Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present disclosure relates to a compound or a pharma- ceutical acceptable salt thereof that can suppress splicing abnormalities that contribute to the onset or progression of a disease.
• RNA splicing is the process of removing introns from transcribed pre-mRNA and splicing exons together. In this process, not only are exons spliced constitutively, but also the recognition of specific exon or intron sequences is controlled at a certain rate depending on the tissue or cell lineage. In addition, even if a region is originally an intron, a splicing control region may be newly created due to gene mutation, resulting in a part of the intron region being recognized as an exon, causing splicing abnormalities. These splicing abnormalities may cause various diseases.
• Fabry disease is a genetic disease, some of which are caused by splicing abnormalities.
• enzyme replacement therapy using recombinant ⁇ -galactosidase A (GLA) enzyme protein has been developed as a treatment for Fabry disease, but there is no treatment that targets the gene itself, which is the underlying cause of the disease.
• Splicing abnormalities are also known to occur in many other genetic diseases, and there is a need to develop new compounds that can suppress splicing abnormalities.
• splicing control compounds e.g., 2-chloro-6-(2-furylmethyl)purine
• diseases caused by splicing abnormalities including cardiac Fabry disease (e.g., Patent Document 1).
• the present disclosure provides a compound or a pharma- ceutical acceptable salt thereof that can suppress splicing abnormalities that contribute to the onset or progression of a disease.
• the present disclosure relates to a compound represented by the following formula (I) or a pharma- ceutically acceptable salt thereof:
• a 1 , A 2 , A 3 and A 4 are each independently CH or N;
• Ar is a 6- to 12-membered aryl group or a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms in the ring selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and the 6- to 12-membered aryl group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more halogen atoms;
• n is 1 or 2;
• R 1 is a halogen atom;
• R2 is a hydrogen atom, a halogen atom, or a C1 - C4 alkoxy group;
• R 3 is a hydrogen atom, a C 3 -C 6 cycloalkyl group, or a 4-6 membered heterocyclyl group having 1
• Group A halogen atom, hydroxy group, C 1 -C 4 alkyl group optionally substituted with halogen atom, C 1 -C 6 hydroxyalkyl group optionally substituted with halogen atom, C 1 -C 2 alkoxy group optionally substituted with halogen atom, C 2 -C 6 alkoxyalkyl group optionally substituted with halogen atom, C 3 -C 6 alkoxyalkoxyalkyl group optionally substituted with halogen atom, C 1 -C 2 alkylsulfonyl group optionally substituted with halogen atom, acetyl group (-C(O)CH 3 ), cyclopropylmethyl group, phenyl group optionally substituted with halogen atom, phenyl-C 1 -C 3 alkyl group optionally substituted with halogen atom, 3- to 5-membered heterocyclyl group having 1 or 2 oxygen atoms, 3- to 5-membered heterocyclyl-C
• the present disclosure relates to a compound represented by the following formula (II) or a pharma- ceutically acceptable salt thereof:
• Ar is a furyl group, a phenyl group, a thienyl group, a pyridyl group, a pyrimidinyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, an isothiazolyl group, or an oxadiazolyl group, the furyl group, the phenyl group, and the pyridyl group being optionally substituted by one fluorine atom;
• R 1 is a halogen atom;
• R 4 , R 5 and R 6 each independently represent a hydrogen atom, a halogen atom, or a methoxy group, and at least two of R 4 , R 5 and R 6 are hydrogen atoms;
• R 3a is a hydrogen atom or any group selected from Group C below.
• R Q1 is a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, an isopropyl group, a fluoroethyl group, a difluoroethyl group, a hydroxyethyl group, a 2-hydroxy-2-methylpropyl group, a methoxyethyl group (-C 2 H 4 OCH 3 ), a methoxyethoxyethyl group (-C 2 H 4 OC 2 H 4 OCH 3 ), a methylsulfonyl group (-S(O) 2 CH 3 ), an acetyl group (-C(O)CH 3 ), a cyclopropylmethyl group, a phenyl group, a benzyl group, an oxetanyl group, an oxetanylmethyl group, a 2-amino-2-oxoethyl group (-CH 2 C(O)NH 2 ), a
• the present disclosure relates to a compound represented by the following formula (III) or a pharma- ceutically acceptable salt thereof:
• Ar is a furyl group or a phenyl group;
• R 1 is a chlorine atom;
• a 2 , A 3 and A 4 each independently represent CH or N, provided that any one of A 2 , A 3 and A 4 represents N;
• R 3b is a hydrogen atom or any group selected from Group D below.
• the present disclosure relates to a compound represented by the following formula (IV) or a pharma- ceutically acceptable salt thereof:
• Ar is a furyl group or a phenyl group;
• R 1 is a chlorine atom;
• R 3c is a hydrogen atom or any group selected from the following Group E.
• Group E R Q1 is a hydrogen atom, a methyl group, an acetyl group, a methylsulfonyl group, a fluoroethyl group, or a hydroxyethyl group;
• R Q5 is a hydrogen atom or a methyl group.
• the present disclosure relates to a compound represented by the following formula (V) or a pharma- ceutically acceptable salt thereof:
• Ar is a furyl group or a phenyl group;
• R 1 is a chlorine atom;
• a 2 , A 3 and A 4 each independently represent CH or N, and any one of A 2 , A 3 and A 4 represents N;
• R 3d is a hydrogen atom or any group selected from the following Group F.
• Group F R Q1 is a hydrogen atom, a methyl group, a fluoroethyl group, or a hydroxyethyl group;
• R Q5 is a hydrogen atom or a methyl group.
• the present disclosure relates to a pharmaceutical composition containing the compound of the present disclosure or a pharma- ceutical acceptable salt thereof as an active ingredient.
• the present disclosure relates to a pharmaceutical composition for treating a genetic disease caused by a splicing defect, comprising the compound of the present disclosure or a pharma- ceutical acceptable salt thereof as an active ingredient.
• the present disclosure relates to a pharmaceutical composition for treating a genetic disease caused by a splicing abnormality, the pharmaceutical composition comprising a compound of the present disclosure or a pharma- ceutical acceptable salt thereof as an active ingredient.
• the present disclosure relates to a method for treating a genetic disease caused by splicing abnormalities, comprising administering to a subject a compound of the present disclosure or a pharma- ceutical acceptable salt thereof.
• the present disclosure relates to the use of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for use in treating a genetic disease caused by a splicing defect.
• the present disclosure provides a compound or a pharma- ceutical acceptable salt thereof that can suppress splicing abnormalities that contribute to the onset or progression of a disease.
• FIG 1 shows a schematic diagram of the GLA splicing reporter vector.
• Normal splicing of exon 4 + exon 5 results in the expression of green fluorescent protein (GFP) as a GST (glutathione S-transferase) fusion protein
• GFP green fluorescent protein
• ⁇ pseudoexon
• RFP red fluorescent protein
• halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom.
• halogen atom may be substituted with a halogen atom
• C 1 -C 4 alkyl group refers to a straight or branched alkyl group having 1 to 4 carbon atoms.
• examples of the C 1 -C 4 alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, and a tert-butyl group.
• the "C 1 -C 4 alkyl group optionally substituted with a halogen atom” may include a group in which 1, 2, or 3 hydrogen atoms of a "C 1 -C 4 alkyl group" are substituted with a halogen atom.
• examples of the "C 1 -C 4 alkyl group optionally substituted with a halogen atom” include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, a difluoroethyl group, a 2,2,2-trifluoroethyl group, and a 1,2-difluoropropyl group.
• C 1 -C 6 hydroxyalkyl group refers to a group in which one or two hydrogen atoms of a straight or branched alkyl group having 1 to 6 carbon atoms are substituted with a hydroxy group.
• examples of the C 1 -C 6 hydroxyalkyl group include a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group, a 1-hydroxyisopropyl group, a 1-hydroxybutyl group, a 2-hydroxybutyl group, a 2-hydroxyisobutyl group, a 1-hydroxypentyl group, a 2-hydroxypentyl group, a 1-hydroxyhexyl group, and a 1,2-hydroxyethyl group.
• a "C 1 -C 4 alkylene group” refers to a straight or branched alkylene group having 1 to 4 carbon atoms.
• examples of the C 1 -C 4 alkylene group include a methylene group, an ethylene group (-(CH 2 ) 2 -), a trimethylene group (-(CH 2 ) 3 -), a tetramethylene group, a methylmethylene group (-CH(CH 3 )-), and a methylethylene group (-CH(CH 3 )CH 2 - and -CH 2 CH(CH 3 )-).
• a "C 2 -C 4 alkylene group (bonded to the same carbon)" can refer to a C 3 -C 5 cycloalkyl group formed when two bonds of a C 2 -C 4 alkylene group are bonded to the same carbon and taken together with the carbon to which they are bonded.
• C 1 -C 4 alkylenedioxy group refers to a straight or branched alkylene group having 1 to 4 carbon atoms and two oxygens (-O-).
• the C 1 -C 4 alkylenedioxy group may include a methylenedioxy group (-O-CH 2 -O-) and an ethylenedioxy group (-O-CH 2 ⁇ CH 2 -O-).
• C 1 -C 4 alkylenedioxy group (bonded to the same carbon) refers to a C 2 -C 4 cycloalkylenedioxy group in which the two bonds of the C 1 -C 4 alkylenedioxy group are bonded to the same carbon and are formed together with the carbons to which they are bonded.
• examples of the C 1 -C 4 alkyleneoxy-C 1 -C 4 alkyl group include a methyleneoxymethyl group (-CH 2 -O-CH 2 -), etc.
• a "C 1 -C 4 alkyleneoxy-C 1 -C 4 alkyl group (bonded to the same carbon)" can be said to be a C 2 -C 4 cycloalkylenedioxy group formed by combining the two bonds of the C 1 -C 4 alkyleneoxy-C 1 -C 4 alkyl group with the carbon to which they are bonded, on the same carbon.
• C 1 -C 4 alkoxy group refers to a group in which an alkyl group having 1 to 4 carbon atoms is bonded to an oxygen atom.
• examples of the C 1 -C 4 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and a t-butoxy group.
• C 1 -C 2 alkoxy group refers to a group in which an alkyl group having 1 to 2 carbon atoms is bonded to an oxygen atom.
• examples of the C 1 -C 2 alkoxy group include a methoxy group (-OCH 3 ) and an ethoxy group.
• the "C 1 -C 2 alkoxy group optionally substituted with a halogen atom” includes a "C 1 -C 2 alkoxy group” in which 1, 2 or 3 hydrogen atoms are substituted with a halogen atom.
• the C 1 -C 2 alkoxy group optionally substituted with a halogen atom includes a fluoromethoxy group, a difluoromethoxy group (-OCHF 2 ), a trifluoromethoxy group, a chloromethoxy group, a dichloromethoxy group, a 1-fluoroethoxy group, a 1-chloroethoxy group, and a 2-fluoroethoxy group.
• C 2 -C 6 alkoxyalkyl group refers to an alkoxyalkyl group having 2 to 6 carbon atoms, in which one hydrogen atom of the alkyl group is substituted with an alkoxy group.
• examples of the C 2 -C 6 alkoxyalkyl group include a C 1 -C 3 alkoxy C 1 -C 3 alkyl group.
• examples of the C 2 -C 6 alkoxyalkyl group include a methoxymethyl group (-CH 2 OCH 3 ), an ethoxymethyl group, an n-propoxymethyl group, an isopropoxymethyl group, a methoxyethyl group (-C 2 H 4 OCH 3 ), an ethoxyethyl group, a propoxyethyl group, and an isopropoxyethyl group.
• the "C 2 -C 6 alkoxyalkyl group optionally substituted with a halogen atom” includes a group in which one, two or three hydrogen atoms of the "C 2 -C 6 alkoxyalkyl group" are substituted with a halogen atom.
• the C 2 -C 6 alkoxyalkyl group optionally substituted with a halogen atom includes a halogenated C 1 -C 3 alkoxy C 1 -C 3 alkyl group.
• the C 2 -C 6 alkoxyalkyl group optionally substituted with a halogen atom includes a fluoromethoxymethyl group, a difluoromethoxymethyl group, a trifluoromethoxymethyl group, a fluoromethoxyethyl group, a difluoromethoxyethyl group, a trifluoromethoxyethyl group, a fluoroethoxyethyl group, a difluoroethoxyethyl group, and a trifluoroethoxyethyl group.
• C 3 -C 6 alkoxyalkoxyalkyl group refers to an alkoxyalkoxyalkyl group having 3 to 6 carbon atoms, in which one hydrogen atom of the alkoxyalkyl group is substituted with an alkoxy group.
• examples of the C 3 -C 6 alkoxyalkoxyalkyl group include a C 1 -C 2 alkoxy C 1 -C 2 alkoxy C 1 -C 2 alkyl group, and the like.
• examples of the C 3 -C 6 alkoxyalkoxyalkyl group include a methoxymethoxymethyl group, a methoxyethoxymethyl group, and a methoxyethoxyethyl group (-C 2 H 4 OC 2 H 4 OCH 3 ).
• the "C 3 -C 6 alkoxyalkoxyalkyl group optionally substituted with a halogen atom” includes a group in which one, two or three hydrogen atoms of the "C 3 -C 6 alkoxyalkoxyalkyl group" are substituted with a halogen atom.
• the C 3 -C 6 alkoxyalkoxyalkyl group optionally substituted with a halogen atom includes a halogenated C 1 -C 2 alkoxy C 1 -C 2 alkoxy C 1 -C 2 alkyl group.
• the C 3 -C 6 alkoxyalkoxyalkyl group optionally substituted with a halogen atom includes a fluoromethoxymethoxymethyl group, a difluoromethoxymethoxymethyl group, a trifluoromethoxymethoxymethyl group, a fluoromethoxyethoxymethyl group, a difluoromethoxyethoxymethyl group, a trifluoromethoxyethoxymethyl group, a fluoromethoxyethoxyethyl group, a difluoromethoxyethoxyethyl group, and a trifluoromethoxyethoxyethyl group.
• C 1 -C 2 alkylsulfonyl group refers to a group in which an alkyl group having 1 to 2 carbon atoms is bonded to the sulfur atom of a sulfonyl group.
• examples of the C 1 -C 2 alkylsulfonyl group include a methylsulfonyl group (-S(O) 2 CH 3 ) and an ethylsulfonyl group.
• the "C 1 -C 2 alkylsulfonyl group optionally substituted with halogen atoms” includes a “C 1 -C 2 alkylsulfonyl group” in which 1, 2 or 3 hydrogen atoms are substituted with halogen atoms.
• the C 1 -C 2 alkylsulfonyl group optionally substituted with halogen atoms includes a fluoromethylsulfonyl group, a difluoromethylsulfonyl group, a trifluoromethylsulfonyl group, a fluoroethylsulfonyl group, a difluoroethylsulfonyl group, and a trifluoroethylsulfonyl group.
• phenyl C 1 -C 3 alkyl group refers to a group in which one hydrogen atom of a phenyl group is substituted with an alkyl group having 1 to 3 carbon atoms.
• examples of the phenyl C 1 -C 3 alkyl group include a benzyl group, a phenylethyl group, and a phenylpropyl group.
• the "phenyl C 1 -C 3 alkyl group optionally substituted with a halogen atom” includes a group in which 1, 2 or 3 hydrogen atoms of the "C 1 -C 3 alkyl group" are substituted with a halogen atom.
• the phenyl C 1 -C 3 alkyl group optionally substituted with a halogen atom includes a fluorobenzyl group, a difluorobenzyl group, a trifluorobenzyl group, a fluorophenylethyl group, a difluorophenylethyl group, a trifluorophenylethyl group, a fluorophenylpropyl group, a diphenylpropyl group, and a trifluorophenylpropyl group.
• aminooxo C 1 -C 3 alkyl group refers to a group in which one hydrogen atom of a C 1 -C 3 alkyl group is replaced with an aminooxo group.
• the aminooxo C 1 -C 3 alkyl group may, for example, be a 2-amino-2-oxoethyl group (-CH 2 C(O)NH 2 ).
• C 2 -C 4 alkynyl group refers to an alkyl group having at least one carbon-carbon triple bond (-C ⁇ C-) in the molecule.
• examples of the C 2 -C 4 alkynyl group include -C ⁇ CH, -C ⁇ CCH 3 , -C ⁇ CCH 2 CH 3 , and a propargyl group (-CH 2 C ⁇ CH).
• a "C 2 -C 4 alkynyl group optionally substituted with a halogen atom” includes a "C 2 -C 4 alkynyl group” in which at least one hydrogen atom is substituted with a halogen atom.
• the C 2 -C 4 alkynyl group optionally substituted with a halogen atom includes -C ⁇ CF, -C ⁇ CCF 3 , -C ⁇ CCH 2 CF 3 , and -CH 2 C ⁇ CF.
• the term "optionally protected C 2 -C 6 (alkoxyalkyl group)" refers to a C 2 -C 6 alkoxyalkyl group in which one hydrogen atom of the C 2 -C 6 alkoxyalkyl group is optionally protected with a protecting group, and a C 2 -C 6 alkoxyalkyl group that is not protected with a protecting group.
• an example of the protecting group is a tert-butoxycarbonyl (Boc) amino group.
• an example of the optionally protected C 2 -C 6 (alkoxyalkyl group) is a tert-butoxycarbonyl-2-aminoethoxyethyl group (-C 2 H 4 OC 2 H 4 NHC(O)O(CH 3 ) 3 ).
• C 1 -C 3 alkylaminocarbonyl group refers to a group in which one hydrogen atom of a C 1 -C 3 alkyl group is replaced with an aminocarbonyl group.
• examples of the C 1 -C 3 alkylaminocarbonyl group include a methylaminocarbonyl group and an ethylaminocarbonyl group (-C(O)NHCH 2 CH 3 ).
• 6- to 12-membered aryl group refers to a monocyclic or polycyclic aromatic hydrocarbon ring system having 6 to 12 carbon atoms.
• the 6- to 12-membered aryl group may be an aromatic hydrocarbon group having 6 to 12 carbon atoms.
• the 6- to 12-membered aryl group may be a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an acenaphthyl group, an azulenyl group, or the like.
• C 3 -C 6 cycloalkyl group refers to a cyclic alkyl group (saturated hydrocarbon group (ring)) having 3 to 6 carbon atoms.
• examples of the C 3 -C 6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
• the term "4- to 6-membered heterocyclyl group” refers to a saturated or unsaturated monocyclic or polycyclic 4- to 6-membered cycloalkyl group having 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms in the ring.
• the 4- to 6-membered heterocyclyl group has one oxygen atom, one sulfur atom, one nitrogen atom, one oxygen atom and one nitrogen atom, one sulfur atom and one nitrogen atom, two oxygen atoms, or two nitrogen atoms.
• the heterocyclyl group includes an oxiranyl group, a thiaarnyl group, an aziridinyl group, an oxetanyl group, a thietanyl group, an azetidinyl group, a tetrahydrofuryl group, a tetrahydrothiophenyl group, a pyrrolidinyl group, a tetrahydropyranyl group, a pyranyl group, a tetrahydrothiopyranyl group, a thiopyranyl group, a piperidinyl group, an imidazolidinyl group, a 1,4-dioxanyl group, a 1,3-dioxolanyl group, a 1,3-dioxolyl group, a 1,4-oxathia ...
• azathianyl group morpholinyl group, thiomorpholinyl group, 1,4-dithianyl group, piperazinyl group, 1,4-azathianyl group, oxepanyl group, thiepanyl group, azepanyl group, isothizolidinyl group, 1,4-dioxepanyl group, 1,4-oxathiepanyl group, 1,4-oxazepanyl group, 1,4-dithiepanyl group, 1,4-thieazepanyl group, 1,4-azaphosphinanyl group, 1,4-diazepanyl group, 1,2-tetrahydrothiazin-2-yl group, 1,3-tetrahydrothiazinyl group, azobenzene-3-yl group, a tetrahydrothiadiazinyl group, a 1,2-tetrahydrodiazin-2-yl group, a 1,3-tetrahydrodiazin-1-
• the 4- to 6-membered heterocyclyl group may have one or two oxo groups ( ⁇ O) on the ring.
• examples of the 4- to 6-membered heterocyclyl group having an oxo group on the ring include a 2-oxooxazolidinyl group, a 2-oxooxazinyl group, a 3-oxomorpholinyl group, a 2-oxoazetidinyl group, a 2-oxopyrrolidinyl group, a 2-oxopiperidinyl group, a 2-oxoimidazolidinyl group, a 2-oxo-1,3-dioxolanyl group, a 2-oxo-1,3-dioxolyl group, a 1,1-dioxo-thietanyl group, a 1,1-dioxo-tetrahydrothiophenyl group, and a 1,1-dioxo-iso
• a "3- to 5-membered heterocyclyl group having one or two oxygen atoms” refers to a saturated or unsaturated monocyclic 3- to 5-membered cycloalkyl group having an oxygen atom as a heteroatom.
• examples of the 3- to 5-membered heterocyclyl group having one or two oxygen atoms include an oxetanyl group, an oxazolyl group, a tetrahydrofuryl group, a furyl group, a tetrahydropyranyl group, a dioxanyl group, and a dioxolanyl group.
• the term "3- to 5-membered heterocyclyl-C 1 -C 3 alkyl group having 1 or 2 oxygen atoms” refers to a group in which one hydrogen atom of a 3- to 5-membered heterocyclyl group having 1 or 2 oxygen atoms as a heteroatom is substituted with a C 1 -C 3 alkyl group.
• examples of the 3- to 5-membered heterocyclyl-C 1 -C 3 alkyl group having 1 or 2 oxygen atoms include an oxetanylmethyl group and an oxadiazolylmethyl group.
• a "5- to 6-membered heteroaryl group” refers to a 5- to 6-membered heteroaryl group having 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms in the ring.
• examples of the 5-membered heteroaryl group include a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, and an oxadiazolyl group.
• examples of the 6-membered heteroaryl group include a diazinylpyridyl group, a pyridyl group, and a pyrimidinyl group.
• the term "5-membered heteroaryl C 1 -C 3 alkyl group” refers to a 5-membered heteroaryl group in which one hydrogen atom is replaced with a C 1 -C 3 alkyl group.
• the 5-membered heteroaryl C 1 -C 3 alkyl group may be an oxadiazolylmethyl group.
• a 1 is N or CH, and 0 or 1 of A 2 , A 3 and A 4 are N and 2 or 3 are CH. In one or more embodiments, A 1 is N and A 2 , A 3 and A 4 are CH; A 1 is N and any one of A 2 , A 3 and A 4 is N; A 1 , A 2 , A 3 and A 4 are all CH; or A 1 is CH and any one of A 2 , A 3 and A 4 is N.
• Ar is a phenyl group which may be substituted with one halogen atom, or a 5- to 6-membered heteroaryl group which may be substituted with one halogen atom.
• examples of the 5-membered heteroaryl group include a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, and an oxadiazolyl group.
• examples of the 6-membered heteroaryl group include a pyridyl group and a pyrimidyl group.
• examples of Ar include a phenyl group, a fluorophenyl group, a furyl group, a fluorofuryl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an oxadiazolyl group, a pyridyl group, a fluoropyridyl group, and a pyrimidyl group.
• R 1 is a chlorine atom or a bromine atom.
• R 2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C 1 -C 2 alkoxy group.
• the heterocyclyl group in R3 has one oxygen atom, one sulfur atom, one nitrogen atom, one oxygen atom and one nitrogen atom, one sulfur atom and one nitrogen atom, two oxygen atoms, or two nitrogen atoms.
• examples of the heterocyclyl group for R3 include an oxetanyl group, a tetrahydrofuryl group, a furyl group, a tetrahydropyranyl group, a dioxolanyl group, and a dioxanyl group.
• examples of the heterocyclyl group having an oxo group on the ring include, in one or more embodiments, a 2-oxooxazolidinyl group, a 2-oxooxazinyl group, a 3-oxomorpholinyl group, a 2-oxoazetidinyl group, a 2-oxopyrrolidinyl group, a 2-oxopiperidinyl group, a 2-oxoimidazolidinyl group, a 2-oxo-1,3-dioxolanyl group, a 2-oxo-1,3-dioxolyl group, a 1,1-dioxo-thietanyl group, a 1,1-dioxo-tetrahydrothiophenyl group, and a 1,1-dioxo-isothizolidinyl group.
• examples of the heterocyclyl group not having an oxo group as a substituent on the ring for R3 include an oxazolyl group, an azetidinyl group, a pyrrolidinyl group, a dioxolanyl group, a dioxanyl group, a tetrahydrofuryl group, a pyranyl group, a furyl group, and an oxetanyl group.
• the substituent of R 3 is selected from Group B below.
• Group B a fluorine atom; a hydroxy group; a methyl group, an ethyl group, an isopropyl group; a fluoroethyl group, a difluoroethyl group, a trifluoromethyl group; a hydroxyethyl group, a 2-hydroxy-2-methylpropyl group; a methoxy group (-OCH 3 ), a difluoromethoxy group (-OCHF 2 ); a methoxymethyl group (-CH 2 OCH 3 ), a methoxyethyl group (-C 2 H 4 OCH 3 ); a methoxyethoxyethyl group (-C 2 H 4 OC 2 H 4 OCH 3 ); a methylsulfonyl group (-S(O) 2 CH 3 ); an acetyl group (-C(O)CH 3 ); a cyclopropyl
• suitable examples of the compound represented by formula (I) in one or more embodiments include compounds represented by formula (II), (III), (IV) or (V) or pharma- ceutically acceptable salts thereof.
• Ar is a furyl group, a phenyl group, a thienyl group, a pyridyl group, a pyrimidinyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, an isothiazolyl group, or an oxadiazolyl group, the furyl group, the phenyl group, and the pyridyl group being optionally substituted by one fluorine atom;
• R 1 is a halogen atom;
• R 4 , R 5 and R 6 each independently represent a hydrogen atom, a halogen atom, or a methoxy group, and at least two of R 4 , R 5 and R 6 are hydrogen atoms;
• R 3a is a hydrogen atom or any group selected
• R Q1 is a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, an isopropyl group, a fluoroethyl group, a difluoroethyl group, a hydroxyethyl group, a 2-hydroxy-2-methylpropyl group, a methoxyethyl group (-C 2 H 4 OCH 3 ), a methoxyethoxyethyl group (-C 2 H 4 OC 2 H 4 OCH 3 ), a methylsulfonyl group (-S(O) 2 CH 3 ), an acetyl group (-C(O)CH 3 ), a cyclopropylmethyl group, a phenyl group, a benzyl group, an oxetanyl group, an oxetanylmethyl group, a 2-amino-2-oxoethyl group (-CH 2 C(O)NH 2 ), a
• the present disclosure relates to a compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof.
• Ar is a furyl group or a phenyl group;
• R 1 is a chlorine atom;
• R 3c is a hydrogen atom or any group selected from the following Group E.
• Group E R Q1 is a hydrogen atom, a methyl group, an acetyl group, a methylsulfonyl group, a fluoroethyl group, or a hydroxyethyl group;
• R Q5 is a hydrogen atom or a methyl group.
• the present disclosure relates to a compound represented by formula (V) or a pharma- ceutically acceptable salt thereof.
• Ar is a furyl group or a phenyl group;
• a 2 , A 3 and A 4 each independently represent CH or N, and any one of A 2 , A 3 and A 4 represents N;
• R 1 is a chlorine atom;
• R 3d is a hydrogen atom or any group selected from the following Group F.
• Group F R Q1 is a hydrogen atom, a methyl group, a fluoroethyl group, or a hydroxyethyl group;
• R Q5 is a hydrogen atom or a methyl group.
• A2 and A3 are CH and A4 is N.
• R3d is the following group.
• the compound of the present disclosure is preferably any one compound selected from the following group or a pharma- ceutically acceptable salt thereof.
• 2-chloro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine 2-chloro-N-(furan-2-ylmethyl)-8-methoxyquinolin-4-amine, 2-chloro-7-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine, 2-chloro-5-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine, 2-bromo-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[3,4-d]pyrimidin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[
• the term "pharmaceutical acceptable salt” refers to a salt that can be used as a medicine, and in one or more embodiments, includes basic salts or acid salts.
• the "basic salt” include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as magnesium salts and calcium salts; organic base salts such as N-methylmorpholine salts, triethylamine salts, tributylamine salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidine salts, pyridine salts, 4-pyrrolidinopyridine salts, and picoline salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, and aspartic acid salts, and the like, with alkali metal salts being preferred
• Examples of the "acid salt” in one or more embodiments include hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkane sulfonate salts such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonate salts such as benzenesulfonate and p-toluenesulfonate, organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and maleate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate, and the like are preferably hydrohalide salts (particularly hydrochloride
• salts of the compounds of the present disclosure may include hydrates.
• salts of compounds may also include solvates that may be formed when the compounds absorb other types of solvents.
• the compounds disclosed herein, their pharma- ceutically acceptable salts, or solvates thereof may exist in various isomers, such as geometric isomers such as cis- and trans-isomers, tautomers, rotational isomers, or optical isomers (enantiomers) such as d- and l-isomers, and diastereomers, depending on the types and combinations of substituents.
• the compounds disclosed herein include all such isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio. Mixtures of these isomers can be separated by known resolution means.
• the compounds of the present disclosure also include labeled compounds, that is, compounds in which one or more atoms of the compound are substituted with an isotope (eg, 2 H, 3 H, 13 C, 14 C, 35 S, etc.).
• labeled compounds that is, compounds in which one or more atoms of the compound are substituted with an isotope (eg, 2 H, 3 H, 13 C, 14 C, 35 S, etc.).
• a prodrug is a compound having a group that can be converted to an amino group, hydroxyl group, carboxyl group, etc. of a compound by hydrolysis or under physiological conditions, and groups that form such prodrugs are groups described in Prog. Med., Vol. 5, pp. 2157-2161, 1985, etc.
• Prodrugs include, when an amino group is present in the compound represented by formula (I), (II), (III), (IV) or (V), compounds in which the amino group has been acylated, alkylated or phosphorylated (e.g., compounds in which the amino group has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated, etc.); and, when a hydroxy group is present in the compound represented by formula (I), (II), (III), (IV) or (V), compounds in which the hydroxy group has been acylated, alkylated, phosphorylated or borated (e.g., compounds in which the hydroxy group has been acetylated, palmitoy
• the carboxy group when a carboxy group is present in the compound represented by formula (I), (II), (III), (IV) or (V), the carboxy group may be esterified or amidated (for example, the carboxy group may be ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, or methylamidated).
• Each compound in Methods A to N below can be isolated and purified as a non-solvate, a salt thereof, or various solvates such as a hydrate.
• the salts can be produced by conventional methods.
• examples of the salt include hydrochloride or sulfate salts, organic amine salts, sodium salts, or potassium salts.
• the solvent used in the reactions in each step of the following Methods A to N is not particularly limited as long as it does not inhibit the reaction and partially dissolves the starting materials.
• examples of the solvent include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, nitriles, carboxylic acids, alcohols, amides, sulfoxides, water, and mixtures thereof.
• Aliphatic hydrocarbons in one or more embodiments, include n-hexane, n-pentane, petroleum ether, cyclohexane, and the like.
• Aromatic hydrocarbons include benzene, toluene, xylene, and the like.
• halogenated hydrocarbons include dichloromethane (DCM, methylene chloride), chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene.
• examples of the ethers include diethyl ether, diisopropyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, and diethylene glycol dimethyl ether.
• examples of the ketones include acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone.
• examples of the esters include ethyl acetate, propyl acetate, and butyl acetate.
• examples of the nitriles include acetonitrile, propionitrile, butyronitrile, and isobutyronitrile.
• the carboxylic acids include acetic acid, propionic acid, and the like.
• examples of the alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol.
• the amides include formamide, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidone (NMP), and hexamethylphosphorotriamide.
• the sulfoxides include dimethyl sulfoxide (DMSO) and tetrahydrothiophene-1,1-dioxide.
• the base used in the reactions in the steps of the following Methods A to N is not particularly limited as long as it does not inhibit the reaction.
• examples of the base include alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal hydrides, alkali metal amides, alkali metal alkoxides, and organic amines.
• examples of the alkali metal carbonate include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate.
• examples of the alkali metal hydrogen carbonate include lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate.
• examples of the alkali metal hydroxide include lithium hydroxide, sodium hydroxide, and potassium hydroxide. In one or a plurality of embodiments, examples of the alkaline earth metal hydroxide include calcium hydroxide and barium hydroxide. In one or more embodiments, examples of the alkali metal hydride include lithium hydride, sodium hydride, and potassium hydride. In one or more embodiments, examples of the alkali metal amide include lithium amide, sodium amide, and potassium amide.
• examples of the organic amine include triethylamine (TEA), tributylamine, N,N-diisopropylethylamine (DIPEA), 1-methylpiperidine, 4-methylmorpholine, 4-ethylmorpholine, pyridine, picoline, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, 2,6-di-tert-butyl-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), and imidazole.
• TAA triethylamine
• DIPEA N,N-diisopropylethylamine
• 1-methylpiperidine 4-methylmorpholine
• Method A is an example of a method for producing a compound represented by formula (II).
• Method A includes the following steps A-1 or A-2, and A-3 to A-7 or A-8.
• Ar, A4 , and R2 are the same as in formula (II) above
• R3a ' is -( CH2 ) n - R3a
• R3a and n are the same as in formula (II) above.
• Step A-1 is a step of obtaining intermediate A-III from intermediate AI.
• the reaction conditions for step A-1 are as follows. [Reaction conditions] Solvent: Acetic acid Reaction temperature: Room temperature to 150°C Reaction time: 30 minutes to 24 hours
• Step A-2 is a step of obtaining intermediate A-II from intermediate AI.
• the reaction conditions for step A-2 are as follows. [Reaction conditions] Solvent: tetrahydrofuran Condensing agent: 1,1'-carbonyldiimidazole Reaction temperature: 0°C to 80°C Reaction time: 30 minutes to 24 hours (3)
• Step A-3 is a step of obtaining intermediate A-III from intermediate A-II. Step A-3 can be carried out, for example, under the following reaction conditions a or b.
• Solvent dichloromethane Reaction temperature: 0°C to 40°C Reaction time: 30 minutes to 24 hours (6)
• Step A-7 is a step for obtaining a compound represented by formula (II) from intermediate A-VI.
• Solvent dimethylformamide Base: potassium carbonate Reaction temperature: room temperature to 100°C Reaction time: 30 minutes to 24 hours
• Step B-1 is a step of obtaining intermediate B-II from intermediate BI.
• the reaction conditions for step B-1 are as follows.
• Protecting reagent tert-butyldimethylsilyl trifluoromethanesulfonate
• Solvent dichloromethane Base: 2,6-lutidine Reaction temperature: 0° C.
• Step B-2 is a step of obtaining intermediate B-III from intermediate B-II.
• the reaction conditions for step B-2 are as follows. [Reaction conditions] Solvent: acetonitrile Base: triethylamine Reaction temperature: room temperature to 80°C (3) Step B-3 is a step of deprotecting intermediate B-III to obtain intermediate B-IV.
• the reaction conditions for step B-3 are as follows. [Reaction conditions] Reagent: Tetrabutylammonium fluoride Solvent: Tetrahydrofuran Reaction temperature: 0°C to 80°C Reaction time: 30 minutes to 24 hours
• Step C-1 is a step of obtaining intermediate C-II from intermediate CI.
• the reaction conditions for step C-1 are as follows.
• Step C-2 is a step of obtaining a compound represented by formula (II) from intermediate C-II.
• the reaction conditions for Step C-2 are as follows.
• Method D is an example of a method for producing a compound represented by formula (IV).
• Ar and R2 are the same as in formula (IV) above
• R3c ' is -( CH2 ) n - R3c
• R3c and n are the same as in formula (IV) above.
• X is a halogen atom such as a chlorine atom.
• Step D-1 is a step of obtaining intermediate D-II from intermediate DI.
• the reaction conditions for step D-1 are as follows.
• Step D-2 is a step of obtaining intermediate D-III from intermediate D-II.
• the reaction conditions for step D-2 are as follows.
• Solvent N-methylpyrrolidone Base: N,N-diisopropylethylamine Reaction temperature: room temperature to 120°C Reaction time: 30 minutes to 24 hours
• Step D-3 is a step of obtaining a compound represented by formula (IV) from intermediate D-III.
• the reaction conditions for Step D-3 are as follows.
• Step D-4 is a step of obtaining a compound represented by formula (IV) from intermediate D-III.
• the reaction conditions for Step D-4 are as follows.
• Step E-1 is a step of obtaining intermediate E-II from intermediate EI.
• the reaction conditions for step E-1 are as follows.
• Base N,N-diethylaniline Reaction temperature: room temperature to 120°C
• Step E-2 is a step of obtaining intermediate E-III from intermediate E-II.
• the reaction conditions for step E-2 are as follows.
• Solvent acetonitrile
• Base triethylamine Reaction temperature: room temperature to 80°C Reaction time: 30 minutes to 24 hours
• Method F is an example of a method for producing a compound represented by formula (V).
• Ar is the same as in formula (V) above
• R 3d' is -(CH 2 ) n -R 3d
• R 3d and n are the same as in formula (V) above.
• Step F-1 is a step of obtaining intermediate F-II from intermediate FI.
• the reaction conditions for step F-1 are as follows.
• Step F-2 is a step of obtaining a compound represented by formula (V) from intermediate F-II.
• the reaction conditions for step F-2 are as follows.
• Step G-1 is a step of obtaining intermediate G-II from intermediate GI.
• the reaction conditions for step G-1 are as follows.
• Solvent Tetrahydrofuran Reaction reagent: Triphosgene Reaction temperature: 0°C to 80°C Reaction time: 30 minutes to 24 hours
• Step G-2 is a step of obtaining intermediate G-III from intermediate G-II.
• the reaction conditions for step G-2 are as follows.
• Step G-3 is a step of obtaining intermediate G-IV from intermediate G-III.
• the reaction conditions for step G-3 are as follows.
• Step G-4 is a step of obtaining intermediate GV from intermediate G-IV.
• the reaction conditions for step G-4 are as follows.
• Step G-5 is a step of obtaining intermediate G-VI from intermediate GV.
• the reaction conditions for step G-5 are as follows.
• Step G-6 is a step of obtaining intermediate G-VII from intermediate G-VI.
• the reaction conditions for step G-6 are as follows.
• Step H-1 is a step of obtaining an intermediate HI from an intermediate HI.
• the reaction conditions for Step H-1 are as follows.
• Base N,N-diisopropylethylamine Reaction temperature: room temperature to 120°C Reaction time: 30 minutes to 24 hours
• Step H-2 is a step of obtaining intermediate H-III from intermediate H-II.
• the reaction conditions for step H-2 are as follows.
• Solvent Acetonitrile Base: Triethylamine Reaction temperature: Room temperature to 80°C Reaction time: 30 minutes to 24 hours
• Step I is an example of a method for producing a compound represented by formula (I).
• Ar, A 1 , A 2 and A 4 are the same as those in formula (I) above
• R 3' is -(CH 2 ) n -R 3
• R 3 and n are the same as those in formula (I) above.
• Step I-1 is a step of obtaining a compound represented by formula (I) from intermediate II.
• the reaction conditions for step I-1 are as follows. [Reaction conditions] Solvent: Tetrahydrofuran Base: Sodium hydride Reaction temperature: Room temperature to 80°C Reaction time: 30 minutes to 24 hours
• Step J-1 is a step of obtaining intermediate J-II from intermediate J-I.
• the reaction conditions for step J-1 are as follows.
• Solvent dimethyl sulfoxide
• Reaction reagent hydrogen peroxide
• Base potassium carbonate
• Reaction temperature 0°C to 80°C
• Reaction time 30 minutes to 24 hours
• Step J-2 is a step of obtaining intermediate J-III from intermediate J-II.
• the reaction conditions for step J-2 are as follows.
• Steps J-3_1) and 2) are steps for obtaining intermediate J-IV from intermediate J-III.
• Step J-3_1) can be carried out, for example, under the following reaction condition 1).
• Step J-3_2) can be carried out, for example, under the following reaction condition 2).
• Step K is an example of a method for producing a compound represented by formula (III).
• Ar is the same as in formula (III) above
• R 3b' is -(CH 2 ) n -R 3b
• R 3b and n are the same as in formula (III) above.
• Step K-1 is a step of obtaining intermediate K-II from intermediate KI.
• the reaction conditions for step K-1 are as follows.
• Solvent Tetrahydrofuran Base: Sodium hydride Reaction temperature: 0°C to 80°C Reaction time: 30 minutes to 24 hours
• Step K-2 is a step of obtaining intermediate K-III from intermediate K-II.
• the reaction conditions for step K-2 are as follows.
• Step K-3 is a step of obtaining intermediate K-IV from intermediate K-III.
• the reaction conditions for step K-3 are as follows.
• Steps K-4_1) and 2) are steps for obtaining a compound represented by formula (III) from intermediate KI.
• Step K-4_1) can be carried out, for example, under the following reaction condition 1).
• Step K-4_2) can be carried out, for example, under the following reaction condition 2).
• reaction conditions 1 Base: N,N-diisopropylethylamine Reaction temperature: room temperature to 120°C Reaction time: 30 minutes to 24 hours
• reaction condition 2 Solvent: tetrahydrofuran
• Base N,N-diisopropylethylamine Reaction temperature: room temperature to 80°C Reaction time: 30 minutes to 24 hours
• Step L is an example of a method for producing an intermediate of the compound represented by formula (III). Ar in the following intermediate is the same as in formula (III) above.
• Step L-1 is a step of obtaining intermediate L-II from intermediate LI.
• the reaction conditions for step L-1 are as follows. [Reaction conditions] Solvent: tetrahydrofuran Base: N,N-diisopropylethylamine Reaction temperature: room temperature to 80°C Reaction time: 30 minutes to 24 hours
• Step M is an example of a method for producing a compound represented by formula (V).
• Ar is the same as in formula (V) above
• R 3d' is -(CH 2 ) n -R 3d
• R 3d and n are the same as in formula (V) above.
• Step M-1 is a step of obtaining intermediate M-II from intermediate MI.
• the reaction conditions for step M-1 are as follows.
• Solvent Acetic anhydride base: Pyridine Reaction temperature: Room temperature to 100°C Reaction time: 30 minutes to 24 hours
• Step M-2 is a step of obtaining intermediate M-III from intermediate M-II.
• the reaction conditions for step M-2 are as follows.
• Step M-3 is a step of obtaining intermediate M-IV from intermediate M-III.
• the reaction conditions for step M-3 are as follows.
• Step M-4 is a step of obtaining intermediate MV from intermediate M-IV.
• the reaction conditions for step M-4 are as follows.
• Step M-5 is a step of obtaining a compound represented by formula (V) from intermediate MV.
• the reaction conditions for step M-5 are as follows.
• Step N is an example of a method for producing a compound represented by formula (I').
• a compound represented by formula (I') is an example of a compound represented by formula (I).
• Ar, A 1 , A 2 , A 3 and A 4 are the same as those in formula (I) above
• R Q1 is the same as those in formula (II) above
• W is an oxygen atom, -NH- or -CH-.
• Step N-1 is a step of obtaining a compound represented by formula (I') from intermediate NI.
• the reaction conditions for step N-1 are as follows. [Reaction conditions] Solvent: tetrahydrofuran, dimethylformamide Base: potassium tert-butoxide Reaction temperature: 0°C to 80°C Reaction time: 30 minutes to 24 hours
• the compound disclosed herein or a pharma- ceutically acceptable salt thereof has an effect of suppressing splicing abnormalities that contribute to the onset or progression of genetic diseases. In one or more embodiments, the compound disclosed herein or a pharma- ceutically acceptable salt thereof can be used to treat genetic diseases caused by splicing abnormalities.
• genetic diseases caused by splicing abnormalities include genetic diseases caused by splicing abnormalities due to exon skipping mutations, genetic diseases caused by splicing abnormalities due to splice site selection, genetic diseases caused by splicing abnormalities due to intron retention, and genetic diseases caused by splicing abnormalities due to pseudoexon.
• An exon skipping mutation refers to a splicing mutation in which an exon that is normally recognized is no longer recognized (skipping occurs) due to a mutation in the exon or surrounding intron sequence.
• a splice site selection mutation refers to a splicing mutation in which multiple 5' splice sites or 3' splice sites are generated due to a mutation in a splicing regulatory sequence in an exon region or intron region.
• An intron retention mutation refers to a splicing mutation in which recognition of the intron region is incomplete due to a mutation in the exon or intron region around the 5' splice site or 3' splice site, inducing intron retention.
• a pseudoexonic mutation is a splicing mutation in which a sequence that is normally an intron region is recognized as an exon due to a mutation.
• Fabry disease is a disease in which glycolipids such as globotriaosylceramide (Gb3) accumulate in the lysosomes of cells due to a deficiency in GLA enzyme, a lysosomal hydrolase, resulting in a variety of symptoms related to various organs, such as the circulatory system, including the heart, and the kidneys.
• Gb3 glycolipids
• GLA enzyme globotriaosylceramide
• a lysosomal hydrolase resulting in a variety of symptoms related to various organs, such as the circulatory system, including the heart, and the kidneys.
• IVS4+919G>A mutation a single base substitution in the fourth intron of the ⁇ -galactosidase (GLA) gene.
• GLA ⁇ -galactosidase
• the IVS4+919G>A mutation causes alternative splicing in the transcription of the GLA gene, resulting in a deficiency of the GLA enzyme in lysosomes. It has been reported that many cardiovascular abnormalities have been confirmed in adult Taiwanese people who have this IVS4+919G>A mutation.
• the abnormal splicing that contributes to Fabry disease is due to a mutation in the spliced gene, and in one or more further embodiments, is splicing that occurs in the pre-mRNA of a mutant GLA gene having the IVS4+919G>A mutation (pseudoexon type splicing abnormality).
• compositions in another aspect, relates to a pharmaceutical composition comprising the compound of the present disclosure or a pharma- ceutical acceptable salt thereof as an active ingredient.
• the pharmaceutical composition of the present disclosure can be used to treat a genetic disease caused by a splicing defect.
• the present disclosure relates to a pharmaceutical composition for treating a genetic disease caused by a splicing defect, comprising the compound of the present disclosure or a pharma- ceutical acceptable salt thereof as an active ingredient.
• the present disclosure relates to a pharmaceutical composition for treating a genetic disease caused by splicing abnormality, the pharmaceutical composition comprising, as an active ingredient, a compound represented by formula (I), (II), (III), (IV) or (V) or a pharma- ceutical acceptable salt thereof.
• the pharmaceutical composition of the present disclosure comprises a compound or a pharma- ceutical acceptable salt of the present disclosure, and may further comprise a pharma- ceutical acceptable carrier, preservative, diluent, excipient, or other pharma- ceutical acceptable ingredient.
• the content of the compound of the present disclosure or a pharma- ceutical acceptable salt thereof, which is the active ingredient can be determined as appropriate depending on the dosage form, administration method, carrier, etc.
• the pharmaceutical composition of the present disclosure can be produced according to conventional methods by adding the compound of the present disclosure in a ratio of 0.01 to 100% (w/w) or 0.1 to 95% (w/w) relative to the total amount of the formulation.
• the pharmaceutical composition of the present disclosure can be made into a dosage form suitable for the administration mode by applying well-known formulation techniques.
• the administration mode can be oral administration, parenteral administration, etc.
• formulations for oral administration can be in the form of tablets, capsules, granules, powders, pills, lozenges, syrups, liquids (e.g., solutions, suspensions), etc.
• formulations for parenteral administration can be in the form of injections, aerosols, etc.
• these formulations can be manufactured by well-known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavorings, diluents, etc.
• the excipient may be starch such as starch, potato starch, or corn starch, lactose, crystalline cellulose, or calcium hydrogen phosphate.
• the lubricant may be ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, or paraffin.
• the binder may be polyvinylpyrrolidone, macrogol, or a compound similar to the excipient.
• the disintegrant may be a compound similar to the excipient, or a chemically modified starch or cellulose such as croscarmellose sodium, sodium carboxymethyl starch, or cross-linked polyvinylpyrrolidone.
• the stabilizer may be paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
• the flavoring agent may be a commonly used sweetener, acidulant, fragrance, etc.
• a solvent such as ethanol, phenol, chlorocresol, purified water, or distilled water can be used to prepare a liquid preparation for oral administration, and a surfactant, preservative, isotonicity agent, pH adjuster, or emulsifier can also be used as necessary.
• the liquid preparation for oral administration may further contain a solubilizer, a wetting agent, a suspending agent, a sweetener, a flavoring agent, a fragrance, or a preservative.
• the injection for parenteral administration may be a sterile aqueous or non-aqueous solution, suspension, or emulsion.
• the aqueous solvent for the injection may be distilled water or physiological saline.
• the non-aqueous solvent for the injection may be vegetable oil, alcohol, or polysorbate 80 (pharmacopoeia name). Examples of vegetable oil include propylene glycol, polyethylene glycol, olive oil, and the like. Examples of alcohol include ethanol, and the like.
• the injection may further contain an isotonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, or a solubilizing agent.
• these preparations may be sterilized by filtration through a bacteria-retaining filter, by blending with a bactericide, or by irradiation.
• a composition obtained by dissolving or suspending a sterile solid composition in sterile water or an injection solvent before use may be used as these preparations.
• the method of use of the pharmaceutical composition according to the present disclosure may vary depending on symptoms, age, administration method, etc.
• the method of use may be intermittently or continuously administered orally, transdermally, submucosally, subcutaneously, intramuscularly, intravascularly, intracerebrally, or intraperitoneally so that the concentration of the compound as the active ingredient in the body is anywhere between 100 pM and 1 mM.
• Non-limiting embodiments include, in the case of oral administration, administering to a subject (an adult human) 0.01 mg/kg to 2000 mg/kg of body weight, 0.1 mg/kg to 500 mg/kg of body weight, or 0.1 mg/kg to 100 mg/kg of body weight per day, calculated as the compound represented by formula (I), once or in multiple divided doses depending on symptoms.
• Non-limiting examples of intravenous administration include administering 0.001 mg/kg to 50 mg/kg of body weight, or 0.01 mg/kg to 50 mg/kg of body weight, to a subject (an adult human) per day in one or more divided doses depending on symptoms.
• the present disclosure relates to a method for treating a genetic disease caused by a splicing defect, comprising administering to a subject a compound of the present disclosure or a pharma- ceutically acceptable salt thereof.
• the present disclosure relates to the use of a compound of the present disclosure or a pharma- ceutical acceptable salt thereof in the manufacture of a pharmaceutical composition for use in treating a genetic disease caused by a splicing defect.
• a compound represented by the following formula (I) or a pharma- ceutically acceptable salt thereof In formula (I), A 1 , A 2 , A 3 and A 4 are each independently CH or N; Ar is a 6- to 12-membered aryl group or a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms in the ring selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and the 6- to 12-membered aryl group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more halogen atoms; n is 1 or 2; R 1 is a halogen atom; R2 is a hydrogen atom, a halogen atom, or a C1 - C4 alkoxy group; R 3 is a hydrogen atom, a C 3 -C 6 cycloalkyl group, or a 4-6 membered hetero
• Group A Halogen atoms, Hydroxy groups, a C 1 -C 4 alkyl group optionally substituted by a halogen atom; a C 1 -C 6 hydroxyalkyl group optionally substituted by a halogen atom; a C 1 -C 2 alkoxy group optionally substituted by a halogen atom; a C 2 -C 6 alkoxyalkyl group optionally substituted by a halogen atom; a C 3 -C 6 alkoxyalkoxyalkyl group optionally substituted by a halogen atom; a C 1 -C 2 alkylsulfonyl group optionally substituted by a halogen atom; acetyl group (-C(O)CH 3 ), cyclopropylmethyl group, a phenyl group optionally substituted by a halogen atom; a phenyl C 1 -C 3 alkyl group optionally substituted by a halogen atom;
• [5] The compound or a pharma- ceutically acceptable salt thereof according to any one of [1] to [4], wherein the halogen atom is fluorine or chlorine.
• [6] The compound according to any one of [1] to [5], or a pharma- ceutically acceptable salt thereof, wherein R1 is a chlorine atom or a bromine atom.
• R 2 is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, and a C 1 -C 2 alkoxy group, or a pharma- ceutically acceptable salt thereof.
• the heterocyclyl group has one oxygen atom, one sulfur atom, one nitrogen atom, one oxygen atom and one nitrogen atom, one sulfur atom and one nitrogen atom, two oxygen atoms, or two nitrogen atoms.
• the heterocyclyl group is selected from the group consisting of an oxetanyl group, a tetrahydrofuryl group, a furyl group, a tetrahydropyranyl group, a dioxolanyl group, and a dioxanyl group.
• the heterocyclyl group having an oxo group on the ring is selected from the group consisting of a 2-oxooxazolidinyl group, a 2-oxooxazinyl group, a 3-oxomorpholinyl group, a 2-oxoazetidinyl group, a 2-oxopyrrolidinyl group, a 2-oxopiperidinyl group, a 2-oxoimidazolidinyl group, a 2-oxo-1,3-dioxolanyl group, a 2-oxo-1,3-dioxolyl group, a 1,1-dioxo-thietanyl group, a 1,1-dioxo-tetrahydrothiophenyl group, and a 1,1-dioxo-isothizolidin
• the heterocyclyl group not having an oxo group as a substituent on the ring is selected from the group consisting of an oxazolyl group, an azetidinyl group, a pyrrolidinyl group, a dioxolanyl group, a dioxanyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a furyl group, and an oxetanyl group, or a pharma- ceutically acceptable salt thereof.
• Ar is a furyl group, a phenyl group, a thienyl group, a pyridyl group, a pyrimidinyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, an isothiazolyl group, or an oxadiazolyl group, the furyl group, the phenyl group, and the pyridyl group being optionally substituted by one fluorine atom;
• R 1 is a halogen atom;
• R 4 , R 5 and R 6 each independently represent a hydrogen atom, a halogen atom, or a methoxy group, and at least two of R 4 , R 5 and R 6 are hydrogen atoms;
• R 3a is a hydrogen atom or any group selected from Group C below.
• R Q1 is a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, an isopropyl group, a fluoroethyl group, a difluoroethyl group, a hydroxyethyl group, a 2-hydroxy-2-methylpropyl group, a methoxyethyl group (-C 2 H 4 OCH 3 ), a methoxyethoxyethyl group (-C 2 H 4 OC 2 H 4 OCH 3 ), a methylsulfonyl group (-S(O) 2 CH 3 ), an acetyl group (-C(O)CH 3 ), a cyclopropylmethyl group, a phenyl group, a benzyl group, an oxetanyl group, an oxetanylmethyl group, a 2-amino-2-oxoethyl group (-CH 2 C(O)NH 2 ), a
• a compound represented by the following formula (III) or a pharma- ceutically acceptable salt thereof In formula (III), Ar is a furyl group or a phenyl group; R 1 is a chlorine atom; A 2 , A 3 and A 4 each independently represent CH or N, provided that any one of A 2 , A 3 and A 4 represents N; R 3b is a hydrogen atom or any group selected from Group D below. Group D: [14] A compound represented by the following formula (IV) or a pharma- ceutically acceptable salt thereof: In formula (IV), Ar is a furyl group or a phenyl group; R 1 is a chlorine atom; R 3c is a hydrogen atom or any group selected from the following Group E.
• R Q1 is a hydrogen atom, a methyl group, a methylsulfonyl group (-S(O) 2 CH 3 ), an acetyl group (-C(O)CH 3 ), a fluoroethyl group, or a hydroxyethyl group
• R Q5 is a hydrogen atom or a methyl group.
• a compound represented by the following formula (V) or a pharma- ceutically acceptable salt thereof is a furyl group or a phenyl group; R 1 is a chlorine atom; A 2 , A 3 and A 4 each independently represent CH or N, and any one of A 2 , A 3 and A 4 represents N; R 3d is a hydrogen atom or any group selected from the following Group F.
• Group F R Q1 is a hydrogen atom, a methyl group, a fluoroethyl group, or a hydroxyethyl group; R Q5 is a hydrogen atom or a methyl group.
• a pharmaceutical composition comprising the compound according to any one of [1] to [16] or a pharma- ceutically acceptable salt thereof as an active ingredient.
• a pharmaceutical composition for treating a genetic disease caused by a splicing defect comprising the compound according to any one of [1] to [16] or a pharma- ceutically acceptable salt thereof as an active ingredient.
• the pharmaceutical composition according to [18], wherein the splicing abnormality is caused by an IVS4+919G>A mutation in the ⁇ -galactosidase gene.
• the pharmaceutical composition according to [18] or [19], wherein the genetic disease caused by a splicing abnormality is Fabry disease.
• a method for treating a genetic disease caused by a splicing defect comprising administering to a subject the compound according to any one of [1] to [16] or a pharma- ceutically acceptable salt thereof.
• the method according to [21], wherein the genetic disease caused by a splicing abnormality is Fabry disease.
• the use according to [23], wherein the genetic disease caused by a splicing abnormality is Fabry disease.
• Proton nuclear magnetic resonance spectra (1H-NMR) were measured using a JEOL 400 MHz, Varian 400 MHz, or Bruker 400 MHz nuclear magnetic resonance spectrometer. Spectral data is shown for significant peaks, with chemical shifts (shown as relative ppm ( ⁇ ) with tetramethylsilane as the standard), proton numbers, peak splitting multiplicities (s: singlet; d: doublet; t: triplet; q: quartet; quint.: quintet; m: multiplet; br: broad; br s: broad singlet, etc.), and, where possible, spin coupling constants shown as J values (units in Hz).
• Mass spectra (MS m/z) were measured using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Mass spectral data are shown for the maximum ionization peak (which in most cases coincided with the maximum UV absorption peak) after passing through a reversed-phase high-performance liquid chromatography column (Agilent system; column: Develosil Combi-RP-5, 2.0 x 50 mm, Cadenza CD-C18, 3.0 x 75 mm, or ZORBAX SB-C18, 1.8 ⁇ m, 2.1 x 50 mm; solvent: acetonitrile/water containing 0.1% formic acid, or acetonitrile/water containing 0.01% trifluoroacetic acid).
• ESI electrospray ionization
• APCI atmospheric pressure chemical ionization
• Silica gel column chromatography was performed using commercially available prepacked columns and automated fractionation and purification equipment (Biotage SP1, Yamazen EPCLC-W-Prep2XY, Shoko Science Purif- ⁇ 2, etc.), and only the types of solvents used in the mobile phase are described. Elution was performed under observation by thin layer chromatography (TLC), and the TLC plates used were Merck silica gel 60F254 or 60NH2F254S, Wako Pure Chemical Industries NH2 silica gel 60F254 plates, or Fuji Silysia Chemical CHROMATOREX NH TLC, the developing solvent was the mobile phase used in column chromatography, and the detection method was a UV detector or a color reagent.
• TLC thin layer chromatography
• sica gel column chromatography refers to silica gel whose surface has been chemically modified with a functional group having an amino group (e.g., Purif-Pack (registered trademark, Shoko Scientific)-EX, NH series, etc.).
• a functional group having an amino group e.g., Purif-Pack (registered trademark, Shoko Scientific)-EX, NH series, etc.
• Example 1 2-chloro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine
• Furfurylamine (44.0 ⁇ L, 0.468 mmol) and triethylamine (75.0 ⁇ L, 0.534 mmol) were added to a suspension of 2,4-dichloro-8-methoxyquinazoline (102 mg, 0.445 mmol) in acetonitrile (1.5 mL), and the mixture was stirred at 60° C. for 7 hours.
• the reaction solution was allowed to cool to room temperature, and water (6 mL) was added to the reaction solution, and the solid was filtered.
• the resulting crude product was washed with water and dried to obtain the title compound (120 mg, yield 93%) as a white solid.
• Example 2 2-Chloro-N-(furan-2-ylmethyl)-8-methoxyquinolin-4-amine J. Mol. Structure, 2017, 1131, 51-72.
• 2,4-dichloro-8-methoxyquinoline 214 mg, 0.938 mmol
• furfurylamine 96.0 ⁇ L, 1.03 mmol
• NMP 1.5 mL
• Example 3 2-chloro-7-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine (Example 3-1) 7-fluoro-8-methoxyquinazoline-2,4(1H,3H)-dione
• 2-amino-3-methoxy-4-fluorobenzoic acid 400 mg, 2.16 mmol
• urea 1.00 g, 21.6 mmol
• acetic acid 3 mL
• Example 3-2 2,4-dichloro-7-fluoro-8-methoxyquinazoline A mixture of 7-fluoro-8-methoxyquinazoline-2,4(1H,3H)-dione (320 mg, 1.53 mmol) obtained in Example 3-1, phosphoryl chloride (4 mL) and N,N-diethylaniline (370 ⁇ L, 2.28 mmol) was stirred at 100° C. for 3 hours.
• reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure.
• Example 3-3 2-chloro-7-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine
• Example 4 2-chloro-5-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine
• Example 4-1 2-amino-6-fluoro-3-methoxybenzamide Hydrazine monohydrate was added to a suspension of 6-fluoro-3-methoxy-2-nitrobenzonitrile (3.93 g, 22.0 mmol), phthalocyanine iron (II) (62.9 mg, 0.111 mmol) and iron sulfate (II) heptahydrate (29.1 mg, 0.105 mmol) described in WO2009/060209 in ethanol (60 mL)/water (60 mL), and the mixture was stirred at 120 ° C.
• Example 4-2 5-fluoro-8-methoxyquinazoline-2,4(1H,3H)-dione Potassium carbonate (3.39 g, 24.5 mmol) and 1,1'-carbonyldiimidazole (3.66 g, 22.6 mmol) were added to a DMF solution (30 mL) of 2-amino-6-fluoro-3-methoxybenzamide (2.04 g, 11.1 mmol) obtained in Example 4-1, and the mixture was stirred at 90°C for 4 hours. Water (200 mL) was added to the reaction solution, which was then washed with ethyl acetate.
• Example 4-3 2,4-dichloro-5-fluoro-8-methoxyquinazoline
• phosphoryl chloride 855 mg, 5.58 mmol
• N,N-diethylaniline 238 ⁇ L, 1.48 mmol
• N,N-diethylaniline was added 3 hours (60.0 ⁇ L, 0.371 mmol) and 5.5 hours (25.0 ⁇ L, 0.148 mmol) after the start of the reaction.
• the reaction solution was allowed to cool to room temperature, concentrated under reduced pressure, and toluene was added to the resulting residue, which was then concentrated again under reduced pressure.
• Chloroform (3 mL) was added to the resulting residue, and a saturated aqueous sodium hydrogen carbonate solution was added little by little to the resulting suspension while stirring until the pH was 5. The mixture was extracted with chloroform and then concentrated under reduced pressure.
• Example 4-4 2-chloro-5-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine
• Furfurylamine (32.0 ⁇ L, 0.347 mmol) and triethylamine (61.0 ⁇ L, 0.434 mmol) were added to an acetonitrile (1.5 mL) solution of 2,4-dichloro-5-fluoro-8-methoxyquinazoline (71.4 mg, 0.289 mmol) obtained in Example 4-3, and the mixture was stirred at 60 ° C.
• reaction solution was concentrated under reduced pressure to obtain a yellow oil.
• THF 5 mL
• furfurylamine 114 ⁇ L, 1.24 mmol
• Example 7 2-chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[4,3-d]pyrimidin-4-amine
• Example 7-1 4-amino-5-methoxypyridine-3-carboxamide 30% hydrogen peroxide solution (10 mL, 104 mmol) and potassium carbonate (1.70 g, 12.3 mmol) were added to a DMSO solution (10 mL) of 4-amino-5-methoxypyridine-3-carbonitrile (900 mg, 6.03 mmol) under ice cooling, and the mixture was stirred at room temperature for 12 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate.
• Example 7-2 8-Methoxypyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione 1M lithium bis(trimethylsilyl)amide-THF (8.40 mL, 8.40 mmol) was added to a 1,4-dioxane solution (10 mL) of 4-amino-5-methoxypyridine-3-carboxamide (480 mg, 2.87 mmol) obtained in Example 7-1 under ice cooling, and the mixture was stirred at 15 ° C. for 1 hour.
• Example 7-3 2-chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[4,3-d]pyrimidin-4-amine
• 8-methoxypyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione 100 mg, 0.518 mmol
• phosphoryl chloride 10.0 mL, 108 mmol
• N,N-diisopropylethylamine (0.900 mL, 5.17 mmol) was stirred at 100° C. for 1 hour.
• the reaction solution was concentrated under reduced pressure, and the resulting residue was added with toluene and concentrated under reduced pressure. This operation was repeated three times.
• Example 18 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine (Example 18-1) 2,4-dichloroquinazolin-8-ol
• a dichloromethane solution (90 mL) of 2,4-dichloro-8-methoxyquinazoline (8.71 g, 38.0 mmol) was added to a dichloromethane suspension (120 mL) of aluminum chloride (30.4 mg, 228 mmol) under ice cooling, and the mixture was stirred for 30 minutes and then stirred at room temperature for 6 hours.
• reaction solution was poured onto ice in a beaker to quench the reaction, and concentrated hydrochloric acid (20 mL) was added and stirred.
• the reaction solution was extracted with dichloromethane, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
• Example 18-2 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol
• acetonitrile 25 mL
• furfurylamine 0.478 mL, 5.17 mmol
• triethylamine 1.30 mL, 9.39 mmol
• Example 18-3 2-chloro-8-(1,4-dioxane-2-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine
• 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol 150 mg, 0.544 mmol
• (1,4-dioxane-2-yl)methanol 86.4 ⁇ L, 0.816 mmol
• cyanomethylenetributylphosphorane (429 ⁇ L, 1.63 mmol
• Example 19 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one 5-(hydroxymethyl)-1,3-oxazolidin-2-one (32.5 mg, 0.277 mmol) and cyanomethylenetributylphosphorane (73.0 ⁇ L, 0.277 mmol) were added to a toluene solution (1.5 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (38.2 mg, 0.139 mmol) obtained in Example 18-2, and the mixture was stirred at 80 ° C.
• Example 20 (5R)-5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one (5R)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (44.1 mg, 0.376 mmol) and cyanomethylenetributylphosphorane (123 ⁇ L, 0.470 mmol) were added to a toluene solution (1 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (66.1 mg, 0.240 mmol) obtained in Example 18-2, and the mixture was stirred at 80° C.
• Example 22 1- ⁇ 3-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]pyrrolidin-1-yl ⁇ ethanone 1-[3-(hydroxymethyl)pyrrolidin-1-yl]ethan-1-one (46.2 mg, 0.323 mmol) and cyanomethylenetributylphosphorane (113 ⁇ L, 0.430 mmol) were added to a toluene solution (1 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (59.3 mg, 0.215 mmol) obtained in Example 18-2, and the mixture was stirred at 80° C.
• the reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure.
• Example 25 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]pyrrolidin-2-one 5-(hydroxymethyl)pyrrolidin-2-one (33.0 mg, 0.287 mmol) and cyanomethylenetributylphosphorane (96.0 ⁇ L, 0.365 mmol) were added to a toluene solution (1 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (50.3 mg, 0.182 mmol) obtained in Example 18-2, and the mixture was stirred at 80° C. for 1.5 hours.
• the reaction solution was allowed to cool to room temperature, and the precipitated solid was collected by filtration.
• the obtained solid was washed with a mixed solvent of ethyl acetate/hexane (50/50) to obtain the title compound (55.4 mg, yield 81%) as a pale brown solid.
• reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure.
• Example 27 2-chloro-8-(1,4-dioxaspiro[4.4]nonan-7-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine 1,4-dioxaspiro[4,4]nonan-8-ylmethanol (90.0 mg, 0.569 mmol) and cyanomethylenetributylphosphorane (220 mg, 0.912 mmol) were added to a toluene solution (5 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (100 mg, 0.363 mmol) obtained in Example 18-2, and the mixture was stirred at 80 ° C.
• Example 28 3-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]cyclopentanone
• 2-chloro-8-(1,4-dioxaspiro[4.4]nonan-7-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine 75.0 mg, 0.180 mmol
• acetone 5 mL
• water (2 mL) p-toluenesulfonic acid
• Example 29 2-chloro-8-(1,4-dioxaspiro[4.4]nonan-6-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine
• the title compound (170 mg, yield 75%) was obtained as a yellow solid by the same procedure as in Example 18-3 using 1,4-dioxaspiro[4,4]nonan-9-ylmethanol (150 mg, 0.948 mmol) in a toluene solution (5 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (150 mg, 0.544 mmol) obtained in Example 18-2.
• Example 30 2-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]cyclopentanone
• 2-chloro-8-(1,4-dioxaspiro[4.4]nonan-6-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine 90.0 mg, 0.216 mmol
• acetone 5 mL
• water (2 mL) p-toluenesulfonic acid monohydrate
• Example 31 4-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]pyrrolidin-2-one
• 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol 37.1 mg, 0.135 mmol
• 4-(hydroxymethyl)pyrrolidin-2-one 31.5 mg, 0.269 mmol
• Example 32 3-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]cyclobutanol
• 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol 102 mg, 0.369 mmol
• 3-(hydroxymethyl)cyclobutan-1-ol 38.4 mg, 0.376 mmol
• Example 33 2-chloro-8- ⁇ [3-(difluoromethoxy)cyclobutyl]methoxy ⁇ -N-(furan-2-ylmethyl)quinazolin-4-amine 3-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]cyclobutanol (16.0 mg, 0.0445 mmol) obtained in Example 32 and copper (I) iodide (1.70 mg, 0.00889 mmol) in acetonitrile solution (1 mL) was added dropwise with 2,2-difluoro-2-(fluorosulfonyl)acetic acid (7.00 ⁇ L, 0.0667 mmol) in acetonitrile solution (0.5 mL) at 50 ° C., and stirred at 50 ° C.
• Example 34 5-[( ⁇ 2,6-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one (Example 34-1) 2-amino-5-chloro-3-methoxybenzamide 1,1'-carbonyldiimidazole (2.82 g, 17.4 mmol) was added to a THF solution (60 mL) of 2-amino-5-chloro-3-methoxybenzoic acid (2.92 g, 14.5 mmol) under ice cooling, and the mixture was then stirred at room temperature for 3 hours.
• Example 34-2 6-chloro-8-methoxyquinazoline-2,4(1H,3H)-dione
• 1.11M lithium bis(trimethylsilyl)amide (26.0mL, 28.7mmol) was added to a THF solution (70mL) of 2-amino-5-chloro-3-methoxybenzamide (2.30g, 11.5mmol) obtained in Example 34-1 under ice cooling, and the mixture was stirred at the same temperature for 15 minutes.
• a THF solution (12mL) of triphosgene (3.57g, 12.0mmol) was added to the reaction solution and stirred for 30 minutes, and then stirred at room temperature for 2 hours.
• Example 34-3 2,4,6-trichloro-8-methoxyquinazoline
• 6-chloro-8-methoxyquinazoline-2,4(1H,3H)-dione (2.08 g, 9.18 mmol) obtained in Example 34-2 phosphoryl chloride (10.0 g, 65.2 mmol) and N,N-diethylaniline (2.95 mL, 18.4 mmol) was stirred at 100° C. for 4 hours. After the reaction solution was allowed to cool to room temperature, toluene was added and the operation of concentrating under reduced pressure was repeated three times.
• Example 34-4 2,4,6-trichloroquinazolin-8-ol
• 2,4,6-trichloro-8-methoxyquinazoline (1.57 g, 5.96 mmol) obtained in Example 34-3
• aluminum chloride (4.77 g, 35.7 mmol) to obtain the title compound (1.45 g, yield 98%) as a pale yellow solid.
• Example 34-5 2,6-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol
• 2,4,6-trichloroquinazolin-8-ol 509 mg, 2.04 mmol obtained in Example 34-4 and furfurylamine (208 ⁇ L, 2.24 mmol) to obtain the title compound (512 mg, yield 81%) as a yellow solid.
• Example 34-6 5-[( ⁇ 2,6-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one Using 2,6-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (50.8 mg, 0.164 mmol) obtained in Example 34-5 and 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (33.4 mg, 0.254 mmol), the same operation as in Example 18-3 was carried out to obtain the title compound (58.3 mg, yield 84%) as a white solid.
• Example 35 (3S,5R)-5-[( ⁇ 2,6-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-methylpyrrolidin-2-one Using 2,6-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (45.5 mg, 0.147 mmol) obtained in Example 34-5 and (3S,5R)-5-(hydroxymethyl)-3-methylpyrrolidin-2-one (29.3 mg, 0.227 mmol), the same operation as in Example 18-3 was carried out to obtain the title compound (24.1 mg, yield 39%) as a white solid.
• Example 36 5-( ⁇ [4-(benzylamino)-2,6-dichloroquinazolin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one
• Example 36-1 4-(benzylamino)-2,6-dichloroquinazolin-8-ol Using 2,4,6-trichloroquinazolin-8-ol (240 mg, 0.962 mmol) obtained in Example 34-4 and benzylamine (116 ⁇ L, 1.06 mmol), the same operation as in Example 18-2 was carried out to obtain the title compound (218 mg, yield 71%) as a pale yellow solid.
• Example 36-2 5-( ⁇ [4-(benzylamino)-2,6-dichloroquinazolin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one Using 4-(benzylamino)-2,6-dichloroquinazolin-8-ol (53.7 mg, 0.168 mmol) obtained in Example 36-1 and 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (34.0 mg, 0.259 mmol), the same operation as in Example 18-3 was carried out to obtain the title compound (58.7 mg, yield 81%) as a white solid.
• Example 37 5-[( ⁇ 2,7-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one (Example 37-1) 2-amino-4-chloro-3-methoxybenzamide
• Example 34-1 2-amino-4-chloro-3-methoxybenzoic acid (1.21 g, 6.00 mmol) to obtain the title compound (1.06 g, yield 88%) as a brown solid.
• Example 37-2 7-chloro-8-methoxyquinazoline-2,4(1H,3H)-dione
• 2-amino-4-chloro-3-methoxybenzamide (1.06 g, 5.28 mmol) obtained in Example 37-1 to obtain the title compound (0.950 g, yield 79%) as a light brown solid.
• Example 37-3 2,4,7-trichloro-8-methoxyquinazoline
• Example 34-3 2,4,7-trichloro-8-methoxyquinazoline
• Example 37-3 2,4,7-trichloro-8-methoxyquinazoline
• Example 37-3 2,4,7-trichloro-8-methoxyquinazoline
• Example 37-3 2,4,7-trichloro-8-methoxyquinazoline (103 mg, 0.391 mmol) obtained in Example 37-3 to obtain the title compound (98.4 mg, yield 100%).
• Example 37-5 2,7-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol
• 2,4,7-trichloroquinazolin-8-ol 97.5 mg, 0.391 mmol obtained in Example 37-4 to give the title compound (103 mg, yield 85%) as a pale white solid.
• Example 37-6 5-[( ⁇ 2,7-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one Using 2,7-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (43.5 mg, 0.140 mmol) obtained in Example 37-5 and 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (27.6 mg, 0.210 mmol), the same operation as in Example 18-3 was carried out to obtain the title compound (51.0 mg, yield 86%) as a white solid.
• reaction solution was ice-cooled, water (2 mL) was added, and the mixture was concentrated under reduced pressure. Water was added to the resulting residue, and the solid was filtered, washed with water, and dried to obtain the title compound (143 mg, yield 99%) as a pale yellow solid.
• Example 38-2 2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-ol
• Furfurylamine (5.20 mL, 56.2 mmol) and N,N-diisopropylethylamine (12.2 mL, 70.0 mmol) were added to a solution of 2,4-dichloroquinolin-8-ol (6.01 g, 28.1 mmol) obtained in Example 38-1 in NMP (112 mL), and the mixture was stirred at 120° C. for 19 hours. After the reaction solution was allowed to cool to room temperature, water (200 mL) was added and the mixture was extracted with ethyl acetate.
• Example 38-3 2-chloro-8-(1,4-dioxane-2-ylmethoxy)-N-(furan-2-ylmethyl)quinolin-4-amine
• Example 39 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one
• 2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-ol 90.7 mg, 0.330 mmol
• 5-(hydroxymethyl)-1,3-oxazolidin-2-one 79.1 mg, 0.675 mmol
• Example 40 5-( ⁇ [4-(benzylamino)-2-chloroquinazolin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one
• Example 40-1 4-(benzylamino)-2-chloroquinazolin-8-ol
• Benzylamine (83.0 ⁇ L, 0.759 mmol) and triethylamine (200 ⁇ L, 1.44 mmol) were added to a mixture of 2,4-dichloroquinazolin-8-ol (156 mg, 0.725 mmol) obtained in Example 18-1 and acetonitrile (3 mL), and the mixture was stirred at 60° C. for 1.5 hours.
• reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure.
• Example 40-2 5-( ⁇ [4-(benzylamino)-2-chloroquinazolin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (103 mg, 0.785 mmol) and cyanomethylenetributylphosphorane (224 ⁇ L, 0.853 mmol) were added to a toluene solution (2 mL) of 4-(benzylamino)-2-chloroquinazolin-8-ol (122 mg, 0.427 mmol) obtained in Example 40-1, and the mixture was stirred at 80° C. for 1.5 hours.
• reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure.
• Example 41 5-( ⁇ [4-(benzylamino)-2-chloroquinazolin-8-yl]oxy ⁇ methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one
• Example 41-1) 5-[(benzyloxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one
• tert-butoxypotassium 0.31 mg, 8.30 mmol
• 1-bromo-2-fluoroethane 0.831 g, 6.54 mmol
• TBAI tetrabutylammonium ammonium iodide
• Example 41-2 3-(2-fluoroethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one 20% palladium hydroxide carbon (90.0 mg) was added to an ethanol solution (7 mL) of 5-[(benzyloxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one (907 mg, 3.58 mmol) obtained in Example 41-1, and the mixture was stirred under a hydrogen atmosphere for 8 hours. The reaction solution was filtered and then concentrated under reduced pressure, and toluene was added to the resulting residue and concentrated again under reduced pressure to obtain the title compound (568 mg, yield 97%) as a colorless oil.
• Example 41-3 5-( ⁇ [4-(benzylamino)-2-chloroquinazolin-8-yl]oxy ⁇ methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one
• 4-(benzylamino)-2-chloroquinazolin-8-ol (40.0 mg, 0.140 mmol) obtained in Example 40-1
• 3-(2-fluoroethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (40.0 mg, 0.245 mmol) obtained in Example 41-2, to obtain the title compound (46.2 mg, yield 77%) as a pale yellow solid.
• Example 42 5-( ⁇ [4-(benzylamino)-2-chloroquinazolin-8-yl]oxy ⁇ methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one
• Example 42-1 5-[(benzyloxy)methyl]-3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-1,3-oxazolidin-2-one
• the same operation as in Example 41-1 was carried out using 5-[(benzyloxy)methyl]-1,3-oxazolidin-2-one (1.13 g, 5.45 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (1.40 mL, 6.54 mmol) described in WO2008/044700, and the title compound (1.26 g, yield 63%) was obtained as a yellow oil.
• Example 42-2 3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one
• Example 42-2 3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one
• 5-[(benzyloxy)methyl]-3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-1,3-oxazolidin-2-one (1.26 g, 3.45 mmol) obtained in Example 42-1, to obtain the title compound (0.948 g, yield 100%) as a colorless oil.
• Example 42-3 5-( ⁇ [4-(benzylamino)-2-chloroquinazolin-8-yl]oxy ⁇ methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one
• 4-(benzylamino)-2-chloroquinazolin-8-ol (40.2 mg, 0.141 mmol) obtained in Example 40-1 and 3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (59.2 mg, 0.215 mmol) obtained in Example 42-2 to obtain crude 5-( ⁇ [4-(benzylamino)-2-chloroquinazolin-8-yl]oxy ⁇ methyl)-3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-1,3-oxazolidin-2-one (33.3 mg) [MS
• Example 43 5-( ⁇ [4-(benzylamino)-2-chloroquinolin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one (Example 43-1) 4-(benzylamino)-2-chloroquinolin-8-ol Benzylamine (306 ⁇ L, 2.80 mmol) and N,N-diisopropylethylamine (488 ⁇ L, 2.80 mmol) were added to a solution of 2,4-dichloroquinolin-8-ol (300 mg, 1.40 mmol) obtained in Example 38-1 in NMP (3.5 mL), and the mixture was stirred at 120° C. for 9 hours.
• Example 43-2 5-( ⁇ [4-(benzylamino)-2-chloroquinolin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (100 mg, 0.763 mmol) and cyanomethylenetributylphosphorane (251 ⁇ L, 0.956 mmol) were added to a toluene solution (2 mL) of 4-(benzylamino)-2-chloroquinolin-8-ol (136 mg, 0.478 mmol) obtained in Example 43-1, and the mixture was stirred at 80° C. for 2 hours.
• reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure.
• Example 104 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)-1,5-naphthyridin-4-amine
• Example 104-1 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-ol
• Furfurylamine (172 ⁇ L, 1.86 mmol) and N,N-diisopropylethylamine (410 ⁇ L, 2.35 mmol) were added to a solution of 6,8-dichloro-1,5-naphthyridin-4-ol (200 mg, 0.930 mmol) described in WO2017/055306 in NMP (3.7 mL), and the mixture was stirred at 120° C.
• Example 104-2 2-chloro-8-(1,4-dioxane-2-ylmethoxy)-N-(furan-2-ylmethyl)-1,5-naphthyridin-4-amine
• Example 18-3 2-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-ol (71.2 mg, 0.258 mmol) obtained in Example 104-1 and (1,4-dioxan-2-yl)methanol (45.0 ⁇ L, 0.420 mmol) to obtain the title compound (36.0 mg, yield 37%) as a white solid.
• Example 105 5-[( ⁇ 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one
• 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-ol (65.0 mg, 0.236 mmol) obtained in Example 104-1 and 5-(hydroxymethyl)-1,3-oxazolidin-2-one (45.6 mg, 0.389 mmol) to obtain the title compound (20.2 mg, yield 23%) as a white solid.
• Example 106 5-[( ⁇ 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one
• 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-ol (162 mg, 0.588 mmol) obtained in Example 104-1 and 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (125 mg, 0.953 mmol) to obtain the title compound (21.9 mg, yield 10%) as a white solid.
• Example 10-7 (3S,5R)-5-[( ⁇ 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl ⁇ oxy)methyl]-3-methylpyrrolidin-2-one
• 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-ol (52.4 mg, 0.190 mmol) obtained in Example 104-1 and (3S,5R)-5-(hydroxymethyl)-3-methylpyrrolidin-2-one (36.8 mg, 0.285 mmol) to obtain the title compound (52.5 mg, yield 71%) as a light brown solid.
• Example 108 5-[( ⁇ 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl ⁇ oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one
• 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-ol 59.9 mg, 0.217 mmol
• 3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one 91.1 mg, 0.331 mmol) obtained in Example 42-2, the same operation as in Example 18-3 was carried out to obtain crude 3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-5-[( ⁇ 6-chloro-8-[(furan-2-yl
• Example 109 5-[( ⁇ 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl ⁇ oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one
• 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-ol (46.4 mg, 0.168 mmol) obtained in Example 104-1 and 3-(2-fluoroethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (49.7 mg, 0.305 mmol) obtained in Example 41-2, to obtain the title compound (54.3 mg, yield 77%) as a light brown solid.
• Example 110 5-( ⁇ [8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy ⁇ methyl)-1,3-oxazolidin-2-one (Example 110-1) 8-(benzylamino)-6-chloro-1,5-naphthyridin-4-ol Benzylamine (591 ⁇ L, 5.49 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.90 mmol) were added to a solution of 6,8-dichloro-1,5-naphthyridin-4-ol (582 mg, 2.71 mmol) described in WO2017/055306 in NMP (11 mL), and the mixture was stirred at 120° C.
• Example 110-2 5-( ⁇ [8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy ⁇ methyl)-1,3-oxazolidin-2-one
• 8-(benzylamino)-6-chloro-1,5-naphthyridin-4-ol 150 mg, 0.525 mmol
• Example 110-1 5-(hydroxymethyl)-1,3-oxazolidin-2-one (104 mg, 0.888 mmol) to obtain the title compound (75.4 mg, yield 37%) as a white solid.
• Example 111 5-( ⁇ [8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one
• 8-(benzylamino)-6-chloro-1,5-naphthyridin-4-ol 150 mg, 0.525 mmol
• Example 110-1 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (107 mg, 0.816 mmol) to obtain the title compound (38.4 mg, yield 18%) as a white solid.
• Example 112 (3S,5R)-5-( ⁇ [8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy ⁇ methyl)-3-methylpyrrolidin-2-one
• 8-(benzylamino)-6-chloro-1,5-naphthyridin-4-ol 47.6 mg, 0.167 mmol
• Example 110-1 3S,5R)-5-(hydroxymethyl)-3-methylpyrrolidin-2-one (32.3 mg, 0.250 mmol) to obtain the title compound (46.1 mg, yield 70%) as a light brown solid.
• Example 113 5-( ⁇ [8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy ⁇ methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one Using 8-(benzylamino)-6-chloro-1,5-naphthyridin-4-ol (60.7 mg, 0.212 mmol) obtained in Example 110-1 and 3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (92.2 mg, 0.335 mmol) obtained in Example 42-2, the same operation as in Example 18-3 was carried out to obtain crude 5-( ⁇ [8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy ⁇ methyl)-3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ eth
• Example 114 5-( ⁇ [8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy ⁇ methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one Using 8-(benzylamino)-6-chloro-1,5-naphthyridin-4-ol (40.5 mg, 0.142 mmol) obtained in Example 110-1 and 3-(2-fluoroethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (40.1 mg, 0.246 mmol) obtained in Example 41-2, the same operation as in Example 18-3 was carried out to obtain the title compound (49.5 mg, yield 81%) as a pale white solid.
• Example 115 5-( ⁇ [4-(benzylamino)-2-chloropyrido[3,2-d]pyrimidin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one (Example 115-1) 2,4-dichloropyrido[3,2-d]pyrimidin-8-ol N,N-diethylaniline (950 ⁇ L, 5.92 mmol) was added to a solution of 8-methoxy-1H-pyrido[3,2-d]pyrimidine-2,4-dione (286 mg, 1.48 mmol) described in WO2020/081636 in phosphoryl chloride (2.11 mL, 23.0 mmol) and stirred at 100 ° C.
• Example 115-2 5-( ⁇ [4-(benzylamino)-2-chloropyrido[3,2-d]pyrimidin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one
• Benzylamine (29 ⁇ L, 0.25 mmol) and triethylamine (75 ⁇ L, 0.541 mmol) were added to a mixture of 2,4-dichloropyrido[3,2-d]pyrimidin-8-ol (46.5 mg, 0.215 mmol) obtained in Example 115-1 and acetonitrile (2 mL), and the mixture was stirred at 80° C. for 2.5 hours.
• the reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure.
• Example 117 3-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]pyrrolidin-2-one 3-(hydroxymethyl)pyrrolidin-2-one (55.7 mg, 0.484 mmol), triphenylphosphine (164 mg, 0.626 mmol) and 40% diethyl azodicarboxylate-toluene (250 ⁇ L, 0.550 mmol) were added to a THF solution (2.0 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (67.6 mg, 0.245 mmol) obtained in Example 18-2, and the mixture was stirred at room temperature for 5 hours.
• Example 12-7 2-chloro-8-[(2S)-1,4-dioxan-2-ylmethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine Potassium carbonate (70.0 mg, 0.506 mmol) was added to a DMF solution (2 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (70.0 mg, 0.253 mmol) obtained in Example 18-2, and the mixture was stirred at 90 ° C. for 0.5 hours.
• Example 128 2-chloro-8-[(2S)-1,4-dioxan-2-ylmethoxy]-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine (Example 128-1) 2,4-dichloro-7-fluoroquinazolin-8-ol
• 2,4-dichloro-7-fluoro-8-methoxyquinazoline 300 mg, 1.21 mmol
• Example 3-2 aluminum chloride (1.30 g, 9.75 mmol) to obtain the title compound (283 mg, yield 100%) as a white solid.
• Example 128-2 2-chloro-7-fluoro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol
• Diisopropylethylamine (500 ⁇ L, 2.87 mmol) and furfurylamine (132 ⁇ L, 1.44 mmol) were added to a THF solution (5 mL) of 2,4-dichloro-7-fluoroquinazolin-8-ol (300 mg, 1.29 mmol) obtained in Example 128-1, and the mixture was stirred at room temperature for 2 hours.
• the reaction solution was concentrated under reduced pressure, water (50 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate.
• Example 128-3 2-chloro-8-[(2S)-1,4-dioxane-2-ylmethoxy]-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine
• 2-chloro-7-fluoro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol 150 mg, 0.511 mmol
• [(2R)-1,4-dioxan-2-yl]methyl 4-methylbenzenesulfonate 150 mg, 0.551 mmol
• Example 129 2-chloro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinolin-4-amine
• Example 125 2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-ol (140 mg, 0.510 mmol) obtained in Example 38-2 and 3-(bromomethyl)oxetane (58.9 ⁇ L, 0.612 mmol) to obtain the title compound (88.0 mg, yield 50%) as a white solid.
• Example 14 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-2-ylmethyl)quinazolin-4-amine
• Example 144-1 2-chloro-4-[(thiophen-2-ylmethyl)amino]quinazolin-8-ol
• Triethylamine (0.154 mL, 1.12 mmol
• thiophene-2-methylamine 0.070 mL, 0.670 mmol
• Example 144-2 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-2-ylmethyl)quinazolin-4-amine
• Potassium carbonate (30.0 mg, 0.206 mmol) and 2-(bromomethyl)-1,1-difluorocyclopropane (26.0 mg, 0.151 mmol) were added to a DMF solution (2 mL) of 2-chloro-4-[(thiophen-2-ylmethyl)amino]quinazolin-8-ol (40.0 mg, 0.137 mmol) obtained in Example 144-1, and the mixture was stirred at 90 ° C. for 1 hour.
• Example 146-2 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-3-ylmethyl)quinazolin-4-amine Potassium carbonate (30.0 mg, 0.206 mmol) and 2-(bromomethyl)-1,1-difluorocyclopropane (26.0 mg, 0.151 mmol) were added to a DMF solution (2 mL) of 2-chloro-4-[(thiophen-3-ylmethyl)amino]quinazolin-8-ol (40.0 mg, 0.137 mmol) obtained in Example 146-1, and the mixture was stirred at 90 ° C. for 2 hours.
• Example 1478 5- ⁇ [(2-chloro-4- ⁇ [(4-fluorofuran-2-yl)methyl]amino ⁇ quinazolin-8-yl)oxy]methyl ⁇ -1,3-oxazolidin-2-one (Example 148-1) 2-[(4-fluorofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione
• Triphenylphosphine (359 mg, 1.37 mmol) and 40% diethyl azodicarboxylate-toluene (580 ⁇ L, 1.30 mmol) were added to a THF solution (1.8 mL) of (4-fluoro-2-furyl)methanol (105 mg, 0.904 mmol) and phthalimide (163 mg, 1.11 mmol) described in US2008/0058395, and the mixture was stirred at room temperature for 5 hours.
• Example 148-2 2-chloro-4- ⁇ [(4-fluorofuran-2-yl)methyl]amino ⁇ quinazolin-8-ol
• Example 148-1 Hydrazine monohydrate (29.0 ⁇ L, 0.598 mmol) was added to an ethanol solution (4.0 mL) of the obtained 2-[(4-fluorofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (110 mg, 0.449 mmol), and the mixture was stirred at 80° C. for 5.5 hours. The reaction solution was allowed to cool to room temperature, and then diluted with dichloromethane.
• 2,4-dichloroquinazolin-8-ol (75.0 mg, 0.349 mmol) obtained in Example 18-1 and triethylamine (90.0 ⁇ L, 0.649 mmol) were added to a mixture of the obtained 4-fluoro-2-furanmethanamine (39.2 mg, 0.341 mmol) and acetonitrile (25 mL), and the mixture was stirred at 60 ° C. for 2 hours.
• Triethylamine (45.0 ⁇ L, 0.325 mmol) was added to the reaction solution, and the mixture was stirred at 60 ° C. for 2 hours. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure.
• Example 148-3 5- ⁇ [(2-chloro-4- ⁇ [(4-fluorofuran-2-yl)methyl]amino ⁇ quinazolin-8-yl)oxy]methyl ⁇ -1,3-oxazolidin-2-one Using 2-chloro-4- ⁇ [(4-fluorofuran-2-yl)methyl]amino ⁇ quinazolin-8-ol (21.0 mg, 0.0715 mmol) obtained in Example 148-2 and 5-(hydroxymethyl)-1,3-oxazolidin-2-one (25.6 mg, 0.219 mmol), the same operation as in Example 18-3 was carried out to obtain the title compound (6.50 mg, yield 23%) as a white solid.
• Example 149-2 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-chloro-N-(1,2-thiazol-5-ylmethyl)quinazolin-4-amine
• a solution (1 mL) of 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2,4-dichloroquinazoline (180 mg, 0.547 mmol) obtained in Example 149-1 in acetonitrile (1,2-thiazol-5-yl)methanamine hydrochloride (90.0 mg, 0.601 mmol) and triethylamine (0.170 mL, 1.20 mmol) were added and stirred at 60° C. for 1 hour.
• Example 149-3 2-chloro-4-[(1,2-thiazol-5-ylmethyl)amino]quinazolin-8-ol 1M TBAF-THF (0.616mL, 0.616mmol) was added to a THF solution (1mL) of 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-chloro-N-(1,2-thiazol-5-ylmethyl)quinazolin-4-amine (209mg, 514mmol) obtained in Example 149-2, and the mixture was stirred at room temperature for 16 hours.
• Example 149-4 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,2-thiazol-5-ylmethyl)quinazolin-4-amine 2-(bromomethyl)-1,1-difluorocyclopropane (26.0 mg, 0.150 mmol) and potassium carbonate (28.0 mg, 0.205 mmol) were added to a DMF solution (1 mL) of 2-chloro-4-[(1,2-thiazol-5-ylmethyl)amino]quinazolin-8-ol (40.0 mg, 0.137 mmol) obtained in Example 149-3, and the mixture was stirred at 90 ° C. for 1 hour.
• Example 150 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-oxazol-4-ylmethyl)quinazolin-4-amine (Example 150-1) 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-chloro-N-(1,3-oxazol-4-ylmethyl)quinazolin-4-amine
• Example 149-2 The same operation as in Example 149-2 was carried out using 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2,4-dichloroquinazoline (180 mg, 0.547 mmol) obtained in Example 149-1 and (1,3-oxazol-4-yl)methanamine hydrochloride (81.0 mg, 0.601 mmol) to give the title compound (184 mg, yield 86%) as a white solid.
• Example 150-2 2-chloro-4-[(1,3-oxazol-4-ylmethyl)amino]quinazolin-8-ol
• Example 149-3 The same operation as in Example 149-3 was carried out using 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-chloro-N-(1,3-oxazol-4-ylmethyl)quinazolin-4-amine (184 mg, 0.471 mmol) obtained in Example 150-1 to obtain the title compound (110 mg, yield 84%) as a white solid.
• Example 150-3 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-oxazol-4-ylmethyl)quinazolin-4-amine
• Example 149-4 2-chloro-4-[(1,3-oxazol-4-ylmethyl)amino]quinazolin-8-ol (40.0 mg, 0.145 mmol) obtained in Example 150-2 and 2-(bromomethyl)-1,1-difluorocyclopropane (33.0 mg, 0.160 mmol) to obtain the title compound (33.0 mg, yield 62%) as a white solid.
• Example 151 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,2-oxazol-3-ylmethyl)quinazolin-4-amine
• Example 151-1 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-chloro-N-(1,2-oxazol-3-ylmethyl)quinazolin-4-amine
• Example 149-2 was carried out using 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2,4-dichloroquinazoline (180 mg, 0.547 mmol) obtained in Example 149-1 and isoxazol-3-ylmethanamine (60.0 mg, 0.601 mmol) to obtain the title compound (195 mg, yield 91%) as a white solid.
• Example 151-2 2-chloro-4-[(1,2-oxazol-3-ylmethyl)amino]quinazolin-8-ol
• Example 149-3 The same operation as in Example 149-3 was carried out using 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-chloro-N-(1,2-oxazol-3-ylmethyl)quinazolin-4-amine (195 mg, 0.499 mmol) obtained in Example 151-1 to obtain the title compound (87.0 mg, yield 63%) as a white solid.
• Example 151-3 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,2-oxazol-3-ylmethyl)quinazolin-4-amine
• Example 149-4 The same operation as in Example 149-4 was carried out using 2-chloro-4-[(1,2-oxazol-3-ylmethyl)amino]quinazolin-8-ol (40.0 mg, 0.145 mmol) obtained in Example 151-2 and 2-(bromomethyl)-1,4-dioxane (27.0 mg, 0.159 mmol) to obtain the title compound (12.0 mg, yield 22%) as a pale yellow solid.
• Example 152 5-[( ⁇ 2-chloro-4-[(1,3-oxazol-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one (Example 152-1) 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-chloro-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine
• Oxazol-2-yl-methylamine hydrochloride (52.1 mg, 0.387 mmol) and N,N-diisopropylethylamine (106 ⁇ L, 0.609 mmol) were added to an NMP solution (1.5 mL) of 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2,4-dichloroquinazoline (99.4 mg, 0.302 mmol) obtained in Example 149-1, and the mixture was stirred at 120° C.
• Example 152-2 2-chloro-4-[(1,3-oxazol-2-ylmethyl)amino]quinazolin-8-ol
• Example 149-3 The same operation as in Example 149-3 was carried out using 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-chloro-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine (94.3 mg, 0.241 mmol) obtained in Example 152-1 to obtain the title compound (59.6 mg, yield 89%) as a white solid.
• Example 152-3 5-[( ⁇ 2-chloro-4-[(1,3-oxazol-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one Using 2-chloro-4-[(1,3-oxazol-2-ylmethyl)amino]quinazolin-8-ol (75.6 mg, 0.273 mmol) obtained in Example 152-2 and 5-(hydroxymethyl)-1,3-oxazolidin-2-one (46.7 mg, 0.399 mmol), the same operation as in Example 18-3 was carried out to obtain the title compound (20.4 mg, yield 20%) as a white solid.
• Example 153 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine (Example 153-1) 2,4-dichloro-8-(1,4-dioxane-2-ylmethoxy)quinazoline
• 2,4-dichloro-8-(1,4-dioxane-2-ylmethoxy)quinazoline To a toluene solution (2 mL) of 2,4-dichloroquinazolin-8-ol (50.0 mg, 0.233 mmol) obtained in Example 18-1, (1,4-dioxane-2-yl)methanol (41.0 mg, 0.349 mmol), bis(2-methoxymethyl)azodicarboxylate (110 mg, 0.465 mmol) and triphenylphosphine (120 mg, 0.465 mmol) were added and stirred at 90° C.
• Example 153-2 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine
• Triethylamine (0.060 mL, 0.413 mmol) and oxazol-2-ylmethanamine hydrochloride (25.0 mg, 0.182 mmol) were added to an acetonitrile solution (1 mL) of 2,4-dichloro-8-(1,4-dioxane-2-ylmethoxy)quinazoline (52.0 mg, 0.165 mmol) obtained in Example 153-1, and the mixture was stirred at 60° C. for 4 hours.
• reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure.
• Example 170 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one (Example 170-1) 8-Methoxy-2H-pyrido[3,4-d][1,3]oxazine-2,4(1H)-dione Triphosgene (1.73 g, 5.84 mmol) was slowly added to a suspension (30 mL) of 3-amino-2-methoxy-isonicotinic acid (1.00 g, 5.96 mmol) in THF, and the mixture was stirred at room temperature overnight.
• Example 170-3 4-hydroxy-8-methoxy-1,7-naphthyridin-2(1H)-one
• Example 170-4 8-Methoxy-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl trifluoromethanesulfonate N-phenylbis(trifluoromethanesulfonimide) (445 mg, 1.24 mmol) was added to a THF solution (2 mL) of 4-hydroxy-8-methoxy-1,7-naphthyridin-2(1H)-one (199 mg, 1.04 mmol) obtained in Example 170-3 and triethylamine (0.430 mL, 3.11 mmol), and the mixture was stirred at room temperature overnight.
• reaction solution was concentrated under reduced pressure, and chloroform (2 mL) was added to the resulting residue, and the insoluble matter was filtered off to obtain the title compound (174 mg) as a white solid.
• Example 170-5 4-[(furan-2-ylmethyl)amino]-8-methoxy-1,7-naphthyridin-2(1H)-one
• Furfurylamine (820 ⁇ L, 8.86 mmol) was added to an acetonitrile suspension (15 mL) of 8-methoxy-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl trifluoromethanesulfonate (958 mg, 2.95 mmol) obtained in Example 170-4, and the mixture was stirred at 60° C. for 6 hours.
• the reaction solution was allowed to cool to room temperature, and then concentrated under reduced pressure until the liquid volume was reduced to about half, and the solid was filtered off.
• Example 170--7 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (106 mg, 0.808 mmol) in THF solution (5 mL) was added with 55% sodium hydride (dispersed in liquid paraffin) (47.0 mg, 1.08 mmol) at room temperature and stirred for 1 hour.
• Example 171 (5S)-5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one
• acetonitrile solution 7.6 mL
• 2,8-dichloro-N-(furan-2-ylmethyl)-1,7-naphthyridin-4-amine (213 mg, 0.724 mmol) obtained in Example 170-6,
• (5S)-5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (123 mg, 0.941 mmol) and cesium carbonate (472 mg, 1.45 mmol) were added and treated with a microwave reaction device at 110 ° C.
• the title compound can also be obtained by resolving 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one obtained in Example 170-7 by chiral HPLC.
• DAICEL CHIRALPAK IC 4.6 x 150 mm
• flow rate 1.00 mL/min
• retention time 4.92 min.
• Example 172 (5R)-5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one
• the title compound (171 mg, yield 62%) was obtained as a white solid by carrying out the same operation as in Example 171 using 2,8-dichloro-N-(furan-2-ylmethyl)-1,7-naphthyridin-4-amine (210 mg, 0.714 mmol) obtained in Example 170-6 and (5R)-5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (122 mg, 0.928 mmol).
• the title compound can also be obtained by resolving 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one obtained in Example 170-7 by chiral HPLC.
• Example 173 5-( ⁇ [4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy ⁇ methyl)-1,3-oxazolidin-2-one (Example 173-1) 4-(benzylamino)-8-methoxy-1,7-naphthyridin-2(1H)-one
• Example 170-5 The same operation as in Example 170-5 was carried out using 8-methoxy-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl trifluoromethanesulfonate (1.09 g, 3.36 mmol) obtained in Example 170-4 and benzylamine (1.10 mL, 10.1 mmol) to obtain the title compound (0.610 g, yield 65%) as a white solid.
• Example 173-2 N-benzyl-2,8-dichloro-1,7-naphthyridin-4-amine
• Example 173-1 4-(benzylamino)-8-methoxy-1,7-naphthyridin-2(1H)-one (610 mg, 2.17 mmol) obtained in Example 173-1 to obtain the title compound (610 mg, yield 93%) as a white solid.
• Example 173-3 5-( ⁇ [4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy ⁇ methyl)-1,3-oxazolidin-2-one Using N-benzyl-2,8-dichloro-1,7-naphthyridin-4-amine (151 mg, 0.496 mmol) obtained in Example 173-2 and 5-(hydroxymethyl)-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one (142 mg, 0.596 mmol) described in WO2014/085413, the same operation as in Example 170-7 was carried out to obtain crude 5-( ⁇ [4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy ⁇ methyl)-3-(4-methoxybenzyl)-1,3-oxazolidin-2-one (58.4 mg) [MS (m/z): 505 (M+H) +
• the reaction solution was concentrated under reduced pressure, and then a saturated aqueous solution of sodium bicarbonate was added as a dichloromethane solution to neutralize it, followed by extraction with dichloromethane and then ethyl acetate, and the entire organic layer was concentrated under reduced pressure.
• Example 174 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl ⁇ oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one
• 2,8-dichloro-N-(furan-2-ylmethyl)-1,7-naphthyridin-4-amine (85.0 mg, 0.289 mmol) obtained in Example 170-6 and 3-(2-fluoroethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (70.7 mg, 0.433 mmol) obtained in Example 41-2, to obtain the title compound (85.1 mg, yield 70%) as a colorless solid.
• Example 175 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl ⁇ oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one (Example 175-1) 3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one
• Example 170-7 The same operation as in Example 170-7 was carried out using 2,8-dichloro-N-(furan-2-ylmethyl)-1,7-naphthyridin-4-amine (46.3 mg, 0.157 mmol) obtained in Example 170-6 and 3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy
• Example 175-2 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl ⁇ oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one 1M TBAF-THF (36.0 ⁇ L, 0.0360 mmol) was added to a THF solution (0.6 mL) of 3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one (12.5 mg, 0.0234 mmol) obtained in Example 175-1, and the mixture was stirred at room temperature for 1 hour.
• Example 176 5-( ⁇ [4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy ⁇ methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one
• N-benzyl-2,8-dichloro-1,7-naphthyridin-4-amine 94.6 mg, 0.311 mmol
• 3-(2-fluoroethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (76.1 mg, 0.467 mmol) obtained in Example 41-2, and the title compound (58.6 mg, yield 44%) was obtained as a white solid.
• Example 17-7 5-( ⁇ [4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one
• N-benzyl-2,8-dichloro-1,7-naphthyridin-4-amine 201 mg, 0.661 mmol
• 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one 104 mg, 0.793 mmol
• Example 178 5-( ⁇ [4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy ⁇ methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one (Example 178-1) 5-( ⁇ [4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy ⁇ methyl)-3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-1,3-oxazolidin-2-one
• N-benzyl-2,8-dichloro-1,7-naphthyridin-4-amine 109 mg, 0.358 mmol
• Example 178-2 5-( ⁇ [4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy ⁇ methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one
• Example 175-2 The same operation as in Example 175-2 was carried out using 5-( ⁇ [4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy ⁇ methyl)-3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-1,3-oxazolidin-2-one (58.9 mg, 0.108 mmol) obtained in Example 178-1 to obtain the title compound (25.6 mg, yield 55%) as a white solid.
• Example 179-2 2-chloro-8-(1,4-dioxane-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,2-d]pyrimidin-4-amine
• 2,8-dichloro-N-(furan-2-ylmethyl)pyrido[3,2-d]pyrimidin-4-amine 35.5 mg, 0.120 mmol
• (1,4-dioxane-2-yl)methanol (14.0 ⁇ L, 0.127 mmol)
• 55% sodium hydride (dispersed in liquid paraffin) (5.3 mg, 0.120 mmol) were added, and the mixture was stirred at 65° C.
• Example 180 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine (Example 180-1) 2,4,8-trichloropyrido[3,4-d]pyrimidine Bioorg. Med. Chem. Lett. , 2013, 23, 5923-5930. 8-Methoxypyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (156 mg, 0.806 mmol) and phosphoryl chloride (0.92 g, 6.00 mmol) were added to the mixture, and the mixture was stirred at 100 ° C. for 7 hours.
• Example 180-2 2,8-dichloro-N-(furan-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine
• Furfurylamine (21.2 ⁇ L, 0.238 mmol) and triethylamine (58.0 ⁇ L, 0.418 mmol) were added to an acetonitrile (1.5 mL) solution of 2,4,8-trichloropyrido[3,4-d]pyrimidine (45.1 mg, 0.192 mmol) obtained in Example 180-1, and the mixture was stirred at 60° C. for 2 hours. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure.
• Example 181 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]pyrido[3,4-d]pyrimidin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one
• 2,8-dichloro-N-(furan-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine 108 mg, 0.366 mmol
• Example 180-2 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (144 mg, 1.10 mmol) to obtain the title compound (20.1 mg, yield 14%) as a white solid.
• Example 182 5-( ⁇ [4-(benzylamino)-2-chloropyrido[3,4-d]pyrimidin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one
• Example 182-1 N-benzyl-2,8-dichloropyrido[3,4-d]pyrimidin-4-amine
• 2,4,8-trichloropyrido[3,4-d]pyrimidine 47.1 mg, 0.201 mmol
• Example 180-1 benzylamine (24.0 ⁇ L, 0.221 mmol)
• Example 182-2 5-( ⁇ [4-(benzylamino)-2-chloropyrido[3,4-d]pyrimidin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one
• N-benzyl-2,8-dichloropyrido[3,4-d]pyrimidin-4-amine 56.8 mg, 0.186 mmol
• 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one 29.3 mg, 0.223 mmol
• Example 183 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]pyrido[4,3-d]pyrimidin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one (Example 183-1) Methyl 4-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]-3-oxobutanoate 55% sodium hydride (dispersed in liquid paraffin) (421 mg, 9.65 mmol) was added to a solution of 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (671 mg, 5.12 mmol) in THF (17 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes.
• Example 183-3 8-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione Trichloroacetyl isocyanate (20.0 ⁇ L, 0.169 mmol) was added to a THF (1 mL) solution of methyl 4-amino-5-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]pyridine-3-carboxylate (30.3 mg, 0.108 mmol) obtained in Example 183-2, and the mixture was stirred at room temperature for 1 hour.
• Example 183-4 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]pyrido[4,3-d]pyrimidin-8-yl ⁇ oxy)methyl]-3-methyl-1,3-oxazolidin-2-one N,N-diisopropylethylamine (330 ⁇ L, 1.90 mmol) was added to a mixture of 8-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (55.4 mg, 0.190 mmol) obtained in Example 183-3 and phosphoryl chloride (1.64 mL, 17.9 mmol), and the mixture was stirred at 115° C.
• Example 184 5-( ⁇ [4-(benzylamino)-2-chloropyrido[4,3-d]pyrimidin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one
• the same operation as in Example 183-4 was carried out using 8-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (178 mg, 0.609 mmol) obtained in Example 183-3 and benzylamine (270 ⁇ L, 2.50 mmol) to obtain the title compound (9.80 mg, yield 4%) as a white solid.
• Example 185 5-( ⁇ [4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy ⁇ methyl)-1,3-oxazolidin-2-one (Example 185-1) Methyl 4- ⁇ [3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy ⁇ -3-oxobutanoate
• the title compound (203 mg, yield 32%) was obtained as a colorless oil by carrying out the same operation as in Example 183-1 using 5-(hydroxymethyl)-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one (434 mg, 1.83 mmol) and methyl 4-chloroacetoacetate (211 ⁇ L, 1.83 mmol) described in WO2014/085413.
• Example 185-2 Methyl 4-amino-5- ⁇ [3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy ⁇ pyridine-3-carboxylate
• the same operation as in Example 183-2 was carried out using methyl 4- ⁇ [3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy ⁇ -3-oxobutanoate (203 mg, 0.578 mmol) obtained in Example 185-1 and 3-methyl-5-nitro-pyrimidin-4-one (80.0 mg, 0.516 mmol) to obtain the title compound (115 mg, yield 58%) as a yellow oil.
• reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure.
• Example 185-4 4-Hydroxy-8- ⁇ [3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy ⁇ -1,6-naphthyridin-2(1H)-one 1M potassium bis(trimethylsilyl)amide-THF (0.530mL, 0.530mmol) was added dropwise to a THF (2mL) solution of methyl 4-(diacetylamino)-5- ⁇ [3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy ⁇ pyridine-3-carboxylate (123mg, 0.261mmol) obtained in Example 185-3 at -78°C, and the mixture was stirred for 2.5 hours while gradually warming to room temperature.
• Example 185-5 8- ⁇ [3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy ⁇ -2-oxo-1,2-dihydro-1,6-naphthyridin-4-yl trifluoromethanesulfonate N-phenylbis(trifluoromethanesulfonimide) (40.2 mg, 0.113 mmol) and a small amount of DMF were added to a solution of 4-hydroxy-8- ⁇ [3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy ⁇ -1,6-naphthyridin-2(1H)-one (35.8 mg, 0.0901 mmol) obtained in Example 185-4 and triethylamine (37.5 ⁇ L, 0.270 mmol) in THF (1 mL), and the mixture was stirred overnight at room temperature.
• Example 185-6 4-(benzylamino)-8- ⁇ [3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy ⁇ -1,6-naphthyridin-2(1H)-one
• Benzylamine (87.6 ⁇ L, 0.801 mmol) was added to a 1,4-dioxane solution (1 mL) of 8- ⁇ [3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy ⁇ -2-oxo-1,2-dihydro-1,6-naphthyridin-4-yl trifluoromethanesulfonate (42.2 mg, 0.0801 mmol) obtained in Example 185-5, and the mixture was stirred at 80 ° C.
• Example 186 5-( ⁇ [4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one (Example 186-1) Methyl 4-(diacetylamino)-5-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]pyridine-3-carboxylate A mixture of methyl 4-amino-5-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]pyridine-3-carboxylate (42.5 mg, 0.151 mmol) obtained in Example 183-2, pyridine (12.0 ⁇ L, 0.151 mmol) and acetic anhydride (1 mL) was stirred at 100° C.
• Example 186-2 8-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]-2-oxo-1,2-dihydro-1,6-naphthyridin-4-yl trifluoromethanesulfonate
• 1M potassium bis(trimethylsilyl)amide-THF (0.270 mL, 0.270 mmol
• Example 186-3 5-( ⁇ [4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy ⁇ methyl)-3-methyl-1,3-oxazolidin-2-one
• Benzylamine (16.0 ⁇ L, 0.143 mmol) and N,N-diisopropylethylamine (7.50 ⁇ L, 0.0429 mmol) were added to a solution of 8-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]-2-oxo-1,2-dihydro-1,6-naphthyridin-4-yl trifluoromethanesulfonate (12.1 mg, 0.0286 mmol) obtained in Example 186-2 in NMP (0.5 mL), and the mixture was stirred for 40 minutes at 50° C.
• Phosphoryl chloride (35.0 mg, 0.228 mmol) and N,N-diethylaniline (13.6 ⁇ L, 0.0783 mmol) were added to the obtained 4-(benzylamino)-8-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]-1,6-naphthyridin-2(1H)-one (14.9 mg, 0.0392 mmol) in 1,4-dioxane solution (2 mL), and the mixture was stirred at 80° C. for 1 hour.
• Phosphoryl chloride (52.0 mg, 0.339 mmol) was added, and the mixture was further stirred for 3 hours at 80° C.
• Example 18-7 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-ethyl-1,3-oxazolidin-2-one
• potassium tert-butoxide 9.10 mg, 0.0811 mmol
• iodoethane (10.0 ⁇ L, 0.125 mmol
• Example 188 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-(propan-2-yl)-1,3-oxazolidin-2-one
• a THF (0.6 mL)/DMF (0.2 mL) mixed solution of 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one (34.3 mg, 0.0915 mmol) obtained in Example 19, potassium tert-butoxide (22.8 mg, 0.203 mmol) and 2-iodopropane (19.0 ⁇ L, 0.183 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 3 hours, and then stirred at room temperature for 4 hours.
• Example 189 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one
• a DMF solution 0.0.4 mL of 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one (29.4 mg, 0.0784 mmol) obtained in Example 19 and TBAI (14.7 mg, 0.0398 mmol), tert-butoxypotassium (19.1 mg, 0.170 mmol) and 1-bromo-2-fluoromethane (18.0 ⁇ L, 0.157 mmol) were added and stirred at room temperature for 1 hour.
• Example 190 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-(cyclopropylmethyl)-1,3-oxazolidin-2-one
• a DMF solution 0. mL
• 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one 31.5 mg, 0.0840 mmol
• TBAI 15.8 mg, 0.0428 mmol
• tert-butoxypotassium 21.2 mg, 0.189 mmol
• (bromomethyl)cyclopropane (16.0 ⁇ L, 0.168 mmol) were added and stirred at room temperature for 1 hour.
• Example 191 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-(2,2-difluoroethyl)-1,3-oxazolidin-2-one
• a DMF solution 0.5 mL
• 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one 31.2 mg, 0.0832 mmol
• tert-butoxypotassium (22.4 mg, 0.200 mmol) and 2-iodo-1,1-difluoroethane (35.3 mg, 0.184 mmol) were added and stirred at room temperature for 3.5 hours.
• Example 192 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one
• Example 192-1 3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one
• TBAI (27.6 mg, 0.0746 mmol) was added to the reaction solution, which was stirred for 2 hours and then stirred at room temperature for 2 hours.
• tert-butoxypotassium (31.3 mg, 0.279 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (39.0 ⁇ L, 0.179 mmol) were added, and the mixture was stirred for another 37 hours.
• Water (5 mL) was then added to the reaction solution, which was then extracted with ethyl acetate and concentrated under reduced pressure.
• Example 192-2 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one 1M TBAF-THF (98.0 ⁇ L, 0.0980 mmol) was added to a THF solution (1 mL) of 3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one (34.8 mg, 0.0653 mmol) obtained in Example 19
• Example 193 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-(oxetan-3-yl)-1,3-oxazolidin-2-one
• Cesium carbonate (67.5 mg, 0.207 mmol) and 3-iodooxetane (32.1 mg, 0.174 mmol) were added to a DMF solution (0.4 mL) of 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one (40.1 mg, 0.107 mmol) obtained in Example 19, and the mixture was stirred at room temperature for 3 hours, and then stirred at 60° C.
• Example 194 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-3-(2-hydroxy-2-methylpropyl)-1,3-oxazolidin-2-one
• potassium tert-butoxide (19.1 mg, 0.170 mmol) and isobutylene oxide (15.0 ⁇ L, 0.158 mmol) were added and stirred at room temperature for 3 hours.
• Example 195 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-N-ethyl-2-oxo-1,3-oxazolidine-3-carboxamide 1,4-diazabicyclo[2.2.2]octane (23.2 mg, 0.207 mmol) and ethyl isocyanate (17.0 ⁇ L, 0.207 mmol) were added to a DMF solution (1 mL) of 5-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1,3-oxazolidin-2-one (38.7 mg, 0.103 mmol) obtained in Example 19, and the mixture was stirred at room temperature for 9 hours.
• Example 196 4-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1-(2-hydroxyethyl)pyrrolidin-2-one Using 4-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]pyrrolidin-2-one (73.9 mg, 0.198 mmol) obtained in Example 31, the same operation as in Example 192-1 was carried out to obtain crude 1-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-4-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]pyrrolidin-2-one (51.8 mg) [MS (m/z): 531 (M) + ] as a colorless solid.
• Example 19-7 4-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]-1-(2-fluoroethyl)pyrrolidin-2-one Using 4-[( ⁇ 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl ⁇ oxy)methyl]pyrrolidin-2-one (40.0 mg, 0.107 mmol) obtained in Example 31 and carrying out the same operation as in Example 189, the title compound (20.4 mg, yield 45%) was obtained as a white solid.
• HeLa cell lines were seeded (2 x 105 cells/well) in a 24-well plate (Corning) in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin (Nacalai Tesque), and the following day, the GLA splicing reporter vector (Figure 1) was transfected using Lipofectamine 2000 (Thermo Fisher Scientific). Five hours after transfection, the medium was replaced, and the evaluation compound prepared in the above example, dissolved in DMSO at 10 mM, was added at 0.1% volume (final concentration: evaluation compound 10 ⁇ M, DMSO 0.1%).
• a group containing no evaluation compound but only DMSO was used as a negative control, and a group containing 10 ⁇ M of a known splicing control compound (2-chloro-6-(2-furylmethyl)purine) was used as a positive control to provide an index of activity evaluation.
• a group containing 10 ⁇ M of a known splicing control compound (2-chloro-6-(2-furylmethyl)purine was used as a positive control to provide an index of activity evaluation.
• the fluorescence intensities of GFP (GLA splicing: exon 4 + exon 5) and RFP (GLA splicing: exon 4 + pseudo exon ( ⁇ ) + exon 5) were then measured using a BZ-X700 fluorescence microscope (Keyence Corporation), and the ratio (GFP signal/RFP signal) was calculated.
• the fluorescence ratio upon treatment with 10 ⁇ M of a known compound (positive control) was set to 1, and the activity value (GLA_Signal_REC10_2) of each evaluation compound was quantified.

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