.
  • the solvent used in the reaction examples include tetrahydrofuran, dioxane, toluene, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Compound (5) can also be obtained by reacting compound (6) with an appropriate aryl halide in the presence of a copper catalyst, a ligand and a base.
  • Compound (6) can be synthesized, for example, by the method shown in WO2007 / 10015, or can be purchased from Enamine.
  • the copper catalyst used include copper iodide.
  • the ligand include trans-N, N′-dimethylcyclohexane-1,2-diamine
  • examples of the base include potassium carbonate and sodium carbonate.
  • the solvent used in the reaction include tetrahydrofuran, dioxane, N, N-dimethylformamide, toluene, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from about room temperature to 200 ° C. or the boiling point of the solvent, but preferably in the range from about room temperature to 180 ° C.
  • the compound (5) can be obtained by reacting with a nitrating agent such as nitric acid or nitrate.
  • a nitrating agent such as nitric acid or nitrate.
  • the solvent used in the reaction include sulfuric acid, trifluoroacetic acid, acetic acid, and the like, or a mixed solvent thereof, and is not particularly limited.
  • nitric acid can be used as a solvent.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from ⁇ 20 ° C. to 100 ° C. If there is labile protecting group to acidic conditions in R 2, replacement stable protecting groups initially acidic conditions at this time, it is also possible to perform the nitration in the manner described above.
  • Synthesis of Compound (A-1) from Compound (7) In a state where compound (7) is dissolved or suspended in a solvent, a reduction catalyst such as palladium carbon is added, and the reaction is carried out in a hydrogen atmosphere to reduce the compound (7).
  • a reduction catalyst such as palladium carbon
  • the solvent used in the reaction include methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, acetic acid and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • the compound (A-1) is a racemic compound having an asymmetric carbon, it can be optically resolved using a chiral column by liquid chromatography under appropriate conditions at this point, or at a later stage. It is also possible to divide.
  • Compound (5) can be obtained by reacting with sodium nitrite under acidic conditions or by reacting with alkyl nitrite in an organic solvent.
  • alkyl nitrite used include tert-butyl nitrite and isoamyl nitrite.
  • the solvent used for the reaction includes hydrochloric acid, acetic acid, sulfuric acid and the like, or a mixed solvent thereof such as water and alcohol, and is not particularly limited.
  • reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from ⁇ 20 ° C. to 100 ° C. If there is labile protecting group to acidic conditions in R 2, replacement stable protecting groups initially acidic conditions at this time, it is also possible to carry out the nitrosation in the manner described above.
  • Compound (8) can be obtained by coexisting with a metal under acidic conditions.
  • the metal used include tin and zinc.
  • the solvent used in the reaction include hydrochloric acid, a mixed solvent of ethanol and water, or acetic acid, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Compound (A-1) can also be obtained by reduction by adding a reduction catalyst such as palladium carbon in a state where compound (8) is dissolved or suspended in a solvent and reacting in a hydrogen atmosphere.
  • a reduction catalyst such as palladium carbon
  • the solvent used in the reaction include methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, acetic acid, and the like, or a mixed solvent thereof, but is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • the compound (A-1) is a racemic compound having an asymmetric carbon, it can be optically resolved using a chiral column by liquid chromatography under appropriate conditions at this point, or at a later stage. It is also possible to divide.
  • Compound (4) can be obtained by reacting with compound benzyl chloroformate in the presence of calcium hydroxide.
  • the solvent used in the reaction include tetrahydrofuran, dioxane, toluene, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 150 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Synthesis of Compound (10) can be obtained by appropriately selecting and using the reaction conditions described in the production method from Compound (4) to Compound (5) for Compound (9).
  • Synthesis of Compound (11) In a state where compound (10) is dissolved or suspended in a solvent, it can be obtained by deprotection by adding a reduction catalyst such as palladium carbon and reacting in a hydrogen atmosphere.
  • a reduction catalyst such as palladium carbon
  • the solvent used in the reaction include methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide and the like, or mixed solvents thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • Synthesis of Compound (A-1) from Compound (11) It can be obtained by reacting compound (11) with diphenylphosphoric acid azide under basic conditions.
  • the base used include triethylamine, N, N-diisopropylethylamine and the like.
  • the solvent used in the reaction include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, water, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 150 ° C. or the boiling point of the solvent, but is preferably in the range from around room temperature to 150 ° C.
  • the compound (A-1) is a racemic compound having an asymmetric carbon, it can be optically resolved using a chiral column by liquid chromatography under appropriate conditions at this point, or at a later stage. It is also possible to divide.
  • R 3 has the same meaning as described above.
  • R 13 represents a protecting group for carboxylic acid, and is preferably a lower alkyl group such as a methyl group or an ethyl group.
  • a 1 and A 2 each independently represents an optionally substituted C 1 -C 2 alkylene group, and the allowable substituents are as described above.
  • a 3 represents an oxygen atom or an optionally substituted nitrogen atom or carbon atom, and the permissible substituents are as described above.
  • X is either a chlorine atom, a bromine atom or an iodine atom.
  • Compound (14) can be obtained by appropriately selecting and using the reaction conditions described in the above production method of compound (3) for commercially available or appropriately synthesized compound (12).
  • a commercial item (12) can be obtained from Tokyo Chemical Industry Co., Ltd.
  • Compound (14) can also be obtained by reacting a commercially available compound (13) available from Tokyo Kasei Kogyo Co., Ltd. with 2 equivalents or more of a base and then reacting with the corresponding halide. it can.
  • Examples of the base to be used include sodium hydride or n-butyllithium, lithium diisopropylamide and the like, or a combined use thereof.
  • Examples of the solvent to be used include tetrahydrofuran, dioxane, hexane, toluene and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent.
  • Compound (14) can be obtained by reacting with an appropriate hydrazine derivative in the presence or absence of a base.
  • Suitable hydrazine derivatives can be obtained from Tokyo Chemical Industry Co., Ltd.
  • potassium carbonate or potassium tert-butoxide can be used.
  • the solvent used in the reaction include ethanol, acetonitrile, N, N-dimethylformamide, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from about room temperature to 100 ° C.
  • Compound (A-2) is compound (A-) from Compound (5) to Compound (7) or Compound (8) with respect to Compound (15). It can be obtained by appropriately selecting and using appropriate reaction conditions from the production method leading to 1) or the production method from compound (9) to compound (10) and compound (11) to compound (A-1). it can.
  • the compound (A-2) is a racemic compound having an asymmetric carbon, it is possible to perform optical resolution using a chiral column by liquid chromatography under an appropriate condition at this time, or in subsequent steps. It is also possible to do.
  • R 3 has the same meaning as described above.
  • R 13 represents a protecting group for carboxylic acid, and in this case, a lower alkyl group such as a methyl group or an ethyl group is preferred.
  • R 14 represents a hydroxyl-protecting group.
  • a 1 and A 2 each independently represents an optionally substituted C 1 -C 2 alkylene group, and the allowable substituents are as described above.
  • a 3 represents an oxygen atom, an optionally substituted nitrogen atom, or an optionally substituted carbon atom, and the permissible substituents are as described above.
  • Examples of the hydroxyl-protecting group include a benzyl group, a tert-butoxycarbonyl group, an acetyl group, and a tert-butyldimethylsilyl group.
  • Compound (17) can be obtained by appropriately selecting and using compound (16), which is appropriately synthesized, from the reaction conditions described in the production method of compound (3).
  • compound (17) can be obtained by appropriately selecting and using compound (13) from the reaction conditions described in the production method of compound (14) from compound (13).
  • R 14 is a benzyl group or the like
  • the compound (18) can be obtained by deprotection by adding a reducing catalyst such as palladium carbon and reacting in a hydrogen atmosphere in a state where the compound (18) is dissolved or suspended in a solvent.
  • a reducing catalyst such as palladium carbon
  • the solvent used for the reaction include methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C.
  • R 14 is a tert-butoxycarbonyl group or the like, it is desirable to treat with trifluoroacetic acid or hydrochloric acid.
  • the solvent used in the reaction include methylene chloride, chloroform, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from ⁇ 20 ° C. to around 100 ° C.
  • R 14 is a tert-butyldimethylsilyl group, it is desirable to treat with hydrochloric acid or the like or with fluoride ions.
  • the solvent used in the reaction examples include ethanol, tetrahydrofuran, dioxane, water and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • the compound (20) can be obtained by reacting the compound (19) with Kakuda reagent.
  • the Kakuda reagent used includes (cyanomethylene) tri n-butylphosphorane or (cyanomethylene) trimethylphosphorane.
  • the solvent used in the reaction include tetrahydrofuran, dimethoxyethane, benzene, toluene and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 150 ° C. or the boiling point of the solvent, but preferably in the range from about room temperature to 120 ° C.
  • Compound (20) can also be obtained by treating with a base after modifying the hydroxyl group of compound (19) to form a leaving group.
  • modifying group used include para-toluenesulfonyl group (tosyl group) and trifluoromethanesulfonyl group.
  • base used include sodium hydride and potassium carbonate.
  • solvent used in the reaction include tetrahydrofuran, acetonitrile, toluene and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • Compound (20) can also be obtained by treating the above-mentioned base after substituting the hydroxyl group of compound (19) with a halogen group.
  • Synthesis of Compound (A-2) from Compound (20) Compound (A-2) is compound (A-1) from Compound (5) to Compound (7) or Compound (8) to Compound (20). ), Or from the compound (9) through the compound (10) and the compound (11) to the compound (A-1) by appropriately selecting and using the appropriate reaction conditions. .
  • the compound (A-1) is a racemic compound having an asymmetric carbon, it is possible to perform optical resolution using a chiral column by liquid chromatography under appropriate conditions at this point, or in subsequent steps. It is also possible to do.
  • (B) is a commercially available product, or can be easily synthesized from a commercially available product by a method known in the literature, or by the method shown in the Examples below.
  • Commercial products can be obtained from Tokyo Chemical Industry Co., Ltd.
  • R 10 represents a hydrogen atom or a carboxylic acid protecting group.
  • the protecting group for carboxylic acid include a methyl group, an ethyl group, a tert-butyl group, and a benzyl group.
  • R 10 of the compound (B-1) is a protecting group other than a hydrogen atom, it must be deprotected before condensation with (A).
  • the method of deprotection varies depending on the type of protecting group, but may be hydrolyzed.
  • R 10 is a methyl group, an ethyl group, a benzyl group or the like
  • the compound (B-1) is treated with sodium hydroxide, hydroxide It can be obtained by treating with a base such as potassium, lithium hydroxide or potassium tert-butoxide, or hydrochloric acid, para-toluenesulfonic acid or the like.
  • examples of the solvent used for the reaction include methanol, ethanol, water, tetrahydrofuran, dioxane, and the like, or a mixed solvent thereof, and an organic solvent that can be mixed with water at an arbitrary ratio is preferable.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • R 10 is a tert-butyl group or the like
  • examples of the solvent used in the reaction include methylene chloride, chloroform, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from ⁇ 20 ° C. to around 100 ° C.
  • Compound (21) can be obtained by reacting compound (A) with carboxylic acid compound (B-1) in the presence of a condensing agent.
  • a condensing agent O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU), 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholine (DMT-MM), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC) and the like.
  • the solvent examples include ethanol, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • (D) is a commercially available product, or can be easily synthesized from a commercially available product by a method known in the literature, or by a method shown in Examples described later.
  • Commercial products can be obtained from Tokyo Chemical Industry Co., Ltd.
  • a commercially available product or an appropriately synthesized compound (D-1) can be obtained by reacting with hydroxylamine.
  • a commercially available product (D-1) can be obtained from Wako Pure Chemical Industries, Ltd.
  • the solvent used in the reaction include methanol, ethanol, dimethyl sulfoxide, water, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • Compound (23) Compound (22) and compound (B-2) can be obtained by reacting in the presence of a condensing agent.
  • Condensation agents used include O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU), 1,1′-carbonyl And diimidazole (CDI).
  • the solvent used in the reaction include tetrahydrofuran, acetonitrile, N, N-dimethylformamide, toluene and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 150 ° C. or the boiling point of the solvent, but preferably in the range from about room temperature to 120 ° C.
  • W is W B below (* binds to R 4 )
  • Synthesis of compound (24) Compound (B-2) can be obtained by reacting with chlorosulfonyl isocyanate and then treating with N, N-dimethylformamide.
  • the solvent used in the reaction include acetonitrile, methylene chloride, toluene, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Synthesis of Compound (25) It can be obtained by reacting compound (24) with hydroxylamine.
  • the solvent used for the reaction include methanol, ethanol, water and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • Compound (25) can be obtained by reacting compound (25) with carboxylic acid compound (D-2) in the presence of a condensing agent.
  • carboxylic acid (D-2) commercially available from Tokyo Kasei Kogyo Co., Ltd. or those appropriately synthesized from commercially available products can be used.
  • Condensation agents used include O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU), 1,1′-carbonyl Examples include diimidazole (CDI), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC), etc.
  • Solvents include tetrahydrofuran, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene and the like. Or a mixed solvent thereof is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 150 ° C. or the boiling point of the solvent, but is preferably in the range from around room temperature to 150 ° C.
  • W is the following W C (* binds to R 4 )
  • R 4 and L are as defined above.
  • It can be obtained by reacting the synthetic carboxylic acid compound (B-2) of compound (27) with hydrazine in the presence of a condensing agent.
  • Condensation agents used include O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU), 1,1′-carbonyl Examples include diimidazole (CDI), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC), etc.
  • Solvents include tetrahydrofuran, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene and the like. Or a mixed solvent thereof is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • carboxylic acid (B-2) can also be obtained by converting carboxylic acid (B-2) to acid chloride and reacting with hydrazine in the presence of a base.
  • the reagent for converting carboxylic acid to acid chloride include thionyl chloride and oxalyl chloride.
  • Solvents used for the reaction include tetrahydrofuran, N, N-dimethylformamide, methylene chloride, toluene and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Examples of the base used for the reaction between acid chloride and hydrazine include triethylamine and pyridine.
  • Examples of the solvent used in the reaction include tetrahydrofuran, acetonitrile, methylene chloride, toluene and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • the carboxylic acid (B-2) can be obtained by reacting with hydrazine after being led to an ester.
  • the conversion method from carboxylic acid to ester include heating in the presence of an acid catalyst in alcohol or a method using a reagent of diazomethanes.
  • the solvent used in the reaction between the ester and hydrazine include methanol, ethanol, water, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • Compound (28) can be obtained by reacting carboxylic acid compound (D-2) with compound (27) in the presence of a condensing agent.
  • Condensation agents used include O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU), 1,1′-carbonyl Examples include diimidazole (CDI), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC), etc.
  • Solvents include tetrahydrofuran, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene and the like. Or a mixed solvent thereof is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • carboxylic acid (D-2) can also be obtained by converting carboxylic acid (D-2) to acid chloride and reacting with compound (27) in the presence of a base.
  • the reagent for converting carboxylic acid to acid chloride include thionyl chloride and oxalyl chloride.
  • Solvents used for the reaction include tetrahydrofuran, N, N-dimethylformamide, methylene chloride, toluene and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Examples of the base used for the reaction between acid chloride and hydrazine include triethylamine and pyridine.
  • Examples of the solvent used in the reaction include tetrahydrofuran, acetonitrile, methylene chloride, toluene and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Compound (28) can also be obtained from compound (D-2) via compound (29) under the same reaction conditions by changing the order of the carboxylic acid compounds used.
  • the compound (30) can be obtained by reacting the compound (28) with a dehydrating agent.
  • a dehydrating agent used include phosphoryl chloride, polyphosphoric acid, sulfuric acid, triphenylphosphine / iodine, and tosylic acid.
  • the solvent used for the reaction include acetonitrile, methylene chloride, dichloroethane, a mixed solvent thereof, and a solvent-free solvent, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 150 ° C. or the boiling point of the solvent, but preferably in the range from about room temperature to 120 ° C.
  • W is W F below (* binds to R 4 )
  • W is W E below (* binds to R 4 )
  • the compound (D-1) can be obtained by reacting with hydrochloric acid gas or acetyl chloride in the presence of ethanol.
  • the solvent used in the reaction include ethanol, tetrahydrofuran, dioxane, diethyl ether, methylene chloride, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Compound (32) can be obtained by reacting the above described compound (27) with a base.
  • the base used include triethylamine, N, N-diisopropylethylamine and the like.
  • the solvent used for the reaction include ethanol, tetrahydrofuran, acetonitrile, and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 180 ° C. or the boiling point of the solvent, but preferably in the range from around room temperature to 150 ° C.
  • W is the following W H (* binds to R 4 )
  • the compound (34) can be obtained by reducing the synthetic compound (B-2).
  • the reducing agent that can be used include lithium aluminum hydride, borane-tetrahydrofuran complex, and the like.
  • the solvent used in the reaction include tetrahydrofuran, diethyl ether, and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from ⁇ 20 ° C. to 100 ° C.
  • the compound (35) can be obtained by oxidizing the compound (34).
  • the oxidizing agent used include Dess-Martin reagent or pyridinium chlorochromate.
  • the solvent used for the reaction include methylene chloride, chloroform and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • the compound (35) can be obtained by reacting with a Gilbert reagent or Bestman reagent in the presence of a base.
  • a base include tert-butoxide potassium and potassium carbonate.
  • the solvent used in the reaction include methanol, tetrahydrofuran, methylene chloride and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • the compound (D-3) can be obtained by diazotizing the amino group and then reacting with sodium azide.
  • Compound (D-3) can be obtained as a commercially available product from Tokyo Kasei Kogyo Co., Ltd. or the like, or can be synthesized appropriately from a commercially available product.
  • Examples of the diazotization method include a method using sodium nitrite under acidic conditions, but are not particularly limited.
  • Examples of the acidic solvent used include hydrochloric acid, sulfuric acid, acetic acid and the like, or a mixed solvent thereof.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Synthesis of compound (38) Compound (37) and compound (36) can be obtained by reacting in the presence of a copper catalyst.
  • a copper catalyst used include copper iodide and copper sulfate.
  • the solvent used in the reaction include tert-butyl alcohol, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, methylene chloride and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • W is W G below (* binds to R 4 )
  • R 4 and L are as defined above.
  • It can be obtained by reacting the synthetic carboxylic acid compound (B-2) of compound (39) with N, O-dimethylhydroxylamine in the presence of a condensing agent.
  • Condensation agents used include O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU), 1,1′-carbonyl Examples include diimidazole (CDI), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC), etc.
  • Solvents include tetrahydrofuran, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene and the like. Or a mixed solvent thereof is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C. It can also be obtained by converting carboxylic acid (B-2) to acid chloride and reacting with N, O-dimethylhydroxylamine in the presence of a base.
  • Examples of the reagent for converting carboxylic acid to acid chloride include thionyl chloride and oxalyl chloride.
  • Solvents used for the reaction include tetrahydrofuran, N, N-dimethylformamide, methylene chloride, toluene and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Examples of the base used for the reaction between acid chloride and hydrazine include triethylamine and pyridine.
  • Examples of the solvent used in the reaction include tetrahydrofuran, acetonitrile, methylene chloride, toluene and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • the compound (39) can be obtained by reacting with methyllithium or methylmagnesium bromide.
  • the solvent used in the reaction include tetrahydrofuran, diethyl ether, and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, but is preferably in the range from ⁇ 78 ° C. to 50 ° C.
  • the compound (40) can be obtained by reacting with a brominating agent.
  • the brominating agent used include bromine, N-bromosuccinimide, copper bromide and the like.
  • the solvent used in the reaction include methanol, chloroform, carbon tetrachloride, acetic acid and the like, or mixed solvents thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • the compound (41) can be obtained by reacting with sodium azide.
  • the solvent used in the reaction include methanol, ethanol, acetic acid, water, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • the compound (42) can be obtained by catalytic hydrogenation in the presence of a palladium catalyst and hydrochloric acid.
  • the solvent used in the reaction include methanol, ethanol and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • the compound (44) can be obtained by reacting the compound (43) with the carboxylic acid compound (B-2) in the presence of a condensing agent.
  • a condensing agent O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU), 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholine (DMT-MM), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC) and the like.
  • the solvent examples include tetrahydrofuran, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • W is W D below (* binds to R 4 )
  • W is W K below (* binds to R 4 )
  • Synthesis of Compound (47) can be obtained by appropriately selecting and using the reaction conditions described in the above production method of compound (41) for compound (D-4).
  • Compound (D-4) may be a commercially available product obtained from Enamine Co., etc., or may be synthesized appropriately from a commercially available product.
  • Synthesis of Compound (48) The compound (47) can be obtained by reacting with hexamethylenetetraamine and then treating with hydrochloric acid. Examples of the solvent used in the reaction include methanol, tetrahydrofuran, chloroform and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C.
  • Synthesis of Compound (49) Compound (49) can be obtained by appropriately selecting and using the reaction conditions described in the production method of compound (44) for compound (48) and compound (B-2).
  • Synthesis of Compound (50) The compound (50) can be obtained by appropriately selecting and using the reaction conditions described in the production method of the compound (30) for the compound (49).
  • W is W I below (* binds to R 4 )
  • Compound (D-5) can be obtained by reacting with trimethylsilylacetylene in the presence of copper iodide and a palladium metal catalyst and a base.
  • Compound (D-5) can be obtained as a commercially available product from Tokyo Kasei Kogyo Co., Ltd. or the like, or it can be synthesized appropriately from a commercially available product.
  • the palladium metal catalyst used include tetrakis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphine) palladium dichloride, palladium acetate / triphenylphosphine, and the like.
  • Examples of the base used include triethylamine and diethylamine.
  • Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, benzene, toluene and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • Compound (51) can be obtained by reacting with a base.
  • the base used include potassium carbonate, potassium hydroxide and tetrabutylammonium fluoride.
  • the solvent used in the reaction include methanol, tetrahydrofuran, dioxane, methylene chloride, water and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • the compound (35) described above can be obtained by reacting with hydroxylamine.
  • the solvent used in the reaction include methanol, water and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • Compound (53) can be obtained by reacting with N-chlorosuccinimide and then reacting with Compound (52) in the presence of a base.
  • the base used include triethylamine.
  • the solvent used in the reaction include N, N-dimethylformamide, methylene chloride, and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • Compound (54) can also be obtained by reacting compound (52) and compound (53) with sodium hypochlorite in the presence of a base.
  • Examples of the base used include triethylamine.
  • Examples of the solvent used in the reaction include methylene chloride, water and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • W is W L below (* binds to R 4 )
  • Production method 15 can be synthesized using, for example, the following production method 15. Production method 15
  • R 15 represents any one of a methoxy group, an ethoxy group, and a chlorine atom.
  • the compound (55) can be obtained by treating the compound (D-4) with a base and then reacting it with the compound (B-3) or the compound (39) described above.
  • the base used include sodium hydride, potassium tert-butoxide, sodium methoxide, lithium bis (trimethylsilyl) amide and the like.
  • the solvent used in the reaction include ethanol, tetrahydrofuran, diethyl ether, benzene, toluene, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C.
  • Compound (55) can be obtained by reacting with hydrazine.
  • the solvent used in the reaction include methanol, ethanol, tetrahydrofuran, acetic acid and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • W is W M below (* binds to R 4 )
  • the compound (57) can be obtained by reacting the compound (D-1) with lithium bis (trimethylsilyl) amide and then treating with an acid.
  • the solvent used in the reaction include tetrahydrofuran, diethyl ether, toluene, and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • the compound (58) can be obtained by reacting the compound (57) and the above-described compound (41) in the presence of a base.
  • a base include potassium carbonate and sodium bicarbonate.
  • the solvent used for the reaction include, but are not limited to, ethanol, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene, water and the like, or a mixed solvent thereof.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • W is W N below (* is bonded to R 4 )
  • the compound (59) can be obtained by reacting trimethylsilylacetylene treated with n-butyllithium or ethylmagnesium bromide with the above described compound (39).
  • the solvent used in the reaction include tetrahydrofuran, diethyl ether, hexane, and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from ⁇ 78 ° C. to around room temperature.
  • Compound (60) can be obtained by appropriately selecting and using the reaction conditions described in the above production method of compound (52) for compound (59).
  • the compound (61) can be obtained by reacting the compound (60) with the above-described compound (57) in the presence of a base.
  • the base used include sodium carbonate and potassium carbonate.
  • the solvent used in the reaction include tetrahydrofuran, acetonitrile, water and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • W is W J below (* binds to R 4 )
  • Synthesis of Compound (62) Compound (62) can be obtained by appropriately selecting and using the reaction conditions described in the above production method of compound (53) for compound (D-6).
  • Compound (D-6) can be obtained as a commercially available product from Enamine or the like, or can be synthesized appropriately from a commercially available product.
  • the compound (63) can be obtained by appropriately selecting and using the reaction conditions described in the production method of the compound (54) for the compound (62) and the compound (36) described above.
  • W is W A below (* is bonded to R 4 )
  • Synthesis of Compound (65) Compound (64) can be obtained by reacting with compound (B-3).
  • the solvent used in the reaction include methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide and the like, or mixed solvents thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 150 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • W is W B below (* binds to R 4 )
  • the compound (66) can be obtained by converting the carboxylic acid of the compound (D-2) into an acid chloride.
  • the reagent for converting carboxylic acid to acid chloride include thionyl chloride and oxalyl chloride.
  • Solvents used for the reaction include tetrahydrofuran, N, N-dimethylformamide, methylene chloride, toluene and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • W is the following W C (* binds to R 4 )
  • Examples of the condensing agent used include (benzotriazo-1-yl) tris (dimethylamino) phosphonium tetrafluorophosphate (BOP).
  • Examples of the solvent used in the reaction include tetrahydrofuran, N, N-dimethylformamide, methylene chloride, and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • W is W F below (* binds to R 4 )
  • Compound (72) can be obtained by reacting compound (D-4) in the presence of a palladium catalyst and a base.
  • Compound (72) can be obtained from Enamine.
  • Compound (73) can be obtained as a commercially available product from Sigma-Aldrich, Inc., or can be synthesized as appropriate.
  • the palladium catalyst used include tetrakis (triphenylphosphine) palladium.
  • Examples of the base used include potassium carbonate and sodium carbonate.
  • the solvent used in the reaction include ethanol, tetrahydrofuran, dimethoxyethane, toluene, water, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 150 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • Compound (73) can be obtained by reacting compound (B-3) in the presence of a base.
  • a base include N, N-diisopropylethylamine and sodium bicarbonate.
  • the solvent used in the reaction include tetrahydrofuran, N, N-dimethylformamide, N-methylpyrrolidin-2-one, water, and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 200 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 150 ° C.
  • the compound represented by the general formula (I) synthesized by the above production method has a protecting group on a hydroxyl group, an amino group, a nitrogen atom in a heterocyclic ring, etc., it can be deprotected.
  • the deprotection conditions differ depending on the protecting group.
  • the protecting group is a carbamate group such as a tert-butoxycarbonyl group, it can be deprotected by treatment with hydrochloric acid or trifluoroacetic acid.
  • the solvent used here include dioxane, ethyl acetate, methylene chloride, and a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C.
  • the protecting group is, for example, a trifluoroacetyl group
  • it can be deprotected by treatment with a base such as sodium hydroxide or potassium hydroxide.
  • a base such as sodium hydroxide or potassium hydroxide.
  • the solvent used here include methanol, ethanol, water, tetrahydrofuran, dioxane, and the like, or a mixed solvent thereof.
  • An organic solvent that can be mixed with water at an arbitrary ratio is preferable.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • the protecting group is an aralkyl group such as a benzyl group
  • it can be deprotected by catalytic hydrogen reduction in the presence of a palladium catalyst or by treatment with a strong acid such as trifluoroacetic acid.
  • a strong acid such as trifluoroacetic acid.
  • the solvent used for the catalytic hydrogen reduction reaction include methanol, ethanol and the like.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
  • Examples of the solvent used in the case of a strong acid treatment include methylene chloride and no solvent.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C.
  • the protecting group is a silyl-based protecting group such as a trimethylsilyl group, it can be deprotected by treatment with hydrochloric acid or the like or treatment with fluoride ions.
  • the solvent used in the reaction include ethanol, tetrahydrofuran, dioxane, water and the like, or a mixed solvent thereof, and are not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • the compound represented by the general formula (I) When the compound represented by the general formula (I) has a hydroxyl group, an amino group or a nitrogen atom in the heterocyclic ring which is deprotected by the above-described production method or the like, it can be modified by alkylation or the like.
  • the conditions for alkylation include conditions for reacting with alkyl halide or alkyl trifluoromethanesulfonate in the presence of a base.
  • the base used include triethylamine, N, N-diisopropylethylamine, and potassium carbonate.
  • the solvent to be used examples include, but are not limited to, tetrahydrofuran, dioxane, N, N-dimethylformamide, methylene chloride and the like, or a mixed solvent thereof.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • the functional group to be modified is an amino group or a nitrogen atom in the heterocyclic ring, it can be alkylated by reacting with the corresponding aldehyde or ketone in the presence of a reducing agent.
  • Examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like.
  • Examples of the solvent to be used include methanol, ethanol, water, tetrahydrofuran, dioxane, N, N-dimethylformamide, methylene chloride, acetic acid and the like, or a mixed solvent thereof, and is not particularly limited.
  • the reaction temperature is usually in the range from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
  • an optically active raw material compound is used, or the compound according to the present invention is synthesized by using an asymmetric synthesis or asymmetric induction method. Alternatively, it can be obtained by isolating the synthesized compound of the present invention using a conventional optical resolution method or separation method, if desired.
  • the compound represented by the general formula (I) includes those labeled with an atomic isotope or a radioisotope. For example, the compound is labeled with an isotope instead of the raw material in the production method of the present invention. It can manufacture by using a raw material.
  • the compound represented by the general formula (I) of the present invention When the compound represented by the general formula (I) of the present invention has a basic group, it can be converted into a salt by reacting with an acid.
  • the compound represented by the general formula (I) of the present invention or a salt thereof absorbs a certain solvent by being left in a solvent or recrystallized in a solvent, You may be able to.
  • the compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms.
  • the administration form include oral administration by tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), etc., or injections (intravenous, intramuscular, subcutaneous or intraperitoneal administration), Examples include parenteral administration such as instillation and suppository (rectal administration).
  • These various preparations are usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. as main ingredients in accordance with conventional methods. It can be formulated with the resulting adjuvant.
  • excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose; disintegrators such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, sodium lauryl sulfate Moisturizers such as glycerin and starch; Adsorbents such as starch
  • the tablet which gave the normal coating for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.
  • excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; laminaran, Disintegrants such as agar can be used.
  • a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.
  • solutions, emulsions or suspensions When used as an injection, it can be used as a solution, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood.
  • the solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters.
  • a sufficient amount of sodium chloride, glucose or glycerin may be included in the preparation to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. may be included. You may go out.
  • the above-mentioned preparation may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as required, and may further contain other medicines.
  • the amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.
  • the amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, particularly human), but in the case of oral administration, the upper limit is 2000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg ( Preferably 1 mg, more preferably 10 mg) is administered to adults 1 to 6 times per day depending on the symptoms.
  • nuclear magnetic resonance (hereinafter, 1 H NMR: 400 MHz or 500 MHz) spectra were described with chemical shift values as ⁇ values (ppm) using tetramethylsilane as a standard substance.
  • the measurement solvent is shown in parentheses.
  • the splitting pattern is indicated by s for a single line, d for a double line, t for a triple line, q for a quadruple line, m for a multiple line, and br for broad.
  • the symbol “MS” means “mass spectrometry”.
  • the ionization method is shown in parentheses.
  • Example 1 4- [3- (5-Chloro-2-methoxyphenyl) -1,2,4-oxadiazol-5-yl] -N- (1,5-dimethyl-3-oxo-2 -Phenyl-2,3-dihydro-1H-pyrazol-4-yl) -3,3-dimethylbutanamide
  • Step 1 A solution of 3.02 g (19.3 mmol) of 5-chloro-2-methoxybenzaldehyde 5-chloro-2-hydroxybenzaldehyde in 70 mL of N, N-dimethylformamide was cooled to 0 ° C., and 0.873 g of sodium hydride was added. (20.0 mmol) was added at once and stirred at 0 ° C. for 15 minutes. Next, 2.40 mL (5.47 g, 39.0 mmol) of iodomethane was added and stirred for 10 minutes, and then the temperature was raised to room temperature and stirred for 16 hours.
  • Step 2 5-Chloro-2-methoxybenzonitrile 3.10 g (18.2 mmol) of 5-chloro-2-methoxybenzaldehyde synthesized in Step 1, 2.25 g (27.4 mmol) of sodium acetate and hydroxylamine hydrochloride To a mixture of 1.52 g (21.9 mmol), 25 mL of formic acid was added and stirred at 110 ° C. for 14 hours. The mixture was cooled to room temperature, added with 40 mL of water, and extracted three times with chloroform. The organic layers were combined and washed sequentially with 5% aqueous ammonia and saturated brine.
  • Step 3 5-Chloro-N′-hydroxy-2-methoxybenzamidine 2.92 g (17.4 mmol) of 5-chloro-2-methoxybenzonitrile synthesized in Step 2 was mixed with 25 mL of ethanol and hydroxylamine (50% aqueous solution). ) 5.38 g (81.4 mmol) was added, and the mixture was stirred at room temperature for 2 hours and at 55 ° C. for 23 hours. The solid obtained by distilling off the solvent was filtered and washed with diethyl ether to obtain 2.63 g (yield: 75.2%) of the title compound as a solid.
  • Step 4 methyl 4- [3- (5-chloro-2-methoxyphenyl) -1,2,4-oxadiazol-5-yl] -3,3-dimethylbutanoate
  • 5-chloro-2-methoxybenzoic acid 5-methoxy-3,3-dimethyl-5-oxopentanoic acid is replaced with 5-amino-N- (1,5-dimethyl-3-oxo-2-phenyl).
  • -Chloro-N'-hydroxy-2-methoxybenzamidine synthesized in Step 3 instead of -2,3-dihydro-1H-pyrazol-4-yl) -5-hydroxyimino-3,3-dimethylpentanamide
  • the title compound was obtained as an oily substance.
  • Step 5 4- [3- (5-Chloro-2-methoxyphenyl) -1,2,4-oxadiazol-5-yl] -3,3-dimethylbutanoic acid 4- [4] synthesized in Step 4 3- (5-Chloro-2-methoxyphenyl) -1,2,4-oxadiazol-5-yl] -3,3-dimethylbutanoate 416 mg (1.23 mmol) in tetrahydrofuran 6.1 mL / methanol 6 To the 1 mL solution, 6.10 mL (6.10 mmol) of 1N aqueous sodium hydroxide solution was added and stirred at room temperature for 15 hours.
  • Step 6 4- [3- (5-Chloro-2-methoxyphenyl) -1,2,4-oxadiazol-5-yl] -N- (1,5-dimethyl-3-oxo-2- Phenyl-2,3-dihydro-1H-pyrazol-4-yl) -3,3-dimethylbutanamide (1R, 3S) -3- [5- (5-chloro-2-ethoxy) of Example 6, Step 6 4- [3- (5-chloro-2-methoxyphenyl) -1,2,4 synthesized in Step 5 instead of (phenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid A similar reaction was carried out using -oxadiazol-5-yl] -3,3-dimethylbutanoic acid to obtain the title compound as a solid.
  • Step 1 Methyl chloride (22 mL) in methyl 4-cyano-3,3-dimethylbutanoate (5-methoxy-3,3-dimethyl-5-oxopentanoic acid) (5.01 g, 28.8 mmol) was refluxed at 55 ° C. The mixture was stirred, and 2.75 mL (4.47 g, 31.6 mmol) of chlorosulfonyl isocyanate was added in 5 portions every 3 minutes, followed by stirring for 60 minutes.
  • Step 2 4-cyano-3,3-dimethylbutanoic acid To a solution of methyl 4-cyano-3,3-dimethylbutanoate synthesized in Step 1 (1.74 g, 11.2 mmol) in tetrahydrofuran 40 mL / methanol 40 mL, 1N Sodium hydroxide aqueous solution 40.0mL (40.0mmol) was added, and it stirred at room temperature for 20 hours. After distilling off the organic solvent, 40 mL of water was added and washed once with diethyl ether.
  • Step 3 4-cyano-N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -3,3-dimethylbutanamide
  • Example 40 instead of (1R, 3S) -3- [5- (5-chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid in step 6, A similar reaction was carried out using the synthesized 4-cyano-3,3-dimethylbutanoic acid to obtain the title compound as a solid.
  • Step 4 5-amino-N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -5-hydroxyimino-3,3-dimethyl 4-cyano-N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -3,3-dimethylbutanamide synthesized in pentanamide step 3 Add 3.0 mL of ethanol (20 mL) to 3.07 g (9.42 mmol), then add hydroxylamine hydrochloride (3.28 g, 49.7 mmol) in ethanol (6.0 mL) at 60 ° C for 5.5 hours, and further to 75 ° C.
  • Step 5 4- [5- (5-Chloro-2-methoxyphenyl) -1,2,4-oxadiazol-3-yl] -N- (1,5-dimethyl-3-oxo-2- Phenyl-2,3-dihydro-1H-pyrazol-4-yl) -3,3-dimethylbutanamide 5-chloro-2-methoxybenzoic acid 200 mg (1.07 mmol) and O- (7-azabenzotriazole-1 N, N-diisopropylethylamine in a solution of 474 mg (1.25 mmol) of N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU) in 4.4 mL of N, N-dimethylformamide 0.535 mL (397 mg, 3.07 mmol) was added and stirred at room temperature for 25 minutes.
  • HATU trimethylronium hexafluorophosphate
  • the extract was washed once with saturated brine and dried over anhydrous sodium sulfate.
  • the obtained solid was filtered and washed with ethyl acetate / diethyl ether to obtain 288 mg (yield 55.2%) of the title compound as a solid.
  • Step 1 3.00 g (19.2 mmol) of 5-chloro-2-ethoxybenzaldehyde 5-chloro-2-hydroxybenzaldehyde was dissolved in 96 mL of acetone, and 5.30 g (38.3 mmol) of potassium carbonate and ethane iodide 1 .84 mL (3.59 g, 23.0 mmol) was added at room temperature, and the mixture was stirred at 60 ° C. for 9 hours. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and hexane.
  • Step 2 5-Chloro-2-ethoxybenzonitrile
  • Step 2 5-Chloro-2-ethoxybenzonitrile
  • Step 2 5-Chloro-2-ethoxybenzonitrile
  • Step 3 Ethyl 5-chloro-2-ethoxybenzenecarboxyimidate 0.500 g (2.75 mmol) of 5-chloro-2-ethoxybenzonitrile synthesized in Step 2 was dissolved in 3.86 mL of ethanol, and the solution was placed in an ice bath. 3.13 mL (3.47 g, 44.1 mmol) of acetyl chloride was added and stirred at room temperature for 24 hours. Volatiles were removed under reduced pressure, 1,4-dioxane and toluene were added, and the volatiles were removed again under reduced pressure.
  • Step 4 4-Amino-5- (methoxymethyl) -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 3-oxo-5- [ The reaction was carried out in the same manner as in Step 53 of Example 53 using ethyl 4-methoxy-3-oxobutanoate instead of (2,2,2-trifluoroacetyl) amino] pentanoic acid. Was obtained as a solid.
  • Step 5 5- ⁇ [5- (Methoxymethyl) -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] amino ⁇ -3,3-dimethyl- Methyl 5-oxopentanoate 5-methoxy-3,3-dimethyl-5-oxopentanoic acid 3.73 g (21.4 mmol) was dissolved in 71.0 mL of N, N-dimethylformamide, and O- (7- Azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU) 8.15 g (21.4 mmol), N, N-diisopropylethylamine 3.73 mL ( 2.77 g, 21.4 mmol) and 4-amino-5- (methoxymethyl) -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazole synthesized
  • Step 6 5-hydrazino-N- [5- (methoxymethyl) -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] -3,3-dimethyl -5-Oxopentanamide 5- ⁇ [5- (methoxymethyl) -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] amino ⁇ synthesized in Step 5 To a solution of 3.00 g (7.70 mmol) of methyl 3,3-dimethyl-5-oxopentanoate in 15.4 mL of ethanol was added 9.64 g (193 mmol) of hydrazine monohydrate at room temperature, and the mixture was stirred at room temperature for 24 hours.
  • Step 7 4- [5- (5-Chloro-2-ethoxyphenyl) -4H-1,2,4-triazol-3-yl] -N- [5- (methoxymethyl) -1-methyl-3 -Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] -3,3-dimethylbutanamide 0.0292 g of ethyl 5-chloro-2-ethoxybenzenecarboxyimidate synthesized in Step 3 ( 0.128 mmol) and 5-hydrazino-N- [5- (methoxymethyl) -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] synthesized in Step 6 0.0500 g (0.128 mmol) of -3,3-dimethyl-5-oxopentanamide was dissolved in 0.65 mL of 2-propanol, and N, N-diisopropylethy
  • Example 4 4- [5- (5-Chloro-2-methoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo-2) -Phenyl-2,3-dihydro-1H-pyrazol-4-yl) -3,3-dimethylbutanamide
  • Step 1 5- [2- (5-chloro-2-methoxybenzoyl) hydrazino] -3,3-dimethyl-5-oxopentanoic acid methyl 5-chloro-2-methoxybenzohydrazide 0.500 g (2.49 mmol) ) Is dissolved in 5.0 mL of N, N-dimethylformamide and 0.478 g (2.74 mmol) of 5-methoxy-3,3-dimethyl-5-oxopentanoic acid and 0.370 g of 1-hydroxybenzotriazole ( 2.74 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) 0.526 g (2.74 mmol) were added, and the mixture was stirred at room temperature for 15 hours.
  • EDC.HCl 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • Step 2 0.655 g of methyl triphenylphosphine 4- [5- (5-chloro-2-methoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethylbutanoate ( 2.50 mmol) was dissolved in 11.0 mL of methylene chloride, and 1.23 g (5.21 mmol) of hexachloroethane and 0.871 mL (0.632 g, 6.25 mmol) of triethylamine were added in an ice bath and stirred for 5 minutes.
  • Step 3 4- [5- (5-Chloro-2-methoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethylbutanoic acid synthesized in Step 2 0.57 g (1.68 mmol) of methyl 5- (5-chloro-2-methoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethylbutanoate was added to 8.4 mL of methanol. After dissolution, 2.52 mL (2.52 mmol) of 1N aqueous sodium hydroxide solution was added at room temperature. The mixture was stirred at 50 ° C.
  • Step 4 4- [5- (5-Chloro-2-methoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo-2- Phenyl-2,3-dihydro-1H-pyrazol-4-yl) -3,3-dimethylbutanamide (1R, 3S) -3- [5- (5-chloro-2-ethoxy) of Example 6, Step 6 4- [5- (5-chloro-2-methoxyphenyl) -1,3,4, synthesized in Step 3, instead of (phenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid A similar reaction was performed using -oxadiazol-2-yl] -3,3-dimethylbutanoic acid to obtain the title compound as a solid.
  • Step 1 2- (6-chloro-2-pyridyl) -5-methyl-4H-pyrazol-3-one (6-chloro-2-pyridyl) hydrazine 51.2 g (357 mmol) and ethyl acetoacetate 45.1 mL (46.5 g, 357 mmol) was dissolved in 400 mL of ethanol and stirred at room temperature for 18 hours. The residue obtained by evaporating the reaction solution under reduced pressure was dissolved again in 400 mL of ethanol, 48.0 g (428 mmol) of potassium t-butoxide was added, and the mixture was stirred at room temperature for 3 days.
  • reaction solution was evaporated under reduced pressure, water was added to the residue, and 40 mL of concentrated hydrochloric acid was added. The precipitated solid was collected by filtration, washed with water, and dried to give 76.0 g of the title compound quantitatively as a solid.
  • Step 2 2- (6-Chloro-2-pyridyl) -1,5-dimethylpyrazol-3-one 2- (6-Chloro-2-pyridyl) -5-methyl-4H-pyrazole synthesized in Step 1 -7-one 76.0 g (357 mmol) was dissolved in 1000 mL of toluene, 145 mL (114 g, 3570 mmol) of methanol and 108 g (428 mmol) of 1,1 ′-(azadicarbonyl) dipiperidine, 176 mL (144 g) of tri-n-butylphosphine. , 0.714 mmol), and stirred at room temperature for 28 hours.
  • Step 3 1,5-Dimethyl-2- (6-methyl-2-pyridyl) pyrazol-3-one 2- (6-Chloro-2-pyridyl) -1,5-dimethylpyrazole- synthesized in Step 2 3-43 g (14.7 mmol) of 3-one was dissolved in 50 mL of 1,4-dioxane, 5 mL of water and 5.54 g (22.1 mmol) of trimethylboroxine (50% tetrahydrofuran solution), 6.10 g of potassium carbonate (44 0.1 mmol) and 1.70 g (1.47 mmol) of tetrakistriphenylphosphine palladium were added and stirred at 90 ° C. for 4 hours.
  • Step 4 1,5-Dimethyl-2- (6-methyl-2-pyridyl) -4-nitropyrazol-3-one 1,5-dimethyl-2- (6-methyl-2-) synthesized in Step 3
  • 3.17 g (15.6 mmol) of pyridyl) pyrazol-3-one was dissolved in 12 mL of concentrated nitric acid and stirred at 70 ° C. for 2 hours.
  • the reaction solution was returned to room temperature, poured into diethyl ether, and the precipitate was collected by filtration.
  • the obtained filtered product was suspended in ethyl acetate, insoluble matter was collected by filtration, washed with ethyl acetate and dried to give 1.87 g (yield 51.1%) of the title compound as a solid.
  • Step 5 4-Amino-1,5-dimethyl-2- (6-methyl-2-pyridyl) pyrazol-3-one 1,5-dimethyl-2- (6-methyl-2-) synthesized in Step 4 1.87 g (8.03 mmol) of pyridyl) -4-nitropyrazol-3-one was suspended in 20 mL of methylene chloride, 20 mL of ethanol, and 20 mL of methanol, 500 mg of 5% platinum sulfide carbon was added, and the mixture was stirred at room temperature for 8 hours in a hydrogen atmosphere. did.
  • Step 6 methyl 5- ⁇ [1,5-dimethyl-2- (6-methyl-2-pyridyl) -3-oxopyrazol-4-yl] amino ⁇ -3,3-dimethyl-5-oxopentanoate
  • 4-amino-5- (methoxymethyl) -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one instead of 4-amino-5- (methoxymethyl) -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one in Step 5 of Example 3, the 4-synthesized in Step 5 A similar reaction was carried out using amino-1,5-dimethyl-2- (6-methyl-2-pyridyl) pyrazol-3-one to obtain the title compound as a solid.
  • Step 7 N- [1,5-dimethyl-2- (6-methyl-2-pyridyl) -3-oxopyrazol-4-yl] -5-hydrazino-3,3-dimethyl-5-oxopentanamide 5- ⁇ [5- (methoxymethyl) -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] amino ⁇ -3,3 of step 6 of Example 3 5- ⁇ [1,5-dimethyl-2- (6-methyl-2-pyridyl) -3-oxopyrazol-4-yl] amino synthesized in Step 6 instead of methyl dimethyl-5-oxopentanoate ⁇ The reaction was conducted in the same manner using methyl 3,3-dimethyl-5-oxopentanoate to obtain the title compound as a solid.
  • Step 8 6- [2- (5-Chloro-2-ethoxybenzoyl) hydrazino] -N- [1,5-dimethyl-2- (6-methyl-2-pyridyl) -3-oxopyrazole-4- Yl] -3,3-dimethyl-5-oxopentanamide
  • 5-chloro-2-ethoxybenzoic acid (0.500 g, 1.09 mmol) was dissolved in 5.5 mL of N, N-dimethylformamide, and 1-hydroxy was dissolved at room temperature.
  • Step 9) 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- [1,5-dimethyl-2- (6-methyl) -2-Pyridyl) -3-oxo-2,3-dihydro-1H-pyrazol-4-yl] -3,3-dimethylbutanamide
  • Step 1 9.66 g (45.0 mmol) of methyl 5-chloro-2-ethoxybenzohydrazide 5-chloro-2-ethoxybenzoate was dissolved in 90 mL of ethanol, and 22.5 g (450 mmol) of hydrazine monohydrate at room temperature. ) And stirred at 80 ° C. for 4 hours and then stirred at 95 ° C. for 30 minutes. After cooling, the solvent was mostly distilled off under reduced pressure, and the precipitated solid was collected by filtration and washed with ethanol and hexane to obtain 7.93 g (yield 82.0%) of the title compound as a solid.
  • Step 2 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethylbutanoic acid Step 1-5 of Example 4 Using 5-chloro-2-ethoxybenzohydrazide synthesized in Step 1 instead of -chloro-2-methoxybenzohydrazide, the reaction was carried out in the same manner as in Step 3 of Example 4 to obtain the title compound. Obtained as a solid.
  • Step 3 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- [5- (methoxymethyl) -1-methyl-3 -Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] -3,3-dimethylbutanamide 4- [5- (5-chloro-2-ethoxyphenyl)-synthesized in Step 2 1,3,4-oxadiazol-2-yl] -3,3-dimethylbutanoic acid 0.399 g (1.18 mmol) was dissolved in 3.6 mL of N, N-dimethylformamide, and O- (7 -Azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU) 0.448 g (1.18 mmol), N, N-diisopropy
  • Example 7 4- [5- (5-Chloro-2-isopropoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- [5- (methoxymethyl) -1-methyl -3-Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] -3,3-dimethylbutanamide
  • Example 8 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethyl-N- (2-oxo-1 -Phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-d] [1,4] diazepin-3-yl) butanamide
  • Step 1 Ethyl acrylate (71.7 mL, 659 mmol) was added dropwise over 15 minutes to 99.6 g (659 mmol) of 2-benzyloxyethanamine under cooling with ethyl 3- (2-benzyloxyethylamino) propionate. After stirring at the same temperature for 20 minutes and then warming to room temperature, the mixture was further stirred for 18 hours to quantitatively obtain 165 g of the title compound as an oily substance.
  • Step 2 Ethyl 3- [2-benzyloxyethyl (tert-butoxycarbonyl) amino] ethyl propionate 165 g (656 mmol) of ethyl 3- (2-benzyloxyethylamino) propionate synthesized in Step 1 in 500 mL of methylene chloride To the solution, 120 mL (87.1 g, 861 mmol) of triethylamine was added, and a solution of 130 g (596 mmol) of di-tertbutyl dicarbonate in 150 mL of methylene chloride was added dropwise over 30 minutes under ice cooling. After raising the temperature to room temperature, the mixture was further stirred for 18 hours.
  • Step 3 3- [2-benzyloxyethyl (tert-butoxycarbonyl) amino] propionic acid
  • Step 4 Ethyl 5- [2-benzyloxyethyl (tert-butoxycarbonyl) amino] -3-oxopentanoate 3- [2-Benzyloxyethyl (tert-butoxycarbonyl) amino] propionic acid synthesized in Step 3 N, N′-carbonyldiimidazole (113 g, 697 mmol) was gradually added to a tetrahydrofuran (1000 mL) solution of 188 g (582 mmol). After stirring for 3 hours, 54.0 g (567 mmol) of magnesium chloride and 149 g (873 mmol) of monoethyl potassium malonate were added, and the mixture was further stirred for 22 hours.
  • Step 5 tert-Butyl N- (2-hydroxyethyl) -N- [2- (5-oxo-1-phenyl-4H-pyrazol-3-yl) ethyl] carbamate 5- [2 synthesized in Step 4
  • ethyl benzyloxyethyl (tert-butoxycarbonyl) amino] -3-oxopentanoate 222 g (565 mmol) in ethanol 1000 mL was added phenylhydrazine 56.0 mL (565 mmol) under ice-cooling, and the mixture was stirred for 30 minutes and then returned to room temperature. The mixture was further stirred for 7 hours.
  • the mixture was ice-cooled again, 76.1 g (678 mmol) of potassium tert-butoxide was gradually added, and the mixture was returned to room temperature and stirred for 22 hours.
  • the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 1200 mL of ethanol, 20 g of 20% palladium hydroxide-carbon catalyst was added, and the mixture was stirred at 50 ° C. for 13 hours in a hydrogen atmosphere.
  • the reaction mixture was allowed to cool, insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (137 g, 69.8%) as a solid.
  • Step 6 1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-2-one 55.0 g (158 mmol) of tert-butyl N- (2-hydroxyethyl) -N- [2- (5-oxo-1-phenyl-4H-pyrazol-3-yl) ethyl] carbamate synthesized in Step 5 in tetrahydrofuran 100 g (414 mmol) of cyanomethylenetributylphosphorane (CMBP) was added to a 500 mL / toluene 500 mL solution, and the mixture was heated and stirred at 70 ° C.
  • CMBP cyanomethylenetributylphosphorane
  • Step 7 3-Nitro-1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine
  • 1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] synthesized in Step 2-one 25.3 g (82.9 mmol) of diazepin-2-one was dissolved in 80 mL of trifluoroacetic acid, and 11.0 mL (249 mmol) of concentrated nitric acid was added dropwise at room temperature.
  • Step 8 3-Amino-1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine -2-one 3-nitro-1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,5-d] [synthesized in Step 7
  • a suspension of 1,4] diazepin-2-one (30.2 g, 81.6 mmol) in tetrahydrofuran (750 mL) / ethanol (750 mL) was added 5% palladium carbon catalyst (PH type) (7.00 g) under a hydrogen atmosphere at room temperature.
  • PH type palladium carbon catalyst
  • Step 9) 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethyl-N- [2-oxo-1- Phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-3-yl] butanamide
  • Example 6 instead of 4-amino-5- (methoxymethyl) -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one in step 3, 3-amino-1- synthesized in step 8 Phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-2-one 0.350 g (1.
  • Step 10 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethyl-N- (2-oxo-1- Phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-d] [1,4] diazepin-3-yl) butanamide 4- [5- (5-chloro-2) synthesized in Step 9 -Ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethyl-N- [2-oxo-1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-3-yl] butanamide (0.220 g, 0.333 mmol) was added to 2.2 mL of tetrahydrofuran and 1.1 mL of m
  • Step 1 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethyl-N- (6-methyl-2- Oxo-1-phenyl-5,6,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-3-yl) butanamide 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethyl-N- (2-oxo-1-phenyl-5,6,7,8 -0.159 g (0.281 mmol) of tetrahydro-4H-pyrazolo [1,5-d] [1,4] diazepin-3-yl) butanamide was dissolved in a mixed solvent of 1.4 mL of methanol and 1.4 mL of methylene chloride.
  • Example 10 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- ⁇ 5- [2- (dimethylamino) ethyl] -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl ⁇ -3,3-dimethylbutanamide
  • Step 1 Ethyl 5- (tert-butoxycarbonylamino) -3-oxopentanoate Instead of N-trifluoroacetyl- ⁇ -alanine in Step 1 of Example 53, 3- (tert-butoxycarbonylamino) propion A similar reaction was carried out using an acid to obtain the title compound as an oily substance.
  • Step 2 tert-Butyl N- [2- (3-oxo-2-phenyl-1H-pyrazol-5-yl) ethyl] carbamate 3-oxo-5-[(2,2 , 2-trifluoroacetyl) amino] pentanoate instead of ethyl 5- (tert-butoxycarbonylamino) -3-oxopentanoate synthesized in Step 1, the same reaction was conducted, and the title compound was solidified. Got as.
  • Step 3 benzyl 5- [2- (tert-butoxycarbonylamino) ethyl] -3-oxo-2-phenyl-1H-pyrazole-4-carboxylate tert-butyl N- [2- ( 10.6 g (35.1 mmol) of 3-oxo-2-phenyl-1H-pyrazol-5-yl) ethyl] carbamate was dissolved in 360 mL of 1,4-dioxane, and 5.72 g (77.2 mmol) of calcium hydroxide was dissolved. added. After the reaction mixture was stirred at 50 ° C.
  • Step 4 tert-Butyl N obtained in Step 3 of benzyl 5- [2- (tert-butoxycarbonylamino) ethyl] -1-methyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxylate -5.00 g (11.4 mmol) of [2- (3-oxo-2-phenyl-1H-pyrazol-5-yl) ethyl] carbamate was dissolved in 60 mL of methylene chloride, and 1.68 g (14.7 mmol) of potassium acetate And 1.68 mL (2.44 g, 14.9 mmol) of methyl trifluoromethanesulfonate were added, and the mixture was stirred at room temperature for 1.5 hours.
  • Step 5 5- [2- (tert-Butoxycarbonylamino) ethyl] -1-methyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxylic acid 5- [2- ( tert-butoxycarbonylamino) ethyl] -1-methyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxylate 3.21 g (7.11 mmol) was dissolved in ethanol 70 mL, and 10% palladium on carbon catalyst (M type) 2.0 g was suspended. After replacing the inside of the reaction system with hydrogen, the mixture was stirred at room temperature for 1 hour.
  • M type 10% palladium on carbon catalyst
  • Step 6 tert-butyl N- [2- (4-amino-2-methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) ethyl] carbamate synthesized in Step 5 2.48 g (6.86 mmol) of 5- [2- (tert-butoxycarbonylamino) ethyl] -1-methyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxylic acid was added to N, N-dimethyl It melt
  • the reaction mixture was added to a mixed solvent of N, N-dimethylformamide / water (35 mL / 35 mL) heated to 100 ° C. over 1.5 hours, and the mixture was further stirred at the same temperature for 1 hour. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Step 7 tert-butyl N- ⁇ 2- [4-( ⁇ 4- [5- (5-chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3, 3-dimethylbutanoyl ⁇ amino) -2-methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl] ethyl ⁇ carbamate 4-amino-5 of Example 6, Step 3 Instead of-(methoxymethyl) -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one, tert-butyl N- [2- (4-amino-2) synthesized in Step 6 was used.
  • Step 9 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- ⁇ 5- [2- (dimethylamino) ethyl]- 1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl ⁇ -3,3-dimethylbutanamide 4- [5- (5-chloro -2-Ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethyl-N- (2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H -Instead of pyrazolo [1,5-d] [1,4] diazepin-3-yl) butanamide, N- [5- (2-aminoethyl) -1-methyl-3-oxo- synthesized in Step 8 2-Phenyl-2,3-dihydro-1H-pyr
  • Example 11 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethyl-N- [1-methyl-5 -(1-Methylpyrrolidin-3-yl) -3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] butanamide
  • Step 1 3- (3-Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-5-yl) pyrrolidine-1-carboxylate tert-butyl N-trifluoroacetyl of Step 1 of Example 53 Using 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid instead of - ⁇ -alanine, the reaction was carried out in the same manner as in Step 2 of Example 53 to obtain the title compound as a solid.
  • Step 2 3- (2-Methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) pyrrolidine-1-carboxylate tert-butyl
  • Step 4 tert 3- (3-oxo-2-phenyl-1H-pyrazole synthesized in Step 1 instead of -butyl N- [2- (3-oxo-2-phenyl-1H-pyrazol-5-yl) ethyl] carbamate
  • a similar reaction was carried out using tert-butyl -5-yl) pyrrolidine-1-carboxylate to give the title compound as a solid.
  • Step 3 Synthesis in tert-butyl 3- (2-methyl-4-nitro-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) pyrrolidine-1-carboxylate 3- (2-methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) pyrrolidine-1-carboxylate 2.52 g (7.34 mmol) at room temperature Concentrated nitric acid (14.7 mL) was added, and the mixture was stirred at room temperature for 24 hours. After adding ice to the reaction solution, 15.0 mL of 8N aqueous sodium hydroxide solution was added in an ice bath.
  • Step 4 Synthesis in tert-butyl 3- (4-amino-2-methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) pyrrolidine-1-carboxylate 0.80 g (2.14 mmol) of tert-butyl 3- (2-methyl-4-nitro-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) pyrrolidine-1-carboxylate ) was dissolved in 21 mL of methanol and 0.415 g of 5% palladium on carbon catalyst was added under a nitrogen atmosphere. The reaction system was replaced with hydrogen gas and stirred at 50 ° C. for 4 hours.
  • Step 5 4- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethyl-N- [1-methyl-5 (1-Methylpyrrolidin-3-yl) -3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] butanamide
  • Step 7 tert-butyl N- [2- ( Instead of 4-amino-2-methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) ethyl] carbamate, the 3- (4-amino-2 synthesized in Step 4 -Methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) pyrrolidine-1-carboxylate with tert-butyl Perform the reaction in the same way It was obtained compound as a solid.
  • Step 1 6- ⁇ [5- (methoxymethyl) -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] amino ⁇ -3, 3-dimethyl- Methyl 6-oxohexanoate
  • 5-methoxy-3,3-dimethyl-5-oxopentanoic acid in Step 5 of Example 3 using 6-methoxy-4,4-dimethyl-6-oxohexanoic acid, The reaction was performed in the same manner to obtain the title compound as an oily substance.
  • Step 2 6- ⁇ [5- (methoxymethyl) -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] amino ⁇ -3, 3-dimethyl- 6-Oxohexanoic acid 4- [5- (5-Chloro-2-methoxyphenyl) -1,3,4-oxadiazol-2-yl] -3,3-dimethylbutanoic acid of Step 3 of Example 4 6- ⁇ [5- (methoxymethyl) -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] amino ⁇ -3 synthesized in Step 1 instead of methyl Then, the reaction was carried out in the same manner as in Step 3 of Example 4 using methyl 3-dimethyl-6-oxohexanoate to obtain the title compound as a solid.
  • Step 3 5- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- [5- (methoxymethyl) -1-methyl-3 -Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] -4,4-dimethylpentanamide 5-methoxy-3,3-dimethyl-5-oxopentane of Example 4, Step 1 6- ⁇ [5- (methoxymethyl) -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] amino ⁇ -3 synthesized in Step 2 instead of acid Thereafter, the reaction was carried out in the same manner as in Step 4 of Example 4 using 3-dimethyl-6-oxohexanoic acid to obtain the title compound as a solid.
  • Step 1 methyl 5- ⁇ (2R) -2- [tert-butyl (dimethyl) silyl] oxypropyl ⁇ -2-phenyl-4H-pyrazol-3-one (3R) -3-hydroxybutanoate 3.34 g (25.3 mmol) was dissolved in 100 ml of N, N-dimethylformamide, 5.17 g (75.9 mmol) of imidazole and 4.58 g (30.4 mmol) of t-butyldimethylsilyl chloride were added, and the mixture was stirred at room temperature for 6 hours. did. Methanol and water were added to stop the reaction, and the mixture was extracted with hexane.
  • N-dicyclohexylcarbodiimide (4.92 g, 30.4 mmol) and stirring at room temperature for 1 hour, 2.41 g of magnesium chloride was added. (25.3 mmol) and 6.46 g (38.0 mmol) of monoethyl potassium malonate were added, and the mixture was further stirred for 3 hours.
  • the reaction solution was diluted with 150 ml of ethyl acetate, and 100 ml of 1N hydrochloric acid was added under ice cooling. The organic layer was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 2 5- ⁇ (2R) -2- [tert-butyl (dimethyl) silyl] oxypropyl ⁇ -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one
  • Example 10 instead of the tert-butyl N- [2- (3-oxo-2-phenyl-1H-pyrazol-5-yl) ethyl] carbamate of Step 4 in step 5, 5- ⁇ (2R) -2- The same reaction was carried out using [tert-butyl (dimethyl) silyl] oxypropyl ⁇ -2-phenyl-4H-pyrazol-3-one to obtain the title compound as an oily substance.
  • Step 3 4-amino-5- ⁇ (2R) -2- [tert-butyl (dimethyl) silyl] oxypropyl ⁇ -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazole-3- 5- ⁇ (2R) -2- [tert-butyl (dimethyl) silyl] oxypropyl ⁇ -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 6 synthesized in on-step 2 .50 g (16.8 mmol) was dissolved in 200 mL of acetonitrile, and 1.99 ml (1.73 g, 16.8 mmol) of tert-butyl nitrite was added at 0 ° C., followed by stirring for 1 hour.
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the crude product obtained by concentrating the filtrate was dissolved in 300 ml of a mixed solution of ethanol-0.5N hydrochloric acid (2: 1), 18 g of zinc powder was added at 0 ° C., and the mixture was vigorously stirred for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added for neutralization, and the reaction solution was filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Step 4 4-amino-5-[(2R) -2-hydroxypropyl] -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 4-amino synthesized in Step 3 -5- ⁇ (2R) -2- [tert-butyl (dimethyl) silyl] oxypropyl ⁇ -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 3.39 g (9.
  • Step 5 tert-butyl 3- (2-ethoxy-2-oxoethylidene) cyclobutanecarboxylate 3.00 g (17.7 mmol) of tert-butyl 3-oxocyclobutanecarboxylate was dissolved in 100 ml of tetrahydrofuran, and (ethoxycarbonylmethylene ) 12.3 g (35.3 mmol) of triphenylphosphorane was added and stirred at 90 ° C. for 16 hours.
  • Step 6 3- ⁇ 2- [2- (5-Chloro-2-isopropoxybenzoyl) hydrazino] -2-oxoethyl ⁇ cyclobutanecarboxylate 3- (2-Ethoxy-2-synthesized in Step 5 1.98 g (8.26 mmol) of tert-butyl oxoethylidene) cyclobutanecarboxylate was dissolved in 50 ml of ethanol, 1.00 g of palladium carbon catalyst was added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated.
  • the obtained crude product was dissolved in 20 ml of ethanol, 2.00 ml (2.07 g, 41.3 mmol) of hydrazine monohydrate was added, and the mixture was stirred at room temperature for 12 hours.
  • the mixture was diluted with methylene chloride, washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the crude product obtained by concentration was dissolved in 50 ml of methylene chloride, and 5.75 ml (4.26 g, 33.0 mmol) of N, N-diisopropylethylamine and 5-chloro-2-isopropoxybenzoyl chloride 1 were added at 0 ° C.
  • Step 7 tert-butyl 3- ⁇ [5- (5-chloro-2-isopropoxyphenyl) -1,3,4-oxadiazol-2-yl] methyl ⁇ cyclobutanecarboxylate
  • Step 2 of Example 4 Instead of methyl 5- [2- (5-chloro-2-methoxybenzoyl) hydrazino] -3,3-dimethyl-5-oxopentanoate, 3- ⁇ 2- [2- (5 Reaction was carried out in the same manner using tert-butyl-chloro-2-isopropoxybenzoyl) hydrazino] -2-oxo-ethyl ⁇ cyclobutanecarboxylate to obtain the title compound as a solid.
  • Step 8 3- ⁇ [5- (5-Chloro-2-isopropoxyphenyl) -1,3,4-oxadiazol-2-yl] methyl ⁇ -N- ⁇ 5-[(2R) -2 -Hydroxypropyl] -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl ⁇ cyclobutanecarboxamide 3- ⁇ [5- (5-chloro- 2-isopropoxyphenyl) -1,3,4-oxadiazol-2-yl] methyl ⁇ cyclobutanecarboxylate 0.241 g (0.592 mmol) of trifluoroacetic acid-methylene chloride (1: 1) It melt
  • Step 1 methyl (1R, 3S) -3- [5- (5-chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclopentanecarboxylate
  • Example 28 (1S, 3R) -3-methoxycarbonylcyclopentanecarboxylic acid was used instead of 1 cis-3-methoxycarbonylcyclohexanecarboxylic acid to carry out the reaction in the same manner as in Step 2 of Example 28, and the title compound was obtained as a solid.
  • Step 2 (1R, 3S) -3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- [5- (methoxymethyl) -1-Methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] cyclopentanecarboxamide cis-3- [5- (5-chloro- (1R, 3S) -3- [5- (5-Chloro-2) synthesized in Step 1 instead of methyl 2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylate -Ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclopentanecarboxylate was used in a similar manner to obtain a substrate obtained by reacting 4-substituent of Step 3 of Example 6.
  • Step 1 (1R, 3S) -3- ⁇ [5- (methoxymethyl) -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] carbamoyl ⁇ cyclo Methyl pentanecarboxylate
  • (1S, 3R) -3-methoxycarbonylcyclopentanecarboxylic acid instead of 5-methoxy-3,3-dimethyl-5-oxopentanoic acid in Step 5 of Example 3.
  • Step 2 (1S, 3R) -3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- [5- (methoxymethyl) -1-Methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] cyclopentanecarboxamide
  • Example 81, step 2, cis-6-[(1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] piperidine-2-carboxylate (1R, 3S) -3- ⁇ [5 Step 4 of Example 81 hereafter using methyl-(methoxymethyl) -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] carbamoyl ⁇ cyclopentanecarboxylate Ma The reaction was conducted in the same manner
  • Step 1 Methyl 2-benzyloxy-5-chlorobenzoate 10.0 g (35.6 mmol) of methyl 5-chloro-2-hydroxybenzoate was dissolved in 54 mL of acetone, and 8.15 g (59.59 of potassium carbonate) at room temperature. 0 mmol) and 7.00 mL (10.1 g, 59.0 mmol) of benzyl bromide were added and stirred at 80 ° C. for 5 hours. After allowing to cool, the solvent was mostly distilled off under reduced pressure, water was added, and the mixture was extracted with diisopropyl ether. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Step 2 2-Benzyloxy-5-chlorobenzohydrazide Instead of methyl 5-chloro-2-ethoxybenzoate in Step 1 of Example 6, 2-benzyloxy-5-chlorobenzoic acid synthesized in Step 1 The same reaction was carried out using methyl to obtain the title compound as an oily substance.
  • Step 3 cis-3- [5- (2-benzyloxy-5-chlorophenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo- 2-Phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide 2-benzyloxy- synthesized in Step 2 instead of 5-chloro-2-ethoxybenzohydrazide in Step 1 of Example 28 Using 5-chlorobenzohydrazide, the reaction was carried out in the same manner as in Step 4 of Example 28 to obtain the title compound as a solid.
  • Step 4 cis-3- [5- (5-Chloro-2-hydroxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo- 2-Phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide cis-3- [5- (2-benzyloxy-5-chlorophenyl) -1,3,4- synthesized in Step 3 Oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide 3.00 g (5.02 mmol) ) Was dissolved in 50 mL of methanol, and 1.50 g of 5% palladium on carbon catalyst was added under a nitrogen atmosphere.
  • Step 1 cis-N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -3- [5- (2-ethoxyphenyl)- 1,3,4-oxadiazol-2-yl] cyclohexanecarboxamide
  • Step 1 [4-Chloro-2- (5- ⁇ cis-3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] ] Cyclohexyl ⁇ -1,3,4-oxadiazol-2-yl) phenyl] trifluoromethanesulfonic acid cis-3- [5- (5-chloro-2-hydroxyphenyl) synthesized in Step 4 of Example 17 -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide 0.500 g (0.984 mmol) was dissolved in 9.80 mL of methylene chloride, 0.229 mL (0.211 g, 1.97 mmol) of 2,6-lutidine, N, N-di
  • Step 2 Cis-3- [5- (5-chloro-2-methylphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo- 2-Phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide [4-Chloro-2- (5- ⁇ cis-3-[(1,5-dimethyl-3 -Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] cyclohexyl ⁇ -1,3,4-oxadiazol-2-yl) phenyl] trifluoromethanesulfonic acid 0.100 g ( 0.156 mmol) is dissolved in 1.6 mL of N, N-dimethylformamide and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride-methylene chloride is
  • Step 1 11.2 g (60.0 mmol) of methyl 2-allyloxy-5-chlorobenzoate and methyl 5-chlorosalicylate are dissolved in 50 mL of N, N-dimethylformamide, and 8.29 g (60.0 mmol) of potassium carbonate and Allyl bromide (5.08 mL, 7.26 g, 60.0 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours. The mixture was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Step 2 Methyl 3-allyl-5-chloro-2-hydroxybenzoate 12.9 g (56.8 mmol) of methyl 2-allyloxy-5-chlorobenzoate synthesized in Step 1 was added to 25 mL of N-methyl-2-pyrrolidone. And stirred at 200 ° C. for 7 hours. The mixture was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Step 3 11.0 g (48.4 mmol) of methyl 3-allyl-5-chloro-2-hydroxybenzoate synthesized in Step 2 of methyl 5-chloro-2-methyl-2,3-dihydrobenzofuran-7-carboxylate ) was dissolved in 100 mL of methylene chloride and stirred at 0 ° C. To this, 13.5 g (58.1 mmol) of zirconium tetrachloride was added little by little, and after completion of the addition, the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate.
  • Step 4 Methyl 5-chloro-2-methyl-2,3-dihydrobenzofuran-7-carboxylate synthesized in Step 3 methyl 5-chloro-2-methylbenzofuran-7-carboxylate 5.22 g (23.0 mmol) ) Is dissolved in 50 mL of carbon tetrachloride, 4.31 g (24.2 mmol) of N-bromosuccinimide and 1.13 g (6.90 mmol) of 2,2′-azobis (isobutyronitrile) are added, and the mixture is heated for 6 hours. Refluxed. The temperature was returned to room temperature, and the precipitate was removed by filtration.
  • Step 5 5-Chloro-2-methylbenzofuran-7-carboxylic acid 3.82 g (17.0 mmol) of methyl 5-chloro-2-methylbenzofuran-7-carboxylate synthesized in Step 4 was dissolved in 90 mL of methanol. 20 mL of 2N sodium hydroxide aqueous solution was added, and it stirred at room temperature for 5 hours. The reaction solution was evaporated under reduced pressure to remove methanol, neutralized with 2N hydrochloric acid under ice cooling, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Step 6 methyl cis-3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] cyclohexanecarboxylate
  • Step 6 of Example 40 instead of (1R, 3S) -3- [5- (5-chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid in cis-3-methoxycarbonyl
  • the same reaction was carried out using cyclohexanecarboxylic acid to obtain the title compound as a solid.
  • Step 7 cis-N- (1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -3- (hydrazinecarbonyl) cyclohexanecarboxamide in Step 6
  • Synthesized methyl cis-3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] cyclohexanecarboxylate 3.00 g (8.08 mmol) was dissolved in 81 mL of methanol, and 10.1 g (202 mmol) of hydrazine monohydrate was added at room temperature, followed by stirring at room temperature for 18 hours and at 50 ° C.
  • Step 8 cis-3- ⁇ [(5-chloro-2-methylbenzofuran-7-carbonyl) amino] carbamoyl ⁇ -N- (1,5-dimethyl-3-oxo-2-phenyl-2,3- Dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide cis-N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl synthesized in Step 7 ) -3- (hydrazinecarbonyl) cyclohexanecarboxyamide 0.400 g (1.08 mmol) was dissolved in 3.60 mL of N, N-dimethylformamide, and 5-chloro-2-methylbenzofuran-7 synthesized in Step 5 at room temperature.
  • Step 9 Cis-3- [5- (5-chloro-2-methylbenzofuran-7-yl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide cis-3- ⁇ [(5-chloro-2-ethoxybenzoyl) amino] of Example 28, step 2 Cis-3- ⁇ [(5-chloro-2-methylbenzofuran-7-carbonyl) amino] carbamoyl ⁇ -N- (1,5-dimethyl-3-synthesized in Step 8 instead of methyl carbamoyl ⁇ cyclohexanecarboxylate Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide was used in the same manner as in Step 2 of Example 28 to give the title Things as
  • Step 1 Methyl 2-benzyloxy-5-fluorobenzoate Using methyl 5-fluoro-2-hydroxybenzoate instead of methyl 5-chloro-2-hydroxybenzoate in Step 1 of Example 17 in the same manner The title compound was obtained as a solid.
  • Step 2 2-Benzyloxy-5-fluorobenzoic acid 2-Benzyloxy-5-synthesized in Step 1 instead of methyl 5-chloro-2-methylbenzofuran-7-carboxylate in Step 5 of Example 25
  • the same reaction was carried out using methyl fluorobenzoate to obtain the title compound as a solid.
  • Step 3 Cis-3- [5- (2-benzyloxy-5-fluorophenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo -2-Phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide Synthesis in Example 2 instead of 5-chloro-2-methylbenzofuran-7-carboxylic acid in Step 8 of Example 25 Using the 2-benzyloxy-5-fluorobenzoic acid thus obtained, the reaction was then carried out in the same manner as in Step 8 to Step 9 of Example 25 to obtain the title compound as a solid.
  • Step 1 methyl cis-3- ⁇ [(5-chloro-2-ethoxybenzoyl) amino] carbamoyl ⁇ cyclohexanecarboxylate 3.50 g of 5-chloro-2-ethoxybenzohydrazide synthesized in Step 1 of Example 6 ( 16.3 mmol) is dissolved in 54 mL of N, N-dimethylformamide, and at room temperature, 3.04 g (16.3 mmol) of cis-3-methoxycarbonylcyclohexanecarboxylic acid, 2.20 g (16.3 mmol) of 1-hydroxybenzotriazole and 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC ⁇ HCl) (3.13 g, 16.3 mmol) was added, and the mixture was stirred at room temperature for 15 hours.
  • EDC ⁇ HCl 1-hydroxybenzotriazole and 1-Ethyl-3- (3-dimethyla
  • Step 2 Methyl cis-3- [5- (5-chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylate synthesized in Step 1 Liquid obtained by dissolving 12.0 g of trimethylsilylpolyphosphate in 18.0 mL of 1,2-dichloroethane in 5.73 g (15.0 mmol) of methyl [(5-chloro-2-ethoxybenzoyl) amino] carbamoyl ⁇ cyclohexanecarboxylate was added at room temperature and stirred at 90 ° C. for 4 hours.
  • Step 3 cis-3- [5- (5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid synthesized in Step 2 -(5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylate (3.74 g, 10.3 mmol) was dissolved in methanol (103 mL) and 1N hydroxylated at room temperature. 51.3 mL (51.3 mmol) of an aqueous sodium solution was added, and the mixture was stirred at 50 ° C. for 1 hour and at room temperature for 13 hours.
  • Step 4 cis-3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo- 2-Phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide cis-3- [5- (5-chloro-2-ethoxyphenyl) -1,3,4- synthesized in Step 3 Oxadiazol-2-yl] cyclohexanecarboxylic acid (0.345 g, 0.984 mmol) is dissolved in 4.9 mL of N, N-dimethylformamide, and O- (7-azabenzotriazol-1-yl) -N is dissolved at room temperature.
  • N, N ′, N ′,-tetramethylronium hexafluorophosphate HATU 0.374 g (0.984 mmol)
  • N, N-diisopropylethylamine 0.171 mL .27g, 0.984mmol
  • 4-aminoantipyrine added 0.200 g (0.984 mmol) was stirred at room temperature for 5.5 hours.
  • Water and sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate.
  • Step 1 5- (3-Benzyloxycyclobutyl) -2-phenyl-1H-pyrazol-3-one 3- [tert-butyl- (dimethyl) silyl] oxy-3-methyl of Step 1 of Example 36
  • the reaction was carried out in the same manner using 3-benzyloxycyclobutanecarboxylic acid instead of cyclobutanecarboxylic acid to obtain a cis isomer (intermediate 35a) and a trans isomer (intermediate 35b) as solids.
  • Step 2 4-Amino-5- (3-benzyloxycyclobutyl) -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 5- ⁇
  • (2R) -2- [tert-butyl (dimethyl) silyl] oxypropyl ⁇ -2-phenyl-4H-pyrazol-3-one the intermediate 35a synthesized in Step 1 was used.
  • the reaction was conducted in the same manner as in Step 3 to obtain the title compound as a solid.
  • Step 3 4-amino-5- (3-hydroxycyclobutyl) -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 4-amino-5-synthesized in Step 2 (3-Benzyloxycyclobutyl) -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one (0.610 g, 1.75 mmol) was dissolved in 20 ml of methanol to prepare a palladium hydroxide carbon catalyst. After adding 160 mg, it stirred at room temperature under hydrogen atmosphere for 36 hours. The reaction solution was filtered through celite, and the solvent was evaporated under reduced pressure.
  • Step 4 3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- [5- (cis-3-hydroxycyclobutyl)- 1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl] cyclohexanecarboxamide 4-amino-5- (3-hydroxycyclobutyl) -1- 0.0880 g (0.339 mmol) of methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one and cis-3- [5- (5-chloro-2) synthesized in Step 3 of Example 28 -Ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid 0.131 g (0.373 mmol) was dissolved in 1.70 mL of methanol and 4- (4,4, - dimethoxy-1,3,5-
  • Step 1 5- ⁇ cis-3- [tert-butyl (dimethyl) silyl] oxy-3-methylcyclobutyl] ⁇ 2-phenyl-4H-pyrazol-3-one Synthesized by the method described in US2011 / 112052A1 5.00 g (20.5 mmol) of 3- [tert-butyl- (dimethyl) silyl] oxy-3-methylcyclobutanecarboxylic acid was dissolved in 50 ml of tetrahydrofuran, and 4.78 g (24.6 mmol) of N, N-dicyclohexylcarbodiimide was dissolved.
  • Step 2 4-Amino-5- (cis-3-hydroxy-3-methylcyclobutyl) -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 5 synthesized in Step 1 instead of 5- ⁇ (2R) -2- [tert-butyl (dimethyl) silyl] oxypropyl ⁇ -2-phenyl-4H-pyrazol-3-one in Step 2 of Example 14 Using ⁇ 3- [tert-butyl (dimethyl) silyl] oxy-3-methylcyclobutyl ⁇ -2-phenyl-4H-pyrazol-3-one, the reaction is carried out in the same manner as in Step 14 of Example 14 hereinafter. The title compound was obtained as a solid.
  • Step 1 5-chloro-2-ethoxypyridine-3-carbohydrazide 5-chloro-2-ethoxypyridine-3-carboxylic acid (3.00 g, 14.9 mmol) was dissolved in 50 mL of methanol, and 5 drops of concentrated sulfuric acid was added. Then, the mixture was heated to reflux for 6 hours. After cooling to room temperature, the precipitated solid was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure to obtain methyl 5-chloro-2-ethoxypyridine-3-carboxylate.
  • methyl ester compound was dissolved in 100 mL of ethanol, hydrazine monohydrate (14.4 mL, 14.9 g, 298 mmol) was added, and the mixture was heated to reflux for 5 hours. After cooling to room temperature, the solvent was distilled off to about 1/3 amount under reduced pressure. The precipitated solid was collected by suction filtration, washed with a small amount of ethanol and ethyl acetate, and then dried under reduced pressure to obtain 1.85 g (yield 57.6%) of the title compound as a solid.
  • Step 2 Methyl cis-3- ⁇ [(5-chloro-2-ethoxypyridine-3-carbonyl) amino] carbamoyl ⁇ cyclohexanecarboxylate Instead of 5-chloro-2-ethoxybenzohydrazide in Step 1 of Example 28 The same reaction was carried out using 5-chloro-2-ethoxypyridine-3-carbohydrazide synthesized in Step 1 to obtain the title compound as a solid.
  • Step 3 methyl cis-3- [5- (5-chloro-2-ethoxy-3-pyridyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylate of step 2 of Example 4
  • step 3 methyl 5- [2- (5-chloro-2-methoxybenzoyl) hydrazino] -3,3-dimethyl-5-oxopentanoate
  • the cis-3- ⁇ [(5-chloro- The same reaction was carried out using methyl 2-ethoxypyridine-3-carbonyl) amino] carbamoyl ⁇ cyclohexanecarboxylate to obtain the title compound as a solid.
  • Step 4 Cis-3- [5- (5-chloro-2-ethoxy-3-pyridyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid cis-3 synthesized in Step 3 -1.53 g (4.72 mmol) of methyl [5- (5-chloro-2-ethoxy-3-pyridyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylate in 20 mL of tetrahydrofuran and 10 mL of methanol 1N sodium hydroxide aqueous solution 9.44mL (9.44mmol) was added, and it stirred at room temperature for 4 hours.
  • Step 5 cis-3- [5- (5-Chloro-2-ethoxy-3-pyridyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3 -Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide cis-3- [5- (5-chloro-2-ethoxyphenyl) -1 of Example 28, step 4 , 3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid, the cis-3- [5- (5-chloro-2-ethoxy-3-pyridyl) -1,3, synthesized in Step 4 4-oxadiazol-2-yl] cyclohexanecarboxylic acid was used for the same reaction to obtain the title compound as a solid.
  • Step 1 After 26.3 g (603 mmol) of 5-chloro-2-isopropoxypyridine-3-carboxylic acid 55% sodium hydride was suspended in 431 mL of tetrahydrofuran under ice-cooling, 40.0 mL of 2-propanol (31 0.1 g, 517 mmol) was added dropwise over 15 minutes. After stirring for 50 minutes under ice cooling, a suspension of 33.1 g (172 mmol) of 2,5-dichloropyridine-3-carboxylic acid in 150 mL of tetrahydrofuran was added dropwise over 30 minutes under ice cooling.
  • Step 2 cis-3- [5- (5-Chloro-2-isopropoxy-3-pyridyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid
  • Step 1 Using 5-chloro-2-isopropoxypyridine-3-carboxylic acid synthesized in Step 1 instead of 5-chloro-2-ethoxypyridine-3-carboxylic acid, and thereafter performing the same procedure as in Step 37 of Example 37. Reaction was performed to give the title compound as a solid.
  • Step 1 Ethyl cis-cyclohexane-1,3-dicarboxylic acid 53.0 g (308 mmol) of cis-cyclohexane-1,3-dicarboxylic acid was dissolved in 500 ml of ethanol, 8.0 ml of concentrated sulfuric acid was added, and the mixture was heated to reflux for 5 hours. . The reaction solution was cooled to room temperature and then concentrated to 1/5 under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 2 (1S, 3R) -3-Ethoxycarbonylcyclohexanecarboxylic acid 22.8 g (99.9 mmol) of ethyl cis-cyclohexane-1,3-dicarboxylate synthesized in Step 1 was used as a starting material.
  • Step 3 (1R, 3S) -3- ⁇ [(5-Chloro-2-ethoxybenzoyl) amino] carbamoyl ⁇ cyclohexanecarboxylate
  • (1S, 3R) -3-ethoxycarbonylcyclohexanecarboxylic acid synthesized in Step 2 1.96 g (9.78 mmol) and 2.00 g (9.32 mmol) of 5-chloro-2-ethoxybenzohydrazide synthesized in Step 1 of Example 6, 1-ethyl-3- (3-dimethylaminopropyl)
  • Carbodiimide hydrochloride (EDC.HCl) 2.14 g (11.2 mmol) and 1-hydroxybenzotriazole 1.51 g (11.2 mmol) were dissolved in 60 ml of N, N-dimethylformamide and stirred overnight at room temperature.
  • Step 4 (1R, 3S) -3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylate ethyltrimethylsilylpolyphosphate 00 g was dissolved in 1,2-dichloroethane (8 mL) and synthesized in Step 3 (1R, 3S) -3- ⁇ [(5-chloro-2-ethoxybenzoyl) amino] carbamoyl ⁇ cyclohexanecarboxylate 2.08 g (5 .24 mmol) was added and stirred at 90 ° C. for 6 hours.
  • Step 5 (1R, 3S) -3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid synthesized in Step 4 (1R , 3S) -3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylate 1.89 g (4.99 mmol) in 50 ml ethanol. After dissolution, 15.0 ml (15.0 mmol) of 1N aqueous sodium hydroxide solution was added and stirred at 60 ° C. for 45 minutes.
  • reaction mixture was cooled to room temperature, 30 ml of 1N hydrochloric acid was added, and the mixture was extracted 4 times with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to quantitatively obtain 1.81 g of the title compound as a solid.
  • Step 6 (1R, 3S) -3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide 4-aminoantipyrine 0.900 g (4.43 mmol) and (1R, 3S) -3 synthesized in Step 5 -[5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid 1.76 g (5.00 mmol), O- (7-azabenzotriazole- 1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU) 2.53 g (6.64 mmol) was added to N, N-dimethyl
  • Step 1 5.00 g (23.3 mmol) of methyl 5-chloro-2-isopropoxybenzoate 5-chloro-2-isopropoxybenzoate was dissolved in a mixed solvent of 46.6 mL of toluene and 4.70 mL of methanol, (Trimethylsilyl) diazomethane (2M hexane solution) 14.0 mL (28.0 mmol) was added dropwise over 15 minutes under water cooling. The mixture was stirred at room temperature for 2 hours, and the solvent was distilled off under reduced pressure.
  • Step 2 5-chloro-2-isopropoxybenzohydrazide methyl 5-chloro-2-isopropoxybenzoate synthesized in step 1 instead of methyl 5-chloro-2-ethoxybenzoate in step 1 of Example 6 was used in the same manner to obtain the title compound as a solid.
  • Step 3 (1R, 3S) -3- [5- (5-Chloro-2-isopropoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid Step 3 of Example 40 Using 5-chloro-2-isopropoxybenzohydrazide synthesized in Step 2 instead of 5-chloro-2-ethoxybenzohydrazide in Example 40, the reaction was conducted in the same manner as in Step 40 of Example 40, and the title compound was converted. Obtained as a solid.
  • Step 1 (1R, 3S) -3- [5- (5-Chloro-2-isopropoxy-3-pyridyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid
  • Step 2 The 5-chloro-2-isopropoxypyridine-3-carboxylic acid synthesized in Step 1 of Example 39 was used in place of the 5-chloro-2-isopropoxybenzoic acid of Step 1 in Step 1 of Example 42.
  • Step 3 To Step 3 to give the title compound as a solid.
  • Step 1 5-ethyl-1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 3-oxo-5-[(2,2,2-) of Step 2 of Example 53
  • the reaction was carried out in the same manner as in Step 53 of Example 53 using methyl 3-oxopentanoate instead of ethyl trifluoroacetyl) amino] pentanoate to obtain the title compound as an oily substance.
  • Step 2 4-Amino-5-ethyl-1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 5- ⁇ (2R) -2- [ tert-Butyl (dimethyl) silyl] oxypropyl ⁇ -1-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one instead of 5-ethyl-1-methyl-synthesized in Step 1
  • the same reaction was carried out using 2-phenyl-2,3-dihydro-1H-pyrazol-3-one to obtain the title compound as an oily substance.
  • Step 1 1-ethyl-5-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 5-methyl-2-phenyl-1H-pyrazol-3-one 554 mg (3.18 mmol)
  • N, N-dimethylformamide was added 0.645 mL (1.25 g, 8.01 mmol) of ethane iodide, and the mixture was heated and stirred at 100 ° C. for 6 hours in a sealed tube.
  • the reaction mixture was cooled to room temperature and then concentrated under reduced pressure.
  • To the resulting residue was added 15 mL of saturated aqueous sodium hydrogen carbonate, and the mixture was extracted twice with ethyl acetate.
  • Step 2 4-Amino-1-ethyl-5-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 1-phenyl-6- (2,2 of Step 7 of Example 8 , 2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-2-one synthesized in Step 1 instead of 1-ethyl-5- Using methyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one, the reaction was carried out in the same manner as in Step 8 of Example 8 to obtain the title compound as an oily substance.
  • Step 1 3-Amino-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-one 1-phenyl-6- (2 of Step 7 of Example 8 , 2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-2-one, synthesized by the method described in US2007 / 49574 1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-one was used in the same manner as in Step 8 of Example 8 to obtain the title compound. Obtained as a solid.
  • Step 1 4-Amino-1,5-dimethyl-2- (2-pyridyl) pyrazol-3-one 1,5-dimethyl-2- (6-methyl-2-pyridyl) of Step 4 of Example 5
  • 2- (6-chloro-2-pyridyl) -1,5-dimethylpyrazol-3-one synthesized in Step 2 of Example 5 was used.
  • the reaction was carried out in the same manner as up to 5, and further purified by amino silica gel column chromatography (Biotage, elution solvent: ethyl acetate) to obtain the title compound as an oily substance.
  • Step 1 Ethyl 3-oxo-5-[(2,2,2-trifluoroacetyl) amino] pentanoate Journal of the Chemical Society, Perkin Tranactions 1, 1985, 1355-1362.
  • Step 2 2,2,2-trifluoro-N- [2- (5-oxo-1-phenyl-4H-pyrazol-3-yl) ethyl] acetamide 3-oxo-5- [synthesized in Step 1
  • a solution of 12.2 g (47.4 mmol) of ethyl (2,2,2-trifluoroacetyl) amino] pentanoate in 250 mL of toluene was added 4.76 mL (5.23 g, 48.4 mmol) of phenylhydrazine. The mixture was stirred for 2 hours while removing generated water.
  • Step 3 2,2,2-trifluoro-N- [2- (2-methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) ethyl] acetamide
  • Step 2 2.00 g (6.68 mmol) of 2,2,2-trifluoro-N- [2- (5-oxo-1-phenyl-4H-pyrazol-3-yl) ethyl] acetamide synthesized in 1
  • dimethylformamide 2.08 mL (4.74 g, 33.4 mmol) of methane iodide, and the mixture was stirred at 100 ° C. for 5 hours in a sealed tube.
  • the reaction solution was poured into ice water and extracted three times with methylene chloride.
  • the organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained solid was suspended in diethyl ether, and the solid was collected by filtration and dried to obtain 1.70 g (yield 86.4%) of the title compound as a solid.
  • Step 5 N- [2- (4-Amino-2-methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) ethyl] -2,2,2-tri 2,2,2-trifluoro-N- [2- (2-methyl-4-nitro-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazole-3- synthesized in Step 4 of fluoroacetamide Yl) ethyl] acetamide
  • ethanol 1.60 g, 4.47 mmol
  • 10% palladium carbon catalyst (0.500 g
  • Step 6 (1R, 3S) -3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1-methyl-3- Oxo-2-phenyl-5- ⁇ 2-[(2,2,2-trifluoroacetyl) amino] ethyl ⁇ pyrazol-4-yl) cyclohexanecarboxamide synthesized in Step 5 of Example 40
  • 2-trifluoroacetamide (0.657 g, 2.00 mmol) was added, and the mixture was stirred at room temperature for 3 hours.
  • Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate / methylene chloride, washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • the mixture was stirred for 1.5 hours at room temperature.
  • the reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate gave 0.388 g (yield 65.8%) of the title compound as a solid.
  • Example 54 Cis-3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- ⁇ 5-[(1R) -2- (Dimethylamino) -1-methylethyl] -1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl ⁇ cyclohexanecarboxamide
  • Step 1 N- [2- (4-Amino-2-methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) propyl] -2,2,2-tri Fluoroacetamide (Intermediate 54a) Instead of N-trifluoroacetyl- ⁇ -alanine in Step 1 of Example 53, European Journal of Organic Chemistry, 2012, 29, 5774-5788. Using N-trifluoroacetyl- ⁇ -aminoisobutanoic acid synthesized according to the method described, the reaction was carried out in the same manner as in Step 53 of Example 53 to obtain the title compound as a solid.
  • Step 2 (+)-N-[(2S) -2- (4-amino-2-methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) propyl] -2,2,2-trifluoroacetamide (intermediate 54b) and (-)-N-[(2R) -2- (4-amino-2-methyl-5-oxo-1-phenyl-2,3- Dihydro-1H-pyrazol-3-yl) propyl] -2,2,2-trifluoroacetamide (Intermediate 54c) N- [2- (4-Amino-2-methyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-3-yl) propyl] -2,2,2-synthesized in Step 1 1.26 g (15.4 mmol) of trifluoroacetamide (intermediate 54a) was resolved by chiral column chromatography (CHIRALPAK IC, ethanol ace
  • Step 1 A solution of 35.0 mL (52.1 g, 414 mmol) of 3-benzyloxypropanal chloride in 500 mL of methylene chloride was cooled to ⁇ 78 ° C., and 38.5 mL (42.4 g, 542 mmol) of dimethyl sulfoxide was added for 18 minutes. Over 25 minutes. Then, 43.0 mL (45.1 g, 271 mmol) of 3-benzyloxypropan-1-ol was added over 20 minutes and stirred for 70 minutes. Furthermore, 151 mL (110 g, 1090 mmol) of triethylamine was added over 5 minutes and stirred for 10 minutes, and then the temperature was raised to room temperature and stirred for 1.5 hours.
  • Step 2 95 mL of an aqueous solution of 86.9 g (629 mmol) of ethyl carbonate (E) -5-benzyloxypent-2-enoate was cooled to 0 ° C., and 63.0 mL (71. 2 g, 318 mmol) was added, and the mixture was stirred at 0 ° C. for 15 minutes.
  • a solution of 39.3 g (239 mmol) of 3-benzyloxypropanal synthesized in Step 1 in 110 mL of diisopropyl ether was added over 6 minutes, stirred for 5 minutes, then warmed to room temperature and stirred for 66 hours.
  • Step 3 46.8 g (200 mmol) of ethyl (E) -5-benzyloxypent-2-enoate synthesized in Step 2 of 5-benzyloxy-3- [tert-butoxycarbonyl (methyl) amino] pentanoic acid
  • the methanol 100 mL solution was cooled to 0 ° C., 61.0 mL (600 mmol) of methylamine (40% methanol solution) was added over 3 minutes, stirred for 10 minutes, then warmed to room temperature and stirred for 3.5 hours.
  • the reaction mixture was concentrated under reduced pressure to obtain 51.7 g of a mixture of ethyl 5-benzyloxy-3- (methylamino) pentanoate and methyl 5-benzyloxy-3- (methylamino) pentanoate as an oily substance.
  • this mixture was dissolved in 500 mL of methylene chloride, the solution was cooled to 0 ° C., and 42.0 mL (30.7 g, 303 mmol) of triethylamine and a solution of 49.6 g (227 mmol) of di-tertbutyl dicarbonate in 150 mL of methylene chloride were added in this order. After stirring for 5 minutes, the mixture was warmed to room temperature and stirred for 90 hours.
  • Step 4 N- (3-amino-2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-5-yl) -2,2,2- Trifluoro-N-methylacetamide (Intermediate 57a) Instead of 3- [2-benzyloxyethyl (tert-butoxycarbonyl) amino] propionic acid in Step 4 of Example 8, 5-benzyloxy-3- [tert-butoxycarbonyl (methyl) amino synthesized in Step 3 The reaction was carried out using pentanoic acid in the same manner as in Step 8 of Example 8 to obtain the title compound (intermediate 57a) as a solid.
  • Step 5 (+)-/ (-)-N- (3-amino-2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-5- Yl) -2,2,2-trifluoro-N-methylacetamide
  • (+)-Isomer (intermediate 57b) and (-)-isomer (intermediate 57c) were obtained as solids.
  • Intermediate 57b [ ⁇ ] D 20 +201.2 (c 0.949, MeOH).
  • Intermediate 57c [ ⁇ ] D 20 -209.3 (c 0.943, MeOH).
  • the reaction was carried out in the same manner as in Step 6 to Step 8 of Example 53, and the following Examples 57 to 60 were synthesized. Table 15 shows.
  • Step 1 N- (3-amino-2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-5-yl) -2,2,2-trifluoro -N-methylacetamide
  • Step 2 of Example 57 Using 2-benzyloxyacetaldehyde instead of 3-benzyloxypropanal in Step 2 of Example 57, the same reaction as in Step 57 of Example 57 was carried out to give the title compound (Intermediate 61a) as an oil Obtained as material.
  • Step 2 (+)-/ (-)-N- (3-amino-2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-5-yl) -2,2,2-trifluoro-N-methylacetamide
  • Step 1 (1R, 3S) -3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-thiadiazol-2-yl] cyclohexanecarboxylate synthesized in Step 3 of Example 40 0.31 g (0.780 mmol) of ethyl (1R, 3S) -3- ⁇ [5- (5-chloro-2-ethoxybenzoyl) amino] carbamoyl ⁇ cyclohexanecarboxylate, and 0.320 g (0.780 mmol) of Lawson's reagent ) was dissolved in 9.0 mL of methylene chloride and heated to reflux for 10 hours.
  • Step 1 Ethyl (1S, 3R) -3- (hydroxymethyl) cyclohexanecarboxylate 5.12 g (25.6 mmol) of (1R, 3S) -3-ethoxycarbonylcyclohexanecarboxylic acid synthesized in Example 41 was added to 100 mL of tetrahydrofuran. Then, 3.64 mL (38.4 mmol) of borane dimethyl sulfide complex was added at ⁇ 78 ° C. over 10 minutes, and the mixture was stirred at ⁇ 78 ° C. for 15 minutes and at room temperature for 20.5 hours.
  • Step 2 (1S, 3R) -3- ⁇ [tert-Butyl (diphenyl) silyl] oxymethyl ⁇ cyclohexanecarboxylate ethyl (1S, 3R) -3- (hydroxymethyl) cyclohexanecarboxylate synthesized in Step 1 3.47 g (18.6 mmol) is dissolved in 90 mL of N, N-dimethylformamide, 1.90 g (27.9 mmol) of imidazole and 5.80 mL (6.15 g, 22.4 mmol) of tert-butyldiphenylchlorosilane are added, Stir at room temperature for 8 hours.
  • Step 3 1-((1S, 3R) -3- ⁇ [tert-butyl (diphenyl) silyl] oxymethyl ⁇ cyclohexyl) ethanone (1S, 3R) -3- ⁇ [tert-butyl ( 7.90 g (18.6 mmol) of ethyl diphenyl) silyl] oxymethyl ⁇ cyclohexanecarboxylate and 2.36 g (24.2 mmol) of N, O-dimethylhydroxylamine hydrochloride were suspended in 200 mL of tetrahydrofuran, and at ⁇ 10 ° C.
  • Step 4 2-Bromo-1-((1S, 3R) -3- ⁇ [tert-butyl (diphenyl) silyl] oxymethyl ⁇ cyclohexyl) ethanone 1-((1S, 3R) -3 synthesized in Step 3 - ⁇ [Tert-Butyl (diphenyl) silyl] oxymethyl ⁇ cyclohexyl) ethanone 7.34 g (18.6 mmol) was dissolved in 100 mL of tetrahydrofuran, and 23.5 mL (24.2 mmol) of lithium diisopropylamide (1.03 M hexane / tetrahydrofuran solution).
  • Step 5 2-Amino-1-((1S, 3R) -3- ⁇ [tert-butyl (diphenyl) silyl] oxymethyl ⁇ cyclohexyl) ethanone hydrochloride 2-bromo-1-(( 1S, 3R) -3- ⁇ [tert-butyl (diphenyl) silyl] oxymethyl ⁇ cyclohexyl) ethanone 5.03 g (10.6 mmol) was dissolved in 50 mL of methanol and 0.830 g (12.8 mmol) of sodium azide was dissolved. A 10 mL water solution was added and stirred at room temperature for 22 hours.
  • Step 6 N- (2-[(1S, 3R) -3- ⁇ [tert-butyl (diphenyl) silyl] oxymethyl ⁇ cyclohexyl] -2-oxoethyl) -5-chloro-2-ethoxybenzamide in Step 5
  • Step 7 tert-Butyl-( ⁇ (1R, 3S) -3- [2- (5-chloro-2-ethoxyphenyl) oxazol-5-yl] cyclohexyl ⁇ methoxy) diphenylsilane N— synthesized in Step 6 (2-[(1S, 3R) -3- ⁇ [tert-butyl (diphenyl) silyl] oxymethyl ⁇ cyclohexyl] -2-oxoethyl) -5-chloro-2-ethoxybenzamide (0.613 g, 1.04 mmol) and 0.155 mL (0.153 g, 1.93 mmol) of pyridine was dissolved in 10 mL of methylene chloride, and 0.648 mL (1.09 g, 3.85 mmol) of trifluoromethanesulfonic anhydride was slowly added at room temperature.
  • Step 8 ⁇ (1R, 3S) -3- [2- (5-Chloro-2-ethoxyphenyl) oxazol-5-yl] cyclohexyl ⁇ methanol synthesized in Step 7 tert-butyl-( ⁇ (1R, 3S ) -3- [2- (5-Chloro-2-ethoxyphenyl) oxazol-5-yl] cyclohexyl ⁇ methoxy) diphenylsilane (0.321 g, 0.559 mmol) was dissolved in 6.0 mL of tetrahydrofuran, and tetra-n- 0.925 mL (0.925 mmol) of butylammonium fluoride (1.0 M tetrahydrofuran solution) was added and stirred at room temperature for 3.5 hours.
  • Step 1 2- (5-chloro-2-ethoxyphenyl) ethynyltrimethylsilane 6.10 g (25.9 mmol) of 2-bromo-4-chloro-1-ethoxybenzene synthesized by the method described in WO2011 / 30652 Dissolved in 50 ml of tetrahydrofuran, 3.05 g (31.1 mmol) of ethynyl (trimethyl) silane, 5.42 ml (3.94 g, 38.9 mmol) of triethylamine, [(diphenylphosphino) ferrocene] palladium (II) dichloride methylene chloride addition 1.27 g (1.55 mmol) of the product and 0.30 g (1.55 mmol) of copper iodide were added and stirred at 80 ° C.
  • Step 2 4-Chloro-1-ethoxy-2-ethynylbenzene 2.00 g (7.91 mmol) of 2- (5-chloro-2-ethoxyphenyl) ethynyltrimethylsilane synthesized in Step 1 was dissolved in 30 ml of methanol and 1.0 ml of water to obtain 2.73 g (19.8 mmol) of potassium carbonate. And stirred at room temperature for 3 days. Under ice-cooling, 1N hydrochloric acid was added to neutralize, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 3 methyl cis-3-hydroxyiminomethyl] cyclohexylcarboxylate Journal of Macromolecular Science, Chemistry (1971), 5 (1), 1873-87.
  • 150 mg (0.88 mmol) of methyl cis-3-formylcyclohexylcarboxylate synthesized by the method described in 1) was dissolved in 8.8 ml of ethanol, and 86.8 mg (11.1 mmol) of sodium acetate was added, followed by hydroxylamine hydrochloride. 73.5 mg (1.06 mmol) was added, and the mixture was stirred overnight at room temperature. Under ice-cooling, 1N aqueous sodium carbonate solution was added, and the mixture was extracted with ethyl acetate.
  • Step 4 methyl cis-3- [5- (5-chloro-2-ethoxyphenyl) isoxazol-3-yl] cyclohexylcarboxylate synthesized in Step 4 cis-3-hydroxyiminomethyl] cyclohexylcarboxyl Dissolve 120 mg (0.65 mmol) of methyl acid in 2.40 ml of methylene chloride, add 86.5 mg (0.65 mmol) of N-chlorosuccinimide under ice cooling, and stir for 15 minutes while slowly returning to room temperature. did.
  • Step 1 Methyl (1R, 3S) -3-carbamoylcyclohexanecarboxylate 1.50 g (13.4 mmol) of (1S, 3R) -3-methoxycarbonylcyclohexanecarboxylic acid synthesized in Step 2 of Example 40 was It melt
  • Step 2 Methyl (1R, 3S) -3-carbamoylcyclohexanecarboxylate synthesized in Step 1 of methyl (1R, 3S) -3-cyanocyclohexanecarboxylate 1.00 g (5.40 mmol) was dissolved in 20 ml of methylene chloride. Then, 1.42 g (5.94 mmol) of methyl N- (triethylammoniumsulfonyl) carbamate (Burges reagent) was added at room temperature, and the mixture was stirred at room temperature overnight.
  • methyl N- (triethylammoniumsulfonyl) carbamate Burges reagent
  • Step 3 (1R, 3S) -3-cyanocyclohexanecarboxylic acid
  • Methyl (1R, 3S) -3-cyanocyclohexanecarboxylate 850 mg (5.08 mmol) synthesized in Step 2 was added to 8.50 ml of methanol and 8.50 ml of tetrahydrofuran.
  • 1N sodium hydroxide aqueous solution 5.08 ml (5.08 mmol) was added at room temperature, and the mixture was stirred at room temperature overnight.
  • the reaction mixture was concentrated, water (2.0 ml) and 1N aqueous sodium hydroxide solution (2.0 ml, 2.0 mmol) were added, and the mixture was washed with diethyl ether.
  • Step 4 (1R, 3S) -3-Cyano-N- (1,5-dimethyl-3-oxo-2-phenylpyrazolyl-4-yl) cyclohexanecarboxamide (1R, 3S in Example 40, Step 6) ) -3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid synthesized in step 3 (1R, 3S)- The same reaction was carried out using 3-cyanocyclohexanecarboxylic acid to obtain 659 mg (yield 98.9%) of the title compound as a solid.
  • Step 5 (1R, 3S) -N- (1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl) -3- (N′-hydroxycarbamimidoyl) cyclohexanecarboxamide
  • Step 4 400 mg (1.18 mmol) of (1R, 3S) -3-cyano-N- (1,5-dimethyl-3-oxo-2-phenylpyrazolyl-4-yl) cyclohexanecarboxamide synthesized in 1) was added to 2.40 ml of ethanol. After dissolution, 0.410 ml (6.23 mmol) of 50% aqueous hydroxylamine solution was added at room temperature, stirred at 80 ° C.
  • Step 6 (1R, 3S) -3- [5- (5-Chloro-2-ethoxyphenyl) -1,2,4-oxadiazol-3-yl] -N- (1,5-dimethyl-3- Oxo-2-phenylpyrazol-4-yl) cyanocyclohexanecarboxamide 5-amino-N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro- of Example 2, Step 5 (1R, 3S) -N- (1,5-dimethyl-3-oxo-2-) synthesized in Step 5 instead of 1H-pyrazol-4-yl) -5-hydroxyimino-3,3-dimethylpentanamide Phenylpyrazol-4-yl) -3- (N′-hydroxycarbamimidoyl) cyclohexanecarboxamide using 5-chloro-2-ethoxybenzoic acid instead of 5-chloro-2-methoxybenzoic acid, A
  • Step 1 5.80 mL (5.80 mmol) of 5-chloro-2-ethoxybenzamidine lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution) was cooled to 0 ° C. Thereto was added a solution of 434 mg (2.39 mmol) of 5-chloro-2-ethoxybenzonitrile synthesized in Step 2 of Example 3 in 3.5 mL of tetrahydrofuran over 3 minutes, followed by stirring for 5 minutes and raising the temperature to room temperature. Warmed and stirred for 25 hours.
  • the reaction mixture was concentrated under reduced pressure, 15.0 mL (15.0 mmol) of 1N aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was then washed twice with diethyl ether. The obtained aqueous layer was cooled to 0 ° C., and 5N sodium hydroxide aqueous solution (3.50 mL, 17.5 mmol) was added to adjust the pH to 11 or more, and methylene chloride / 2-propanol (3: 1) three times. The organic layers were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 418 mg (yield 88.1%) of the title compound as a solid.
  • Step 2 4-[(2,4-dimethoxyphenyl) methylamino] -1,5-dimethyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one 4-aminoantipyrine 5.00 g ( 24.6 mmol) and 4.10 g (24.7 mmol) of 2,4-dimethoxybenzaldehyde in 160 mL of methylene chloride were stirred for 15 minutes, 16.0 g (75.5 mmol) of sodium triacetoxyborohydride, 3.80 mL of acetic acid ( 3.99 g, 66.4 mmol) in this order and stirred at room temperature for 26 hours.
  • Step 4 (1S, 3R) -3-[(2,4-Dimethoxyphenyl) methyl- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4- Yl) carbamoyl] cyclohexanecarboxylic acid (1S, 3R) -3-[(2,4-dimethoxyphenyl) methyl- (1,5-dimethyl-3-oxo-2-phenyl-2,3- Dihydro-1H-pyrazol-4-yl) carbamoyl] cyclohexanecarboxylate 3.14 g (5.85 mmol) in tetrahydrofuran 30 mL / ethanol 30 mL was added 2N aqueous sodium hydroxide solution 6.11 mL (12.2 mmol), Stir at room temperature for 65 hours.
  • Step 6 (1R) -N-[(2,4-dimethoxyphenyl) methyl] -N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4 -Yl) -3- (3-trimethylsilylprop-2-inoyl) cyclohexanecarboxamide (1R, 3S) -N1-[(2,4-dimethoxyphenyl) methyl] -N1- (1,5 -Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -N3-methoxy-N3-methyl-cyclohexane-1,3-dicarboxamide 0.724 g (1.32 mmol) ) In tetrahydrofuran (1.7 mL) was cooled to 0 ° C.
  • Step 7 (1R) -N-[(2,4-dimethoxyphenyl) methyl] -N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4 -Yl) -3-prop-2-inoylcyclohexanecarboxamide
  • (1R) -N-[(2,4-dimethoxyphenyl) methyl] -N- (1,5-dimethyl-3-oxo synthesized in Step 6 -2-Phenyl-2,3-dihydro-1H-pyrazol-4-yl) -3- (3-trimethylsilylprop-2-inoyl) cyclohexanecarboxamide 459 mg (0.781 mmol) methanol 5.1 mL / water 0.
  • Step 1 Cis-3- [5- (5-chloro-2-ethoxyphenyl) -4H-1,2,4-triazol-3-yl] -N- (1,5-dimethyl-3-oxo- 2-Phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide cis-N- (1,5-dimethyl-3-oxo-2-phenyl-2) synthesized in Step 7 of Example 25 , 3-Dihydro-1H-pyrazol-4-yl) -3- (hydrazinecarbonyl) cyclohexanecarboxamide 0.160 g (0.431 mmol) and ethyl 5-chloro-2-ethoxybenzene synthesized in Step 3 of Example 3 Carboximidate 0.0981 g (0.431 mmol) was dissolved in 2.15 mL of n-butanol, and N, N-diisopropylamine 0.700 was
  • Example 72 cis-3- [1- (5-Chloro-2-ethoxyphenyl) -1H-1,2,3-triazol-4-yl] -N- (1,5-dimethyl-3-oxo -2-Phenyl-2,3-dihydro-1H-pyrazol-4-yl) cyclohexanecarboxamide
  • Step 1 Methyl cis-3-ethynylcyclohexylcarboxylate Journal of Macromolecular Science, Chemistry (1971), 5 (1), 1873-87. 500 mg (2.94 mmol) of methyl cis-3-formylcyclohexylcarboxylate synthesized by the method described in 1) was dissolved in 45 ml of methanol, 812 mg (5.88 mmol) of potassium carbonate was added, followed by 698 mg (3.53 mmol) of Gilbert reagent. And stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with diethyl ether.
  • Step 2 2-Azido-4-chloro-1-ethoxybenzene Dissolve 2.0 g (11.7 mmol) of 5-chloro-2-ethoxyaniline in 23.3 ml of acetonitrile and add 2.07 ml (1.80 g, 17.5 mmol) of tert-butyl nitrite under ice cooling. After stirring for 15 minutes, a solution prepared by dissolving 1.86 ml (1.60 g, 14.0 mmol) of (trimethylsilyl) diazomethane in 3.30 ml of acetonitrile was added dropwise over 10 minutes. The mixture was gradually warmed to room temperature and stirred for 2 hours.
  • Step 3 Cis-3- [1- (5-Chloro-2-ethoxyphenyl) -1H-1,2,3-triazol-4-yl] cyclohexylcarboxylate synthesized in Step 1 -320 mg (1.93 mmol) of methyl ethynylcyclohexylcarboxylate and 381 mg (1.93 mmol) of 2-azido-4-chloro-1-ethoxybenzene synthesized in Step 2 were dissolved in 19.0 ml of tetrahydrofuran at room temperature.
  • Step 1 5- (5-Chloro-2-ethoxyphenyl) -3H-1,3,4-oxadiazol-2-one 5-Chloro-2-ethoxybenzohydrazide synthesized in Step 1 of Example 6 3.30 g (15.4 mmol) was dissolved in 77 mL of tetrahydrofuran, 2.99 g (18.4 mmol) of 1,1′-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 16 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in methylene chloride, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate.
  • Step 2 (3R) -1- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] piperidine-3-carboxylate (3R) -piperidine 5- (5-Chloro-2-ethoxyphenyl) -3H-1,3,4-oxadiazole-2 synthesized in Step 1 with 0.640 mL (0.650 g, 4.20 mmol) of ethyl-3-carboxylate 0.50 g (2.10 mmol) of -one was dissolved in 10 mL of N, N-dimethylformamide, 0.720 mL (0.540 g, 4.20 mmol) of N, N-diisopropylethylamine and (benzotriazol-1-yloxy) tris (Dimethylamino) phosphonium hexafluorophosphate 1 (BOP) 1.40 g (3.10 mmol) was added and stirred at room temperature for 42 hours.
  • Step 3 (3R) -1- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] piperidine-3-carboxylic acid synthesized in Step 2 (Step 3) 3R) -1- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazolo-2-yl] piperidine-3-carboxylate (0.640 g, 1.70 mmol) in ethanol (17 mL) After dissolution, 2.5 mL of 2N aqueous sodium hydroxide solution was added and stirred at room temperature for 15 hours.
  • Step 4 (3R) -1- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3- Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidine-3-carboxamide
  • Step 6 (1R, 3S) -3- [5- (5-Chloro-2 (3R) -1- [5- (5-chloro-2-ethoxyphenyl) synthesized in Step 3 instead of -ethoxyphenyl) -1,3,4-oxadiazol-2-yl] cyclohexanecarboxylic acid Reaction was carried out in the same manner using [-1,3,4-oxadiazol-2-yl] piperidine-3-carboxylic acid to obtain the title compound as a solid.
  • Example 78 (3R) -1- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3 -Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) pyrrolidine-3-carboxamide instead of the ethyl (3R) -piperidine-3-carboxylate used in Step 2 of Example 75
  • the following Examples 78 to 79 were conducted in the same manner as in Examples 75 and 76 using (3R) -pyrrolidine-3-carboxylic acid ethyl hydrochloride and 3.0 equivalents of N, N-diisopropylethylamine. Synthesized. It shows in Table 22.
  • Step 1 cis-6-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] piperidine-2-carboxylic acid methyl cis-piperidine- 1.40 g (5.89 mmol) of dimethyl 2,6-dicarboxylate hydrochloride was dissolved in 29 mL of methanol, and 12.4 mL (12.4 mmol) of 1N aqueous sodium hydroxide solution was added at room temperature. The mixture was stirred at room temperature for 14 hours, and 6.48 mL of 1N hydrochloric acid was added to the reaction solution.
  • Step 2 cis-6-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] piperidine-2-carboxylic acid synthesized in Step 1 0.350 g of methyl cis-6-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] piperidine-2-carboxylate (940 mmol) was dissolved in 9.4 mL of methanol, and 4.70 mL (4.70 mmol) of 1N aqueous sodium hydroxide solution was added at room temperature.
  • the mixture was stirred at 50 ° C. for 1 hour, allowed to cool, and then 5.00 mL of 1N hydrochloric acid was added to the reaction solution.
  • the solvent was distilled off under reduced pressure, 1,4-dioxane was added to the obtained residue, and then the solvent was distilled off again under reduced pressure to quantitatively obtain 0.337 g of the title compound as a solid.
  • Step 3 cis-6- ⁇ [(5-chloro-2-ethoxybenzoyl) amino] carbamoyl ⁇ -N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H- Pyrazol-4-yl) piperidin-2-carboxamide cis-6-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) synthesized in Step 2 ) Carbamoyl] piperidine-2-carboxylic acid 0.312 g (0.871 mmol) was dissolved in 8.7 mL of N, N-dimethylformamide, and 5-chloro-2-ethoxybenzo synthesized in Step 1 of Example 6 at room temperature.
  • Step 4 cis-6- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo- 2-Phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidin-2-carboxamide
  • Step 2 cis-3- ⁇ [(5-chloro-2-ethoxybenzoyl) amino] carbamoyl ⁇
  • Cis-6- ⁇ [(5-chloro-2-ethoxybenzoyl) amino] carbamoyl ⁇ -N- (1,5-dimethyl-3-oxo-2-phenyl) synthesized in Step 3 instead of methylcyclohexanecarboxylate -2,3-Dihydro-1H-pyrazol-4-yl) piperidine-2-carboxamide was reacted in the same manner to obtain the title compound as a solid.
  • Step 1 (3R, 5S) -3- [5- (5-Chloro-2-isopropoxyphenyl) -1,3,4-oxadiazol-2-yl] -5-[(1,5- Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] tert-butyl piperidine-1-carboxylate cis-3-methoxycarbonylcyclohexane- of Example 37, step 2 Instead of 1-carboxylic acid, (3R, 5S) -1-tert-butoxycarbonyl-5-methoxycarbonylpiperidine-3-carboxylic acid synthesized by the method described in Bioorganic & Medicinal Chemistry Letters 22 (2012) 7679-7682 was used.
  • Example 4 instead of chloro-2-ethoxypyridine-3-carbohydrazide Using the step 2 was synthesized by 5-chloro-2-isopropoxyphenyl benzohydrazide respectively, since, to give the title compound subjected to the reaction as before Step 5 of Example 37 as a solid.
  • Step 2 (3S, 5R) -5- [5- (5-chloro-2-isopropoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl -3-Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidine-3-carboxamide (3R, 5S) -3- [5- (5-chloro- 2-Isopropoxyphenyl) -1,3,4-oxadiazol-2-yl] -5-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole- 4-yl) carbamoyl] piperidine-1-carboxylate tert-butyl (0.780 g, 1.20 mmol) in methylene chloride (6.0 mL) was added with trifluoroacetic acid (6.0 mL) under ice cooling.
  • Step 1 O1-tert-butyl O2, O5-dimethyl (2S, 5S) -pyrrolidine-1,2,5-tricarboxylate Synthesis, 1993, 3, 298-302 (2S, 5S) ) -1-[(1R) -1-phenylethyl] pyrrolidine-2,5-dicarboxylate 2.00 g (6.87 mmol) in methanol 35 mL solution was added 20% palladium hydroxide carbon catalyst 0.700 g, The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. After purging with nitrogen, the reaction solution was filtered and concentrated under reduced pressure.
  • Step 2 (2S, 5S) -1-tert-butoxycarbonyl-5-methoxycarbonylpyrrolidine-2-carboxylic acid O1-tert-butyl O2, O5-dimethyl (2S, 5S) -pyrrolidine synthesized in Step 1
  • To a solution of 1.97 g (6.86 mmol) of 1,2,5-tricarboxylate in 35 mL of methanol was added 6.86 mL (6.86 mmol) of 1N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 2 days. Methanol was distilled off under reduced pressure, water was added to the residue, and the mixture was washed twice with diethyl ether.
  • Step 3 O1-tert-butyl O2-methyl (2S, 5S) -5- ⁇ [(5-chloro-2-ethoxybenzoyl) amino] carbamoyl ⁇ pyrrolidine-1,2-dicarboxylate synthesized in Step 2 1.72 g of (2S, 5S) -1-tert-butoxycarbonyl-5-methoxycarbonyl-pyrrolidine-2-carboxylic acid mixed with (2S, 5S) -1-tert-butoxycarbonylpyrrolidine-2,5-dicarboxylic acid To a 30 mL solution of N, N-dimethylformamide, 1.49 g (6.92 mmol) of 5-chloro-2-ethoxybenzohydrazide synthesized in Step 1 of Example 6, O- (7-azabenzotriazol-1-yl) -N, N, N ', N',-tetramethylronium hexafluorophosphate (HATU) 2.63 g (6.9 m
  • Step 4 tert-butyl (2S, 5S) -2- [5- (5-chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -5-[(1, 5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] pyrrolidine-1-carboxylate 5- [2- (5-chloro] of Example 2, Step 2 Instead of methyl-2-methoxybenzoyl) hydrazino] -3,3-dimethyl-5-oxopentanoate, the O1-tert-butyl O2-methyl (2S, 5S) -5- ⁇ [(5 Using -chloro-2-ethoxybenzoyl) amino] carbamoyl ⁇ pyrrolidine-1,2-dicarboxylate, the reaction was carried out in the same manner as in Step 4 of Example 4 to obtain the title compound as a solid.
  • Step 1 tert-butyl (2R, 5S) -2- ⁇ [(5-chloro-2-ethoxybenzoyl) amino] carbamoyl ⁇ -5-[(1,5-dimethyl-3-oxo-2-phenyl- 2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] pyrrolidine-1-carboxylate
  • step 6 Tetrahedron: Asymmetry, 2008, vol.
  • Step 2 tert-butyl (2R, 5S) -2- [5- (5-chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -5-[(1, 5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] pyrrolidine-1-carboxylate 5- [2- (5-chloro] of Example 2, Step 2 Instead of methyl-2-methoxybenzoyl) hydrazino] -3,3-dimethyl-5-oxopentanoate, tert-butyl (2R, 5S) -2- ⁇ [(5-chloro-2- Ethoxybenzoyl) amino] carbamoyl ⁇ -5-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbamoyl] pyrrolidine-1-carboxy
  • Step 1 (2R, 5S) -5- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl- 3-Oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) pyrrolidine-2-carboxamide (2S, 5S) -1-tert-butoxycarbonyl-5 of Example 86, step 3 (2S, 5R) -1-tert-butoxycarbonyl-5-methoxycarbonylpyrrolidine-synthesized according to the method described in Tetrahedron: Asymmetry, 2008, 19, 11, 1333-1338 instead of methoxycarbonylpyrrolidine-2-carboxylic acid The reaction was carried out using 2-carboxylic acid in the same manner as in Step 5 of Example 86 to obtain the title compound as a solid.
  • Step 2 (2R, 5S) -5- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -1-methylpyrrolidine-2-carboxamide
  • (2R, 5S) -5- [5- (5 -Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole -4-yl) pyrrolidine-2-carboxamide was subjected to the same reaction as in Step 1 of Example 9 to obtain the title compound as a solid.
  • Step 1 2-[(2R, 5S, 6S) -6- ⁇ [tert-Butyl (diphenyl) silyl] oxymethyl ⁇ -5-methyltetrahydropyran-2-yl] ethanol Australian Journal of Chemistry, 2000, 53 , 659-664, 5.00 g (23.2 mmol) of methyl 2-[(2R, 5S, 6S) -6- (hydroxymethyl) -5-methyltetrahydropyran-2-yl] acetate was synthesized.
  • the product was dissolved in 100 ml of N, N-dimethylformamide, 4.73 g (69.5 mmol) of imidazole and 7.01 g (25.5 mmol) of tert-butyldiphenylsilyl chloride were added, and the mixture was stirred at room temperature for 24 hours. The reaction was stopped by adding methanol, and diluted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate.
  • Step 2 tert-Butyl- ⁇ [(2S, 3S, 6R) -3-methyl-6-vinyltetrahydropyran-2-yl] methoxy ⁇ diphenylsilane 2-[(2R, 5S, 6S) synthesized in Step 1 ) -6- ⁇ [tert-Butyl (diphenyl) silyl] oxymethyl ⁇ -5-methyltetrahydropyran-2-yl] ethanol 6.50 g (15.8 mmol) was dissolved in tetrahydrofuran 150 ml, and 2-nitrophenyl was dissolved at room temperature.
  • Step 3 [(2S, 3S, 6R) -3-Methyl-6-vinyltetrahydropyran-2-yl] methanol Dissolve 5.85 g (14.9 mmol) of tert-butyl- ⁇ [(2S, 3S, 6R) -3-methyl-6-vinyltetrahydropyran-2-yl] methoxy ⁇ diphenylsilane synthesized in Step 2 in 100 ml of tetrahydrofuran. Then, 17.8 ml (17.8 mmol) of tetrabutylammonium fluoride (1M tetrahydrofuran solution) was added at 0 ° C. and stirred for 12 hours.
  • tetrabutylammonium fluoride (1M tetrahydrofuran solution
  • Step 4 Methyl (2S, 3S, 6R) -3-methyl-6-vinyltetrahydropyran-2-carboxylate synthesized in Step 3 [[(2S, 3S, 6R) -3-methyl-6-vinyltetrahydro Pyran-2-yl] methanol 2.11 g (13.5 mmol) was dissolved in 100 ml of acetonitrile, 30 ml of water, 13.0 g (40.6 mmol) of bisacetoxyiodobenzene and 1-oxy-2,2,6,6 -Add 1.05 g (6.76 mmol) of tetramethylpiperidine and stir at room temperature for 16 hours.
  • Step 5 (2R, 5S, 6S) -6-methoxycarbonyl-5-methyltetrahydropyran-2-carboxylic acid (2S, 3S, 6R) -3-methyl-6-vinyltetrahydropyran- synthesized in Step 4
  • 1.61 g (8.75 mmol) of methyl 2-carboxylate was dissolved in 50 ml of methylene chloride and treated with ozone gas at ⁇ 78 ° C. for 1 hour. After confirming the formation of ozonide by TLC, the gas was replaced with nitrogen gas, 3.93 g (15.0 mmol) of triphenylphosphine was added, and the mixture was stirred at room temperature for 12 hours.
  • Step 1 Ethyl 4-methylenetetrahydropyran-2-carboxylate 540 mg (3.14 mmol) of ethyl 4-oxotetrahydropyran-2-carboxylate was dissolved in 13.5 ml of tetrahydrofuran, and 493 mg (4.39 mmol) of potassium tert-butoxide was dissolved. ) And 1680 mg (4.70 mmol) of methyltriphenylphosphonium bromide were added, and the mixture was stirred at room temperature for 3 days. Water was 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 sodium sulfate.
  • Step 2 Ethyl cis-4- (hydroxymethyl) tetrahydropyran-2-carboxylate 390 mg (2.29 mmol) of ethyl 4-methylenetetrahydropyran-2-carboxylate synthesized in Step 1 was dissolved in 8.0 ml of tetrahydrofuran. Under ice-cooling, 4.82 ml (4.58 mmol) of borane-tetrahydrofuran complex (1.05 M tetrahydrofuran solution) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 2 hours.
  • Step 3 Ethyl cis-4-formyltetrahydropyran-2-carboxylate 110 mg (0.58 mmol) of ethyl cis-4- (hydroxymethyl) tetrahydropyran-2-carboxylate synthesized in Step 2 was added to 3.30 ml of methylene chloride. Into the solution, 307 mg (0.70 mmol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (desmartin reagent) was added at room temperature. Stir for 1.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform.
  • Step 4 Cis-2-ethoxycarbonyltetrahydropyran-4-carboxylic acid 55.0 mg (0.29 mmol) of cis-4-formyltetrahydropyran-2-carboxylate synthesized in Step 3 was added to 2.0 ml of tert-butanol. In water and 0.50 ml of water, 91.2 mg (0.58 mmol) of sodium dihydrogen phosphate dihydrate, 0.155 mL (102 mg, 1.46 mmol) of 2-methyl-2-butene and Sodium chlorite 52.9 mg (0.86 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • Example 95 3- [5- (5-Chloro-2-ethoxyphenyl) -1,3,4-oxadiazol-2-yl] -N- (1,5-dimethyl-3-oxo-2 -Phenyl-2,3-dihydro-1H-pyrazol-4-yl) benzamide Using 3-methoxycarbonylbenzoic acid instead of (1S, 3R) -3-ethoxycarbonylcyclohexanecarboxylic acid in Step 3 of Example 40 Thereafter, the reaction was carried out in the same manner as in Step 6 of Example 40, and the following Examples 95 to 96 were synthesized. Table 25 shows.

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Abstract

　La présente invention concerne un composé ou un sel pharmaceutiquement acceptable de celui-ci qui est utile dans le traitement des tumeurs en raison de son exceptionnel effet inhibiteur sur l'activité ATPase du complexe TIP48/TIP49. Un composé ayant la structure représentée par la formule générale (I), un sel pharmaceutiquement acceptable de celui-ci, ou une composition pharmaceutique le contenant sont en outre décrits. (Dans la formule, R1, R2, R3, R4, W, Z, et y sont tels que définis dans la description).
PCT/JP2015/054316 2014-02-18 2015-02-17 Dérivé de pyrazolone portant de mulitples substituants Ceased WO2015125785A1 (fr)

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CN112239407A (zh) * 2019-07-17 2021-01-19 信越化学工业株式会社 具有二甲基环丁烷环的二酯化合物及其制备方法及其衍生的二甲基环丁烷化合物的制备方法
JP2021017438A (ja) * 2019-07-17 2021-02-15 信越化学工業株式会社 ジメチルシクロブタン環を有するジエステル化合物及びその製造方法、並びにそれから誘導されるジメチルシクロブタン化合物の製造方法
CN112778156A (zh) * 2019-11-08 2021-05-11 中国科学院上海药物研究所 双酰肼结构类化合物、其制备方法及其应用
JP2021519332A (ja) * 2018-03-28 2021-08-10 深▲チェン▼市塔吉瑞生物医薬有限公司Ｓｈｅｎｚｈｅｎ ＴａｒｇｅｔＲｘ， Ｉｎｃ． 置換ジアミノ複素環式カルボキサミド化合物、該化合物を含む組成物およびその使用
WO2021249517A1 (fr) * 2020-06-10 2021-12-16 National Institute Of Biological Sciences, Beijing Colle moléculaire régulant l'interaction cdk12-ddb1 pour déclencher une dégradation de la cycline k
CN114315723A (zh) * 2020-09-28 2022-04-12 中国农业大学 安乃近残留标识物半抗原和人工抗原及其制备方法与应用
US11384043B2 (en) 2019-07-17 2022-07-12 Shin-Etsu Chemical Co., Ltd. Dimethylcyclobutanone compounds, dimethylcyclobutane compounds, and processes for preparing the same

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US12264151B2 (en) 2018-03-28 2025-04-01 Shenzhen Targetrx, Inc. Substituted diamino heterocyclic carboxamide compound and a composition containing the compound and use thereof
JP7492742B2 (ja) 2018-03-28 2024-05-30 深▲チェン▼市塔吉瑞生物医薬有限公司 置換ジアミノ複素環式カルボキサミド化合物、該化合物を含む組成物およびその使用
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JP2021519332A (ja) * 2018-03-28 2021-08-10 深▲チェン▼市塔吉瑞生物医薬有限公司Ｓｈｅｎｚｈｅｎ ＴａｒｇｅｔＲｘ， Ｉｎｃ． 置換ジアミノ複素環式カルボキサミド化合物、該化合物を含む組成物およびその使用
US11384043B2 (en) 2019-07-17 2022-07-12 Shin-Etsu Chemical Co., Ltd. Dimethylcyclobutanone compounds, dimethylcyclobutane compounds, and processes for preparing the same
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JP7335849B2 (ja) 2019-07-17 2023-08-30 信越化学工業株式会社 ジメチルシクロブタン環を有するジエステル化合物及びその製造方法、並びにそれから誘導されるジメチルシクロブタン化合物の製造方法
CN112239407B (zh) * 2019-07-17 2024-05-28 信越化学工业株式会社 具有二甲基环丁烷环的二酯化合物及其制备方法及其衍生的二甲基环丁烷化合物的制备方法
JP2021017438A (ja) * 2019-07-17 2021-02-15 信越化学工業株式会社 ジメチルシクロブタン環を有するジエステル化合物及びその製造方法、並びにそれから誘導されるジメチルシクロブタン化合物の製造方法
US12139454B2 (en) 2019-07-17 2024-11-12 Shin-Etsu Chemical Co., Ltd. Dimethylcyclobutanone compounds, dimethylcyclobutane compounds, and processes for preparing the same
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US12281069B2 (en) 2019-07-17 2025-04-22 Shin-Etsu Chemical Co., Ltd. Diester compound having a dimethylcyclobutane ring, a process for preparing the same, and a process for preparing dimethylcyclobutane compound derived from the diester compound
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WO2021249517A1 (fr) * 2020-06-10 2021-12-16 National Institute Of Biological Sciences, Beijing Colle moléculaire régulant l'interaction cdk12-ddb1 pour déclencher une dégradation de la cycline k
CN114315723A (zh) * 2020-09-28 2022-04-12 中国农业大学 安乃近残留标识物半抗原和人工抗原及其制备方法与应用
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