WO2019112024A1 - Composé de pyrrolidine - Google Patents

Composé de pyrrolidine Download PDF

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Publication number
WO2019112024A1
WO2019112024A1 PCT/JP2018/045009 JP2018045009W WO2019112024A1 WO 2019112024 A1 WO2019112024 A1 WO 2019112024A1 JP 2018045009 W JP2018045009 W JP 2018045009W WO 2019112024 A1 WO2019112024 A1 WO 2019112024A1
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reference example
mixture
alkyl
added
reduced pressure
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PCT/JP2018/045009
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Japanese (ja)
Inventor
近藤　敦志
直英 森田
健宏 石川
正子 吉田
彰博 森山
勲 和南城
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キッセイ薬品工業株式会社
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Publication of WO2019112024A1 publication Critical patent/WO2019112024A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to pyrrolidine compounds useful as medicaments.
  • the present invention provides a pyrrolidine compound or a pharmacologically acceptable compound thereof which has calcitonin gene related peptide (CGRP) receptor antagonistic activity and is useful as a therapeutic agent for various diseases mediated by CGRP receptor. It is about salt.
  • CGRP calcitonin gene related peptide
  • CGRP is a neuropeptide consisting of 37 amino acids and has vasodilator activity and the like.
  • a heterodimer consisting of calcitonin receptor-like receptor (CLR) and receptor activity regulatory protein 1 (RAMP1) is known.
  • CLR calcitonin receptor-like receptor
  • RAMP1 receptor activity regulatory protein 1
  • CGRP receptors are present in the trigeminal spinal caudal caudal subnucleus, the trigeminal ganglia, and around the blood vessels of the brain stem. An increase in CGRP is said to cause allodynia (Non-patent Document 1).
  • CGRP receptor antagonists for example, Olcegepant, Telcagepant, etc.
  • a CGRP receptor antagonist for example, Telcagepant, LY2951742 and the like
  • CGRP receptors 3 and 4 have also been reported to have a migraine headache prevention (suppressing the onset of migraine attack)
  • Patent documents 1 and non-patent document 5 describe compounds containing a pyrrolidine ring.
  • Patent documents 2 and 3 are mentioned as documents about a CGRP receptor antagonist, and compounds containing a pyrrolidine ring are described in the documents.
  • Patent Document 4 describes a heterocyclic compound that is a tyrosine kinase inhibitor.
  • An object of the present invention is to provide a novel compound which has CGRP receptor antagonistic activity and is useful for the treatment of various diseases mediated by CGRP receptor.
  • the present invention relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
  • Ring W is a group selected from the group consisting of (a) to (d) below: (A) C 3-6 cycloalkyl, (B) phenyl optionally having any group selected from Substituent Group A, (C) A 6-membered aromatic heterocycle optionally having any group selected from Substituent Group A, and (d) having any group selected from Substituent Group A Good 5-membered aromatic heterocycles;
  • V is a single bond, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, or -O-C 1-3 alkylene;
  • R 1 is a group selected from the group consisting of (a) to (f) below: (A) -OH, (B) -OZ 1 , (C) -NH 2, (D)-NHZ 2 , And (f)-NZ 2 Z 3 ;
  • R d is C 1-6 alkoxy, —NR a R b , —CONR a R b , 1-
  • Ring W is C 3-6 cycloalkyl, or phenyl optionally having any group selected from Substituent Group A; Compounds in which the substituent group A has the same meaning as in the above [1]; Or a pharmacologically acceptable salt thereof.
  • R 8 is a hydrogen atom, a halogen atom, C 1-6 alkyl or hydroxy
  • R 9 and R 10 are each independently a hydrogen atom or C 1-6 alkyl
  • a compound according to any one of the above [1] to [8], which Z 2 is, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl sulfonyl, hydroxy, -L-R f, or L is the same as in the above [1];
  • R f is C 3-6 cycloalkyl, -NR g R h or 4-morpholinyl;
  • Compounds wherein R g and R h are C 1-6 alkyl; Or a pharmacologically acceptable salt thereof.
  • Substituent group A is a group consisting of a halogen atom, C 1-6 alkyl, and halo C 1-6 alkyl; Compounds wherein substituent group B is hydroxy; and substituent group C is C 1-6 alkyl; Or a pharmacologically acceptable salt thereof.
  • the present invention relates to a method for treating migraine headache, which comprises administering to a patient a necessary amount of the pharmaceutical composition according to the above [14].
  • the present invention provides a compound according to any one of the above [1] to [13] or a pharmaceutically acceptable compound thereof for producing a pharmaceutical composition for the treatment of migraine. It relates to the use of salt.
  • the compounds of the present invention have excellent CGRP receptor antagonism. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof is useful as a therapeutic agent for various diseases mediated by CGRP receptor.
  • each term has the following meaning, unless otherwise specified.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl means a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like can be mentioned.
  • C 1-6 alkoxy means a linear or branched alkoxy group having 1 to 6 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy and the like can be mentioned.
  • C 1-6 alkylsulfanyl means a group represented by (C 1-6 alkyl) —S—.
  • methylsulfanyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl and the like can be mentioned.
  • C 1-6 alkylsulfinyl means a group represented by (C 1-6 alkyl) —SO—.
  • C 1-6 alkylsulfonyl means a group represented by (C 1-6 alkyl) —SO 2 —.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like can be mentioned.
  • C 1-3 alkylene means a linear or branched alkylene group having 1 to 3 carbon atoms. For example, methylene, ethylene, trimethylene, methylmethylene, ethylmethylene, dimethylmethylene, 1-methylethylene and the like can be mentioned.
  • the “C 2-3 alkenylene” means a linear or branched alkenylene group having 2 to 3 carbon atoms. For example, vinylene, 1-methylvinylene, propenylene and the like can be mentioned.
  • the "C 2-3 alkynylene” means a linear alkynylene group having 2 to 3 carbon atoms. For example, ethynylene, propynylene and the like can be mentioned.
  • “Hydroxy C 1-6 alkyl” means C 1-6 alkyl substituted with 1 to 3 hydroxyl groups. For example, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1,1-dimethylmethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl and the like can be mentioned.
  • “Halo C 1-6 alkyl” means C 1-6 alkyl substituted with one to three same or different halogen atoms. For example, fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and the like can be mentioned. .
  • Halo C 1-6 alkoxy means C 1-6 alkoxy substituted by 1 to 3 same or different halogen atoms. For example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy and the like can be mentioned.
  • C 3-6 cycloalkyl means a saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like can be mentioned.
  • C 3-6 cycloalkylsulfonyl means a group represented by (C 3-6 cycloalkyl) —SO 2 —.
  • cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and the like can be mentioned.
  • the “5-membered ring heteroaromatic ring” means a 5-membered aromatic hetero ring group containing 1 to 4 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom in the ring.
  • heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom in the ring.
  • “Six-membered ring heteroaromatic ring” means a six-membered heteroaromatic group containing 1 to 4 nitrogen atoms in the ring.
  • C 7-10 aralkyl means an alkyl group having 1 to 4 carbon atoms which is substituted by phenyl.
  • phenyl For example, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl and the like can be mentioned.
  • benzyl is mentioned.
  • phenyl optionally having any group selected from Substituent Group A means a phenyl optionally having 1 to 5 identical or different groups selected from Substituent Group A Do. Unsubstituted phenyl or phenyl having one or two of the above groups is preferred. “A 6-membered ring aromatic heterocycle optionally having one or more groups selected from Substituent group A” has 1 to 4 identical or different groups selected from Substituent group A which may be a 6-membered aromatic heterocyclic ring. An unsubstituted 6-membered aromatic heterocycle or a 6-membered aromatic heterocycle having one or two of the above-mentioned groups is preferable.
  • the “5-membered ring aromatic heterocycle optionally having any group selected from Substituent group A” has 1 to 3 identical or different groups selected from Substituent group A Which may be a 5-membered aromatic heterocyclic ring.
  • An unsubstituted 5-membered aromatic heterocyclic ring or a 5-membered aromatic heterocyclic ring having one or two of the above-mentioned groups is preferable.
  • a carbon atom which may have an arbitrary group selected from Substituent group B” means a carbon atom which may have one or two identical or different groups selected from Substituent group B Means Preferred is —CH 2 — or a carbon atom having one of the aforementioned groups.
  • the “nitrogen atom which may have an arbitrary group selected from Substituent Group C” means a nitrogen atom which may have one group selected from Substituent Group C. -NH- or a nitrogen atom having one of the aforementioned groups is preferred.
  • the present invention when one or more asymmetric carbon atoms are present, the present invention provides compounds in which each asymmetric carbon atom is in the R configuration, compounds in the S configuration, and any of them Also included are compounds of combinations of Also, their racemates, racemic mixtures, single enantiomers and diastereomeric mixtures are included within the scope of the present invention.
  • the present invention includes any of the cis-trans isomers.
  • the present invention includes any of the tautomers.
  • tautomers of the formula (I) represented by the following formula (II) can be mentioned.
  • determination of stereochemistry can also be performed by methods well known in the art.
  • the compound represented by the formula (I) can also be converted into a pharmacologically acceptable salt thereof according to a conventional method as required.
  • Such salts may include acid addition salts or salts with bases.
  • acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-Toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, and organic acids such as aspartic acid And acid addition salts of mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-Toluenesul
  • salts with bases salts with inorganic bases such as lithium, sodium, potassium, calcium and magnesium, N-methyl-D-glucamine, N, N'-dibenzylethylenediamine, triethylamine, piperidine, morpholine, pyrrolidine, arginine And salts with organic bases such as lysine and choline.
  • inorganic bases such as lithium, sodium, potassium, calcium and magnesium, N-methyl-D-glucamine, N, N'-dibenzylethylenediamine, triethylamine, piperidine, morpholine, pyrrolidine, arginine
  • organic bases such as lysine and choline.
  • the present invention includes any crystal form.
  • pharmacologically acceptable salts also include solvates with pharmaceutically acceptable solvents such as water or ethanol, co-crystals with a suitable co-crystal former, and the like.
  • a part of each atom may be replaced by the corresponding isotope.
  • the present invention also includes compounds substituted with these isotopes.
  • isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, respectively.
  • One embodiment includes a compound in which a part of hydrogen atoms of the compound represented by the formula (I) is replaced with 2 H (D: deuterium).
  • a compound in which some atoms are replaced by isotopes is produced by using a commercially available building block into which isotopes have been introduced, in the same manner as the production method described later.
  • a compound in which a part of hydrogen atoms of the compound represented by the formula (I) is replaced by deuterium is a method described in the above method and literature (for example, Journal of Organic Synthetic Chemistry, Vol. 65, No. 12, 1179-1190 (see 2007)).
  • a compound in which a part of carbon atoms of the compound represented by the formula (I) is replaced by 13 C can be obtained by the above-mentioned method and the method described in the literature (eg, RADIOISOTOTES, 56, 11, 35- (See p. 44, 2007).
  • the compounds represented by the formula (I) of the present invention can be produced, for example, according to the method shown in Schemes 1 to 10 (Scheme 1 to 10) or a method analogous thereto, or the method described in the literature or a method analogous thereto .
  • the compound represented by formula (I) corresponds to the compound represented by compound (Ia), (Ib) or (Ic).
  • the reaction time varies depending on the starting materials used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 3 days unless otherwise specified.
  • reaction temperature varies depending on the starting materials used, the solvent and the like, but is generally ⁇ 78 ° C. to reflux temperature unless otherwise specified.
  • the pressure varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 1 atm to 20 atm unless otherwise specified.
  • a microwave reactor such as Initiator manufactured by Biotage may be used.
  • the pressure range is 1 to 30 bar
  • the power range is 1 to 400 W
  • the reaction temperature is room temperature to 300 ° C.
  • the reaction time varies depending on the starting materials, solvents and models used.
  • the reaction can be carried out under the conditions of 1 minute to 1 day.
  • these reactions are carried out without solvent or using a suitable solvent.
  • suitable solvents include solvents inert to the reaction.
  • Specific examples of the solvent include the solvents described in Reference Examples or Examples corresponding to the respective steps, or the following solvents.
  • the following solvents may be used as a mixture of two or more in an appropriate ratio.
  • Alcohols methanol, ethanol, tert-butyl alcohol, 2-propanol etc .; Ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, CPME, etc .; Aromatic hydrocarbons: chlorobenzene, 1,2-dichlorobenzene, toluene, xylene etc .; Saturated hydrocarbons: cyclohexane, n-hexane etc .; Amides: DMF, DMA, NMP, etc .; Halogenated hydrocarbons: dichloromethane, 1,2-dichloroethane, carbon tetrachloride etc .; Nitriles: acetonitrile, etc .; Sulfoxides: dimethyl sulfoxide and the like; Aromatic organic bases: pyridine and the like; Acid anhydrides: acetic anhydride etc .; Organic acids: Formic acid, acetic acid, triflu
  • Inorganic bases sodium hydroxide, lithium hydroxide, potassium hydroxide etc .
  • Basic salts sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate etc .
  • Organic bases triethylamine, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, 1,8-diazabicyclo [5.4.0] -7-undecene, imidazole, piperidine etc .
  • Metal alkoxides sodium ethoxide, sodium methoxide, potassium tert-butoxide etc .
  • Alkali metal hydrides sodium hydride etc .
  • Metal amides sodium amide, LDA, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis
  • Inorganic acids hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid etc .
  • Organic acids acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .
  • Lewis acid boron trifluoride diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium (IV) chloride and the like.
  • condensing agent When a condensing agent is used in the reaction of each step, these reactions are performed using a condensing agent suitable for each reaction.
  • Specific examples of the condensing agent include the condensing agents described in Reference Examples or Examples corresponding to the respective steps, or the following condensing agents.
  • Carbodiimides EDC.HCl, N, N'-dicyclohexylcarbodiimide etc .
  • Carbodiimidazoles such as CDI
  • Uronium salts, phosphonium salts O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, 1H-benzotriazol-1-yloxytris ( Dimethylamino) phosphonium hexafluorophosphate etc .
  • Triazines 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride and the like
  • Others T3P etc.
  • a reducing agent When a reducing agent is used in the reaction of each step, these reactions are carried out using a reducing agent suitable for each reaction.
  • the reducing agent include the reducing agents described in Reference Examples or Examples corresponding to the respective steps, or the following reducing agents.
  • Metal hydrides LAH, lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride and the like; Boranes: Borane-tetrahydrofuran complex, picoline borane and the like.
  • oxidizing agents When oxidizing agents are used in the reaction of each step, these reactions are carried out using an oxidizing agent suitable for each reaction.
  • the oxidizing agent include the oxidizing agents described in Reference Examples or Examples corresponding to the respective steps, or the following oxidizing agents.
  • Peracids m-chloroperbenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, etc .; Chlorates: sodium hypochlorite, sodium chlorite, etc .; Iodates: sodium periodate etc; Hypervalent iodine reagents: iodobenzene diacetate, DMP, etc .; Reagents having chromium: pyridinium dichromate, Jones reagent, etc .; Reagents having manganese: manganese dioxide, potassium permanganate and the like.
  • a protective group when a protective group is required depending on the type of functional group, the procedure of introduction and removal may be appropriately combined and practiced according to a conventional method.
  • types of protecting groups, protection, and deprotection for example, those described in "Greene's Protective Groups in Organic Synthesis", edited by Theodora W. Greene & Peter G. M. Wuts, fourth edition, Wiley-Interscience, 2006. I can mention the method.
  • these reactions can be performed using a hydrolysis reaction, a hydrogenolysis reaction, or the like.
  • these reactions can carry out the reaction in the presence of hydrogen and a catalyst.
  • the catalyst include palladium carbon powder, Raney nickel and the like.
  • an oxidation reaction When an oxidation reaction is carried out in each step, these reactions can be carried out in the presence of an oxidizing agent.
  • an oxidizing agent As an oxidizing agent, the above-mentioned example is mentioned.
  • a nitroxy radical oxidation catalyst When a nitroxy radical oxidation catalyst is used, the reaction can be carried out in the presence of a re-oxidant.
  • the nitroxyl radical oxidation catalyst include TEMPO, 2-azaadamantane-N-oxyl and the like.
  • the re-oxidizing agent sodium hypochlorite, iodobenzene diacetate and the like can be mentioned. If necessary, additives such as tetrabutylammonium hydrogen sulfate and potassium bromide may be added to the reaction.
  • each step when the esterification reaction is carried out, these reactions can be carried out in the presence of an acid and an alcohol (Fisher ester synthesis reaction) or in the presence of a base and an alkyl halide.
  • an acid and an alcohol include the examples described above.
  • examples of the alcohol include methanol and ethanol.
  • examples of the halogenated alkyl include iodomethane and the like.
  • an amidation reaction When an amidation reaction is carried out in each step, these reactions can be carried out in the presence of a condensing agent and a base, or in the presence of a condensing agent.
  • a condensing agent and the base examples include the examples described above.
  • carbodiimides when using carbodiimides as a condensing agent, you may add additives, such as HOBT and DMAP, to reaction as needed.
  • the amidation reaction can also be carried out using an acyl halide or an acid anhydride.
  • these reactions can carry out the reaction in the presence of an acid.
  • the acid include the above-mentioned examples.
  • phosphorus ylides can be prepared by known methods, for example, by reacting a phosphonium salt with a base.
  • a phosphonium salt methyl triphenyl phosphonium bromide etc. are mentioned.
  • these reactions can carry out the reaction in the presence of carbon monoxide, an alcohol and a palladium catalyst.
  • palladium catalysts include [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (II).
  • the alcohol include methanol and ethanol. If necessary, additives such as 1,1′-bis (diphenylphosphino) ferrocene, DMAP and a base may be added to the reaction.
  • R 1 is a group selected from the group consisting of (c) to (f) in the definition of R 1 above.
  • PG 1 is a protecting group.
  • Process 1-1 (Process 1-1)
  • the compound (1-5) can also be produced by an amidation reaction of the compound (1-1) and the compound (1-3).
  • Process 1-2 The compound (1-5) can also be produced by an amidation reaction of the compound (1-2) and the compound (1-4).
  • Process 1-3 Compound (Ia) can also be produced by removing the protecting group of compound (1-5).
  • Process 1-4 Compound (Ib) can also be produced by an amidation reaction of compound (Ia) with an amine (Amine).
  • R 1 is a group selected from the group consisting of (b) to (f) in the definition of R 1 above.
  • Process 2-1 Compound (Ic) can also be produced by an amidation reaction of compound (2-1) with compound (1-3).
  • Process 2-2 Compound (Ic) can also be produced by an amidation reaction of compound (2-2) and compound (1-4).
  • R 1 is a group selected from the group consisting of (b) to (f) in the definition of R 1 above.
  • Process 3-1 (Process 3-1)
  • the compound (3-3) can also be produced by reacting the compound (3-1) with the compound (3-2) in the presence of a base.
  • the compound (3-3) can also be produced according to the method described in Japanese Patent Publication No. 2514855.
  • Process 3-2 Compound (3-4) can also be produced by reacting compound (3-3) with oxalyl chloride or thionyl chloride. In addition, you may add additives, such as DMF, to reaction as needed.
  • Process 3-3 Compound (3-5) can also be produced by reacting compound (1-1) with compound (3-4) in the presence of a base. Similarly, compound (3-6) can also be produced by reacting compound (2-1) with compound (3-4).
  • Process 3-4 Compound (1-2) can also be produced by reacting compound (3-5) with hydrazine monohydrate.
  • compound (2-2) can also be produced by reacting compound (3-6) with hydrazine monohydrate.
  • the compound (1-3) can be produced, for example, according to the method of Process 4-1 and Process 4-2 described in Scheme 4.
  • the symbols in the formula have the same meaning as described above.
  • PG 2 is a protecting group.
  • Process 4-1 (Process 4-1)
  • the compound (4-2) can also be produced by an amidation reaction of the compound (1-4) with the compound (4-1).
  • Process 4-2 Compound (1-3) can also be produced by removing the protecting group of compound (4-2).
  • the compound (5-10) can be produced, for example, according to the method of Process 5-1 to 5-9 described in Scheme 5.
  • the symbols in the formula have the same meaning as described above.
  • X 1P is a chlorine atom, a bromine atom or an iodine atom; R 1P is a C 1-6 alkyl.
  • Process 5-1 The compound (5-2) can also be produced by reacting the compound (5-1) with a Grignard reagent (5-11).
  • Process 5-2 Compound (5-3) can also be produced by a ring closure reaction of compound (5-2).
  • Process 5-3 The compound (5-4) can also be produced by a catalytic reduction reaction or a reduction reaction of the compound (5-3).
  • Process 5-4 Compound (5-5) can also be produced by reacting compound (5-4) with di-tert-butyl dicarbonate in the presence of a base.
  • Process 5-5 Compound (5-6) can also be produced by reacting compound (5-5) with N, O-dimethylhydroxylamine hydrochloride in the presence of a base.
  • the preferred base is isopropyl magnesium chloride.
  • Process 5-6 (Process 5-6)
  • the compound (5-7) can also be produced by reacting the compound (5-6) with a Grignard reagent (5-12).
  • Process 5-7 Compound (5-8) can also be produced by Wittig reaction of compound (5-7).
  • Process 5-8 Compound (5-9) can also be produced by reacting compound (5-8) with p-toluenesulfonyl cyanide in the presence of a cobalt catalyst and phenylsilane.
  • a cobalt catalyst 1,1,2,2-tetramethyl-1,2-ethanediamino-N, N'-bis (3,5-di-tert-butyl salicylidene) -cobalt (II) and the like It can be mentioned.
  • Process 5-9 Compound (5-10) can also be produced by a hydrolysis reaction of compound (5-9) and then an esterification reaction.
  • Compound (6-10) can be produced, for example, according to the method of Process 6-1 to 6-9 described in Scheme 6.
  • the symbols in the formula have the same meaning as described above.
  • R 2P and R 3P are each independently a hydrogen atom or C 1-6 alkyl, and R 2P and R 3P may combine to form a ring with the adjacent carbon atom.
  • PG 3 is a protecting group.
  • Process 6-1 Compound (6-2) can also be produced by amidation reaction of compound (6-1) with N, O-dimethylhydroxylamine hydrochloride.
  • Process 6-2 The compound (6-3) can also be produced by reacting the compound (6-2) with a Grignard reagent (6-11).
  • Process 6-3 Compound (6-4) can also be produced by reacting compound (6-3) with ethylene glycol in the presence of an acid catalyst.
  • the acid catalyst includes p-toluenesulfonic acid and the like.
  • Process 6-4 Compound (6-5) can also be produced by removing the protecting group of compound (6-4).
  • Process 6-5 Compound (6-6) can also be produced by the oxidation reaction of compound (6-5).
  • Process 6-6 Compound (6-7) is produced by reacting compound (6-6) with (R)-(+)-2-methyl-2-propanesulfinamide in the presence of titanium (IV) ethoxide or a dehydrating agent. You can also As a dehydrating agent, copper (II) sulfate, magnesium sulfate and the like can be mentioned.
  • the compound (6-8) can also be produced by reacting the compound (6-12) with the compound (6-7) after deprotonation using a strong base.
  • strong bases include LDA, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide and the like.
  • additives such as hexamethylphosphoric acid triamide and chlorotriisopropoxytitanium (IV) may be added to the reaction.
  • Process 6-8 Compound (6-9) can also be produced by a ring closure reaction of compound (6-8).
  • Process 6-9 Compound (6-10) can also be produced by catalytic reduction reaction or reduction reaction of compound (6-9).
  • R 1 is a group selected from the group consisting of (c) to (f) in the definition of R 1 above.
  • Process 7-1 Compound (7-1) can also be produced by removing the protecting group of compound (6-9).
  • Process 7-2 Compound (7-2) can also be produced by reacting compound (7-1) with oxalyl chloride or thionyl chloride. In addition, you may add additives, such as DMF, to reaction as needed.
  • Process 7-3 Compound (7-3) can also be produced by reacting compound (7-2) with an amine (Amine) in the presence or absence of a base.
  • Process 7-4 Compound (7-4) can also be produced by catalytic reduction reaction or reduction reaction of compound (7-3).
  • R 4P is a hydrogen atom or C 1-6 alkyl
  • X 2P is a chlorine atom, a bromine atom, an iodine atom or a trifluoromethanesulfonyloxy group
  • PG 4 is a protecting group.
  • Process 8-1 Compound (8-2) can also be produced by reacting compound (8-1) with compound (8-6) in the presence of a base.
  • Process 8-2 Compound (8-3) can also be produced by the carbonylation cross coupling reaction of compound (8-2).
  • Process 8-3 Compound (8-5) can also be produced by removing the protecting group of compound (8-3).
  • Process 8-4 Compound (8-5) can also be produced by reacting compound (8-4) with compound (8-6) in the presence of a base.
  • Compound (9-6) can be produced, for example, according to the method of Process 9-1 to 9-5 described in Scheme 9.
  • the symbols in the formula have the same meaning as described above.
  • Process 9-1 Compound (9-2) can also be produced by reacting compound (9-1) with 4-methoxybenzyl chloride in the presence of a base.
  • Process 9-2 Compound (9-4) can also be produced by reacting compound (9-2) with compound (9-3) in the presence of a base.
  • Process 9-3 Compound (9-5) can also be produced by removing the 4-methoxybenzyl group of compound (9-4). Removal of the 4-methoxybenzyl group can be performed, for example, in the presence of CAN.
  • Process 9-4 Compound (9-6) can also be produced by removing the protecting group of compound (9-5).
  • Process 9-5 Compound (9-6) can also be produced by removing the 4-methoxybenzyl group and the protective group of compound (9-4).
  • Compound (9-4) and compound (9-6) can also be produced, for example, according to the method of Process 10-1 to 10-5 described in Scheme 10.
  • the symbols in the formula have the same meaning as described above.
  • Process 10-1 Compound (10-2) can also be produced by reacting compound (9-2) with compound (10-1) in the presence of a base.
  • Process 10-2 (Process 10-2) Compound (9-4) can also be produced by the carbonylation cross coupling reaction of compound (10-2).
  • the compound (10-3) can also be produced by the cross coupling reaction of the compound (10-2) with an inorganic cyanide compound.
  • the cross coupling reaction can be carried out in the presence or absence of a palladium catalyst.
  • the inorganic cyanide include zinc cyanide and copper cyanide.
  • the palladium catalyst include tetrakis (triphenylphosphine) palladium (0).
  • Process 10-4 Compound (10-4) can also be produced by removing the 4-methoxybenzyl group of compound (10-3). Removal of the 4-methoxybenzyl group can be performed, for example, in the presence of CAN.
  • Process 10-5 (Process 10-5) Compound (9-6) can also be produced by a hydrolysis reaction of compound (10-4).
  • the scheme shown above is an illustration of a method for producing a compound represented by formula (I) or a production intermediate thereof.
  • the above scheme is capable of various modifications to the scheme that can be easily understood by those skilled in the art.
  • the compound represented by the formula (I) and the production intermediates thereof may be, if necessary, solvent extraction, crystallization, recrystallization, chromatography, which is a means of isolation and purification well known to those skilled in the art. It can also be isolated and purified by preparative high performance liquid chromatography or the like.
  • the compounds of the present invention have excellent CGRP receptor antagonistic activity, and thus can be used as a preventive or therapeutic agent for various CGRP receptor-mediated diseases.
  • the compounds of the present invention can be used, for example, as therapeutic agents for "primary headaches” (migraine, headache headache (TTH), trigeminal and autonomic headaches (TACs), and other primary headache disorders).
  • the compound of the present invention is, for example, “secondary headache” (headache due to head and neck trauma / injury; headache due to head and neck angiopathy; headache due to non-vascular intracranial disease; headache due to substance or its withdrawal; Headache due to homeostasis disorder; headache due to damage to the skull, neck, eyes, ears, ears, nose, sinus, teeth, mouth or other facial / cervical constituent tissue; headache or facial pain due to mental illness), It can also be used as a therapeutic agent for "painful cranial nerve neuropathy and other facial pain", “other headache diseases” and the like.
  • the headache and the like can also be classified, for example, according to International Classification of Headaches, Edition 3 beta (ICHD-3 ⁇ ).
  • the compounds of the present invention can also be used as an acute treatment for migraine.
  • the compounds of the present invention can be administered at the onset of a headache. If the effect is insufficient, the compounds of the present invention can be additionally administered.
  • the treatment of migraine headache includes, in addition to the treatment of acute phase of migraine headache, preventive treatment of migraine headache (suppression of migraine headache attack).
  • preventive treatment of migraine headache suppression of migraine headache attack
  • the compounds of the present invention can be administered to migraine patients for the purpose of suppressing a migraine attack.
  • the compounds of the present invention are particularly useful as an acute treatment and preventive treatment for migraine.
  • the compound of the present invention is also expected to be useful as a therapeutic agent for headache (drug abuse headache) (MOH) due to cluster headache or overuse of drugs.
  • MOH drug abuse headache
  • the compound of the present invention has excellent light and light aversion due to excellent CGRP receptor antagonism (See JP-A-2014-515375); Neuropathic pain and allodynia (See JP-A-2014-517699); Bladder pain and interstitial cystitis (Refer to JP 2011-046710); Irritable Bowel Syndrome (IBS) (Refer to JP 2014-517699); Overactive bladder (Refer to JP 2014-517699); Diarrhea (JP 2014) Or as a therapeutic agent for osteoarthritis (OA) (see JP-A-2013-532143).
  • IBS Irritable Bowel Syndrome
  • OA osteoarthritis
  • CGRP receptor antagonism of the compounds of the present invention can be confirmed according to methods known in the art. For example, evaluations on facial blood flow such as CGRP receptor binding affinity assay, CGRP receptor functional assay (cAMP activity assay), marmoset and the like can be mentioned.
  • the drug efficacy persistence (sustained antagonism) of the compound of the present invention can also be evaluated by a PD analysis method or the like in in vivo tests known in the art.
  • the pharmaceutical composition of the present invention is used in various dosage forms depending on the usage.
  • a dosage form include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, and oral or parenteral. Administered.
  • the pharmaceutical composition of the present invention comprises a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition of the present invention is prepared using the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutical additive.
  • the pharmaceutical composition of the present invention can be prepared according to the method known pharmaceutically depending on the dosage form, with suitable excipients, disintegrants, binders, lubricants, diluents, buffers, buffers, isotonic agents, preservatives It can also be prepared by suitably mixing, diluting or dissolving with pharmaceutical additives such as agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, and solubilizing agents.
  • the dose of the compound represented by the formula (I) or the pharmacologically acceptable salt thereof, which is the active ingredient depends on the patient's age, sex, weight, disease And the degree of treatment etc.
  • the dose for adults can be determined, for example, in the range of 0.1 to 1000 mg / day, 0.01 to 100 mg / day, 0.1 to 100 mg / day, or 1 to 100 mg / day for oral administration, and the daily dose can be determined. It may be administered once, twice, three times or four times.
  • parenteral administration it can be determined, for example, in the range of 0.1 to 1000 mg / day, 0.01 to 100 mg / day, 0.1 to 100 mg / day, or 0.1 to 10 mg / day.
  • the administration may be divided into two, three or four times.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can also be used in combination with other agents other than CGRP receptor antagonists.
  • agents that can be used in combination in the acute treatment of migraine include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), ergotamine preparations, triptans, antiemetics, sedatives, Corticosteroids and the like can be mentioned.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • ergotamine preparations e.g., ergotamine preparations, triptans, antiemetics, sedatives, Corticosteroids and the like
  • antiepileptic drugs, antidepressants, beta blockers, calcium antagonists, angiotensin receptor antagonists (ARBs) / angiotensin converting enzymes Inhibitors (ACE) etc. may be mentioned.
  • the compound of formula (I) or a pharmacologically acceptable salt thereof is used in combination with another agent, a preparation containing these active ingredients together or an individual of these active ingredients is used. It can be administered as a separately formulated formulation. When formulated separately, the formulations can be administered separately or simultaneously. In addition, the dose of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may be appropriately reduced depending on the dose of the other drug used in combination.
  • the compounds represented by the formula (I) may be appropriately converted into prodrugs and used.
  • the prodrug of the compound represented by the formula (I) is one or more selected from hydroxy or amino of the formula (I) by a conventional method using a prodrug forming reagent such as a corresponding halide After introducing a group constituting a prodrug into an arbitrary group according to a conventional method, it can also be produced by appropriately isolating and purifying according to a conventional method, as desired.
  • groups constituting a prodrug for example, “Development of pharmaceuticals” (Ashikawa Shoten, 1990), Volume 7 p. And groups described in 163-198.
  • the residue was diluted with ethyl acetate, and water and hydrochloric acid (2 mol / L, 10 mL) were added to the mixture. Separate the organic layer. The organic layer was washed three times with water and then successively with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and water and hydrochloric acid (2 mol / L, 10 mL) were added to the mixture. Separate the organic layer. The organic layer was washed 6 times with water and then successively with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (4.13 g).
  • Reference Example 2-1-B Hydrogen chloride (4 mol / L, ethyl acetate solution, 80 mL) was added to a solution of Reference Example 2-1-A (16.7 g) in ethyl acetate (80 mL), and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution and water were added. Separate the organic layer. The aqueous layer was extracted twice with ethyl acetate, and the extract was combined with the organic layer.
  • Reference Example 2-1-D Isopropylmagnesium chloride (2.0 mol / L at ⁇ 15 ° C.) was suspended in a THF (10 mL) suspension of Reference Example 2-1-C (600 mg) and N, O-dimethylhydroxylamine hydrochloride (346 mg) under an argon atmosphere. THF solution, 3.56 mL) was added and the mixture was stirred at the same temperature for 40 minutes. To the reaction mixture was added saturated aqueous ammonium chloride solution and water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (542 mg).
  • Reference Example 2-1-F To a suspension of methyltriphenylphosphonium bromide (4.06 g) in THF (22 mL) is added dropwise potassium bis (trimethylsilyl) amide (1.0 mol / L, THF solution, 10.9 mL) at room temperature and the mixture is allowed to stand at room temperature for 1 hour It stirred. To the reaction mixture was added dropwise a solution of Reference Example 2-1-E (1.40 g) in THF (5 mL) under ice-cooling. The mixture was stirred for 1 hour under ice cooling and 2 hours at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution and water under ice-cooling. The mixture was extracted twice with ethyl acetate.
  • Reference Example 2-1-G To a solution of Reference Example 1-1 (0.178 g) in ethanol (20 mL) was added a solution of Reference Example 2-1-F (3.00 g) in ethanol (80 mL) and p-toluenesulfonyl cyanide (5.34 g). To the mixture was added phenylsilane (1.57 mL) under an argon atmosphere. After stirring at room temperature for 4 hours, to the reaction mixture were added saturated aqueous ammonium chloride solution and water under ice-cooling. After stirring for 40 minutes at room temperature, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was extracted twice with ethyl acetate.
  • Reference Example 2-1-I A mixture of Reference Example 2-1-H (418 mg), concentrated sulfuric acid (2.89 mL) and water (9 mL) was refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure. After adding ethanol to the residue, the mixture was concentrated under reduced pressure. The same operation was repeated four times. To the residue was added ethanol (15 mL) and the mixture was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and water and then neutralized with potassium carbonate. Separate the organic layer. The aqueous layer was extracted with ethyl acetate and the extract was combined with the organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (486 mg).
  • Reference Example 2-2-A to Reference Example 2-2-G were synthesized in the same manner as in Reference Example 2-1-A to Reference Example 2-1-G, using the corresponding raw materials.
  • Reference Example 2-2-H A mixture of Reference Example 2-G (316 mg), concentrated sulfuric acid (1.50 mL) and water (5 mL) was refluxed for 6 hours. After adding etal to the reaction mixture, the mixture was concentrated under reduced pressure. After adding ethanol to the residue, the mixture was concentrated under reduced pressure. The same operation was repeated four times. To the residue was added ethanol (30 mL). The mixture was refluxed for 6 hours, then stirred at room temperature for 1 week, and further refluxed for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and water and then neutralized with potassium carbonate. Separate the organic layer.
  • Reference Example 2-3-B to Reference Example 2-3-F were synthesized in the same manner as in Reference Example 2-1-B to Reference Example 2-1-F.
  • Reference Example 2-3-G To a solution of Reference Example 2-3-F (1.58 g) in ethanol (50 mL), Reference Example 1-1 (0.089 g) and p-toluenesulfonyl cyanide (2.67 g) were added. To the mixture was added phenylsilane (0.790 mL) under an argon atmosphere. After stirring for 2 hours at room temperature, to the reaction mixture was added saturated aqueous ammonium chloride solution and water. After stirring at room temperature for 20 minutes, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was extracted twice with ethyl acetate.
  • Reference Example 2-3-H A mixture of Reference Example 2-3-G (200 mg), concentrated sulfuric acid (1.00 mL) and water (3 mL) was refluxed for 15 hours. After ethanol was added to the reaction mixture, the mixture was concentrated under reduced pressure. After adding ethanol to the residue, the mixture was concentrated under reduced pressure. The same operation was repeated three times. To the residue was added ethanol (8 mL) and the mixture was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and water and then neutralized with potassium carbonate. Separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (142 mg).
  • Reference Examples 2-4-B through 2-4-E were synthesized in the same manner as in Reference Examples 2-1-C through 2-1-F, using the corresponding raw materials.
  • Reference Example 2-4-G was synthesized in the same manner as in Reference Example 2-3-H, using Reference Example 2-4-F instead of Reference Example 2-3-G.
  • Reference Example 2-5-B was synthesized in the same manner as Reference Example 2-1-C, using Reference Example 2-5-A instead of Reference Example 2-1-B.
  • Reference Example 2-5-F was synthesized in the same manner as in Reference Example 2-5-D, using Reference Example 2-5-E instead of Reference Example 2-5-C.
  • Reference Example 2-5-G was synthesized in the same manner as in Reference Example 2-1-F, using Reference Example 2-5-F instead of Reference Example 2-1-E.
  • Reference Example 2-5-H was synthesized in the same manner as in Reference Example 2-4-F, using Reference Example 2-5-G instead of Reference Example 2-4-E.
  • Reference Example 2-5-I was synthesized in the same manner as in Reference Example 2-3-H, using Reference Example 2-5-H instead of Reference Example 2-3-G.
  • Reference Example 2-6-D To a solution of Reference Example 2-6-C (3.02 g) in ethanol (20 mL) and THF (20 mL) was added palladium-carbon (10%, wet, 0.600 g) under ice-cooling. The mixture was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (2.12 g).
  • Reference Example 2-7-A was synthesized in the same manner as Reference Example 2-6-G, using ethyl 2-ethyl butyrate instead of methyl cyclopentanecarboxylate.
  • Reference Example 2-7-B and Reference Example 2-7-C were synthesized by the same method as Reference Example 2-6-H and Reference Example 2-6-I, using the corresponding raw materials.
  • Reference Example 2-9-E and Reference Example 2-9-F were synthesized using the corresponding raw materials and in the same manner as Reference Example 2-6-F and Reference Example 2-8-A.
  • Reference Example 2-9-H was synthesized by the same method as Reference Example 2-8-C, using Reference Example 2-9-G instead of Reference Example 2-8-B.
  • Reference Example 2-10 by the same method as Reference Example 2-6-C to Reference Example 2-6-F, and Reference Example 2-8-A to Reference Example 2-8-B using the corresponding raw materials.
  • Reference Example 2-11-A was synthesized in the same manner as Reference Example 2-6-B, using 3-chloro-5-fluorophenyl magnesium bromide instead of 3-fluorophenyl magnesium bromide.
  • Reference Example 2-11-D and Reference Example 2-11-E were synthesized by the same method as Reference Example 2-6-F and Reference Example 2-8-A, using the corresponding raw materials.
  • Reference Example 2-12-B In an argon atmosphere, a solution of Reference Example 2-12-A (160 mg) and tetrakis (triphenylphosphine) palladium (0) (28.5 mg) in THF (4 mL), tert-butyl allyl carbonate (156 mg) in THF (0.5 mL) The solution was added. The mixture was stirred at 65 ° C. for 1 hour, and then a solution of tert-butylallyl carbonate (156 mg) in THF (0.5 mL) was added. The mixture was stirred at 85 ° C. for 1 hour, and then a solution of tert-butyl allyl carbonate (156 mg) in THF (0.5 mL) was added.
  • Reference Example 2-12-C A mixture of Reference Example 2-12-B (78.0 mg) and hydrogen chloride (4 mol / L, 1,4-dioxane solution, 1 mL) was stirred at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted three times with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (53.8 mg).
  • Reference Example 2-13-A Titanium (IV) chloride (0.895 mL) was added to a solution of Reference Example 2-8-B (300 mg) in dichloromethane (8 mL), and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture under ice cooling. The mixture was extracted three times with dichloromethane. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (193 mg).
  • Reference Example 2-13-C Platinum-carbon (5%, 12.0 mg) was added to a solution of Reference Example 2-13-B (57.0 mg) in ethanol (1.2 mL) under ice-cooling. The mixture was stirred at room temperature under hydrogen atmosphere for 4.5 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (53.8 mg).
  • Reference Example 2-14-A was synthesized in the same manner as Reference Example 2-13-B, using methylamine instead of aqueous ammonia.
  • Reference Example 2-14-B Platinum-carbon (5%, 20.0 mg) was added to a mixture of Reference Example 2-1-A (97.0 mg), ethanol (2 mL) and THF (1 mL) under ice-cooling. The mixture was stirred at room temperature under hydrogen atmosphere for 6 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (83.6 mg).
  • Reference Example 2-19-B Sodium triacetoxyborohydride (about 80%, 153 mg) was added to a solution of Reference Example 2-19-A (91.6 mg) and acetic acid (0.166 mL) in THF (2 mL). The mixture was stirred at room temperature for 50 minutes and then at 45 ° C. for 50 minutes. Further, sodium triacetoxyborohydride (about 80%, 153 mg) was added to the mixture. The mixture was stirred at 45 ° C. for 1 hour. To the reaction mixture was added water (4 mL), potassium carbonate (600 mg) and dichloromethane (6 mL) and the mixture was stirred. Separate the organic layer. The aqueous layer was extracted twice with dichloromethane and the extract was combined with the organic layer. The combined organic layer was concentrated under reduced pressure to give the title compound (90.9 mg).
  • Reference Example 2-20-B An ice salt bath of a mixture of Reference Example 2-20-A (5.60 g), TEMPO (0.072 g), potassium bromide (0.274 g), dichloromethane (20 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL) under an argon atmosphere. Below, a mixture of sodium hypochlorite pentahydrate (4.17 g), water (18 mL) and saturated aqueous sodium hydrogen carbonate solution (3 mL) was added dropwise. The mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of sodium hypochlorite pentahydrate (0.758 g) in water (3.2 mL) under an ice-salt bath.
  • Reference Example 2-20-C Reference Example 2-20-B (5.13 g) and (R)-(+)-2-Methyl-2-propanesulfinamide (2.58 g) in toluene (50 mL) with copper (II) sulfate (2.04 g) was added and the mixture was stirred at 60.degree. C. for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound (7.67 g).
  • Reference Example 2-20-H Aqueous ammonia (28%, 1.5 mL) was added to a solution of Reference Example 2-20-G (318 mg) in THF (1.5 mL). The mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and the mixture was extracted three times with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (279 mg).
  • Reference Example 2-21-A was synthesized in the same manner as Reference Example 2-20-H, using hydroxylamine instead of aqueous ammonia.
  • Reference Example 2-21-B was synthesized in the same manner as Reference Example 2-20-J, using Reference Example 2-21-A instead of Reference Example 2-20-I.
  • Reference Example 2-23-B To a solution of Reference Example 2-23-A (93.6 mg) in dichloromethane (2 mL) was added DMP (152 mg) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, aqueous sodium thiosulfate solution (1 mol / L, 2 mL) and saturated aqueous sodium hydrogen carbonate solution (4 mL) were added. After stirring for 10 minutes at room temperature, the mixture was extracted twice with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (92.3 mg).
  • Reference Example 2-23-D A mixture of Reference Example 2-23-C (256 mg), trifluoroacetic acid (1.8 mL) and dichloromethane (1.8 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted twice with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (189 mg).
  • Reference Example 2-24-A A mixture of Reference Example 2-1-C (711 mg), aqueous sodium hydroxide (2 mol / L, 3.20 mL) and methanol (10 mL) was refluxed for 1 hour. After cooling to room temperature, hydrochloric acid (2 mol / L, 3.20 mL) was added. The mixture was concentrated under reduced pressure. To the residue was added ethanol. The mixture was filtered and the insolubles were filtered off. The filtrate was concentrated under reduced pressure to give the title compound (590 mg).
  • Reference Example 2-24-B T2P (50% ethyl acetate solution, about 1.7 mol / l) was added to a mixture of Reference Example 2-24-A (100 mg), dimethylamine hydrochloride (39.5 mg), DIPEA (0.253 mL) and dichloromethane (2 mL) under an argon atmosphere. L, 0.379 mL) was added. The mixture was stirred at room temperature for 3 hours. Water and dichloromethane were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. A mixture of the obtained compound, hydrogen chloride (4 mol / L, 1,4-dioxane solution, 1 mL) and dichloromethane (3 mL) was stirred at 50 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (85.0 mg).
  • Reference Example 2-25 A mixture of Reference Example 2-1-A (195 mg), hydrogen chloride (4 mol / L, ethyl acetate solution, 2 mL) and ethyl acetate (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. A mixture of the residue, palladium-carbon (10%, wet, 40.0 mg) and ethanol (5 mL) was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the crude title compound (176 mg).
  • Reference Example 2-24 Using (2R, 5S) -1- (tert-butoxycarbonyl) -5-phenylpyrrolidine-2-carboxylic acid and piperidine in place of Reference Example 2-24-A and dimethylamine hydrochloride, Reference Example 2-24 Reference Example 2-26 was synthesized in the same manner as -B.
  • Reference Example 3-2-C Aqueous solution of sodium hydroxide (2 mol / L, 1.75 mL) was added to a solution of Reference Example 3-2-B (315 mg) in THF (8 mL), methanol (4 mL) and water (0.25 mL), and the mixture was added at 50 ° C. Stir for 1.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added hydrochloric acid (2 mol / L, 1.90 mL) and water (8 mL), and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration. The obtained solid was washed with water and then dried under reduced pressure to give the title compound (277 mg).
  • Reference Example 3-3-C A mixture of Reference Example 3-3-B (70.0 mg), aqueous sodium hydroxide solution (2 mol / L, 0.482 mL), and ethanol (5 mL) was stirred at 60 ° C. for 5 hours. After cooling to room temperature, hydrochloric acid (2 mol / L, 0.482 mL) was added to the reaction mixture. The mixture was stirred under ice-cooling for 1 hour, and the precipitated solid was collected by filtration to give the title compound (65.0 mg).
  • Reference Example 3-4-B and Reference Example 3-4-C were synthesized in the same manner as in Reference Example 3-2-B and Reference Example 3-2-C.
  • Reference Example 3-6-C To a solution of Reference Example 3-6-B (83.0 mg) in dichloromethane (3 mL) was added boron tribromide (1.0 mol / L, dichloromethane solution, 1.81 mL) under ice-cooling, and the mixture was stirred overnight at room temperature. did. After further addition of boron tribromide (1.0 mol / L, 1.81 mL of dichloromethane solution), the mixture was stirred at 30 ° C. for 5 hours. To the reaction mixture was added water under ice-cooling, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dichloromethane and then dried under reduced pressure to give the title compound (60.1 mg).
  • Reference Example 3-7-B Reference Example 3-7-A (872 mg), [1,1-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane adduct (121 mg), 1,1′-bis (diphenylphosphino) ferrocene (164 mg)
  • Reference Example 3-7-C An aqueous solution of sodium hydroxide (2 mol / L, 6.00 mL) was added to a solution of Reference Example 3-7-B (845 mg) in THF (24 mL) and methanol (6 mL), and the mixture was stirred at 30 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added hydrochloric acid (2 mol / L, 6.20 mL) and the mixture was stirred for 10 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added dichloromethane, methanol and anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (137 mg).
  • Reference Example 3-8-B was synthesized in the same manner as Reference Example 3-7-B, using Reference Example 3-8-A instead of Reference Example 3-7-A.
  • Reference Example 3-8-C Sodium hydroxide aqueous solution (2 mol / L, 0.240 mL) was added to a solution of Reference Example 3-8-B (46.0 mg) in THF (2 mL), methanol (1 mL) and water (0.76 mL), and the mixture was added at room temperature Stir overnight. Hydrochloric acid (2 mol / L, 0.400 mL) was added to the reaction mixture. The mixture was concentrated under reduced pressure to give the crude title compound (74.6 mg).
  • Reference Example 3-9 is carried out in the same manner as Reference Example 3-8-A, using 6-bromo-3-iodo-2-methylpyridine instead of 2-bromo-5-iodo-4-methylpyridine. A was synthesized.
  • Reference Example 3-9-B was synthesized in the same manner as Reference Example 3-7-B, using Reference Example 3-9-A instead of Reference Example 3-7-A.
  • Reference Example 3-9-C was synthesized by the same method as Reference Example 3-8-C, using Reference Example 3-9-B instead of Reference Example 3-8-B.
  • Reference Example 3-10-A Concentrated sulfuric acid (0.100 mL) was added to a suspension of Reference Example 3-1 (200 mg) in ethanol (4 mL), and the mixture was refluxed for 3 hours. To the reaction mixture was added dichloromethane and water and the mixture was stirred. Separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (218 mg).
  • Reference Example 3-10-C Sodium hydroxide aqueous solution (2 mol / L, 0.100 mL) was added to a solution of Reference Example 3-10-B (14.0 mg) in THF (1 mL), methanol (0.5 mL) and water (0.4 mL), and the mixture was allowed to room temperature The mixture was stirred for 1.5 hours. Hydrochloric acid (2 mol / L, 0.200 mL) was added to the reaction mixture. The mixture was concentrated under reduced pressure to give the crude title compound (23.0 mg).
  • Reference Example 3-11-C A mixture of Reference Example 3-11-B (2.25 g), concentrated hydrochloric acid (18 mL) and acetic acid (15 mL) was stirred at 100 ° C. for 1 hour. Dichloromethane and water were added to the reaction mixture. After stirring for 1 hour under ice-cooling, the precipitated solid was collected by filtration. The obtained solid was washed with water and then dried under reduced pressure to give the title compound (0.942 g).
  • Reference Example 3-12-B A mixture of Reference Example 3-12-A (2.53 g), concentrated hydrochloric acid (22 mL) and acetic acid (18 mL) was stirred at 100 ° C. for 1 hour. After cooling to room temperature, dichloromethane and water were added to the reaction mixture. After stirring for 1 hour under ice-cooling, the organic layer was separated and concentrated under reduced pressure. The residue was washed with diethyl ether to give the title compound (1.41 g).
  • Reference Example 3-13-C Aqueous solution of sodium hydroxide (2 mol / L, 0.385 mL) was added to a solution of Reference Example 3 3-B (78.9 mg) in THF (2 mL), methanol (1 mL) and water (0.115 mL), and the mixture was added at room temperature Stir for 2 hours. To the reaction mixture was added hydrochloric acid (2 mol / L, 0.450 mL). After stirring for 10 minutes at room temperature, the mixture was concentrated under reduced pressure. To the residue was added water (4 mL) and the suspension was filtered. The obtained solid was washed with water and then dried under reduced pressure at 60 ° C. to give the title compound (51.2 mg).
  • Reference Example 3-14-C A solution of CAN (13.8 g) in water (25 mL) was added to a solution of Reference Example 3 4-B (1.83 g) in acetonitrile (25 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the mixture was extracted three times with dichloromethane. The combined organic layer was washed with brine. Aqueous sodium thiosulfate solution (1 mol / L) was added to the aqueous layer, and the mixture was extracted with dichloromethane. The extract was washed with brine and then combined with the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added ethanol and the mixture was triturated. The obtained solid was collected by filtration, washed with ethanol and dried under reduced pressure to give the title compound (0.743 g).
  • Reference Example 3-14-D A mixture of Reference Example 3 4-C (1.00 g) and concentrated hydrochloric acid (15 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, insolubles were filtered off. The filtrate was concentrated under reduced pressure. To the residue was added water (25 mL) and aqueous sodium hydroxide (2 mol / L, 10 mL), and the mixture was stirred at room temperature for 1.5 hours. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give the title compound (617 mg).
  • Reference Example 3-15 by the same method as Reference Example 3-14-A using 6-bromo-4-methylpyridin-3-ol instead of 6-bromo-2-methylpyridin-3-ol. A was synthesized.
  • Reference Example 3-15-B Reference Example 3 15-A (1.24 g), [1,1-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane adduct (0.243 g), 1,1′-bis (diphenylphosphino) ferrocene
  • a solution of (0.331 g), triethylamine (1.25 mL), DMAP (0.108 g) and ethanol (12.5 mL) in NMP (12.5 mL) was stirred at 110 ° C. overnight under a carbon monoxide atmosphere.
  • Reference Example 3-15-D An aqueous solution of sodium hydroxide (2 mol / L, 2.25 mL) was added to a suspension of Reference Example 3-15-C (433 mg) in water (4.3 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added hydrochloric acid (2 mol / L, 2.30 mL). The mixture was concentrated under reduced pressure. To the residue was added water (6 mL) and the suspension was filtered. The obtained solid was washed with water and then dried under reduced pressure to give the title compound (282 mg).
  • Reference Example 3-16-A A mixture of Reference Example 3-11-A (753 mg), 4-bromo-2-fluoro-6-methylphenol (500 mg), potassium carbonate (675 mg) and DMA (9 mL) was heated at 150 ° C. under microwave irradiation 1 Stir for hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate (4 mL) was added to the residue and the suspension was filtered. The obtained solid was washed with ethyl acetate and then dried under reduced pressure to give the title compound (612 mg).
  • Reference Example 3-16-B Reference Example 3-16-A (600 mg), [1,1-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane adduct (112 mg), 1,1′-bis (diphenylphosphino) ferrocene (153 mg)
  • a solution of triethylamine (0.585 mL), DMAP (50.5 mg) and ethanol (5 mL) in NMP (5 mL) was stirred at 110 ° C. for 4 hours under carbon monoxide atmosphere. After cooling to room temperature, the mixture was stirred overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate.
  • Reference Example 3-16-C CAN (1.33 g) was added to a solution of Reference Example 3-16-B (344 mg) in acetonitrile (17 mL) and water (3.4 mL), and the mixture was stirred at room temperature for 5 hours. To the reaction mixture were added water and saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added THF (2 mL) and the suspension was filtered. The obtained solid was washed with THF and then dried under reduced pressure to give the title compound (115 mg).
  • Reference Example 3-16-D Sodium hydroxide aqueous solution (2 mol / L, 0.560 mL) was added to a solution of Reference Example 3-16-C (115 mg) in THF (2 mL), methanol (1 mL) and water (0.54 mL), and the mixture was stirred at room temperature 1 Stir for hours. To the reaction mixture was added hydrochloric acid (2 mol / L, 0.650 mL). After stirring for 10 minutes at room temperature, the mixture was concentrated under reduced pressure. To the residue was added water (2 mL) and the suspension was filtered. The obtained solid was washed with water and then dried under reduced pressure at 50 ° C. to give the title compound (96.8 mg).
  • Reference Example 3-17-A was synthesized in the same manner as Reference Example 3-11-B, using methyl 4-hydroxybenzoate instead of methyl 3-fluoro-4-hydroxybenzoate.
  • Reference Example 3-17-C A mixture of Reference Example 3-17-B (551 mg), aqueous sodium hydroxide (2 mol / L, 3.20 mL) and methanol (7 mL) was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was concentrated under reduced pressure. To the residue were added water, hydrochloric acid (2 mol / L, 3.20 mL) and dichloromethane. The mixture was concentrated under reduced pressure. The residue was washed with water to give the title compound (439 mg).
  • Reference Example 3-18-A was prepared by the same method as Reference Example 3-11-B using methyl 4-hydroxy-3,5-dimethylbenzoate instead of methyl 3-fluoro-4-hydroxybenzoate. Synthesized.
  • Reference Example 3-18-B A suspension of Reference Example 3-18-A (308 mg) in acetic acid (1.5 mL) was heated to 65 ° C., and concentrated hydrochloric acid (1.5 mL) was added. The mixture was stirred at 110 ° C. for 2 hours. After cooling to room temperature, water (7.5 mL) was added to the reaction mixture. The mixture was stirred under ice cooling, and the precipitate was collected by filtration to give the title compound (198 mg).
  • Reference Example 3-19-A was synthesized in the same manner as Reference Example 3-14-A using 2-bromo-5-hydroxypyridine instead of 6-bromo-2-methylpyridin-3-ol. .
  • Reference Examples 3-19-B and 3-19-C were synthesized in the same manner as in Reference Examples 3-15-B and 3-15-C, using the corresponding raw materials.
  • Reference Example 3-19-D To a solution of Reference Example 3-19-C (73.4 mg) in THF (2 mL), methanol (1 mL) and water (0.6 mL), aqueous sodium hydroxide solution (2 mol / L, 0.400 mL) was added, and the mixture was added at room temperature. Stir for 3 hours. Hydrochloric acid (2 mol / L, 0.500 mL) was added to the reaction mixture. The mixture was concentrated under reduced pressure to give the crude title compound (122 mg).
  • Reference Example 3-20-A was synthesized in the same manner as Reference Example 3-12-A, using benzyl alcohol instead of methyl 4-hydroxy-3-methylbenzoate.
  • Reference Example 3-20-B To a suspension of Reference Example 3-20-A (771 mg) in ethyl acetate (35 mL), palladium-carbon (10%, wet, 300 mg) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound (538 mg).
  • Reference Example 3-20-F A mixture of Reference Example 3-20-E (135 mg) and hydrogen chloride (4 mol / L, 1,4-dioxane solution, 4 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the crude title compound (123 mg).
  • Reference Example 3-21-A was synthesized in the same manner as Reference Example 3-20-C, using 6-fluoronicotinic acid instead of 5-chloro-6-fluoronicotinic acid.
  • Reference Example 3-21-C was synthesized in the same manner as Reference Example 3-20-E, using Reference Example 3-21-B instead of Reference Example 3-20-D.
  • Reference Example 3-21-D A mixture of Reference Example 3-21-C (35.5 mg) and hydrogen chloride (4 mol / L, 1,4-dioxane solution, 4.5 mL) was stirred at room temperature for 5 hours and then at 30 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give crude title compound (33.1 mg).
  • Reference Example 3-22-D Aluminum chloride (264 mg) was added to a solution of Reference Example 3-22-C (90.0 mg) in toluene (2.5 mL), and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was diluted with dichloromethane and then water was added under ice cooling. The mixture was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added diethyl ether (5 mL), and the precipitated solid was collected by filtration. The obtained solid was washed with diethyl ether and dried under reduced pressure to give the title compound (57.2 mg).
  • Reference Example 3-22-E To a solution of Reference Example 3-22-D (55.0 mg) in methanol (1 mL) and THF (1 mL) was added aqueous sodium hydroxide solution (2 mol / L, 0.400 mL) at room temperature, and the mixture was stirred at 60 ° C. for 4 hours did. The reaction mixture was concentrated under reduced pressure. To the residue was added water (2 mL) and hydrochloric acid (2 mol / L, 0.410 mL). After stirring for 30 minutes at room temperature, the precipitated solid was collected by filtration. The obtained solid was washed with water and then dried under reduced pressure to give the title compound (49.8 mg).
  • Reference Example 3-23-A Sodium hydride (about 60%, 15.0 mg) was added to a solution of Reference Example 3-2-C (100 mg) in DMF (1.5 mL) under ice-cooling. After stirring for 30 minutes under ice cooling, iodomethane (0.026 mL) was added. The mixture was stirred at room temperature for 3 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution and water. The mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • a reference example 3-23-B was synthesized in the same manner as the reference example 3-22-E, using the reference example 3-2-A instead of the reference example 3 2-D.
  • Reference Example 4-1-B Hydrazine monohydrate (about 80%, 0.191 mL) was added to a solution of Reference Example 4-1-A (155 mg) in ethanol (6 mL), and the mixture was stirred at 50 ° C. for 4 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture. After stirring for 5 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (119 mg).
  • Reference Example 4-3-B Hydrazine monohydrate (about 80%, 0.970 mL) was added to a solution of Reference Example 4-3-A (769 mg) in ethanol (30 mL), and the mixture was stirred at 45 ° C. for 3 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (4 mL) and water (2 mL). The mixture was concentrated under reduced pressure. To the residue were added ethyl acetate, water and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude title compound (586 mg).
  • Reference Example 4-4-A was synthesized in the same manner as Reference Example 4-2-A, using Reference Example 2-9-H instead of Reference Example 2-8-C.
  • Reference Example 4-4-B was synthesized in the same manner as Reference Example 4-2-B, using Reference Example 4-4-A instead of Reference Example 4-2-A.
  • Reference Example 4-5-B A mixture of Reference Example 4-5-A (164 mg), hydrazine monohydrate (0.062 mL) and ethanol (8 mL) was stirred at 50 ° C. for 1 hour. After cooling to room temperature, diethyl ether (20 mL) was added to the reaction mixture. The mixture was filtered. The filtrate was concentrated under reduced pressure. To the residue was added diethyl ether (20 mL) and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude title compound (136 mg).
  • Reference Example 4-6-A A reference example 4-6-A was synthesized in the same manner as the reference example 4-5-A, using the reference example 2-11-G in place of the reference example 2-10-I.
  • Reference Example 4-6-B A mixture of Reference Example 4-6-A (232 mg), hydrazine monohydrate (0.093 mL) and ethanol (2 mL) was stirred at 50 ° C. for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude title compound (192 mg).
  • a reference example 4-7-A was synthesized in the same manner as the reference example 4-5-A, using the reference example 2-1-I instead of the reference example 2-10-I.
  • Reference Example 4-7-B was synthesized in the same manner as Reference Example 4-6-B, using Reference Example 4-7-A instead of Reference Example 4-6-A.
  • Reference Example 4-8-B was synthesized in the same manner as Reference Example 4-6-B, using Reference Example 4-8-A instead of Reference Example 4-6-A.
  • Reference Example 4-9-A was synthesized in the same manner as Reference Example 4-2-A, using Reference Example 1-3 instead of (R) -2-phthalimidopropionic acid.
  • Reference Example 4-9-B Hydrazine monohydrate (about 80%, 0.254 mL) was added to a solution of Reference Example 4-9-A (237 mg) in ethanol (7 mL), and the mixture was stirred at 50 ° C. for 4 hours. After cooling to room temperature, ethyl acetate (20 mL) was added to the reaction mixture. After stirring for 5 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution and water, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and sequentially with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (167 mg).
  • Reference Example 4-10-B was synthesized in the same manner as Reference Example 4-9-B, using Reference Example 4-10-A instead of Reference Example 4-9-A.
  • Reference Example 1-3 and Reference Example 2-11-G are used instead of (R) -2-phthalimidopropionic acid and Reference Example 2-10-I, and in the same manner as in Reference Example 4-5-A, Reference Example 4-11-A was synthesized.
  • Reference Example 4-11-B was synthesized in the same manner as Reference Example 4-6-B, using Reference Example 4-11-A instead of Reference Example 4-6-A.
  • Reference Example 4-12-A was synthesized by the same method as Reference Example 4-2-A, using N-phthaloylglycine instead of (R) -2-phthalimidopropionic acid.
  • Reference Example 4-12-B was synthesized in the same manner as Reference Example 4-9-B, using Reference Example 4-12-A instead of Reference Example 4-9-A.
  • Reference Example 4-13-B was synthesized in the same manner as in Reference Example 4-6-B, using Reference Example 4-13-A instead of Reference Example 4-6-A.
  • Reference Example 4-14-A Oxalyl chloride (0.031 mL) and DMF (0.010 mL) were sequentially added to a solution of Reference Example 1-4 (88.0 mg) in dichloromethane (2 mL) under an argon atmosphere, and the mixture was stirred at room temperature for 1 hour . The reaction mixture was concentrated under reduced pressure to give crude (R) -3- (benzyloxy) -2- (1,3-dioxoisoindolin-2-yl) propanoyl chloride (93.0 mg). To a suspension of the obtained compound and Reference Example 2-8-C (50.0 mg) in THF (2 mL), DIPEA (0.094 mL) was added, and the mixture was stirred at room temperature overnight.
  • Reference Example 4-14-B Hydrazine monohydrate (about 80%, 0.062 mL) was added to a solution of Reference Example 4-14-A (33.5 mg) in ethanol (2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound (26.4 mg).
  • Reference Example 4-15-A Palladium-carbon (10%, wet, 100 mg) was added to a solution of Reference Example 4-2-A (118 mg) in ethanol (4 mL). The mixture was stirred at room temperature under hydrogen atmosphere for 1 hour and then at 30 ° C. for 2 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (99.9 mg).
  • Reference Example 4-15-B To a suspension of Reference Example 4-15-A (10.0 mg), potassium carbonate (9.5 mg) and potassium iodide (3.5 mg) in DMF (0.5 mL) was added chloromethyl pivalate (0.009 mL). The mixture was stirred at room temperature overnight. Water and dichloromethane were added to the reaction mixture and the mixture was stirred. The organic layer was separated and concentrated under reduced pressure. The residue was dissolved in ethanol (2 mL) and then hydrazine monohydrate (about 80%, 0.039 mL) was added. The mixture was stirred at 30 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (14.2 mg).
  • Reference Example 4-16-B A mixture of Reference Example 4-16-A (303 mg), palladium-carbon (10%, wet, 30.0 mg) and ethanol (5 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the crude title compound (260 mg).
  • Reference Example 4-16-D A mixture of Reference Example 4-16-C (43.4 mg) and hydrogen chloride (4 mol / L, ethyl acetate solution, 2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (34.0 mg).
  • Reference Example 4-17-A, Reference Example 4-18-A, Reference Example 4-19-A using the corresponding raw materials instead of chloromethyl pivalate and following the same procedure as in Reference Example 4-16-C.
  • Reference Examples 4-20-A, 4-21-A, and 4-22-A were respectively synthesized.
  • Reference Example 4-17-B, Reference Example 4-18-B, Reference Example 4-4 in the same manner as in Reference Example 4-16-D, using the corresponding starting materials instead of Reference Example 4-16-C.
  • 19-B, Reference Example 4-20-B, Reference Example 4-21-B, and Reference Example 4-22-B were respectively synthesized.
  • Reference Example 4-23 To a suspension of Reference Example 4-15-A (20.0 mg), potassium carbonate (19 mg) and potassium iodide (7.0 mg) in DMF (0.5 mL) was added 1-chloroethylcyclohexyl carbonate (0.023 mL). The mixture was stirred at room temperature overnight. Water and dichloromethane were added to the reaction mixture and the mixture was stirred. The organic layer was separated and concentrated under reduced pressure. The residue was dissolved in ethanol (2 mL) and then hydrazine monohydrate (about 80%, 0.026 mL) was added. The mixture was stirred at room temperature for 2 hours and then at 30 ° C. for 2 hours.
  • Reference Example 4-24-B A mixture of Reference Example 4-4-A (47.5 mg) and hydrogen chloride (4 mol / L, ethyl acetate solution, 2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude title compound (43.1 mg).
  • Reference Example 4-25-A, Reference Example 4-26-A, and Reference Example 4-4 in the same manner as in Reference Example 4-24-A, using the corresponding raw materials instead of 1-chloroethylcyclohexyl carbonate. 27-A was synthesized respectively.
  • Reference Example 4-28-B was synthesized in the same manner as Reference Example 4-24-B, using Reference Example 4-28-A instead of Reference Example 4-24-A.
  • Reference Example 4-29-B A mixture of Reference Example 4-29-A (33.0 mg) and hydrogen chloride (4 mol / L, ethyl acetate solution, 1 mL) was stirred at room temperature for 3 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (22.0 mg).
  • Example 4-32-A, Reference Example 4-33-A, Reference Example 4-32-A, Reference Example 4-35-A, and Reference Example 4-36-A were respectively synthesized.
  • 32-B, Reference Example 4-33-B, Reference Example 4-34-B, Reference Example 4-35-B, and Reference Example 4-36-B were respectively synthesized.
  • Reference Example 4-37-B Hydrazine monohydrate (about 80%, 0.077 mL) was added to a solution of Reference Example 4-37-A (59.0 mg) in ethanol (2 mL), and the mixture was stirred at 50 ° C. for 4 hours. After cooling to room temperature, ethyl acetate (8 mL) was added to the reaction mixture. After stirring for 5 minutes, the mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (40.2 mg).
  • Reference Example 4-41-B A mixture of Reference Example 4-41-A (71.8 mg), hydrazine monohydrate (about 80%, 0.082 mL) and ethanol (1.3 mL) was stirred at 50 ° C. for 2 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture. After stirring for 5 minutes, the mixture was filtered. The filtrate was concentrated under reduced pressure. To the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was separated and extracted five times with dichloromethane. The combined organic layer was concentrated under reduced pressure to give the title compound (28.0 mg).
  • a reference example 4-42-A was synthesized by the same method as the reference example 4-41-A, using the reference example 2-17-B instead of the reference example 2-18-B.
  • Reference Example 4-42-B was synthesized in the same manner as Reference Example 4-41-B, using Reference Example 4-42-A instead of Reference Example 4-41-A.
  • 45-A and Reference Example 4-46-A were synthesized respectively.
  • Reference Example 4-43-B, Reference Example 4-44-B, Reference Example 4-4 using the corresponding raw materials instead of Reference Example 4-3-A and using the same method as Reference Example 4-3-B.
  • 45-B and Reference Example 4-46-B were synthesized respectively.
  • Reference Example 5-1-B Aqueous sodium hydroxide solution (2 mol / L, 4.75 mL) was added to a mixture of Reference Example 5-1-A (5.96 g), THF (30 mL) and methanol (30 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure. To the residue were added water and hydrochloric acid (2 mol / L, 4.75 mL). The precipitated solid was collected by filtration to give the title compound (5.15 g).
  • Reference Example 5-2-B An aqueous solution of sodium hydroxide (2 mol / L, 11 mL) was added to a solution of Reference Example 5- 2-A (2.42 g) in methanol (25 mL) and THF (25 mL) at room temperature. After stirring at room temperature for 8 hours, the reaction mixture was concentrated under reduced pressure. To the residue was added water (100 mL) and hydrochloric acid (2 mol / L, 12 mL), and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration. The obtained solid was washed with water and then dried under reduced pressure to give the title compound (1.97 g).
  • Reference Example 6-2 was synthesized in the same manner as Reference Example 6-1, using Reference Example 2-12-C instead of Reference Example 2-9-H.
  • Reference Examples 6-4 to 6-23 were respectively synthesized using the corresponding raw materials instead of Reference Example 3-1 and Reference Example 4-7-B and in the same manner as in Reference Example 6-3.
  • Reference Examples 6-25 to 6-30 were respectively synthesized using the corresponding raw materials instead of Reference Example 3-1 and Reference Example 4-2-B and in the same manner as in Reference Example 6-24.
  • Reference Examples 6-32 to 6-35 were synthesized respectively using the corresponding raw materials instead of Reference Example 3-22-E and Reference Example 4-2-B and in the same manner as Reference Example 6-31. did.
  • Reference Examples 6-47 to 6-53 were respectively synthesized by using the corresponding raw materials instead of Reference Example 3-19-D and in the same manner as in Reference Example 6-46.
  • Reference Example 6-55 was synthesized in the same manner as Reference Example 6-54 using Reference Example 3-13-C instead of Reference Example 3-12-B.
  • Reference Example 6-57 Lithium hydroxide monohydrate (135 mg) was added to a solution of Reference Example 6-56 (405 mg) in water (2 mL), methanol (2 mL) and THF (4 mL). The mixture was stirred at 60 ° C. for 21 hours. Hydrochloric acid (2 mol / L, 5 mL) and water were added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (373 mg).
  • Example 1A-1 2-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) ) Benzyl) glycyl) pyrrolidin-2-yl) 2-methylpropanoate
  • Reference Example 2-1-I 115 mg
  • Reference Example 5-1-B 168 mg
  • T3P 50% ethyl acetate solution, about 1.7
  • a solution of mol / L, 0.485 mL) and DIPEA (0.215 mL) in 1,2-dichloroethane (3.5 mL) was stirred at 130 ° C.
  • Example 1A-2 and Example 1A-3 were respectively synthesized by the same method as Example 1A-1 using the corresponding raw materials instead of Reference Example 2-1-I.
  • Example 1A-4 2-Methyl-2-((2R, 5S) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) benzoyl) glycyl) Ethyl -5- (m-tolyl) pyrrolidin-2-yl) propanoate
  • Reference Example 2-4-G (75.0 mg)
  • Reference Example 5-1-B 120 mg
  • T3P 50% solution in ethyl acetate, about 1.7 A solution of mol / L, 0.320 mL) and DIPEA (0.142 mL) in 1,2-dichlorobenzene (1.5 mL) was stirred at 130 ° C.
  • Examples 1A-5 to 1A-8 were respectively synthesized by the same method as Example 1A-4 using the corresponding raw materials instead of Reference Example 2-4-G.
  • Example 1B-1 2-ethyl-2-((2R, 5S) -5- (3-fluorophenyl) -1-((4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) oxy) ) Benzoyl) -D-alanyl) pyrrolidin-2-yl) ethyl butanoate
  • Reference Example 4-1-B 38.4 mg
  • Reference Example 3-17-C (27.5 mg)
  • EDC.HCl 29.2 mg
  • Example 1B-2 to Example 1B-4 are each carried out in the same manner as in Example 1B-1 using the corresponding starting materials instead of Reference Example 4-1-B and Reference Example 3-17-C. Synthesized.
  • Example 1B-5 2-((2R, 5S) -5- (3-chlorophenyl) -1-((6-methyl-5-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) oxy) oxy) Picolinoyl) -D-alanyl) pyrrolidin-2-yl) -2-methylpropanoate
  • Reference Example 4- 3 -B 200 mg
  • Reference Example 3 4-D (156 mg), HOBT (95.9 mg) and triethylamine
  • EDC.HCl 136 mg
  • Example 1B-6 was synthesized in the same manner as Example 1B-5, using Reference Example 3-12-B instead of Reference Example 3-14-D.
  • Example 2A-1 2-ethyl-2-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazine-4) -Yl) methyl) benzoyl) -D-alanyl) pyrrolidin-2-yl) butanoic acid (pivaloyloxy) methyl
  • Reference Example 3-1 (10.7 mg), Reference Example 4-15-B (9.7 mg), EDC.HCl ( A solution of 8.8 mg), HOBT (6.2 mg) and triethylamine (0.024 mL) in DMF (2 mL) was stirred at room temperature for 70 minutes.
  • Example 2A-2 2-ethyl-2-((2R, 5S) -5- (3-fluorophenyl) -1-((4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) oxy) ) Benzoyl) -D-alanyl) pyrrolidin-2-yl) butanoic acid (pivaloyloxy) methyl Reference Example 3-17-C (23.4 mg), Reference Example 4-16-D (34.0 mg), EDC.HCl (26.0 mg) A solution of HOBT (18.4 mg) and triethylamine (0.057 mL) in DMF (1 mL) was stirred at room temperature for 3 hours.
  • Examples 2A-3 to 2A-11 are each obtained in the same manner as Example 2A-2. Synthesized.
  • Example 2B-1 was synthesized in the same manner as in Example 2A-1, except that Reference Example 4-23 was used instead of Reference Example 4-15-B.
  • Example 2B-2 to Example 2B-4 were respectively synthesized by the same method as Example 2A-2 using the corresponding raw materials instead of Reference Example 4-16-D.
  • Example 2B-5 2-ethyl-2-((2R, 5S) -5- (3-fluorophenyl) -1-((4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) oxy) ) Benzoyl) -D-alanyl) pyrrolidin-2-yl) butanoic acid 1-((methoxycarbonyl) oxy) ethyl Reference Example 3-17-C (18.3 mg), Reference Example 4-27-B (33.0 mg), To a mixture of HOBT (11.0 mg), triethylamine (0.035 mL) and DMF (9 mL), EDC.HCl (19.4 mg) was added.
  • Examples 2B-6 to 2B-9 are respectively obtained by the same method as Example 2B-5. Synthesized.
  • Example 2C-1 to Example 2C-3 are each carried out in the same manner as in Example 2A-2 using the corresponding starting materials instead of Reference Example 3-17-C and Reference Example 4-16-D. Synthesized.
  • Example 2D-1 2-ethyl-2-((2R, 5S) -5- (3-fluorophenyl) -1-((4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) oxy) ) Benzoyl) -D-alanyl) pyrrolidin-2-yl) 2-morpholinoethyl butanoate
  • Reference Example 4-29-B (21.0 mg), Reference Example 3-17-C (11.7 mg), HOBT (8.0 mg) and To a solution of triethylamine (0.013 mL) in DMF (0.8 mL), EDC.HCl (13.1 mg) was added and the mixture was stirred at room temperature for 13 hours.
  • Examples 2D-2 to 2D-10 are respectively obtained by the same method as Example 2D-1. Synthesized.
  • Example 3A-1 2-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) ) Benzoyl) Glycyl) pyrrolidin-2-yl) -2-methylpropanoic acid Lithium hydroxide in a solution of Example 1A-1 (20.0 mg) in water (0.5 mL), methanol (0.5 mL) and THF (0.5 mL) Monohydrate (7.3 mg) was added. The mixture was stirred at 40 ° C. for 13 hours and then at 60 ° C. for 5 hours.
  • Lithium hydroxide monohydrate (7.3 mg) was again added and the mixture was stirred at 60 ° C. for 18 hours. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The aqueous layer was separated and washed twice with ethyl acetate. Hydrochloric acid (2 mol / L, 2.0 mL) was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (12.4 mg).
  • Example 3A-2 2-((2R, 5S) -5- (3,4-difluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) ) Methyl) benzoyl) glycyl) pyrrolidin-2-yl) -2- methylpropanoic acid
  • Example 1 A-2 (280 mg), lithium hydroxide monohydrate (197 mg), THF (4 mL), methanol (4 mL) and water The mixture of (4 mL) was stirred at 60 ° C. for 6 hours. Lithium hydroxide monohydrate (197 mg) was again added and the mixture was stirred at 60 ° C. overnight.
  • Example 3A-3 2-((2R, 5S) -5- (3-chlorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl)) Benzoyl) glycyl) pyrrolidin-2-yl) -2-methylpropanoic acid Lithium hydroxide monohydrate in a solution of water (1 mL), methanol (1 mL) and THF (1 mL) in Example 1A-3 (43.6 mg) (61.7 mg) was added. After stirring overnight at 60 ° C., water and ethyl acetate were added to the reaction mixture.
  • Example 3A-4 was synthesized in the same manner as in Example 3A-3, using Example 1A-4 instead of Example 1A-3.
  • Example 3A-5 2-((2R, 5S) -5-Cyclohexyl-1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) benzoyl) glycyl) Pyrrolidin-2-yl) -2-methylpropanoic acid
  • Lithium hydroxide monohydrate (114 mg) was added to a solution of 76.7 mg of water in 2 mL of methanol, 2 mL of methanol and 2 mL of THF. added. After stirring overnight at 60 ° C., the reaction mixture was concentrated under reduced pressure.
  • Example 3A-6 1-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) ) Benzoyl) glycyl) pyrrolidin-2-yl) cyclopentane-1-carboxylic acid
  • Example 1A-6 (44.0 mg) in water (0.8 mL), methanol (0.8 mL) and THF (0.8 mL) solution, hydroxylated Lithium monohydrate (47.0 mg) was added. The mixture was stirred at 60 ° C. for 24 hours.
  • Example 3A-7 2-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) ) Benzoyl) -D-alanyl) pyrrolidin-2-yl) -2-methylpropanoic acid Reference Example 6-3 (44.0 mg), lithium hydroxide monohydrate (31.2 mg), THF (2 mL), methanol (2 mL) ) And water (2 mL) were stirred at 50 ° C. for 6 hours. Lithium hydroxide monohydrate (15.6 mg) was added and the mixture was stirred at 60 ° C. overnight.
  • Examples 3A-8 to 3A-10 were respectively synthesized by the same method as Example 3A-7 using the corresponding raw materials instead of Reference Example 6-3.
  • Example 3A-11 2-((2R, 5S) -5- (3-chlorophenyl) -1-((6-methyl-5-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) oxy) oxy) Picolinoyl) -D-alanyl) pyrrolidin-2-yl) -2-methylpropanoic acid
  • Example 1 B-5 (100 mg) in water (1 mL), methanol (1 mL) and THF (2 mL) in lithium hydroxide aqueous solution The hydrate (137 mg) was added. The mixture was stirred at 60 ° C. for 6 hours and then at room temperature overnight. The mixture was further stirred at 60 ° C. for 2 hours.
  • Example 3A-12 was synthesized in the same manner as in Example 3A-11, using Example 1B-6 instead of Example 1B-5.
  • Example 3B-1 2-ethyl-2-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazine-4) -Ill) Methyl) benzoyl) Glycyl) Pyrrolidin-2-yl) butanoic acid
  • Example 1A-8 53.0 mg
  • palladium-carbon (10%, wet, 5.0 mg) and ethanol (5 mL) under hydrogen atmosphere The mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (35.0 mg).
  • Example 3B-2 2-ethyl-2-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazine-4) -Yl) methyl) benzoyl) -D-alanyl) pyrrolidin-2-yl) butanoic acid Palladium-carbon (10%, wet, under ice-cooling) to a solution of Reference Example 6-24 (33.0 mg) in ethanol (1 mL) 17.0 mg) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 4.5 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. To the residue was added methanol. The mixture was filtered and the insolubles were filtered off. The filtrate was concentrated under reduced pressure to give the title compound (25.1 mg).
  • Examples 3B-3 to 3B-9 were respectively synthesized by the same method as Example 3B-2 using the corresponding raw materials instead of Reference Example 6-24.
  • Example 3B-10 2-ethyl-2-((2R, 5S) -1-((R) -2- (3-fluoro-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl)) Methyl) benzamido) butanoyl) -5- (3-fluorophenyl) pyrrolidin-2-yl) butanoic acid
  • palladium-carbon (10%, wet, 60.0) mg was added. The mixture was stirred at room temperature under hydrogen atmosphere for 1.5 hours.
  • the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
  • Examples 3B-11 to 3B-15 were respectively synthesized by the same method as Example 3B-10 using the corresponding raw materials instead of Reference Example 6-36.
  • Example 3B-16 2-ethyl-2-((2R, 5S) -5- (3-fluorophenyl) -1-((4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) oxy) ) Benzoyl) -D-alanyl) pyrrolidin-2-yl) butanoic acid
  • Example 1 B-4 81.0 mg
  • palladium-carbon (10%, wet, 20.0 mg) and ethanol (5 mL) under hydrogen atmosphere Stir at room temperature for 2 hours.
  • the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (40.0 mg).
  • Examples 3B-17 and 3B-19 to 3B-23 were respectively synthesized by the same method as in Example 3B-16, using the corresponding raw materials instead of Example 1B-4.
  • Example 3B-18 and Example 3B-24 to Example 3B-31 were respectively synthesized by the same method as Example 3B-10 using the corresponding raw materials instead of Reference Example 6-36.
  • Example 3B-32 2-ethyl-2-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazine-4) -Yl) amino) benzoyl) -D-alanyl) pyrrolidin-2-yl) butanoic acid Palladium on carbon (10%, wet, under ice-cooling) to a solution of Reference Example 6-31 (44.0 mg) in ethanol (1 mL) 22.0 mg) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
  • Examples 3B-33 to 3B-35 were respectively synthesized by the same method as Example 3B-32 using the corresponding raw materials instead of Reference Example 6-31.
  • Example 3B-36 was synthesized in the same manner as in Example 3B-2, except that Reference Example 6-33 was used instead of Reference Example 6-24.
  • Example 3B-37 was synthesized in the same manner as in Example 3B-1, except that Reference Example 6-54 was used instead of Example 1A-8.
  • Example 3C-2 2-((2R, 5S) -5- (3-chloro-5-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazine-4)
  • Reference Example 6-16 (54.8 mg), a mixture of titanium (IV) chloride (0.106 mL) and dichloromethane (2 mL) Stir at room temperature overnight.
  • dichloromethane and hydrochloric acid (1 mol / L).
  • the organic layer was separated and concentrated under reduced pressure.
  • Example 3C-3 to Example 3C-16 were respectively synthesized by the same method as Example 3C-2 using the corresponding raw materials instead of Reference Example 6-16.
  • Example 4A-1 N-((R) -1-((2R, 5S) -2- (3-carbamoylpentan-3-yl) -5- (3-fluorophenyl) pyrrolidin-1-yl) -1-oxopropane-2 -Yl) -3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) benzamide
  • Reference Example 4-37-B 39.0 mg
  • Reference Example 3- To a suspension of 1 (37.4 mg), HOBT (19.6 mg) and triethylamine (0.031 mL) in DMF (0.6 mL) and acetonitrile (1.2 mL), add EDC.HCl (32.1 mg) and mix the mixture at room temperature 14 Stir for hours.
  • Example 4A-2 N-((R) -1-((2S, 5R) -2- (3-fluorophenyl) -5- (3- (methylcarbamoyl) pentan-3-yl) pyrrolidin-1-yl) -1-oxo Propan-2-yl) -3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) benzamide
  • Reference Example 4-38-B (30.0 mg), Reference To a suspension of Example 3-1 (27.6 mg), HOBT (14.5 mg) and triethylamine (0.023 mL) in acetonitrile (0.9 mL), EDC.HCl (23.7 mg) was added and the mixture was stirred at room temperature for 12 hours .
  • Example 4A-3 was synthesized in the same manner as Example 4A-2, except that Reference Example 4-39-B was used instead of Reference Example 4-38-B.
  • Example 4A-4 N-((R) -1-((2R, 5S) -2- (3- (ethylcarbamoyl) pentan-3-yl) -5- (3-fluorophenyl) pyrrolidin-1-yl) -1-oxo Propan-2-yl) -3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) benzamide
  • Reference Example 4-40-B (25.0 mg), Reference To a solution of Example 2.1 (22.1 mg), HOBT (11.6 mg) and triethylamine (0.018 mL) in DMF (0.8 mL), EDC.HCl (19.0 mg) was added and the mixture was stirred at room temperature for 3 hours.
  • Example 4A-5 to Example 4A-7 were synthesized respectively by the same method as Example 4A-4 using the corresponding raw materials. .
  • Example 4A-8 N-((R) -1-((2S, 5R) -2- (3-fluorophenyl) -5- (3-((2-morpholinoethyl) carbamoyl) pentan-3-yl) pyrrolidin-1-yl ) -1-Oxopropan-2-yl) -3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) oxy) benzamide
  • Reference Example 4-42-B A mixture of 35.1 mg), Reference Example 3-12-B (21.5 mg), EDC.HCl (21.5 mg), HOBT (12.3 mg), triethylamine (0.032 mL) and DMF (1 mL) was stirred at 50 ° C.
  • Example 4A-9 was synthesized in the same manner as in Example 4A-8, using Reference Example 4-41-B instead of Reference Example 4-42-B.
  • Example 4A-11 was synthesized in the same manner as in Example 4A-10, using Reference Example 3-16-D instead of Reference Example 3-14-D.
  • Example 4B-1 N-((R) -1-((2S, 5R) -2- (3-chlorophenyl) -5- (1- (ethylamino) -2-methyl-1-oxopropan-2-yl) pyrrolidine-1 -Yl) -1-oxopropan-2-yl) -6-methyl-5-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) oxy) picolinamide
  • Example 3A-11 To a solution of (20.0 mg), ethylamine hydrochloride (14.0 mg), HOBT (9.3 mg) and triethylamine (0.043 mL) in DMF (0.2 mL), add EDC.HCl (13.2 mg) and mix the mixture at 50 ° C.
  • Example 4B-2 to Example 4B-4 were respectively synthesized by the same method as Example 4B-1 using the corresponding raw materials instead of ethylamine hydrochloride.
  • Example 4B-5 N-((R) -1-((2S, 5R) -2- (3-chlorophenyl) -5- (1- (ethylamino) -2-methyl-1-oxopropan-2-yl) pyrrolidine-1 -Yl) -1-oxopropan-2-yl) -3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) oxy) benzamide
  • Example 3A-12 To a solution of 29.9 mg), ethylamine hydrochloride (21.0 mg), HOBT (13.9 mg) and triethylamine (0.065 mL) in DMF (0.3 mL), add EDC.HCl (19.8 mg) and stir the mixture at 50 ° C.
  • Example 4B-6 was synthesized in the same manner as Example 4B-5, using ammonium chloride instead of ethylamine hydrochloride.
  • Example 4B-7 N - ((R) -1 - ((2S, 5R) -2- (3- chlorophenyl) -5- (1 - ((ethyl -d 5) amino) -2-methyl-1-oxo-2- Yl) pyrrolidin-1-yl) -1-oxopropan-2-yl) -3-fluoro-5-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) Oxy) benzamide Reference Example 6-57 (30.0 mg), ethyl-d 5 -amine hydrochloride (21.7 mg), HOBT monohydrate (15.3 mg) and triethylamine (0.070 mL) in DMF (1 mL) in EDC HCl (19.3 mg) was added and the mixture was stirred at 50 ° C.
  • Examples 4B-8 to 4B-11 were respectively synthesized by the same method as Example 4B-7 using the corresponding raw materials instead of ethyl-d 5 -amine hydrochloride.
  • Example 4C-1 N-((R) -1-((2S, 5R) -2- (3-chlorophenyl) -5- (3- (hydroxycarbamoyl) pentan-3-yl) pyrrolidin-1-yl) -1-oxopropane -2-yl) -6-methyl-5-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) oxy) picolinamide
  • Reference Example 3 4-D (26.3 mg), Reference Triethylamine (0.038 mL) was added to a solution of Example 4-44-B (35.0 mg), EDC.HCl (26.3 mg) and HOBT (18.6 mg) in DMF (0.5 mL), and the mixture was stirred at room temperature for 2 hours .
  • Example 4C-2 to Example 4C-4 were synthesized in the same manner as in Example 4C-1, using the corresponding raw materials instead of Reference Example 3-14-D and Reference Example 4-44-B. did.
  • Example 5A-1 (2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) benzoyl) (Glycyl) ethyl pyrrolidine-2-carboxylate
  • T3P 50% ethyl acetate solution, about 1.7 mol / L, 0.111 mL
  • Example 5A-2 (E) -4-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazine-4) -Yl) methyl) benzoyl) glycyl) pyrrolidin-2-yl) 4-methylpent-2-enoic acid
  • Reference Example 2 3-D (189 mg), Reference Example 5-1-B (272 mg), T 3 P (50 mg) % Solution of ethyl acetate, about 1.7 mol / L, 0.728 mL) and a solution of DIPEA (0.292 mL) in 1,2-dichloroethane (4 mL) were stirred at 130 ° C.
  • Example 5A-3 4-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) ) Benzyl) Glycyl) Pyrrolidin-2-yl) -4-Methylpentanoate
  • methanol 0.9 mL
  • THF 0.9 mL
  • platinum-carbon 5%, 12.0 mg
  • Example 5A-4 2-((2-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazine-4) -Yl) methyl) benzoyl) glycyl) pyrrolidin-2-yl) propan-2-yl) oxy) acetic acid methyl Reference Example 6-2 (75.0 mg), ruthenium (III) chloride monohydrate (1.5 mg), water Sodium periodate (143 mg) was added to a mixture of (1.5 mL), acetonitrile (1 mL) and ethyl acetate (1 mL). The mixture was stirred at room temperature for 40 minutes.
  • the reaction mixture was diluted with dichloromethane and then to the mixture was added aqueous sodium bisulfite solution, water and hydrochloric acid (2 mol / L). Separate the organic layer. The aqueous layer was extracted three times with dichloromethane and the extract was combined with the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (1.6 mL), then methanol (0.16 mL) and trimethylsilyldiazomethane (about 10% hexane solution, about 0.6 mol / L, 0.267 mL) were sequentially added. The mixture was stirred at room temperature for 2 hours.
  • the title compound (19.8 mg) was obtained.
  • Example 5B-1 (E) -4-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazine-4) -Yl) methyl) benzoyl) glycyl) pyrrolidin-2-yl) -4-methylpent-2-enoic acid
  • Example 5A-2 (68.0 mg) in methanol (1 mL) and THF (1 mL) solution in sodium hydroxide aqueous solution (2 mol / L, 0.226 mL) was added and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure.
  • Example 5B-2 4-((2R, 5S) -5- (3-fluorophenyl) -1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) ) Benzoyl) Glycyl) pyrrolidin-2-yl) -4-methylpentanoic acid
  • a solution of sodium hydroxide aqueous solution (2 mol / L, 0.175 mL) in a solution of methanol (1 mL) and THF (1 mL) in Example 5A-3 (53.0 mg) ) was added and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure.
  • Example 5B-3 was synthesized in the same manner as in Example 5B-2, except that Example 5A-4 was used instead of Example 5A-3.
  • Example 5C-1 (2R, 5S) -5- (3-fluorophenyl) -N, N-dimethyl-1-((3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazine-4-) (I) methyl) benzoyl) glycyl) pyrrolidine-2-carboxamide
  • Reference Example 2-24-B (22.4 mg)
  • Reference Example 5-1-B (30.0 mg)
  • DIPEA 0.074 mL
  • dichloromethane (2 mL)
  • T3P 50% ethyl acetate solution, about 1.7 mol / L, 0.110 mL).
  • Example 5C-2 N- (2-((2R, 5S) -2- (5-amino-2-methyl-5-oxopentan-2-yl) -5- (3-fluorophenyl) pyrrolidin-1-yl) -2- Oxoethyl) -3-methyl-4-((6-methyl-3-oxo-2,3-dihydropyridazin-4-yl) methyl) benzamide
  • Example 5B-2 (66.0 mg), ammonium chloride (24.5 mg), To a solution of HOBT monohydrate (21.2 mg) and triethylamine (0.096 mL) in DMF (1.2 mL), EDC.HCl (33.0 mg) was added and the mixture was stirred at room temperature for 44 hours.
  • Example 5C-3 was synthesized.
  • Test Example 1 Determination of binding affinity to CGRP receptor by evaluation of binding of radioligand in SK-N-MC cell membrane
  • the binding affinity test of compounds to human CGRP receptor was performed by inhibition of the binding of radiolabeled ligand [ 125 I] -CGRP in human neuroblastoma cell line SK-N-MC cell membrane.
  • radioisotope binding evaluation cell membranes prepared from SK-N-MC cells endogenously expressing CGRP receptor (Muff et al., Ann NY Acad Sci. 1992; see 657: 106-116). It was used. The radioligand binding test was performed using a 96-well microplate in a total volume of 200 ⁇ L in each well.
  • Test buffer (pH 7.4) consisting of 50 mM Tris-HCl, 5 mM MgCl 2 and 0.1% bovine serum albumin in 2.5 ⁇ L of serially diluted compounds dissolved in dimethyl sulfoxide (DMSO)
  • DMSO dimethyl sulfoxide
  • SK-N-MC cell membranes 40 ⁇ g of membrane protein in each well
  • [ 125 I] -CGRP [PerkinElmer NEX 354, final concentration 150 pM.
  • the evaluation plate was incubated for 90 minutes while shaking on a plate shaker at room temperature. Incubation was stopped by filtration through GF / C glass fiber filter plates (MerckMillipore) presoaked with 0.3% polyethyleneimine (PEI).
  • Y is the measured radioactivity
  • Y max is the total binding activity
  • Y min is the nonspecific binding activity
  • IC 50 concentration of compound required to inhibit radioligand binding by 50%
  • [L] is the concentration of radioligand and Kd is the apparent dissociation constant of the radioligand for the receptor identified by the saturation binding assay performed with [ 125 I] -CGRP.
  • Test example 2 Determination of functional receptor antagonism by inhibition of CGRP-induced cAMP production in SK-N-MC cells
  • the cAMP production test was performed using a 96 well microplate (NUNC) in a total volume of 100 ⁇ l in each well, and the amount of cAMP produced was determined using the HTRF cAMP HiRange kit (Cisbio). Briefly, after addition of 50 ⁇ L of SK-N-MC cell suspension containing 15000 cells to each well, 25 ⁇ L of test compound solution was added and incubated for 30 minutes at 37 °. Then, 25 ⁇ L of human ⁇ -CGRP (Bachem, 3 nM final concentration) was added and further incubated at 37 ° C. for 15 minutes. The reaction was stopped by incubation with cell lysate (Cisbio) for 30 minutes at 37 ° C.
  • the resulting cell lysates were processed in 384-well white microplates (CORNING) according to the manufacturer's instructions and then fluorescence was measured using a microplate reader (Infinity M1000, Tecan). Raw data were converted to cAMP content for each sample using a standard curve. Data were plotted against test compound concentration using Prism (GraphPad Software Inc.) as a percentage of control values to give the IC 50 values shown below.
  • the compounds of the present invention were found to exhibit human CGRP receptor antagonism.
  • the compound of the present invention or a pharmacologically acceptable salt thereof has excellent CGRP receptor antagonistic activity, and thus is useful as a therapeutic agent for various diseases mediated by CGRP receptor.

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Abstract

Le problème à résoudre par la présente invention concerne la fourniture d'un nouveau composé qui présente une action antagoniste du récepteur CGRP et qui est utile pour le traitement de diverses maladies à médiation par les récepteurs CGRP. La présente invention concerne un composé de pyrrolidine représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci [dans la formule, R1 ou similaire représente -OH, -OZ1, NH2, -NHZ2, -NZ2Z3, ou similaire]. Le composé selon la présente invention ou un sel pharmaceutiquement acceptable de celui-ci a une excellente action antagoniste du récepteur CGRP et est utile en tant que médicament thérapeutique pour diverses maladies à médiation par les récepteurs CGRP.
PCT/JP2018/045009 2017-12-08 2018-12-07 Composé de pyrrolidine WO2019112024A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112679407A (zh) * 2021-03-17 2021-04-20 南京桦冠生物技术有限公司 一种手性5-取代脯氨酸类化合物的制备方法
CN116178295A (zh) * 2023-01-28 2023-05-30 山东亿盛实业股份有限公司 一种苯唑草酮代谢物t283的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005538959A (ja) * 2002-06-05 2005-12-22 ブリストル−マイヤーズ　スクイブ　カンパニー カルシトニン遺伝子関連ペプチド受容体拮抗薬
JP2007519729A (ja) * 2004-01-29 2007-07-19 メルク　エンド　カムパニー　インコーポレーテッド Ｃｇｒｐ受容体拮抗薬
JP2009539997A (ja) * 2006-06-13 2009-11-19 バーテックス ファーマシューティカルズ インコーポレイテッド Ｃｇｒｐ受容体アンタゴニスト
WO2017027345A1 (fr) * 2015-08-12 2017-02-16 Eli Lilly And Company Antagonistes du récepteur cgrp
WO2018016547A1 (fr) * 2016-07-22 2018-01-25 キッセイ薬品工業株式会社 Dérivé de pyrrolidine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005538959A (ja) * 2002-06-05 2005-12-22 ブリストル−マイヤーズ　スクイブ　カンパニー カルシトニン遺伝子関連ペプチド受容体拮抗薬
JP2007519729A (ja) * 2004-01-29 2007-07-19 メルク　エンド　カムパニー　インコーポレーテッド Ｃｇｒｐ受容体拮抗薬
JP2009539997A (ja) * 2006-06-13 2009-11-19 バーテックス ファーマシューティカルズ インコーポレイテッド Ｃｇｒｐ受容体アンタゴニスト
WO2017027345A1 (fr) * 2015-08-12 2017-02-16 Eli Lilly And Company Antagonistes du récepteur cgrp
WO2018016547A1 (fr) * 2016-07-22 2018-01-25 キッセイ薬品工業株式会社 Dérivé de pyrrolidine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112679407A (zh) * 2021-03-17 2021-04-20 南京桦冠生物技术有限公司 一种手性5-取代脯氨酸类化合物的制备方法
CN112679407B (zh) * 2021-03-17 2021-06-04 南京桦冠生物技术有限公司 一种手性5-取代脯氨酸类化合物的制备方法
CN116178295A (zh) * 2023-01-28 2023-05-30 山东亿盛实业股份有限公司 一种苯唑草酮代谢物t283的制备方法

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