Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/433—Thidiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

• the present invention relates to a bicyclic heteroaromatic ring derivative having anti-picornavirus activity, or a pharmaceutical composition containing the same and a pharmaceutical use thereof.
• the Picornavirus family is classified into the genus Enterovirus, the genus Hepatovirus, the genus Palechovirus, the genus Cobuvirus, the genus Cardiovirus, and many of them Viruses have been implicated in human disease.
• enterovirus infection in children can cause acute respiratory tract inflammation, gastroenteritis, herpangina, hand-foot-and-mouth disease, viral eruption, aseptic meningitis, acute encephalomyelitis, acute gray myelitis (Polio), myocarditis, hemorrhagic conjunctivitis, etc.
• Rhinovirus also causes cold (cold syndrome), asthma and exacerbation of COPD (chronic obstructive pulmonary disease).
• hepatitis virus infections hepatitis A infection caused by hepatitis A virus is known.
• Gastroenteritis (diarrhea, vomiting) is a common symptom of human parecovirus infection of the genus pareccovirus, followed by cold symptoms (cough, nose). It is known that rarely causes myocarditis and aseptic meningitis.
• Aichivirus which is classified into the genus Cobbvirus in the Picornavirus family, is known to be the causative virus of gastroenteritis.
• viruses belonging to the Picornavirus family are known as pathogens causing various diseases corresponding to the virus species.
• Non-Patent Document 1 imidazopyrazines (Non-Patent Document 1) and the like are known as antiviral drugs containing a bicyclic heteroaromatic skeleton, for example, but have a different structure from the compound of the present invention.
• An object of the present invention is to provide a compound having an antiviral action against viruses belonging to the Picornavirus family, in particular, rhinovirus.
• compound (1) a bicyclic heteroaromatic ring compound represented by the following general formula (1) (hereinafter sometimes referred to as compound (1)) has a strong anti-picornavirus action. Have been found to be sufficiently satisfactory as a medicament, and have completed the present invention.
• R 4 is H, a halogen atom, a C 1 -C 6 alkoxy group, a deuterated C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a halo C 1 -C 6 alkyl group, a halo C 1 -C A 6 alkoxy group, a hydroxy C 1 -C 6 alkyl group, a hydroxyl group, a cyano group, —C (O) R 9 , —C (O) NR 10 R 11 or NR 10 R 11 ;
• Q 2 is CR 3
• R 3 and R 4 may combine with each other to form a ring
• G is, -R 5 -R 6 -R
• W 3 and W 4 may be bonded to each other to form a ring), a 3- to 10-membered heterocycloalkylene group (the 3- to 10-membered heterocycloalkylene group may be substituted with W 3 and W 4)
• Yo , W 3 and W 4 are each independently H, halogen atom, hydroxyl group, C 1 ⁇ C 6 alkyl group, C 3 ⁇ C 10 cycloalkyl group, C 1 ⁇ C 6 acyl group, a hydroxy C 1 ⁇ C 6 alkyl group , A C 1 -C 6 alkoxy group, a C 1 -C 6 alkoxycarbonyl group, —SO 2 R 12 , —C (O) N (R 13 ) 2 , and an oxo group, and W 3 and W 4 may be bonded to each other to form a ring), C 1 ⁇ C 6 alkylene group (the C 1 ⁇ C 6 alkylene group may be substituted with W 5 and W 6, W 5 and W 6
• a heteroarylene group which may be a halogen atom, a C 1 -C 6 alkyl group, a hydroxy C 1 -C 6 alkyl group, a C 1 -C 6 acyl group, a carboxy group, a hydroxyl group, B C 1 -C 6 alkyl group, cyano group, C 3 -C 10 cycloalkyl group, 3-10 membered heterocycloalkyl group, —NR 10 R 11 , —C (O) R 9 , —C (O) NR 10 R 11 , C 1 -C 6 alkoxycarbonyl group, —SO 2 R 12 , and one or more substituents selected from the group consisting of C 1 -C 6 alkoxy group);
• R 6 represents a bond or a C 3 -C 6 cycloalkylene group;
• R 7 represents H or a hydroxyl group;
• R 8 each independently represents H or a C 1 -C 6 alkyl group;
• G is hydroxy C 1 ⁇ C 6 alkyl group (the hydroxy C 1 ⁇ C 6 alkyl groups W 1 and W 2 may be substituted with, W 1 and W 2 H or C 1 are each independently ⁇ C 6 An alkyl group, W 1 and W 2 may be bonded to each other to form a ring, and when W 1 and W 2 form a ring, one or more halogen atoms may be substituted on the ring) , C 3 ⁇ C 6 cycloalkyl group (said C 3 ⁇ C 6 cycloalkyl group may be substituted with W 3 and W 4, W 3 and W 4 are each independently H, hydroxyl, or C 1 ⁇ C A 6- alkoxy group, W 3 and W 4 may combine with each other to form a ring), a 3- to 10-membered heterocycloalkyl group, a phenyl group (the phenyl group is a halogen atom, a C 1 -C 6 alkyl group, hydroxy C 1 -
• a method for treating or preventing a viral infection caused by an enterovirus, a rhinovirus or a Coxsackievirus which comprises administering the compound according to any one of [1] to [11].
• a pharmaceutical composition comprising a carrier.
• a method for treating or preventing exacerbation of asthma or COPD which comprises administering the compound according to any one of [1] to [11].
• a pharmaceutical composition comprising the compound according to any one of [1] to [11] and a pharmaceutically acceptable carrier for use in the treatment or prevention of exacerbation of asthma or COPD.
• the present invention it is possible to provide a compound having an antiviral action against a virus belonging to the Picornavirus family, particularly a rhinovirus.
• C n -C m means n-m carbon atoms, where n and m are independent natural numbers, and m is a number greater than n.
• C 1 -C 6 means 1 to 6 carbon atoms.
• Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Preferably, it is a fluorine atom or a chlorine atom.
• ⁇ The“ alkyl group ”shown in the present specification means a group obtained by removing one hydrogen atom from a linear or branched aliphatic saturated hydrocarbon.
• the alkyl group include a methyl group, an ethyl group, a 1-propyl group, an isopropyl group, a 1-butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a 1-pentyl group, an isopentyl group, a neopentyl group, -Methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, 1-hexyl group, isohexyl group and the like.
• deuterated C 1 -C 6 alkyl group refers to an alkyl group having 1 to 6 carbon atoms of the above-mentioned “alkyl group” in which one or more hydrogen atoms are further added. It means a group replaced by a hydrogen atom.
• ⁇ The“ alkylene group ”shown in the present specification indicates a divalent group derived by removing one arbitrary hydrogen atom from the above“ alkyl group ”.
• Specific examples include methanediyl, 1,1-ethanediyl, 1,2-ethanediyl, 1,1-propanediyl, 1,2-propanediyl, 1,3-propanediyl, 2,2- Propanediyl group, 1,4-butanediyl group, 2-methyl-1,1-propanediyl group, 2-methyl-1,2-propanediyl group, 1,5-pentanediyl group, 3-methyl-1,3- Butanediyl, 1,6-hexanediyl and the like.
• hydroxy C 1 -C 6 alkyl group refers to the above alkyl group in which one hydrogen atom of an alkyl group having 1 to 6 carbon atoms is substituted with a hydroxyl group.
• examples of the hydroxy C 1 -C 6 alkyl group include a hydroxymethyl group, a 1-hydroxyethyl group, a 1-hydroxy-1,1-dimethylmethyl group, a 2-hydroxyethyl group, a 2-hydroxy-2-methylpropyl group, And a 3-hydroxypropyl group.
• hydroxy C 1 -C 6 alkylene group refers to a divalent group derived from the above “hydroxy C 1 -C 6 alkyl group” by removing any one hydrogen atom. Show. Examples of the hydroxy C 1 -C 6 alkylene group include a hydroxymethylene group, a 1-hydroxyethylene group, a 1-hydroxy-1,1-dimethylmethylene group, a 2-hydroxyethylene group, a 2-hydroxy-2-methylpropylene group, And a 3-hydroxypropylene group.
• alkoxy group means a group in which a linear or branched alkyl group is bonded to an oxygen atom.
• alkoxy group include a methoxy group, an ethoxy group, a 1-propoxy group, an isopropoxy group, an isobutoxy group, a 1-butoxy group, a sec-butoxy group, a t-butoxy group, a 1-pentyloxy group, and a 1-hexyloxy group And the like.
• deuterated C 1 -C 6 alkoxy group refers to any of the above “alkoxy groups” in which one or more hydrogen atoms further denote an alkoxy group having 1 to 6 carbon atoms. It means a group replaced by a hydrogen atom.
• Cycloalkyl group "as used herein means a monocyclic or bicyclic saturated alicyclic hydrocarbon group.
• the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a spiroheptyl group, a spirooctyl group, an octahydropentenyl group, and the like.
• cycloalkoxy group refers to a group in which the above-mentioned “cycloalkyl group” is bonded to an oxygen atom, and includes, for example, a cyclopropyl group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyl Oxy groups and the like.
• cycloalkylene group refers to a divalent group derived from the above-mentioned “cycloalkyl group” by removing one arbitrary hydrogen atom, such as a cyclopropylene group and a cyclobutylene group. Group, cyclopentylene group, cyclohexylene group and the like.
• ⁇ The“ alkenyl group ”as used herein means a straight-chain or branched-chain hydrocarbon group containing an unsaturated bond.
• vinyl group 1-propenyl group, 2-propenyl group, 2-methylethenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3 -Pentenyl group, 4-pentenyl group, 3-methyl-1-butenyl group, 3-methyl-2-butenyl group, 3-methyl-3-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group , 4-hexenyl group, 5-hexenyl group and the like.
• Acyl group "as used herein means an acyl group derived from a linear or branched aliphatic carboxylic acid. For example, a formyl group, an acetyl group, a propanoyl group, a butanoyl group, a pentanoyl group, a hexanoyl group and the like can be mentioned.
• ⁇ The“ alkoxycarbonyl group ”shown in the present specification means a linear or branched alkoxycarbonyl group.
• the alkoxycarbonyl group include, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a 1-propoxycarbonyl group, an isopropoxycarbonyl group, an isobutoxycarbonyl group, a 1-butoxycarbonyl group, a sec-butoxycarbonyl group, a t-butoxycarbonyl group, -Pentyloxycarbonyl group, 1-hexyloxycarbonyl group and the like.
• bicycloalkyl group means a saturated alicyclic hydrocarbon group having 5 to 8 carbon atoms in which two non-adjacent carbon atoms of a cycloalkyl are bridged by C 1 or C 2. I do.
• a bicyclo [1.1.1] pentyl group, a bicyclo [2.1.1] hexyl group, a bicyclo [2.2.1] heptyl group, a bicyclo [2.2.2] octyl group and the like can be mentioned.
• ⁇ The“ bicycloalkylene group ”shown in the present specification indicates a divalent group derived by removing one arbitrary hydrogen atom from the above“ bicycloalkyl group ”.
• Specific examples include a bicyclo [1.1.1] pentylene group, a bicyclo [2.1.1] hexylene group, a bicyclo [2.2.1] heptylene group, and a bicyclo [2.2.2] octylene group.
• 3 to 10 membered heterocycloalkyl group is independently one to four rings selected from the group consisting of N, N-oxide, O, S, SO and SO 2 A monocyclic, bicyclic, or tricyclic 3,4,5,6,7,8,9, or 10-membered saturated heterocycloalkyl group containing an internal heteroatom.
• 3 to 10 membered heterocycloalkyloxy group refers to a group in which the above “3 to 10 membered heterocycloalkyl group” is bonded to an oxygen atom, such as an aziridinyloxy group And an azetidinyloxy group.
• phenylene group shown in this specification means a divalent group derived by removing one arbitrary hydrogen atom from a phenyl group.
• heteroaryl group is a partially unsaturated or fully unsaturated, 1, 2, 3 or 4 carbon atom and independently selected from the group consisting of N, O and S.
• the nitrogen atom may be substituted.
• N or NR where R, if defined, is H, —C (O) R 9 , —C (O) NR 10 R 11 or a C 1 -C 6 alkyl group (the alkyl The group is a halogen atom, a hydroxyl group, a C 1 -C 6 alkoxy group, a halo C 1 -C 6 alkyl group, a cyano group, a C 3 -C 10 cycloalkyl group, a 3-10 membered heterocycloalkyl group, a C 3 -C 10 A cycloalkyloxy group, a 3- to 10-membered heterocycloalkyloxy group, —C (O) R 9 , and —C (O) NR 10 R 11, which are substituted with one or more substituents selected from the group consisting of Is also good).
• heteroaryl groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl Group, benzotetrazolyl group, benzisoxazolyl group, benzoisothiazolyl group, benzimidazolinyl group, furanyl group, imidazolidinyl group, imidazolinyl group, imidazolyl group, 1H-indazolyl group, imidazolopyridinyl group, Indolenyl group, indolinyl group, indolizinyl group, indolyl group, 3H-indolyl group, isobenzofuranyl group, isoindazolyl group, isoindolinyl group, isoindolyl group, isoquinolinyl group, isothiazo
• heteroarylene group shown in the present specification means a divalent group derived by removing one arbitrary hydrogen atom from a heteroaryl group.
• 3 to 10-membered heterocycloalkylene group refers to a divalent group derived from the above-described "3 to 10-membered heterocycloalkyl group” by removing one arbitrary hydrogen atom. means.
• 3 to 10-membered heterocycloalkyloxy group refers to a group in which the above “3 to 10-membered heterocycloalkyl group” is bonded to an oxygen atom. Can be mentioned.
• halo C 1 -C 6 alkyl group refers to the above alkyl group in which a hydrogen atom of an alkyl group having 1 to 6 carbon atoms is substituted with 1 to 8 same or different halogen atoms.
• halo C 1 -C 6 alkyl group for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2,2-difluoroethyl group, a 1,1-difluoroethyl Group, 1,2-difluoroethyl group, 1-chloro-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 1,1,2,2,2-pentafluoroethyl group, 2,2 2-trichloroethyl group, 3-fluoropropyl group, 2-fluoropropyl group, 1-fluoropropyl group, 3,3-difluoropropyl group, 2,2-difluoropropyl group, 1,1-difluoropropyl group, 4- Examples thereof include a fluorobutyl group, a 5-fluoroe
• halo C 1 -C 6 alkoxy group refers to the above alkoxy group in which a hydrogen atom of an alkyl group having 1 to 6 carbon atoms is substituted with 1 to 8 same or different halogen atoms.
• halo C 1 -C 6 alkoxy group examples include a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 2-chloroethoxy group, a 2-fluoroethoxy group, a 2,2-difluoroethoxy group, and a 1,1- Difluoroethoxy group, 1,2-difluoroethoxy group, 1-chloro-2-fluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group, 2, 2,2-trichloroethoxy group, 3-fluoropropoxy group, 2-fluoropropoxy group, 1-fluoropropoxy group, 3,3-difluoropropoxy group, 2,2-difluoropropoxy group, 1,1-difluoropropoxy group, 4-fluorobutoxy, 5-fluoropentyloxy, 6-fluorohexyloxy and the like. It
• Phenylmethyl group as used herein means a group in which a phenyl group is directly connected to a methylene group.
• Heteroarylmethyl group as used herein means a group in which one hydrogen atom of a methyl group is substituted by a heteroaryl group as defined above.
• the “phenylmethyl group which may have a substituent”, the “heteroarylmethyl group which may have a substituent”, the “phenyl group that may have a substituent”, and the “having a substituent” A heteroaryl group which may be substituted ", a" C 1 -C 6 alkyl group which may have a substituent "" a deuterated C 1 -C 6 alkyl group which may have a substituent " C 2 -C 6 alkenyl group which may be substituted ”,“ C 3 -C 6 cycloalkyl group which may have a substituent ”,“ C 5 -C 8 bicycloalkyl group which may be substituted ”,“ Substitution ” good hydroxy C 1 may have a member 3-10 may have a group heterocycloalkyl group "" substituent ⁇ C 6 alkyl group "," an optionally substituted C 3 ⁇ C 5 cycloalkylene
• the group acceptable as the “substituent” in the “group”
• the substituent may have one or more substituents.
• substituents include a halogen atom, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxy group, a C 1 -C 6 acyl group, and a C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, hydroxy C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, halo C 1 -C 6 alkoxy group, C 1 -C 6 alkoxycarbonyl group, C 3 A C 6 cycloalkyl group, a 3- to 10-membered heterocycloalkyl group, a phenyl group, a heteroaryl group, a t-butyldimethylsilyloxy group, an oxo group and the like.
• bonded together to form a ring refers to the removal of any one hydrogen atom from each of the two substituents forming the ring, and the bonding of the sites excluding hydrogen.
• Means For example, when the methylene group has two substituents, and when the two substituents forming the ring are a methyl group and a 1-hydroxyethyl group, the following cyclic structure is exemplified.
• the present embodiment relates to a compound represented by the following general formula (1), a pharmacologically acceptable salt thereof, or a hydrate thereof. These are also collectively referred to as compounds of the present embodiment.
• R 4 is H, a halogen atom, a C 1 -C 6 alkoxy group, a deuterated C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a halo C 1 -C 6 alkyl group, a halo C 1 -C A 6 alkoxy group, a hydroxy C 1 -C 6 alkyl group, a hydroxyl group, a cyano group, —C (O) R 9 , —C (O) NR 10 R 11 or NR 10 R 11 ;
• Q 2 is CR 3
• R 3 and R 4 may combine with each other to form a ring
• G is, -R 5 -R 6 -R
• C 1 ⁇ C 6 alkyl group (the C 1 ⁇ C 6 alkyl group may be substituted with W 5 and W 6, W 5 and W 6 being independently H, Selected from the group consisting of a cyano group, a hydroxy C 1 -C 6 alkyl group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxycarbonyl group, a carboxy group, and —C (O) N (R 13 ) 2 , W 5 and W 6 are bonded to each other to form a ring May be formed), a phenyl group (the phenyl group is a halogen atom, a C 1 -C 6 alkyl group, a hydroxy C 1 -C 6 alkyl group, a C 1 -C 6 acyl group, a carboxy group, a hydroxyl group, a halo C 1 -C 6 alkyl group, cyano group, C 3 -C 10
• aryl group a halogen atom, C 1 ⁇ C 6 alkyl group, a hydroxy C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 acyl group, a carboxyl group, a hydroxyl group, halo C 1 ⁇ C 6 alkyl group, a cyano , C 3 ⁇ C 10 cycloalkyl group, 3-10-membered heterocycloalkyl group, -NR 10 R 11, -C ( O) R 9, -C (O) NR 10 R 11, C 1 ⁇ C 6 alkoxycarbonyl
• R 5 is hydroxy C 1 ⁇ C 6 alkylene group (the hydroxy C 1 ⁇ C 6 alkylene group may be substituted with W 1 and W 2, W 1 and W 2 are each independently H, C 1 ⁇ C 6 alkyl groups, deuterated C 1
• a ring may be formed, when W 1 and W 2 form a ring, one or more halogen atoms may be substituted on the ring), a C 3 -C 6 cycloalkylene group (the C 3 -C 6 6 cycloalkylene group may be substituted with W 3 and W 4, W 3 and W 4 are each independently H, halogen atom, hydroxyl group, C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 acyl group, a hydroxy C 1 ⁇ C 6 alkyl group, C 1 ⁇ 6 alkoxy group, C 1 ⁇ C 6 alkoxycarbonyl group, selected from the group consisting of -SO 2 R 12, and oxo group, W 3 and W 4 may be bonded to each other to form a ring), C 5 ⁇ C 8 bicycloalkylene group (said C 5 ⁇ C 8 bicycloalkylene group may be substituted with W 3 and W 4, W 3 and W 4 are each independently H, halogen atom,
• R 6 represents a bond or a C 3 -C 6 cycloalkylene group
• R 7 represents H or a hydroxyl group
• R 8 each independently represents H or a C 1 -C 6 alkyl group
• R 9 represents H, a hydroxyl group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a C 3 -C 6 cycloalkoxy group
• R 10 represents H or a C 1 -C 6 alkyl group
• R 11 represents H or a C 1 -C 6 alkyl group
• R 12 represents H or a C 1 -C 6 alkyl group
• R 13 each independently represents H, a C 1 -C 6 alkyl group or a hydroxy C 1 -C 6 alkyl group].
• Preferred compounds of the present embodiment include, for example, the compounds in Tables 12 to 22 below.
• the compound of the present embodiment includes both hydrates and solvates of the compound (1) or a pharmacologically acceptable salt thereof.
• the above-mentioned compound (1) can be converted into a pharmacologically acceptable salt thereof according to a conventional method, if necessary.
• a pharmacologically acceptable salt means a salt with a pharmaceutically acceptable non-toxic base or acid (eg, an inorganic or organic base and an inorganic or organic acid).
• Salts derived from pharmaceutically acceptable non-toxic bases include salts with inorganic bases such as sodium, potassium, calcium and magnesium salts, and salts with organic bases such as piperidine, morpholine, pyrrolidine, arginine and lysine Can be mentioned.
• salts derived from pharmaceutically acceptable non-toxic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, acid addition salts with mineral acids such as nitric acid, formic acid, acetic acid, maleic acid, fumaric acid, succinic acid, Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, paratoluenesulfonic acid, salicylic acid, stearic acid and palmitic acid can be mentioned.
• the compound of this embodiment includes an optically active substance, a stereoisomer, or a rotamer in addition to the racemic form.
• the compound of the present embodiment is an optical isomer having one or more asymmetric carbon atoms
• the compound of the present embodiment has a configuration at any of the asymmetric carbon atoms in any one of the R configuration and the S configuration. It may be.
• any optical isomer is included in the present invention, and a mixture of those optical isomers is also included.
• racemic forms composed of equal amounts of each optical isomer are also included in the scope of the present invention.
• the compound (1) of the present embodiment is a racemic solid or crystal
• a racemic body, a racemic mixture, and a racemic solid solution are also included in the scope of the present invention.
• the present invention when a geometric isomer exists, includes any of the geometric isomers.
• the present invention includes any of the tautomers.
• the compound of the present embodiment may be a compound labeled with an isotope (eg, 3 H, 14 C, 35 S, etc.). Such compounds are also included in the present invention.
• an isotope eg, 3 H, 14 C, 35 S, etc.
• the compound of the present embodiment may be a deuterium converter obtained by converting 1 H to 2 H (D). Such compounds are also included in the present invention.
• the compound of the present embodiment can be produced, for example, according to the method described in detail in Synthesis Route A or a method analogous thereto, or a method described in other literature or a method analogous thereto. it can. [Synthetic route A]
• Y represents R 1 or —C (O) R 9 , R 14 each independently represents a bromine atom, an iodine atom or a chlorine atom; M represents —B (OH) 2 , a tri-C 1 -C 6 alkyltin group, or Represents; R 1 , R 2 , R 4 , R 9 , G, Q 1 , Q 2 , X, and L are the same as those defined in the general formula (1).
• Step A-1 Compound represented by the general formula (3), the R 14 of the compound represented by the general formula (2) can be produced by converting into M.
• M of the compound (3) is —B (OH) 2 or a functional group having the following structure, a compound such as 1,4-dioxane, dimethylsulfoxide, N, N-dimethylformamide, toluene, benzene, etc.
• Step A-2 The compound represented by the general formula (1) can be produced by subjecting a compound represented by the general formula (4) and a compound represented by the general formula (3) to a coupling reaction.
• M of the compound (3) is -B (OH) 2 or a functional group having the following structure
• general conditions of the Suzuki-Miyaura coupling reaction can be applied.
• M of compound (3) is a tri-C 1 -C 6 alkyltin group
• general conditions of Migita-Kosugi-Still cross-coupling reaction can be applied.
• reaction accelerator tetrakis (triphenylphosphine) palladium (Pd (Ph 3 P) 4), palladium acetate (Pd (OAc) 2), tris ( Using palladium such as dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ) as a catalyst, the reaction can be carried out at room temperature to heating under reflux. In some cases, lithium chloride can be added as a reaction accelerator.
• Z represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom
• R 15 each independently represent C 1 ⁇ C 6 alkyl group, a deuterated C 1 ⁇ C 6 alkyl group, C 3 ⁇ C 10 cycloalkyl group, a 3-10 membered heterocycloalkyl group, R 15 is May combine with each other to form a ring
• R 16 represents a C 1 -C 6 alkyl group, a deuterated C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, or a 3- to 10-membered heterocycloalkyl group
• R 17 represents a chlorine atom, a bromine atom, an iodine atom, paratoluenesulfonate, methanesulfonate, trifluoromethanesulfonate
• R 14 , R 2 , and X are the same as defined in the above
• Step B-1 The compound represented by the general formula (4a) can be produced by alkylating the hydroxyl group of the compound represented by the general formula (4b) using R 16 -R 17 .
• reaction conditions general S N 2 reaction conditions can be applied.
• An alkylating agent represented by R 16 -R 17 such as alkyl iodide, alkyl bromide, alkyl chloride, alkyl paratoluenesulfonate, alkylmethanesulfonate, alkyltrifluoromethanesulfonate, etc.
• a solvent such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, tripotassium phosphate, cesium fluoride, triethylamine, or N, N
• An alkylating agent represented by R 16 -R 17 such as alkyl iodide, alkyl bromide, alkyl chloride, alkyl paratoluenesulfonate, alkylmethanesulfonate, alkyltrifluoromethanesulfonate, etc.
• reaction accelerators such as sodium iodide, potassium iodide, tetra-n-butylammonium iodide, sodium bromide, potassium bromide, and tetra-n-butylammonium bromide can be added.
• R 15 is trifluoromethyl or the like, it can be produced by alkylating the hydroxyl group of the compound represented by the general formula (4b) with R 16 -OH in addition to the above reaction conditions. .
• reaction conditions for example, triphenylphosphine, tributylphosphine, trimethylphosphine, or the like in a solvent such as tetrahydrofuran, 1,4-dioxane, toluene, benzene, or without solvent.
• a phosphorus reagent such as phosphine and a diazo compound such as diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD) and 1,1′-azobis (N, N-dimethylformamide), R 16 -OH, for example
• the reaction can be carried out at 0 ° C. to reflux while adding methanol or the like.
• Step B-2 The compound represented by the general formula (4c) can be produced by halogenating, preferably fluorinating, a hydroxyl group of the compound represented by the general formula (4b).
• the reaction can be carried out by adding a halogenating reagent in a solvent such as methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane and the like, and heating at ⁇ 78 ° C. to reflux.
• Z of the compound (4c) is a fluorine atom, N, N-diethylaminosulfur trifluoride (DAST), bis (2-methoxyethyl) aminosulfur trifluoride and the like can be used as the halogenating reagent.
• DAST N-diethylaminosulfur trifluoride
• bis (2-methoxyethyl) aminosulfur trifluoride and the like can be used as the halogenating reagent.
• Step B-3 The compound represented by the general formula (4a) can also be produced by reacting the compound represented by the general formula (4c) with an alcohol represented by R 16 —OH.
• the reaction conditions are as follows: without solvent, or in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, etc., an alcohol represented by R 16 -OH, for example, 3-oxetanol, and the like, and room temperature to reflux under heating. Can be performed.
• acids such as hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, and sulfuric acid, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, cesium fluoride, triethylamine,
• a base such as N, N-diisopropylethylamine can be added.
• R 14 and Y are the same as defined in the synthetic route A described above; R 2 and X are the same as defined in the above general formula (1).
• Step C-1 The compound represented by the general formula (4) can be produced by halogenating, preferably iodinating, the compound represented by the general formula (5).
• the reaction can be carried out at 0 ° C. to room temperature by adding a halogenating agent in a solvent such as acetonitrile, N, N-dimethylformamide, methanol, ethanol, methylene chloride, chloroform, acetic acid, and water.
• a solvent such as acetonitrile, N, N-dimethylformamide, methanol, ethanol, methylene chloride, chloroform, acetic acid, and water.
• an iodinating agent such as N-iodosuccinimide, 1,3-diiodo-5,5-dimethylhydantoin, or iodine can be added.
• a brominating agent such as N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, or bromine can be added.
• an acid such as acetic acid, trifluoroacetic acid, sulfuric acid, iron (III) chloride, or aluminum chloride, or a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate, or cesium carbonate can be added.
• M ′ represents —MgBr, —MgCl, —MgI, lithium
• a 1 each independently represents a C 1 -C 6 alkylene group, a deuterated C 1 -C 6 alkylene group, a C 3 -C 6 cycloalkylene group
• R 18 and R 19 each independently represent a C 1 -C 6 alkyl group, a C 3 -C 10 cycloalkyl group, a deuterated C 1 -C 6 alkyl group
• X, R 2 , R 16 , and R 17 have the same definitions as described in Synthesis Route B above.
• Step D-1 The compound represented by the general formula (5c) can be produced by alkylating the ester site of the compound represented by the general formula (5b) using R 19 -M ′.
• alkylating agents such as alkylmagnesium bromide, alkylmagnesium chloride and alkyllithium represented by R 19 -M ′ in a solvent such as tetrahydrofuran, diethylether, t-butylmethylether, toluene and hexane, for example, Methylmagnesium bromide, methylmagnesium chloride, cyclopropylmagnesium bromide and the like are added, and the reaction can be carried out at -78 ° C to heating under reflux.
• an alkyl lithium or an alkyl magnesium halide prepared at the time of use using an alkyl halide may be used as the alkylating agent.
• Step D-2 The compound represented by the general formula (5a) is produced by alkylating the hydroxyl group of the compound represented by the general formula (5c) using R 16 -R 17 in the same manner as in the step B-1. Can be.
• Step D-3 The compound represented by the general formula (5d) can be produced by using an ester site of the compound represented by the general formula (5b) under the condition of Kulinkovich reaction.
• reaction conditions general Clinkovich reaction conditions can be used.
• tetraalkoxy titanium preferably tetraisopropyl orthotitanate, and halogen in a solvent such as diethyl ether, tetrahydrofuran, or 1,4-dioxane
• Ethyl magnesium bromide desirably ethyl magnesium bromide is added, and the reaction can be carried out at -78 ° C to heating under reflux.
• Step D-4 In the synthesis route D, the compound represented by the general formula (5e) is obtained by cyclizing an ester of the compound represented by the general formula (5b) using M′-A 1 -A 1 -M ′. Can be manufactured. As a reaction condition, a cyclizing agent represented by M′-A 1 -A 1 -M ′ is added in a solvent such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, toluene, and hexane, and the mixture is heated to ⁇ 78 ° C. to reflux.
• a solvent such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, toluene, and hexane
• dialkylene dilithium or dimagnesium alkylene dihalide prepared from a dihalogenated alkane may be used as the cyclizing agent.
• (butane-1,4-diyl) dimagnesium dibromide generated by reacting 1,4-dibromobutane with metallic magnesium can be prepared and used at the time of use.
• R 20 represents a C 1 -C 6 alkyl group, a deuterated C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group
• R 21 represents a C 1 -C 6 alkyl group, a deuterated C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group
• R 22 represents a chlorine atom, a bromine atom, an iodine atom, paratoluenesulfonate, methanesulfonate, trifluoromethanesulfonate
• a 2 each independently represents a C 1 -C 6 alkylene group, a deuterated C 1 -C 6 alkylene group
• R 2 and X are the same as defined in the synthetic route D described above.
• Step E-1 The compound represented by the general formula (5g) can be produced by alkylating the compound represented by the general formula (6) using R 21 to R 22 .
• the reaction conditions include hydrogenation in a solvent such as dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and the like.
• a base such as sodium, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, cesium fluoride, triethylamine, or N, N-diisopropylethylamine is added, and represented by R 21 -R 22 .
• an alkylating agent such as alkyl iodide, alkyl bromide, alkyl chloride, alkyl paratoluenesulfonate, alkylmethanesulfonate, alkyltrifluoromethanesulfonate, for example, methyl iodide, 1,2-dibromoethane, etc. From 0 ° C to reflux Ukoto can.
• reaction accelerators such as sodium iodide, potassium iodide, tetra-n-butylammonium iodide, sodium bromide, potassium bromide, and tetra-n-butylammonium bromide can be added.
• Step E-2 The compound represented by the general formula (7) can be produced by primary amidation of the compound represented by the general formula (5g).
• the reaction conditions are as follows: without solvent or in a solvent such as methanol, ethanol, dimethylsulfoxide, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, water, etc., ammonia or methanol containing ammonia, ethanol, 1,4-
• the reaction can be carried out using a solution of dioxane, water or the like, ammonium chloride, ammonium acetate, ammonium formate or the like at 0 ° C. to heating under reflux.
• a base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, cesium fluoride, triethylamine, or N, N-diisopropylethylamine can be added.
• Step E-3 The compound represented by the general formula (5f) can be produced by subjecting a primary amide of the compound represented by the general formula (7) to a dehydration reaction to convert the compound into a cyano group.
• the reaction conditions are as follows: potassium carbonate, sodium carbonate, cesium carbonate, tripotassium phosphate, cesium fluoride, pyridine, triethylamine, or N, N-diisopropylethylamine in a solvent such as methylene chloride, 1,4-dioxane, tetrahydrofuran, or acetonitrile.
• the reaction can be carried out using trifluoroacetic anhydride, acetic anhydride, trifluoromethanesulfonic anhydride, paratoluenesulfonyl chloride, methanesulfonyl chloride, or the like, at 0 ° C. to heating under reflux.
• Step E-4 The compound represented by the general formula (5h) can be produced by cycloalkylating the compound represented by the general formula (6) using R 22 -A 2 -A 2 -R 22 .
• the reaction conditions include hydrogenation in a solvent such as dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and the like.
• R 22 -A 2 -A 2 -R cycloalkyl agents represented by 22, using, for example 1,2-dibromoethane or the like, can be carried out at 0 ° C.
• reaction accelerators such as sodium iodide, potassium iodide, tetra-n-butylammonium iodide, sodium bromide, potassium bromide, and tetra-n-butylammonium bromide can be added.
• the above compound (5) can be produced according to the method shown in synthetic route F, a method analogous thereto, a method described in other literatures or a method analogous thereto. [Synthetic route F]
• Step F-1 The compound represented by the general formula (5) can be produced by mixing the compound represented by the general formula (8) with a corresponding ⁇ -halocarbonyl compound.
• R 2 is a methyl group
• bromoacetone or chloroacetone is used as an ⁇ -halocarbonyl compound
• the reaction can be carried out in a solvent such as benzene or the like from room temperature to heating under reflux.
• acids such as hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, sulfuric acid, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate
• a base such as cesium fluoride, triethylamine, or N, N-diisopropylethylamine can also be added.
• sodium iodide, potassium iodide, tetra-n-butylammonium iodide, sodium bromide, potassium bromide, tetra-n-butylammonium bromide and the like can be added.
• R 18 , R 19 , M ′ and X have the same definitions as described in the synthetic route D described above.
• Step G-1 The compound represented by the general formula (8a) can be produced by alkylating the ester moiety of the compound represented by the general formula (8b) with R 19 -M ′. The reaction can be carried out in the same manner as in Step D-1.
• W 7 is a bromine atom, an iodine atom, a chlorine atom, trifluoromethanesulfonate or And; R 18 , R 19 , M ′ and X are the same as defined in the synthetic route D above, and R 1 , R 2 , Q 1 , Q 2 , L, R 4 , R 5 , and R 13 are the same as defined in the above general formula (1).
• Step H-1 The compound represented by the general formula (2a) can be produced by alkylating the ester site of the compound represented by the general formula (2b) using R 19 -M ′. The reaction can be carried out in the same manner as in Step D-1.
• Step H-2 The compound represented by the general formula (2c) can be produced by reducing the ester moiety of the compound represented by the general formula (2b).
• Reaction conditions include methanol, ethanol, tetrahydrofuran, diethyl ether, methylene chloride, toluene, benzene, hexane, and the like, or a mixed solvent thereof in diisobutylaluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride
• the reaction can be carried out using a hydride reducing agent such as sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) or lithium tri (sec-butyl) borohydride at -78 ° C. to heating under reflux.
• a hydride reducing agent such as sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) or lithium tri (sec-butyl) borohydride at -78 ° C. to heating
• Step H-3 The compound represented by the general formula (2f) can be produced by hydrolyzing an ester site of the compound represented by the general formula (2b).
• Reaction conditions include water, methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, or a mixed solvent thereof containing lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, Using an alkali metal salt such as sodium carbonate or cesium carbonate, the reaction can be carried out at -78 ° C to heating under reflux.
• Step H-4 The compound represented by the general formula (2e) can be produced by subjecting a carboxylic acid of the compound represented by the general formula (2f) to primary amidation.
• the reaction conditions are as follows: a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, methylene chloride, acetonitrile, toluene, benzene, 1,4-dioxane, tetrahydrofuran, etc.
• HATU pyridinium-3-oxidehexafluorophosphate
• a condensing agent such as carbodiimide (EDCI) or N, N'-dicyclohexylcarbodiimide (DCC)
• ammonium chloride or ammonia-containing solvent such as methanol, ethanol, 1,4-dioxane, water or the like as an ammonia source.
• the reaction can be carried out at 0 ° C. to room temperature, and optionally under reflux.
• a base such as triethylamine or N, N-diisopropylethylamine can be added.
• N, N-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAt) and the like can be added as a reaction accelerator.
• Step H-5 The compound represented by the general formula (2d) can be produced by subjecting a primary amide of the compound represented by the general formula (2e) to a dehydration reaction to convert the compound into a cyano group.
• the reaction can be carried out in the same manner as in Step E-3.
• Step H-6 In the synthesis route H, the compound represented by the general formula (2g) is produced by amidating the carboxylic acid of the compound represented by the general formula (2f) with R 13 —NH—R 13. Can be.
• a primary amine represented by R 13 —NH—R 13 instead of the ammonia source, a primary amine represented by R 13 —NH—R 13 , a secondary amine, or a salt thereof, for example, methylamine, dimethylamine, or tetrahydrofuran containing them
• the reaction can be carried out in the same manner as in Step H-4, using a solvent or 1-amino-2-methyl-2-propanol.
• R 23 and R 24 each represent a C 1 -C 6 alkyl group, a deuterated C 1 -C 6 alkyl group, or a C 3 -C 6 cycloalkyl group
• R 25 and R 26 each represent H, a C 1 -C 6 alkyl group, a deuterated C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, or a hydroxy C 1 -C 6 alkyl group
• R 16 and R 17 have the same definitions as described in the synthesis route B described above
• W 7 has the same definition as described in the synthesis route H described above
• Q 1 , Q 2 , R 4 have the same definitions as those described above. It is the same as the definition described in the general formula (1).
• Step I-1 The compound represented by the general formula (2m) can be produced by removing the t-butyloxycarbonyl group of the compound represented by the general formula (2n).
• Reaction conditions include methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, water, and other solvents in trifluoroacetic acid, paratoluenesulfonic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, boron trifluoride.
• An acid such as a diethyl ether complex, boron tribromide, or aluminum chloride is added, and the reaction can be carried out at ⁇ 78 ° C. to room temperature, and in some cases, heating under reflux.
• Step I-2 The compound represented by the general formula (2h) can be produced by reacting the compound represented by the general formula (2m) with R 16 -R 17 .
• the reaction can be carried out in the same manner as in Step B-1 using R 16 -R 17 .
• Step I-3 The compound represented by the general formula (2i) can be produced by subjecting the compound represented by the general formula (2m) to sulfonylation using R 23 -SO 2 Cl.
• Reaction conditions include methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, water and the like, or a mixed solvent thereof, preferably potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, hydroxide
• a base such as potassium, tripotassium phosphate, cesium fluoride, pyridine, N, N-dimethyl-4-aminopyridine, N-methylimidazole, triethylamine, or N, N-diisopropylethylamine is added, and R 23 -SO 2 Cl
• a sulfonylating agent such as a sulfonyl chloride represented by, for example, methanesulfonyl chloride or
• Step I-4 The compound represented by the general formula (2j) is obtained by acylating the compound represented by the general formula (2m) using (R 24 —CO) 2 O or R 24 —C (O) Cl. Can be manufactured.
• the reaction conditions include, in a solvent such as methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, and water, preferably potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and phosphoric acid.
• a base such as tripotassium, cesium fluoride, pyridine, N, N-dimethyl-4-aminopyridine, N-methylimidazole, triethylamine, or N, N-diisopropylethylamine is added, and (R 24 —CO) 2 O or R
• An acylating agent such as an acyl chloride represented by 24 -C (O) Cl or the like, carboxylic anhydride or the like, for example, acetic anhydride or the like is added, and the reaction can be carried out at -78 ° C to room temperature, or in some cases, by heating under reflux.
• Step I-5 The compound represented by the general formula (2k) can be produced by ureaizing the compound represented by the general formula (2m).
• the reaction conditions are as follows. A solvent such as methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene or water is added with a urea agent such as trimethylsilyl isocyanate, and the mixture is heated to 0 ° C. to room temperature, and sometimes heated to reflux. Can be done.
• Step I-6 The compound represented by the general formula (2l) can be produced by subjecting the compound represented by the general formula (2m) to reductive alkylation using R 25 C (O) R 26 .
• the reaction conditions are as follows: aldehydes and ketones represented by R 25 C (O) R 26 or compounds equivalent thereto in a solvent such as methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, methanol and ethanol.
• an aqueous formalin solution or glycolaldehyde dimer is added, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, borane-dimethylsulfide complex, lithium aluminum hydride is added.
• a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, borane-dimethylsulfide complex, lithium aluminum hydride is added.
• the reaction can be carried out at -78 ° C to room temperature, and in some cases, by heating to reflux.
• an acid such as trifluoroacetic acid, paratoluenesulfonic acid, boron trifluoride diethyl ether complex, boron tribromide, aluminum chloride, chlorotrimethylsilane, or a reaction accelerator such as tetraalkoxytitanium.
• an acid such as trifluoroacetic acid, paratoluenesulfonic acid, boron trifluoride diethyl ether complex, boron tribromide, aluminum chloride, chlorotrimethylsilane, or a reaction accelerator such as tetraalkoxytitanium.
• W 8 and W 8 ′ each independently represent a C 1 -C 6 alkylene group
• R 27 and R 28 are each independently selected from the group consisting of H, a C 1 -C 6 alkyl group, a deuterated C 1 -C 6 alkyl group, and a C 3 -C 6 cycloalkyl group
• 27 and R 28 may combine with each other to form a ring
• R 19 and M ′ are the same as the definitions described in the synthetic route D described above
• W 7 is the same as the definition described in the synthetic route H described above
• Q 1 , Q 2 and R 4 are The definition is the same as that described in the equation (1).
• Process J-1 The compound represented by the general formula (2r) can be produced by converting an acetal of the compound represented by the general formula (2s) into a ketone.
• Reaction conditions include water, acetone, methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, methanol, ethanol, and other solvents in a solvent such as trifluoroacetic acid, paratoluenesulfonic acid, sulfuric acid, sulfuric acid, hydrochloric acid, and hydrogen bromide.
• An acid, boron trifluoride diethyl ether complex, boron tribromide, aluminum chloride and other acids are added, and the reaction can be carried out at -78 ° C to heating under reflux.
• Step J-2 The compound represented by the general formula (2q) can be produced by reducing the ketone of the compound represented by the general formula (2r). The reaction can be performed in the same manner as in Step H-2.
• Step J-3 The compound represented by the general formula (2o) can be produced by inverting the stereochemistry of the hydroxyl group of the compound represented by the general formula (2q) using a Mitsunobu reaction. That is, it can be carried out by introducing an O-acyl group by a general Mitsunobu reaction in the first step, and then removing the introduced acyl group in the second step.
• the reaction conditions include a phosphorus reagent such as triphenylphosphine, tributylphosphine, or trimethylphosphine in a solvent such as tetrahydrofuran, 1,4-dioxane, toluene, or benzene, or without solvent.
• a phosphorus reagent such as triphenylphosphine, tributylphosphine, or trimethylphosphine in a solvent such as tetrahydrofuran, 1,4-dioxane, toluene, or benzene, or without solvent.
• diazo compounds such as diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD), and 1,1′-azobis (N, N-dimethylformamide), and carboxylic acid such as acetic acid and paranitrobenzoic acid.
• the reaction can be carried out at 0 ° C. to reflux.
• the reaction conditions include water, methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, potassium carbonate, sodium carbonate,
• the reaction can be carried out using an alkali metal salt such as lithium hydroxide, sodium hydroxide, potassium hydroxide or the like at 0 ° C. to heating under reflux.
• Step J-4 The compound represented by the general formula (2p) can be produced by alkylating the ketone of the compound represented by the general formula (2r) using R 19 -M ′. The reaction can be carried out in the same manner as in Step D-1.
• W 9 represents a C 1 -C 6 alkylene group
• R 29 , R 30 and R 31 are each independently selected from H, a C 1 -C 6 alkyl group, a deuterated C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group
• W 7 is the same as the definition described in the above synthesis route H
• Q 1 , Q 2 , and R 4 are the same as the definitions described in the above general formula (1).
• the compound represented by the general formula (2t) can be produced by diolating a double bond of the compound represented by the general formula (2u).
• an oxidizing agent such as osmium tetroxide or ruthenium tetroxide is added in water, tetrahydrofuran, acetone, t-butanol, 1,4-dioxane or a mixed solvent thereof, and N-methylmorpholine-N-oxide is preferably used.
• a reoxidant such as trimethylamine-N-oxide, t-butyl hydroperoxide, etc., in the presence of 0 ° C. to room temperature, if necessary, by heating under reflux.
• pyridine, 2,6-lutidine, methanesulfonylamide, or the like can be added as a reaction accelerator.
• R 32 represents a C 1 -C 6 alkyl group, a deuterated C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 6 cycloalkyl group, or a C 1 -C 6 alkoxycarbonyl group.
• R 21 , R 22 , and A 2 are the same as defined in the synthetic route E described above
• W 7 is the same as the definition described in the synthetic route H described above
• Q 1 , Q 2 , R 4 Is the same as the definition described in the general formula (1).
• Step L-1 The compound represented by the general formula (2w) can be produced by alkylating the compound represented by the general formula (2z) using R 32 -R 22 .
• the reaction conditions are as follows: lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexaxide in a solvent such as tetrahydrofuran, diethylether, t-butylmethylether, N, N-dimethylformamide, toluene, and hexane.
• Methyldisilazide n-butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, potassium t-butoxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, etc.
• alkyl iodide represented by R 32 -R 22, alkyl bromides, alkyl chlorides, alkyl paratoluene sulfonate, alkyl methanesulfonate, alkyl trifluoromethanesulfonate, chloroformate Alkylating agents or alkoxycarbonyl agent such as ester, for example using methyl iodide and 1-bromo-3-methyl-2-butene, -78 ° C. ⁇ room temperature, in some cases can be carried out by heating under reflux.
• Step L-2 The compound represented by the general formula (2x) can be produced by alkylating the compound represented by the general formula (2w) using R 21 to R 22 .
• the reaction conditions for example, methyl iodide or the like can be used, and the reaction can be carried out in the same manner as in Step L-1.
• Step L-3 The compound represented by the general formula (2x) can also be produced by alkylating the compound represented by the general formula (2y) using R 32 -R 22 .
• the reaction conditions for example, methyl iodide or the like can be used, and the reaction can be carried out in the same manner as in Step L-1.
• Step L-4 The compound represented by the general formula (2v) can be produced by cycloalkylating the compound represented by the general formula (2w) using R 22 -A 2 -A 2 -R 22 .
• the reaction conditions for example, 1,2-dibromoethane or the like can be used, and the reaction can be carried out in the same manner as in Step E-4.
• R 33, R 34 are each independently C 1 to ⁇ C 6 alkyl group, a deuterated C 1 ⁇ C 6 alkyl group, C 2 ⁇ C 6 alkenyl group, C 3 ⁇ C 6 cycloalkyl group, a ;
• W 7 is the same as the definition described in the above synthesis route H, and Q 1 , Q 2 , and R 4 are the same as the definitions described in the above general formula (1).
• Step M-1 The compound represented by the general formula (9) can be produced by epoxidizing a double bond of the compound represented by the general formula (10).
• the reaction conditions are as follows: methylene chloride, chloroform, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, water, etc., in a solvent such as 3-chloroperbenzoic acid, hydrogen peroxide, An oxidizing agent such as dimethyldioxirane is added, and the reaction can be carried out at ⁇ 20 ° C. to heating under reflux.
• a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like can be added.
• Step M-2 The compound represented by the general formula (2aa) can be produced by intramolecular cyclopropanation of the compound represented by the general formula (9).
• the reaction conditions are as follows: lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n in a solvent such as tetrahydrofuran, diethylether, t-butylmethylether, toluene and hexane.
• a base such as -butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, etc .; In some cases, it can be carried out by heating under reflux.
• W 7 is the same as the definition described in the above synthesis route H, and Q 1 , Q 2 , and R 4 are the same as the definitions described in the above general formula (1).
• Step N-1 The compound represented by the general formula (2ab) can be produced by reacting the compound represented by the general formula (11) or (11 ′) with 2-cyclopenten-1-one.
• Reaction conditions include tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, methylene chloride, chloroform, water, or a mixed solvent thereof in hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, hydrobromic acid, and boron trifluoride diethyl.
• An ether complex, an acid such as aluminum chloride, trimethylsilyl chloride or the like is added, 2-cyclopenten-1-one is allowed to act, and the reaction can be carried out at room temperature to heating under reflux.
• R 35 is G, a hydroxy C 1 -C 6 alkyl group optionally having a substituent, a C 1 -C 6 alkyl group optionally having a substituent, or deuterated optionally having a substituent.
• a C 1 -C 6 alkyl group, an optionally substituted C 2 -C 6 alkenyl group, an optionally substituted C 3 -C 6 cycloalkyl group, an optionally substituted C 5 ⁇ C 8 bicycloalkyl group may have a substituent 3-10 membered heterocycloalkyl group, a phenyl group which may have a substituent group, an optionally substituted heteroaryl group, a substituent A phenylmethyl group which may have a heteroarylmethyl group which may have a substituent;
• R 36 represents a chlorine atom, a bromine atom, an iodine atom, paratoluenesulfonate, methanesulfonate, trifluoromethan
• Step O-1 The compound represented by the general formula (2ac) can be produced by alkylating the compound represented by the general formula (11) or (11 ′) using R 35 to R 36 .
• reaction conditions general S N 2 reaction conditions can be applied.
• a base such as N, N-diisopropylethylamine and the like, and alkyl iodide, alkyl bromide, alkyl chloride, alkyl paratoluenesulfonate, alkylmethanesulfonate, alkyltrifluoromethanesulfonate represented by R 35 to R 36 are added.
• Alkylating agents such as With c methyl and methyl bromoacetate can be carried out at 0 ° C. ⁇ heated to reflux.
• reaction accelerators such as sodium iodide, potassium iodide, tetra-n-butylammonium iodide, sodium bromide, potassium bromide, and tetra-n-butylammonium bromide can be added.
• Step O-2 The compound represented by the general formula (2ac) can also be produced by oxidizing a sulfide of the compound represented by the general formula (12).
• the reaction conditions include, for example, 3-chloroperbenzoic acid, monoperoxyphthalic acid in a solvent such as methylene chloride, chloroform, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and water.
• An oxidizing agent such as magnesium hexahydrate, hydrogen peroxide, sodium hypochlorite or the like is added, and the reaction can be performed at ⁇ 20 ° C. to heating under reflux.
• a base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like can be added.
• W 8 , W 8 ′ , R 19 and M ′ are the same as the definitions described in the above-mentioned synthesis route J
• W 7 is the same as the definition described in the above-mentioned synthesis route H
• Q 1 , Q 2 and R 4 have the same definitions as those described in the general formula (1).
• Step P-1 The compound represented by the general formula (12c) can be produced by reducing the compound represented by the general formula (12b). The reaction can be performed in the same manner as in Step H-2.
• Process P-2 The compound represented by the general formula (12a) can be produced by inverting the stereochemistry of the hydroxyl group of the compound represented by the general formula (12c) using Mitsunobu reaction. The reaction can be performed in the same manner as in Step J-3.
• Step P-3 The compound represented by the general formula (12d) can be produced by alkylating a ketone of the compound represented by the general formula (12b) with R 19 -M ′ .
• the reaction can be carried out in the same manner as in Step D-1.
• the above compound (12) can be produced according to the method shown in the synthetic route Q, a method analogous thereto, a method described in other literatures or a method analogous thereto. [Synthetic route Q]
• R 37 represents a fluorine atom or a chlorine atom
• R 35 and R 36 have the same definition as described in the synthetic route O described above
• W 7 has the same definition as described in the synthetic route H described above
• Q 1 , Q 2 , R 4 have the same definitions as described above. It is the same as the definition described in the general formula (1).
• the compound represented by the general formula (13) obtained in the step Q-1 can be used in the step Q-2 without purification to produce the general formula (12).
• the compound represented by the general formula (13) can be produced by thiolating the compound represented by the general formula (14).
• the reaction conditions include, for example, sodium hydrogen sulfide or sodium sulfide in a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, methylene chloride, 1,4-dioxane, and tetrahydrofuran.
• a base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, or N, N-diisopropylethylamine can be added.
• thioacetic acid instead of the above-mentioned sodium hydrogen sulfide, sodium sulfide and the like, thioacetic acid, thiourea and the like can be used.
• water, methanol, ethanol, 1-propanol, 2-propanol, In tetrahydrofuran, 1,4-dioxane, or a mixed solvent thereof an additional operation using an alkali metal salt such as lithium hydroxide, sodium hydroxide, or potassium hydroxide at 0 ° C. to reflux may be required. is there.
• Process Q-2 The compound represented by the general formula (12) can be produced by alkylating the compound represented by the general formula (13) with R 35 -R 36 .
• the reaction can be performed in the same manner as in Step O-1.
• the compound (11) or (11 ′) or the compound represented by the general formula (20) is produced according to the method shown in the synthetic route R, a method analogous thereto, a method described in other documents, or a method analogous thereto. be able to.
• Synthetic route R
• W 10 is a bromine atom, an iodine atom, a chlorine atom, trifluoromethanesulfonate or And;
• R 38 represents R 1 or —C (O) R 9 , R 35 and R 37 are the same as defined in the above-mentioned synthesis route Q, and Q 1 , Q 2 , X, R 1 , R 2 , R 4 and R 9 are described in the above-mentioned general formula (1). It is the same as the definition given.
• Step R-1 The compound represented by the general formula (18) can be produced by sulfidizing the compound represented by the general formula (19).
• the reaction conditions are as follows: in a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, methylene chloride, 1,4-dioxane, tetrahydrofuran or the like, a corresponding sulfidizing agent such as benzyl Mercaptan, thioglycolic acid ester, etc. are added, and the reaction can be carried out at 0 ° C. to room temperature, or in some cases, by heating under reflux.
• a base such as sodium hydride, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, or N, N-diisopropylethylamine can be added.
• Step R-2 The compound represented by the general formula (15) can be produced by converting a thiobenzyl group to a sulfonyl chloride when R 35 of the compound represented by the general formula (18) is a benzyl group.
• Reaction conditions include methylene chloride, chloroform, acetonitrile, 1,4-dioxane, tetrahydrofuran, water, acetic acid, sulfuric acid, and the like, or a mixed solvent thereof in N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylimidazo. Lysine-2,4-dione, sulfuryl chloride, chlorine and the like are added, and the reaction can be carried out at ⁇ 78 ° C. to heating under reflux.
• Step R-3 When R 35 of the compound represented by the general formula (18) is a benzyl group, the compound represented by the general formula (16) can be produced by converting a thiobenzyl group into a sulfonic acid. The reaction can be carried out in the same manner as in Step R-2.
• Step R-4 The compound represented by the general formula (15) can be produced by subjecting the compound represented by the general formula (17) to sulfonylation.
• the reaction can be carried out in a solvent such as methylene chloride or chloroform or under a solvent-free condition by adding a sulfonylation reagent such as chlorosulfuric acid and the like, at -78 ° C to heating under reflux.
• a sulfonylation reagent such as chlorosulfuric acid and the like
• Step R-5 the compound represented by the general formula (15) can be produced by converting the sulfonic acid moiety of the compound represented by the general formula (16) to sulfonyl chloride.
• thionyl chloride, oxalyl chloride, phosphorus oxychloride, triphosgene, phosphorus pentachloride and the like are added in a solvent such as methylene chloride, chloroform, acetonitrile, 1,4-dioxane and tetrahydrofuran, and the mixture is heated to -78 ° C and refluxed. It can be carried out.
• N, N-dimethylformamide can be added as a reaction accelerator.
• Step R-6 The compound represented by the general formula (11) or (11 ′) can be produced by converting the sulfonyl chloride moiety of the compound represented by the general formula (15) to sulfinic acid or a salt thereof.
• the reaction conditions include, for example, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide in water or a solvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene and benzene.
• a base such as tripotassium phosphate, sodium bicarbonate, potassium bicarbonate and the like
• a base such as tripotassium phosphate, sodium bicarbonate, potassium bicarbonate and the like
• the reaction can be carried out at room temperature to heating under reflux with a reducing agent.
• a reducing agent sodium sulfite, zinc, tin (II) chloride, sodium borohydride, lithium aluminum hydride, sodium iodide, potassium iodide and the like can be used.
• Step R-7 The compound represented by the general formula (20) can be produced by reacting the compound represented by the general formula (15) with an amine represented by R 35 -NH 2 or a hydrochloride thereof.
• Reaction conditions include methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, water, pyridine, and the like, or a mixed solvent thereof, if necessary, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, A base such as potassium hydroxide, tripotassium phosphate, sodium bicarbonate, potassium bicarbonate, pyridine, triethylamine, or N, N-diisopropylethylamine is added, and the reaction can be carried out at ⁇ 78 ° C. to reflux with heating.
• Examples of the amine represented by R 35 -NH 2 or its hydrochloride include cis-4-aminocyclohexanol hydrochloride, paraaminophenol
• L ′ represents —O— or —NR 41 ⁇
• R 39 represents a fluorine atom or a chlorine atom
• R 40 and R 41 each independently represent a C 1 -C 6 alkyl group or a deuterated C 1 -C 6 alkyl group
• M ′′ represents lithium, sodium or potassium
• W 7 is the same as the definition described in the synthesis route H
• Q 1 , Q 2 , G, and L are the same as the definitions described in the general formula (1).
• Step S-1 Formula (2ad) compound represented by the the compound represented by the general formula (2ae), it can be prepared by replacing the -L'-R 40.
• reaction conditions general aromatic nucleophilic substitution reaction conditions can be applied.
• reaction accelerators such as tetra-n-butylammonium fluoride, hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, paratoluenesulfonic acid, hydrobromic acid, boron trifluoride diethyl ether complex, and acids such as aluminum chloride Can also be added.
• R 36 is the same as the definition described in the synthetic route O described above
• R 40 is the same as the definition described in the synthetic route S described above
• W 7 is the same as the definition described in the synthetic route H described above.
• Q 1 , Q 2 , G, and L are the same as the definitions described in the general formula (1).
• Step T-1 The compound represented by the general formula (2af) can be produced by alkylating the hydroxyl group of the compound represented by the general formula (2ag) with R 40 —OH or R 40 —R 36. .
• the reaction can be carried out in the same manner as in step B-1, and can be carried out by any of the above-mentioned S N 2 reaction and Mitsunobu reaction.
• R 18 , R 19 , and M ′ are the same as the definitions described in the above-mentioned synthesis route D
• R 35 is the same as the definition described in the above-mentioned synthesis route Q
• Q 1 , Q 2 , R 2 , R 4 and X have the same definitions as those described in the general formula (1).
• Step U-1 The compound represented by the general formula (22) can be produced by brominating the compound represented by the general formula (21).
• the reaction conditions include bromine, N-bromosuccinimide, trimethylphenylammonium tribromide, and bromine such as pyridinium bromide perbromide in a solvent such as diethyl ether, tetrahydrofuran, benzene, 1,4-dioxane, methylene chloride, chloroform, acetonitrile, and acetic acid.
• the reaction can be carried out at ⁇ 78 ° C. to reflux while adding an agent.
• Step U-2 The compound represented by the general formula (24) can be produced by reacting the compound represented by the general formula (23) with the compound represented by the general formula (22).
• the reaction can be carried out in a solvent such as ethanol, 2-propanol, acetonitrile, N, N-dimethylformamide, ethyl methyl ketone, or acetone from room temperature to heating under reflux.
• acids such as hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, sulfuric acid, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate,
• a base such as cesium fluoride, triethylamine, or N, N-diisopropylethylamine can also be added.
• Step U-3 The compound represented by the general formula (25) can be produced by subjecting the compound represented by the general formula (24) to sulfonylation. The reaction can be carried out in the same manner as in Step R-4.
• Step U-4 The compound represented by the general formula (26) can be produced by reacting the compound represented by the general formula (25) with an amine represented by R 35 -NH 2 or a hydrochloride thereof. The reaction can be carried out in the same manner as in Step R-7.
• Step U-5 The compound represented by the general formula (1a) can be produced by alkylating an ester of the compound represented by the general formula (26) using R 19 -M ′. The reaction can be carried out in the same manner as in Step D-1.
• Step U-6 The compound represented by the general formula (1b) can be produced by subjecting an ester of the compound represented by the general formula (26) to Clinkovich reaction conditions. The reaction can be carried out in the same manner as in Step D-3.
• Q 1 , Q 2 , R 1 , R 2 , G, L, and X are the same as those defined in the general formula (1).
• Step V-1 The compound represented by the general formula (1c) can be produced by removing the paramethoxybenzyl group of the compound represented by the general formula (27).
• Reaction conditions include methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, water, and other solvents in trifluoroacetic acid, paratoluenesulfonic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, boron trifluoride.
• An acid such as a diethyl ether complex, boron tribromide, or aluminum chloride is added, and the reaction can be carried out at ⁇ 78 ° C. to room temperature, and in some cases, heating under reflux. If necessary, anisole, pentamethylbenzene, dimethyl sulfide and the like can be added.
• Q 1 , Q 2 , R 1 , R 2 , G, L, and X are the same as those defined in the general formula (1).
• Step W-1 The compound represented by the general formula (28) can be produced by reducing the cyano group of the compound represented by the general formula (1d) to an aldehyde.
• the reaction conditions include diisobutylaluminum hydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) in a solvent such as tetrahydrofuran, diethyl ether, methylene chloride, toluene, benzene, and hexane.
• the reaction can be carried out by using a hydride reducing agent such as lithium tri (sec-butyl) borohydride at -78 ° C. to room temperature and, if necessary, by heating under reflux.
• Step W-2 The compound represented by the general formula (1e) can be produced by reducing the aldehyde of the compound represented by the general formula (28) to hydroxymethyl. The reaction can be performed in the same manner as in Step H-2.
• R 42 each independently represents H, a C 1 -C 5 alkyl group
• R 18 is the same as the definition described in the above-mentioned synthesis route D, and Q 1 , Q 2 , R 2 , R 4 , G, R 10 , R 11 , L, and X are represented by the general formula (1) described above. The definition is the same as described.
• Step X-1 The compound represented by the general formula (1g) can be produced by hydrolyzing an ester site of the compound represented by the general formula (1f). The reaction can be performed in the same manner as in Step H-3.
• Step X-2 The compound represented by the general formula (1h) can be produced by amidating the carboxylic acid of the compound represented by the general formula (1g) with R 10 —NH—R 11 .
• the reaction conditions include tetrahydrofuran containing, in addition to the ammonia source shown in Step H-4, a primary amine or a secondary amine represented by R 10 —NH—R 11 , or a salt thereof, for example, dimethylamine. Using a solution or the like, the reaction can be performed in the same manner as in step H-4.
• Step X-3 The compound represented by the general formula (1i) can be produced by reducing the ester moiety of the compound represented by the general formula (1f). The reaction can be performed in the same manner as in Step H-2.
• R 43 represents a C 1 -C 5 alkylene group or a C 3 -C 5 cycloalkylene group which may have a substituent
• R 18 , R 19 , and M ′ are the same as defined in the synthesis route D described above, R 18 can be independently selected, and R 4 , Q 1 , Q 2 , R 2 , L, and X are Is the same as the definition described in the general formula (1).
• Step Y-1 The compound represented by the general formula (1k) can be produced by alkylating two esters of the compound represented by the general formula (1j) with R 19 -M ′. The reaction can be carried out in the same manner as in Step D-1.
• W 7 is the same as the definition described in the synthetic route H, and Q 1 , Q 2 , R 1 , R 2 , R 4 , G, and X are the same as those described in the general formula (1). Same as the definition.
• Step Z-1 The compound represented by the general formula (1l) can be produced by N-methylating the compound represented by the general formula (1m). The reaction can be carried out in the same manner as in Step B-1 using methyl iodide.
• Step Z-2 The compound represented by the general formula (2ah) can be produced by N-methylating the compound represented by the general formula (2ai).
• the reaction can be carried out in the same manner as in Step B-1 using methyl iodide.
• alkylating agents such as alkyl iodide, alkyl bromide, alkyl chloride, alkyl paratoluenesulfonate, alkylmethanesulfonate and alkyltrifluoromethanesulfonate described in the present production method are easily available reagents.
• a compound represented by the following general formula (33) can be produced according to synthetic route AA. [Synthetic route AA]
• R 44 represents a C 1 -C 6 alkyl group or a phenyl group which may have a substituent; R 19 and M ′ are the same as defined in the synthesis route D described above. )
• Step AA-1 The compound represented by the general formula (30) can be produced by subjecting a hydroxyl group of the compound represented by the general formula (29) to t-butyldimethylsilylation.
• reaction conditions general silylation reaction conditions can be applied.
• N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,4-dioxane, tetrahydrofuran In a solvent such as 2,2-dimethoxyethane, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, cesium fluoride, imidazole, pyridine, triethylamine, or N, N-diisopropylethylamine And using t-butyldimethylchlorosilane (TBSCl) at 0 ° C. to heating under reflux.
• a solvent such as 2,2-dimethoxyethane, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, cesium fluoride, imidazole, pyridine, triethylamine, or N, N-diisopropyleth
• a reaction accelerator such as sodium iodide, potassium iodide, tetra-n-butylammonium iodide, sodium bromide, potassium bromide, tetra-n-butylammonium bromide, silver nitrate and the like can be added.
• Step AA-2 The compound represented by the general formula (31) can be produced by alkylating the ketone of the compound represented by the general formula (30) using R 19 -M ′. The reaction can be carried out in the same manner as in Step D-1.
• Step AA-3 The compound represented by the general formula (32) can be produced by removing the t-butyldimethylsilyl group of the compound represented by the general formula (31).
• the reaction conditions include water, acetone, methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, methanol, ethanol, etc., or a mixed solvent thereof in tetra-n-butylammonium fluoride, cesium fluoride.
• the reaction can be carried out at ⁇ 78 ° C. to reflux under heating with the addition of an acid.
• Step AA-4 The compound represented by the general formula (33) can be produced by sulfonylating the hydroxyl group of the compound represented by the general formula (32) with R 44 -SO 2 Cl.
• Reaction conditions include methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, water, and other solvents in a solvent such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate,
• a base such as cesium fluoride, pyridine, N, N-dimethyl-4-aminopyridine, N-methylimidazole, triethylamine or N, N-diisopropylethylamine is added, and alkylsulfonyl chloride represented by R 44 -SO 2 Cl is added.
• a sulfonylating agent such as alkylsulfonic anhydride, for example
• R 18 , R 19 , and M ′ are the same as the definitions described in the synthetic route D
• W 7 is the same as the definition in the synthetic route H
• R 43 is the same as the synthetic route Y described above.
• R 4 , Q 1 , and Q 2 are the same as the definitions described in the general formula (1).
• Step AB-1 The compound represented by the general formula (12e) can be produced by alkylating an ester of the compound represented by the general formula (12f) using R 19 -M ′. The reaction can be carried out in the same manner as in Step D-1.
• R 45 represents a C 1 -C 6 alkyl group
• M is the same as the definition described in the synthetic route A described above
• R 14 and Z are the same as the definitions described in the synthetic route B described above
• L, X, Q 1 , Q 2 , R 2 , R 4 , G are the same as the definitions described in the general formula (1).
• Process AC-1 The compound represented by the general formula (1n) can be produced by subjecting the compound represented by the general formula (3) and the compound represented by the general formula (34) to a coupling reaction.
• the reaction can be performed in the same manner as in step A-2.
• W 7 is the same as the definition described in the above-mentioned synthesis route H
• W 8 is the same as the definition described in the above-mentioned synthesis route J
• Q 1 , Q 2 , R 4 are the above-mentioned general formulas.
• the definition is the same as that described in the equation (1).
• Process AD-1 The compound represented by the general formula (2ak) can be produced by removing the t-butyldimethylsilyl group of the compound represented by the general formula (2aj). The reaction can be performed in the same manner as in Step AA-3.
• alkylating agents such as alkyl iodide, alkyl bromide, alkyl chloride, alkyl paratoluenesulfonate, alkylmethanesulfonate and alkyltrifluoromethanesulfonate described in the present production method are easily available reagents.
• a compound represented by the following general formula (35) can be produced according to synthetic route AE. [Synthetic route AE]
• W 11 independently represents a bond, a C 1 -C 6 alkylene group
• W 12 and W 13 are each independently selected from H, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkoxycarbonyl group, and a t-butyldimethylsilyloxy group
• W 12 and W 13 may combine with each other to form a ring.
• two W 11 present in the ring do not simultaneously select a bond.
• Step AE-1 The compound represented by the general formula (35) can be produced by sulfonylating the hydroxyl group of the compound represented by the general formula (36) with paratoluenesulfonyl chloride. The reaction can be carried out in the same manner as in step AA-4.
• R 46 represents a C 1 -C 5 alkyl group
• R 21 has the same definition as described in the synthesis route E
• R 2 and X have the same definitions as described in the general formula (1).
• Step AF-1 The compound represented by the general formula (5i) can be produced by subjecting an ester of the compound represented by the general formula (5j) to methyl esterification.
• the reaction may be carried out in the absence of a solvent or in a solvent such as methanol, methylene chloride, 1,4-dioxane, tetrahydrofuran, toluene, benzene, or water, by adding an ammonia / methanol solution, and then heating at 0 ° C. to reflux. it can.
• an acid such as trifluoroacetic acid, paratoluenesulfonic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, boron trifluoride diethyl ether complex, boron tribromide, and aluminum chloride is added. , -78 ° C to heating under reflux.
• W 14 represents a C 1 -C 4 alkylene group
• Z is the same as the definition described in the above-mentioned synthesis route B
• W 7 is the same as the definition described in the above-mentioned synthesis route H
• Q 1 , Q 2 , R 4 are the above-mentioned general formula (1) It is the same as the definition described in.
• Process AG-1 In the synthetic route AG, the compound represented by the general formula (2al) can be produced by intramolecularly alkylating the compound represented by the general formula (36). The reaction can be carried out in the same manner as in Step M-2.
• R 47 represents a C 1 -C 5 alkyl group or a C 3 -C 6 cycloalkyl group; W 7 is the same as the definition described in the above synthesis route H, and Q 1 , Q 2 , and R 4 are the same as the definitions described in the above general formula (1). )
• Step AH-1 The compound represented by the general formula (2am) can be produced by allowing epichlorohydrin to act on the compound represented by the general formula (2an). The reaction can be performed in the same manner as in Step M-2 using epichlorohydrin.
• R 48 is each independently H, a C 1 -C 6 alkyl group which may have a substituent, a hydroxy C 1 -C 6 alkyl group which may have a substituent, also represents optionally C 3 ⁇ C 6 cycloalkyl group, a, may be R 48 together are bonded to each other to form a ring;
• R 49 and R 50 each independently represent H, a C 1 -C 6 alkyl group which may have a substituent, a deuterated C 1 -C 6 alkyl group, a halo C 1 -C 6 alkyl group, A hydroxy C 1 -C 6 alkyl group which may have a substituent, wherein R 49 and R 50 may combine with each other to form a ring;
• W 7 is the same as the definition described in the above synthesis route H, and Q 1 , Q 2 , and R 4 are the same as the definitions described in the above general formula (1).
• Step AI-1 The compound represented by the general formula (2ao) can be produced by subjecting the compound represented by the general formula (2ap) to hydroxyalkylation using R 49 C (O) R 50 .
• R 49 C (O) R 50 As a reaction condition, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexaxide in a solvent such as tetrahydrofuran, diethylether, t-butylmethylether, N, N-dimethylformamide, toluene and hexane.
• Aldehyde and ketone represented by R 49 C (O) R 50 for example, acetone, cyclobutanone, 4,4-difluorocyclohexanone, 3-oxetanone, heavy acetone, etc., at ⁇ 78 ° C. to room temperature.
• Te By Can be carried out by heating under reflux is Te.
• X ′ each independently represents N or CH;
• Q 1 , Q 2 , R 4 , and L are the same as the definitions described in the general formula (1).
• the compound represented by the general formula (2aq) can be produced by reducing a nitro group to an amino group with respect to the compound represented by the general formula (2ar).
• reaction conditions general nitro group reduction conditions can be used.
• a solvent such as a mixed solvent thereof, iron powder, zinc powder, tin (II) chloride, metal tin, metal indium, metal samarium, Raney nickel, formic acid, sodium borohydride, nickel borohydride, cobalt borohydride Using lithium aluminum hydride, sodium dithionite, sodium sulfide, sodium hydrogen
• acids such as ammonium chloride, hydrochloric acid, acetic acid, trifluoroacetic acid, and sulfuric acid, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, sodium hydrogen carbonate, and potassium hydrogen carbonate , Pyridine, triethylamine or N, N-diisopropylethylamine.
• reduction can be performed by adding a catalyst such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide.
• R 1 , R 2 , Q 1 , Q 2 , R 4 , L, G and X are the same as defined in the general formula (1).
• HY is hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, paratoluenesulfone Acid, salicylic acid, stearic acid, palmitic acid, and n represents 1/3 to 3.
• the compound represented by the general formula (1-salt) can be produced by converting the compound represented by the general formula (1) into a corresponding salt.
• a general method of salification can be used.
• hydrochloric acid or hydrobromic acid instead of hydrochloric acid or hydrobromic acid, hydrogen chloride gas or hydrogen bromide gas, or ethyl acetate, 1,4-dioxane, methanol, ethanol, 2-propanol, diethyl ether containing hydrogen chloride or hydrogen bromide Solutions such as acetic acid and acetic acid can be used.
• the synthetic route shown above is an example of a method for producing the compound of the present embodiment, and the compound of the present embodiment may be obtained by the method shown above or a method analogous thereto, or a method described in other literatures or a method described therein. It can be manufactured according to the method according to. These manufacturing methods are capable of various modifications to the scheme as can be readily understood by those skilled in the art.
• the introduction and elimination operations can be appropriately combined according to a standard method.
• introduction and elimination of protecting groups see, for example, Theodora @ W. Green & Peter G. M. Wuts, edited by "Greene's Protective Groups in Organic Synthesis", fourth edition, Wiley-Interscience, 2006.
• Intermediates used to produce the compounds of this embodiment may, if necessary, be solvent extraction, crystallization, recrystallization, chromatography, separation, and other isolation and purification means well known to those skilled in the art. It can be isolated and purified by high-performance liquid chromatography. In some cases, the crude product is used for the next reaction without isolation / purification.
• Antiviral action in the present embodiment means to suppress the growth of virus.
• the “anti-picornavirus action” in the present embodiment means to suppress the growth of viruses belonging to the Picornaviridae family.
• RNA viruses belonging to the Picornaviridae family are single-stranded RNA viruses, which synthesize virus proteins using the protein synthesis function of host cells.
• Viruses belonging to the Picornavirus family further include the genus Enterovirus, the genus Hepatovirus, the genus Parecovirus, the genus Cobvirus, the genus Cardiovirus, the genus Aphtovirus, the genus Aquamavirus, the genus Abihepatovirus, the genus Cosavirus, The genus is classified into the genus Disipivirus, the genus Elbovirus, the genus Sarivirus, the genus Saperovirus, the genus Senecavirus, the genus Teschovirus, the genus Turemovirus, and the like.
• Enterovirus examples include enteroviruses, rhinoviruses, and coxsackieviruses.
• Hepatitis A virus is included as a virus included in the genus hepatvirus.
• the compound of the present embodiment exhibits a strong antiviral effect particularly against viruses contained in the genus Enterovirus.
• the compound of the present embodiment exhibits a strong antiviral effect particularly against enterovirus, coxsackievirus, or rhinovirus.
• the compound of this embodiment strongly suppresses, for example, the growth of picornavirus.
• the compound of the present embodiment is useful as a remedy for picornavirus infection, particularly a viral infectious disease such as enterovirus, coxsackievirus, rhinovirus and the like, or a preventive drug therefor. More preferably, it is useful as a therapeutic or prophylactic agent for rhinovirus infection.
• a medicament containing the compound of the present embodiment as an active ingredient can be used, for example, as a prophylactic or therapeutic agent against asthma or exacerbation of COPD caused by respiratory virus infection.
• the medicament containing the compound of the present embodiment as an active ingredient can be made into various dosage forms depending on the usage.
• dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, and sublinguals.
• These medicaments can be constituted as a pharmaceutical composition containing the compound of the present embodiment as an active ingredient and a pharmaceutically acceptable additive by a known method according to the dosage form.
• Additives contained in the pharmaceutical composition include excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, and stabilizers. And solubilizers.
• the pharmaceutical composition can be prepared by appropriately mixing the compound of the present embodiment with the additive, or diluting and dissolving the compound with the additive.
• the medicament according to the present embodiment can be administered systemically or locally by oral or parenteral (nasal, pulmonary, intravenous, rectal, subcutaneous, muscle, transdermal, etc.).
• 1 H-NMR means a spectrum measured by proton nuclear magnetic resonance spectroscopy.
• CDCl 3 chloroform -d, DMSO-d 6 means dimethylsulfoxide -d 6.
• MS (ESI + ) and MS (ESI ⁇ ) are electrospray ionization, MS (FI + ) is field ionization, MS (FD + ) is field desorption ionization, and MS (EI + ) is electron ionization.
• (CI + ) means mass spectrometry spectrum data measured by the chemical ionization method. Room temperature means 1-30 ° C.
• the compound (500 mg) obtained in Reference Example 8-1 was dissolved in N, N-dimethylformamide (7.7 mL), and iodomethane (0.482 ml) and potassium carbonate (855 mg) were added. , And then allowed to stand at room temperature for 16 hours and 40 minutes. After the reaction solution was poured into a saturated aqueous ammonium chloride solution (20 mL) and water (10 mL) at room temperature, the vessel was washed with ethyl acetate (20 mL) and water (10 mL). Ethyl acetate (20 mL) was added, and the organic layer was extracted.
• Tetraisopropyl orthotitanate (0.418 mL) was added dropwise to a solution of the compound (500 mg) obtained in Reference Example 21-5 in tetrahydrofuran (12 mL) under ice cooling, and the mixture was heated at the same temperature for 30 minutes under an argon atmosphere. And stirred at room temperature for 10 minutes.
• Ethyl magnesium bromide (1.0 mol / L tetrahydrofuran solution, 7.14 mL) was added dropwise to the reaction solution at room temperature over 1 hour, and the mixture was stirred at room temperature for 3 days under an argon atmosphere.
• a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
• N-Iodosuccinimide (68.4 mg) was added to a solution of the compound (63.9 mg) obtained in Reference Example 23 in acetonitrile (1.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere.
• a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium thiosulfate were added to the reaction solution, and the mixture was extracted with ethyl acetate.
• N-methylmorpholine N-oxide (76.1 mg) and osmium tetroxide (76.1 mg) were added to a mixed solution of the compound (132 mg) obtained in Reference Example 8-8 in tetrahydrofuran (3 mL) and water (1 mL) at room temperature. 2.5% 2-methyl-2-propanol solution, 0.0881 mL) was added, and the mixture was stirred at room temperature for 19 hours.
• a saturated aqueous solution of sodium hydrogen carbonate and a 10% aqueous solution of sodium sulfate were added at 0 ° C, and the mixture was extracted with ethyl acetate.
• Lithium bis (trimethylsilyl) amide (1.0 mol / L tetrahydrofuran solution, 0.157 mL) was added to a solution of the compound (45.9 mg) obtained in Reference Example 41 in tetrahydrofuran (1.3 mL) at 0 ° C., and the mixture was added under argon atmosphere. Stirred at 40 ° C. for 40 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent of the organic layer was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (39.0 mg).
• N, N, N ', N'-tetramethylethylenediamine (0.0308 mL), diisopropylethylamine (0.285 mL), and paratoluenesulfonyl chloride (175 mg) were added, and the mixture was stirred for 4.5 hours.
• Water (5 mL) was added to the reaction solution, and after stirring for 1 hour, a saturated aqueous solution of ammonium chloride (5 mL) and water (10 mL) were added, and the mixture was extracted with ethyl acetate (20 mL).
• Examples 1-2 to 1-53 Using the corresponding compounds of the general formulas (3) and (4), the reaction was carried out in the same manner as in Example 1-1, the method described in Step A-2, or a method analogous thereto. Examples 1-2 to 1-53 were obtained.
• Examples 2-2 to 2-98> Using the corresponding compound of the general formula (2), the corresponding general formula (3) synthesized by reacting in the same manner as in Reference Example 50-1, the method described in Step A-1 or a method analogous thereto was used as a crude product and reacted in the same manner as in Example 1-1 or Example 2-1 or in the method described in Step A-2 or a method analogous thereto, to obtain the following Example 2-2 2-2-98 were obtained.
• Examples 3-2 to 3-3 Using the corresponding compound of the general formula (2b), the reaction was carried out in the same manner as in Example 3-1 or in the manner described in Step H-1 or a method analogous thereto, and the following Examples 3-2 to 3 -3 was obtained.
• Example 1-41 (18.8 mg) was dissolved in tetrahydrofuran (0.400 mL), 1.01 mol / L diisobutylaluminum hydride-toluene solution (0.199 mL) was added, and the mixture was stirred at room temperature for 5 hours. It was left for 14 hours. After dilution with tetrahydrofuran (0.400 mL), water (5 mL), potassium sodium (+)-tartrate (100 mg) and ethyl acetate (5 mL) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. Water (15 mL) and ethyl acetate (15 mL) were added for extraction.
• Examples 4-2 to 4-5> Using the corresponding compound of the general formula (2b), the reaction was carried out in the same manner as in Example 4-1, the method described in Step H-2 or a method analogous thereto, and the following Examples 4-2 to 4 -5 was obtained.
• Example 1-41 The compound (199 mg) obtained in Example 1-41 was suspended in methanol (2.1 mL), a 2 mol / L aqueous sodium hydroxide solution (0.640 mL) was added, and the mixture was stirred at 50 ° C for 2 hours. After evaporating the solvent and the like under reduced pressure, water (2 mL) is added, 1 mol / L hydrochloric acid (1.28 mL) is added, water (6 mL) is added, and the mixture is filtered and dried at 70 ° C under reduced pressure. Thus, the title compound (180.9 mg) was obtained.
• Example 5 Using the corresponding compound of the general formula (2b), the reaction was carried out in the same manner as in Reference Example 53-1, the method described in Step H-3, or a method analogous thereto, to give Example 5 below.
• Examples 6-2 to 6-4> Using the corresponding compound of the general formula (2f), a reaction was carried out in the same manner as in Example 6-1 or in the manner described in Step H-4, or a method analogous thereto, to give the following Examples 6-2 to 6 -4 was obtained.
• Example 6-1 Under an argon atmosphere, the compound (33.9 mg) obtained in Example 6-1 was suspended in dichloromethane (0.750 mL), pyridine (0.0302 mL) and trifluoroacetic anhydride (0.0315 mL) were added, and the mixture was added at room temperature for 7 hours. After stirring for 30 minutes, the mixture was allowed to stand for 15 hours. Dichloromethane (0.750 mL) was added, and the mixture was stirred for 1 hour and 30 minutes. Pyridine (0.0302 mL) and trifluoroacetic anhydride (0.0315 mL) were added, and the mixture was stirred at room temperature for 5 hours and 30 minutes, and then allowed to stand for 17 hours.
• Example 7-2 Using the corresponding compound of the general formula (2e), the reaction was carried out in the same manner as in Example 7-1, the method described in Step H-5, or a method analogous thereto, to obtain the following Example 7-2.
• Example 7-1 the corresponding compound of the general formula (2e)
• the reaction was carried out in the same manner as in Example 7-1, the method described in Step H-5, or a method analogous thereto, to obtain the following Example 7-2.
• Examples 8-2 to 8-4> Using the corresponding compound of the general formula (2f), the reaction was carried out in the same manner as in Example 8-1, the method described in Step H-6, or a method analogous thereto, to give the following Examples 8-2 to 8-8 -4 was obtained.
• Example 9-2 to 9-3> Using the corresponding compound of the general formula (2m), the reaction was carried out in the same manner as in Example 9-1, the method described in Step I-3, or a method analogous thereto, and the following Examples 9-2 to 9 -3 was obtained.
• Examples 10-2 to 10-3> Using the corresponding compound of the general formula (2m), the reaction was carried out in the same manner as in Example 10-1, the method described in Step I-4, or a method analogous thereto, to give the following Examples 10-2 to 10 -3 was obtained.
• Example 12-2> Using the corresponding compound of the general formula (2m), the reaction was carried out in the same manner as in Example 12-1, the method described in Step I-6, or a method analogous thereto, to obtain the following Example 12-2.
• Example 12-2 Using the corresponding compound of the general formula (2m), the reaction was carried out in the same manner as in Example 12-1, the method described in Step I-6, or a method analogous thereto, to obtain the following Example 12-2.
• Example 14 Using the corresponding compound of the general formula (2r), the reaction was carried out in the same manner as in Reference Example 55, the method described in Step J-2, or a method analogous thereto, to thereby convert the following Example 14 into a cis form and a trans form. As a mixture.
• Example 18-2 Using the corresponding compound of the general formula (1f), the reaction was carried out in the same manner as in Example 18-1, the method described in Step X-1, or a method analogous thereto, to obtain the following Example 18-2.
• Example 18-2 Using the corresponding compound of the general formula (1f), the reaction was carried out in the same manner as in Example 18-1, the method described in Step X-1, or a method analogous thereto, to obtain the following Example 18-2.
• Example 18-2 Using the corresponding compound of the general formula (1f), the reaction was carried out in the same manner as in Example 18-1, the method described in Step X-1, or a method analogous thereto, to obtain the following Example 18-2.
• Example 18-1 The compound (19.2 mg) obtained in Example 18-1 was dissolved in N, N-dimethylformamide (0.2 mL), and N, N-diisopropylethylamine (0.00950 mL), 1- [bis (dimethyl Amino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxidehexafluorophosphate (HATU) (17.2 mg) and dimethylamine (2.0 mol / L tetrahydrofuran solution, 0.0283 mL) ) was added and the mixture was stirred at room temperature for 1 hour.
• HATU 1- [bis (dimethyl Amino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxidehexafluorophosphate
• Example 1-22 The compound (30.2 mg) obtained in Example 1-22 was dissolved in methylene chloride (0.6 mL), diisobutylaluminum hydride (1.0 mol / L hexane solution, 0.282 mL) was added at 0 ° C, and the mixture was added under an argon atmosphere. The mixture was stirred at the same temperature for 1 hour. Water (0.5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. Ethyl acetate and anhydrous sodium sulfate were added to the reaction solution, and the mixture was further stirred at room temperature for 30 minutes. The reaction solution was filtered using celite, and the solvent of the filtrate was distilled off under reduced pressure.
• methylene chloride 0.6 mL
• diisobutylaluminum hydride 1.0 mol / L hexane solution, 0.282 mL
• Example 20-2 Using the corresponding compound of the general formula (1f), the reaction was carried out in the same manner as in Example 20-1, the method described in Step X-3, or a method analogous thereto, to obtain the following Example 20-2.
• Example 20-1 the method described in Step X-3, or a method analogous thereto, to obtain the following Example 20-2.
• Step X-3 the method described in Step X-3, or a method analogous thereto, to obtain the following Example 20-2.
• Examples 21-2 to 21-20> Using the corresponding compound of the general formula (26), the reaction was carried out in the same manner as in Example 21-1, the method described in Step U-5, or a method analogous thereto, to give the following Examples 21-2 to 21-21 -20 was obtained.
• Example 24 The corresponding compound of the general formula (1m) was reacted in the same manner as in Reference Example 60, the method described in Step Z-1 or a method analogous thereto, to obtain the following Example 24.
• Example 1-38 The compound (100.0 mg) obtained in Example 1-38 was suspended in ethyl acetate (1.5 mL), and 1 mol / L hydrogen chloride-ethyl acetate (0.30 mL) was added. After stirring at room temperature for 10 minutes, the mixture was collected by filtration and washed with ethyl acetate (1 mL). The obtained product was dried at 50 ° C. under reduced pressure to obtain the title compound (90.4 mg).
• Example 27-2 to 27-10> Using the corresponding compound of the general formula (1), a reaction was carried out in the same manner as in Example 27-1, the method described in Step AK-1 or a method analogous thereto, and the following Examples 27-2 to 27 -10 was obtained.
• DMSO dimethyl sulfoxide
• cell culture medium MEM containing 10% fetal bovine serum
• transfer MRC-5 human fetal lung fibroblasts: ATCC
• ⁇ L was seeded and cultured at 37 ° C. under 5% CO 2 .
• immediately use 625 ⁇ L of the test compound solution prepared immediately before use. was added.
• cDNA was synthesized using a High-Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific).
• HRV14 and 18s rRNA were measured by quantitative real-time PCR using a 7500 Fast Real-time PCR system (Life technologies). The measurement was performed under the conditions of initial denaturation at 95 ° C for 20 seconds, 40 cycles of denaturation at 95 ° C for 3 seconds, and annealing / extension reaction at 60 ° C for 30 seconds.
• the primers used were the HRV14 forward primer shown in SEQ ID NO: 1 and the HRV14 reverse primer shown in SEQ ID NO: 2, and the probe used was the probe shown in SEQ ID NO: 3.
• results at ⁇ 100 ⁇ nmol / L are shown in the following table for each example.
• the inhibition rate was shown as> 80%: +++, 80% ⁇ inhibition rate> 50%: ++, 50% ⁇ inhibition rate: +.
• the compounds of the present invention are useful as therapeutics for picornavirus infections, particularly rhinovirus infections, or as preventives thereof.
• SEQ ID NO: 1 is a sequence of a forward primer that recognizes a complementary DNA sequence of HRV14 RNA.
• SEQ ID NO: 2 is a reverse primer sequence that recognizes a complementary DNA sequence of HRV14 RNA.
• SEQ ID NO: 3 is a sequence of a probe having a fluorescent dye FAM sequence added to its 5 ′ end.

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