Nitrogen-containing heterocyclic compound

Abstract

The present invention provides, in one embodiment, a compound capable of suppressing splicing abnormalities, which are a cause of the onset or progression of a disease, or a pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to a compound or a pharmaceutically acceptable salt thereof that is capable of suppressing abnormal splicing that is a cause of the onset or progression of a disease. Background Art

[0002] RNA splicing refers to the process of removing introns from transcribed mRNA precursors and connecting exons to each other. In this process, not only are exons always spliced, but there are also cases where the recognition of specific exon sequences or intron sequences is controlled at a certain ratio depending on the tissue or cell lineage.

[0003] In addition, there are cases where a splicing control region is newly formed due to a gene mutation, even though it is originally an intron region, and as a result, part of the intron region is recognized as an exon, causing abnormal splicing. This abnormal splicing may cause various diseases.

[0004] Fabry disease is a genetic disease, some of which are caused by splicing abnormalities. As a treatment for Fabry disease, enzyme replacement therapy using genetically recombinant α-galactosidase A (GLA) enzyme protein has been developed in addition to symptomatic treatment, but treatment that acts on the gene itself, which is the root cause, has not been carried out.

[0005] Abnormal splicing is also known to occur in many other genetic diseases, and development of new compounds capable of inhibiting abnormal splicing is desired.

[0006] The present inventors have discovered a splicing-controlling compound (eg, 2-chloro-6-(2-furanylmethyl)purine) for diseases caused by abnormal splicing, such as cardiac Fabry disease (eg, Patent Document 1).

[0007] Prior art literature

[0008] Patent Literature

[0009] Patent Document 1: WO2018 / 151326 Summary of the invention

[0010] Problems to be solved by the invention

[0011] The present disclosure provides a compound or a pharmaceutically acceptable salt thereof that is capable of suppressing abnormal splicing that is a cause of the onset or progression of a disease.

[0012] Means for solving problems

[0013] The present disclosure, in one embodiment, relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[0014] [Chemical formula 1]

[0015]

[0016] In formula (I),

[0017] A 1 、A 2 、A 3 and A 4 are each independently CH or N,

[0018] Ar is an aryl group having 6 to 12 ring members, or a heteroaryl group having 5 to 6 ring members and having 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring, and the aryl group having 6 to 12 ring members and the heteroaryl group having 5 to 6 ring members may be substituted with one or more halogen atoms,

[0019] n is 1 or 2,

[0020] R 1 is a halogen atom,

[0021] R 2 is a hydrogen atom, a halogen atom, or a C1-C4 alkoxy group,

[0022] R 3 is a hydrogen atom, a C3-C6 cycloalkyl group, or a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring,

[0023] R 3 The C3-C6 cycloalkyl group and the 4- to 6-membered heterocyclic group in may have one or two oxo groups (=O) on the ring, and / or the C3-C6 cycloalkyl group and the 4- to 6-membered heterocyclic group may be substituted with one or two substituents selected from the following Group A.

[0024] Group A:

[0025] A halogen atom, a hydroxyl group, a C1-C4 alkyl group which may be substituted by a halogen atom, a C1-C6 hydroxyalkyl group which may be substituted by a halogen atom, a C1-C2 alkoxy group which may be substituted by a halogen atom, a C2-C6 alkoxyalkyl group which may be substituted by a halogen atom, a C3-C6 alkoxyalkoxyalkyl group which may be substituted by a halogen atom, a C1-C2 alkylsulfonyl group, an acetyl group (-C(O)CH3), a cyclopropylmethyl group, a phenyl group which may be substituted by a halogen atom, a phenyl C1-C3 alkyl group which may be substituted by a halogen atom, a 3- to 5-membered heterocyclic group having 1 or 2 oxygen atoms, a 3- to 5-membered heterocyclic group-C1-C3 alkyl group having 1 or 2 oxygen atoms, an aminooxy C1-C3 alkyl group, a C2-C4 alkynyl group which may be substituted by a halogen atom, a protected amino C2-C6 (alkoxyalkyl), a C1-C3 alkylaminocarbonyl group, a 5-membered heteroaryl C1-C3 alkyl group, a C2-C4 alkylene (bonded to the same carbon), a C1-C4 alkylenedioxy (bonded to the same carbon), a C1-C4 alkoxy-C1-C4 alkyl (bonded to the same carbon).

[0026] In one aspect, the present disclosure relates to a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof.

[0027] [Chemical formula 2]

[0028]

[0029] In formula (II),

[0030] 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, and the furyl group, the phenyl group and the pyridyl group may be substituted by one fluorine atom,

[0031] R 1 is a halogen atom,

[0032] R 4 , R 5 and R 6 are each independently 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,

[0033] R 3a is a hydrogen atom or any group selected from the following Group C.

[0034] Group C:

[0035] [Chemical formula 3]

[0036]

[0037] 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 (-C2H4OCH3), a methoxyethoxyethyl group (-C2H4OC2H4OCH3), a methanesulfonyl group (-S(O)2CH3), an acetyl group (-C(O)CH3), a cyclopropylmethyl group, a phenyl group, a benzyl group, an oxetanyl group, an oxetanylmethyl group, a 2-amino-2-oxoethyl group (-CH2C(O)NH2), a propargyl group (-CH2C≡CH), a tert-butoxycarbonyl-2-aminoethoxyethyl group (-C2H4OC2H4NHC(O)O(CH3)3), an ethylaminocarbonyl group (-C(O)NHCH2CH3) or an oxadiazolylmethyl group,

[0038] R Q2 、R Q3 and R Q4 are each independently a hydrogen atom, a fluorine atom, a hydroxy group, a methyl group or a trifluoromethyl group,

[0039] R Q5 and R Q6 are each independently a hydrogen atom, a fluorine atom, a hydroxy group, a methyl group, a methoxy group (-OCH3), a difluoromethoxy group (-OCHF2) or a methoxymethyl group,

[0040] R Q7 is a hydrogen atom, a fluorine atom, a methyl group or an ethyl group, or is an ethylenedioxy group (bonded to the same carbon) or a methylenedioxymethyl group (bonded to the same carbon).

[0041] This disclosure in one aspect relates to a compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof.

[0042] [Chemical formula 4]

[0043]

[0044] In formula (III),

[0045] Ar is a furanyl group or a phenyl group,

[0046] R 1 is a chlorine atom,

[0047] A 2 、A 3 and A 4 are each independently CH or N, and any one of A 2 、A 3 and A 4 is N, and R 3b is a hydrogen atom or any group selected from the following Group D.

[0048] Group D:

[0049] [Chemical Formula 5]

[0050]

[0051] In one aspect, the present disclosure relates to a compound represented by the following formula (IV) or a pharmaceutically acceptable salt thereof.

[0052] [Chemical Formula 6]

[0053]

[0054] In formula (IV),

[0055] Ar is furyl or phenyl,

[0056] R 1 is a chlorine atom,

[0057] R 3c is a hydrogen atom or any group selected from the following Group E.

[0058] Group E:

[0059] [Chemical Formula 7]

[0060]

[0061] R Q1 is a hydrogen atom, methyl, acetyl, methanesulfonyl, fluoroethyl or hydroxyethyl,

[0062] R Q5 is a hydrogen atom or methyl.

[0063] In one aspect, the present disclosure relates to a compound represented by the following formula (V) or a pharmaceutically acceptable salt thereof.

[0064] [Chemical Formula 8]

[0065]

[0066] In formula (V),

[0067] Ar is furyl or phenyl,

[0068] R 1 is a chlorine atom,

[0069] A 2 、A 3 and A 4 are each independently CH or N, and any one of A 2 、A 3 and A 4 is N, R 3dis a hydrogen atom or any group selected from the following Group F.

[0070] Group F:

[0071] [Chemical Formula 9]

[0072]

[0073] R Q1 is a hydrogen atom, methyl group, fluoroethyl group or hydroxyethyl group,

[0074] R Q5 is a hydrogen atom or methyl group.

[0075] In another aspect, the present disclosure relates to a pharmaceutical composition containing the compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient.

[0076] In another aspect, the present disclosure relates to a pharmaceutical composition for treating a genetic disease caused by splicing abnormality, which contains the compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient.

[0077] In another aspect, the present disclosure relates to a pharmaceutical composition for treating a genetic disease caused by splicing abnormality, which uses the compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient.

[0078] In another aspect, the present disclosure relates to a method for treating a genetic disease caused by splicing abnormality, which includes the step of administering the compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject.

[0079] In another aspect, the present disclosure relates to the use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for treating a genetic disease caused by splicing abnormality.

[0080] Effect of the Invention

[0081] The present disclosure can provide a compound or a pharmaceutically acceptable salt thereof that can inhibit splicing abnormality which is a cause of the onset or progression of a disease. Description of the Drawings

[0082] Figure 1 A schematic diagram showing a GLA splicing reporter vector is presented. Through normal splicing of exon 4 + exon 5, green fluorescent protein GFP is expressed as a GST (glutathione S-transferase) fusion protein. However, when disease-type splicing of exon 4 + pseudo-exon (Ψ) + exon 5 occurs, the translation frame shifts by one base, and red fluorescent protein RFP is expressed. Detailed Description

[0083] In the present disclosure, the "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, more preferably a chlorine atom.

[0084] In the present disclosure, "being capable of being substituted by a halogen atom" means unsubstituted or one or more hydrogen atoms are substituted by a halogen atom.

[0085] In the present disclosure, "C1-C4 alkyl" represents a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. As the C1-C4 alkyl, in one or more embodiments, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl etc. can be cited.

[0086] In the present disclosure, as the "C1-C4 alkyl that can be substituted by a halogen atom", it may include a group formed by substituting 1, 2 or 3 hydrogen atoms of the "C1-C4 alkyl" with a halogen atom. As the "C1-C4 alkyl that can be substituted by a halogen atom", in one or more embodiments, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, difluoroethyl, 2,2,2-trifluoroethyl and 1,2-difluoropropyl etc. can be cited.

[0087] In the present disclosure, "C1-C6 hydroxyalkyl" represents a group formed by substituting one or two hydrogen atoms of a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms with a hydroxyl group. As the C1-C6 hydroxyalkyl, in one or more embodiments, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1-hydroxyisopropyl, 1-hydroxybutyl, 2-hydroxybutyl, 2-hydroxyisobutyl, 1-hydroxypentyl, 2-hydroxypentyl, 1-hydroxyhexyl and 1,2-hydroxyethyl etc. can be cited.

[0088] In the present disclosure, "C1-C4 alkylene" represents a straight-chain or branched-chain alkylene group having 1 to 4 carbon atoms. As the C1-C4 alkylene, in one or more embodiments, methylene, ethylene (-(CH2)2-), trimethylene (-(CH2)3-), tetramethylene, methylmethylene (-CH(CH3)-) and methylethylene (-(CH(CH3)CH2- and -CH2CH(CH3)-)) etc. can be cited.

[0089] In the present disclosure, "C2-C4 alkylene (bonded to the same carbon)" may refer to a C3-C5 cycloalkyl group formed by bonding two bonding arms of the C2-C4 alkylene to the same carbon and the carbon to which they are bonded.

[0090] In the present disclosure, "C1-C4 alkylenedioxy" represents a straight-chain or branched alkylene group having 2 oxygens (-O-) and 1 to 4 carbon atoms. As C1-C4 alkylenedioxy, in one or more embodiments, methylenedioxy (-O-CH2-O-), ethylenedioxy (-O-CH2=CH2-O-), etc. may be cited. In the present disclosure, "C1-C4 alkylenedioxy (bonded to the same carbon)" may refer to a C2-C4 cycloalkylenedioxy formed by bonding the two bonding arms of C1-C4 alkylenedioxy to the same carbon and the carbon to which they are bonded.

[0091] In the present disclosure, as C1-C4 alkoxy-C1-C4 alkyl, in one or more embodiments, methyloxymethyl (-CH2-O-CH2-), etc. may be cited. In the present disclosure, "C1-C4 alkoxy-C1-C4 alkyl (bonded to the same carbon)" may refer to a C2-C4 cycloalkylenedioxy formed by bonding the two bonding arms of C1-C4 alkyleneoxy-C1-C4 alkyl to the same carbon and the carbon to which they are bonded.

[0092] In the present disclosure, "C1-C4 alkoxy" represents a group formed by bonding an alkyl group having 1 to 4 carbon atoms to an oxygen atom. As C1-C4 alkoxy, in one or more embodiments, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, etc. may be cited.

[0093] In the present disclosure, "C1-C2 alkoxy" represents a group formed by bonding an alkyl group having 1 to 2 carbon atoms to an oxygen atom. As C1-C2 alkoxy, in one or more embodiments, methoxy (-OCH3), ethoxy, etc. may be cited.

[0094] In the present disclosure, as "C1-C2 alkoxy that may be substituted by a halogen atom", it includes a group formed by substituting 1, 2, or 3 hydrogen atoms of "C1-C2 alkoxy" with a halogen atom. As C1-C2 alkoxy that may be substituted by a halogen atom, in one or more embodiments, fluoromethoxy, difluoromethoxy (-OCHF2), trifluoromethoxy, chloromethoxy, dichloromethoxy, 1-fluoroethoxy, 1-chloroethoxy, 2-fluoroethoxy, etc. may be cited.

[0095] In the present disclosure, "C2-C6 alkoxyalkyl" refers to an alkoxyalkyl having 2 to 6 carbon atoms, which represents a group in which one hydrogen atom of the alkyl group is replaced by an alkoxy group. As C2-C6 alkoxyalkyl, in one or more embodiments, C1-C3 alkoxy C1-C3 alkyl and the like can be cited. As C2-C6 alkoxyalkyl, in one or more embodiments, methoxymethyl (-CH2OCH3), ethoxymethyl, n-propoxymethyl, isopropoxymethyl, methoxyethyl (-C2H4OCH3), ethoxyethyl, propoxyethyl, and isopropoxyethyl can be cited.

[0096] In the present disclosure, as "C2-C6 alkoxyalkyl that can be substituted by a halogen atom", it includes a group in which 1, 2, or 3 hydrogen atoms of "C2-C6 alkoxyalkyl" are replaced by a halogen atom. As C2-C6 alkoxyalkyl that can be substituted by a halogen atom, in one or more embodiments, halogenated C1-C3 alkoxy C1-C3 alkyl and the like can be cited. As C2-C6 alkoxyalkyl that can be substituted by a halogen atom, in one or more embodiments, fluoromethoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, fluoromethoxyethyl, difluoromethoxyethyl, trifluoromethoxyethyl, fluoroethoxyethyl, difluoroethoxyethyl, and trifluoroethoxyethyl can be cited.

[0097] In the present disclosure, "C3-C6 alkoxyalkoxyalkyl" refers to an alkoxyalkoxyalkyl having 3 to 6 carbon atoms, which represents a group in which one hydrogen atom of the alkoxyalkyl is replaced by an alkoxy group. As C3-C6 alkoxyalkoxyalkyl, in one or more embodiments, C1-C2 alkoxy C1-C2 alkoxy C1-C2 alkyl and the like can be cited. As C3-C6 alkoxyalkoxyalkyl, in one or more embodiments, methoxymethoxymethyl, methoxyethoxymethyl, and methoxyethoxyethyl (-C2H4OC2H4OCH3) can be cited.

[0098] In the present disclosure, as "C3-C6 alkoxyalkoxyalkyl that can be substituted by a halogen atom", it includes a group in which 1, 2, or 3 hydrogen atoms of "C3-C6 alkoxyalkoxyalkyl" are replaced by a halogen atom. As C3-C6 alkoxyalkoxyalkyl that can be substituted by a halogen atom, in one or more embodiments, halogenated C1-C2 alkoxy C1-C2 alkoxy C1-C2 alkyl and the like can be cited. As C3-C6 alkoxyalkoxyalkyl that can be substituted by a halogen atom, in one or more embodiments, fluoromethoxymethoxymethyl, difluoromethoxymethoxymethyl, trifluoromethoxymethoxymethyl, fluoromethoxyethoxymethyl, difluoromethoxyethoxymethyl, trifluoromethoxyethoxymethyl, fluoromethoxyethoxyethyl, difluoromethoxyethoxyethyl, and trifluoromethoxyethoxyethyl can be cited.

[0099] In the present disclosure, "C1-C2 alkylsulfonyl" represents a group formed by bonding an alkyl group having 1 to 2 carbon atoms to the sulfur atom of the sulfonyl group. As the C1-C2 alkylsulfonyl, in one or more embodiments, methylsulfonyl (-S(O)2CH3) and ethylsulfonyl can be cited.

[0100] In the present disclosure, as the "C1-C2 alkylsulfonyl that can be substituted by a halogen atom", it includes a group formed by substituting 1, 2, or 3 hydrogen atoms of the "C1-C2 alkylsulfonyl" with a halogen atom. As the C1-C2 alkylsulfonyl that can be substituted by a halogen atom, in one or more embodiments, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, fluoroethylsulfonyl, difluoroethylsulfonyl, and trifluoroethylsulfonyl can be cited.

[0101] In the present disclosure, "phenyl C1-C3 alkyl" represents a group formed by substituting 1 hydrogen atom of the phenyl group with an alkyl group having 1 to 3 carbon atoms. As the phenyl C1-C3 alkyl, in one or more embodiments, benzyl, phenethyl, and phenylpropyl can be cited.

[0102] In the present disclosure, as the "phenyl C1-C3 alkyl that can be substituted by a halogen atom", it includes a group formed by substituting 1, 2, or 3 hydrogen atoms of the "C1-C3 alkyl" with a halogen atom. As the phenyl C1-C3 alkyl that can be substituted by a halogen atom, in one or more embodiments, fluorobenzyl, difluorobenzyl, trifluorobenzyl, fluorophenethyl, difluorophenethyl, trifluorophenethyl, fluorophenylpropyl, diphenylpropyl, and trifluorophenylpropyl can be cited.

[0103] In the present disclosure, "aminooxo C1-C3 alkyl" represents a group formed by substituting 1 hydrogen atom of the C1-C3 alkyl with an aminooxo group. As the aminooxo C1-C3 alkyl, in one or more embodiments, 2-amino-2-oxoethyl (-CH2C(O)NH2) can be cited.

[0104] In the present disclosure, "C2-C4 alkynyl" represents an alkyl group having at least one carbon-carbon triple bond (-C≡C-) in the molecule. As the C2-C4 alkynyl, in one or more embodiments, -C≡CH, -C≡CCH3, -C≡CCH2CH3, and propargyl (-CH2C≡CH) can be cited.

[0105] In the present disclosure, "C2-C4 alkynyl that can be substituted by a halogen atom" includes a group formed by substituting at least one hydrogen atom of "C2-C4 alkynyl" with a halogen atom. As C2-C4 alkynyl that can be substituted by a halogen atom, in one or more embodiments, -C≡CF, -C≡CCF3, -C≡CCH2CF3, -CH2C≡CF, etc. can be cited.

[0106] In the present disclosure, "C2-C6 (alkoxyalkyl) that can be protected" means C2-C6 alkoxyalkyl in which one hydrogen atom of C2-C6 alkoxyalkyl can be protected by a protecting group and C2-C6 alkoxyalkyl not protected by a protecting group. As the protecting group, in one or more embodiments, tert-butoxycarbonyl (Boc) amino, etc. can be cited. As C2-C6 (alkoxyalkyl) that can be protected, in one or more embodiments, tert-butoxycarbonyl-2-aminoethoxyethyl (-C2H4OC2H4NHC(O)O(CH3)3), etc. can be cited.

[0107] In the present disclosure, "C1-C3 alkylaminocarbonyl" means a group formed by substituting one hydrogen atom of C1-C3 alkyl with aminocarbonyl. As C1-C3 alkylaminocarbonyl, in one or more embodiments, methylaminocarbonyl, ethylaminocarbonyl (-C(O)NHCH2CH3), etc. can be cited.

[0108] In the present disclosure, "aryl having 6 to 12 members" means a monocyclic and polycyclic aromatic hydrocarbon ring system having 6 to 12 carbon atoms. As aryl having 6 to 12 members, in one or more embodiments, an aromatic hydrocarbon group having 6 to 12 carbon atoms can be cited. As aryl having 6 to 12 members, in one or more embodiments, phenyl, 1-naphthyl, 2-naphthyl, acenaphthyl, azulenyl, etc. can be cited.

[0109] In the present disclosure, "C3-C6 cycloalkyl" means a cyclic alkyl (saturated hydrocarbon group (ring)) having 3 to 6 carbon atoms. As C3-C6 cycloalkyl, in one or more embodiments, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. can be cited.

[0110] In the present disclosure, "heterocyclic group having 4 to 6 members" means a saturated or unsaturated monocyclic or polycyclic 4- to 6-membered cycloalkyl group having 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring. The heterocyclic group having 4 to 6 members 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 in one or more embodiments.

[0111] As a heterocyclic group, in one or more embodiments, examples include oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, pyranyl, tetrahydrothiopyranyl, thiopyranyl, piperidinyl, imidazolidinyl, 1,4-dioxanyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 1,4-oxathianyl, morpholinyl, thiomorpholinyl, 1,4-dithianyl, piperazinyl, 1,4-thiazepinyl, oxepanyl, thiepanyl, azepanyl, isothiazolidinyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, 1,4-azaphosphanyl, 1,4-diazepanyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, chromanyl, chromenyl, oxazolidinyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, oxazinyl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, 7-oxa-1-aza-spiro[4.4]nonyl, 3-azabicyclo[3.1.0]hexyl, indolinyl, dihydroindolinyl, octahydro-1H-indolyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptyl, 3,4-dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridyl, 1,2,5,6-tetrahydropyridyl, and tetrahydro-1H-benzo[d]azepinyl, etc. As the heterocyclic group having 4 to 6 members, it may have one or two oxo groups (=O) on the ring. As the heterocyclic group having 4 to 6 members with an oxo group on the ring, in one or more embodiments, examples include 2-oxooxazolidinyl, 2-oxooxazinyl, 3-oxomorpholinyl, 2-oxoazetidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxoimidazolidinyl, 2-oxo-1,3-dioxolanyl, 2-oxo-1,3-dioxolenyl, 1,1-dioxothietanyl, 1,1-dioxotetrahydrothienyl, and 1,1-dioxoisothiazolidinyl, etc. and so on.

[0112]

[0113] ​In the present disclosure, the "3- to 5-membered heterocyclic group having 1 or 2 oxygen atoms" refers to a saturated or unsaturated monocyclic 3- to 5-membered cycloalkyl group having an oxygen atom as a heteroatom. As the 3- to 5-membered heterocyclic group having 1 or 2 oxygen atoms, in one or more embodiments, oxetanyl, oxazolyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, dioxolanyl, and dioxolyl can be mentioned, etc.

[0114] In the present disclosure, the "3- to 5-membered heterocyclic group having 1 or 2 oxygen atoms-C1-C3 alkyl" refers to a group in which one hydrogen atom of the 3- to 5-membered heterocyclic group having 1 or 2 oxygen atoms as a heteroatom is substituted by a C1-C3 alkyl group. As the 3- to 5-membered heterocyclic group having 1 or 2 oxygen atoms-C1-C3 alkyl, in one or more embodiments, oxetanylmethyl and oxadiazolylmethyl can be mentioned, etc.

[0115] In the present disclosure, the "5- to 6-membered heteroaryl" refers to a 5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring. As the 5-membered heteroaryl, in one or more embodiments, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and oxadiazolyl can be mentioned, etc. As the 6-membered heteroaryl, in one or more embodiments, diazinylpyridyl, pyridyl, and pyrimidinyl can be mentioned, etc.

[0116] In the present disclosure, the "5-membered heteroaryl C1-C3 alkyl" refers to a group in which one hydrogen atom of the 5-membered heteroaryl is substituted by a C1-C3 alkyl group. As the 5-membered heteroaryl C1-C3 alkyl, in one or more embodiments, oxadiazolylmethyl can be mentioned, etc.

[0117] [Compound represented by formula (I)]

[0118] The preferred substituents or examples in the compound represented by formula (I) in the present disclosure are described below.

[0119] In one or more embodiments, A 1 is N or CH, A 2 , A 3 and A 4 0 or 1 of them is N, and 2 or 3 of them are CH. In one or more embodiments, A 1 is N, and A 2 , A 3 and A 4 are CH; or A 1 is N, and any one of A 2 , A 3 and A 4 is N; or A 1, A 2 , A 3 and A 4 are all CH; or A 1 is CH, and among A 2 , A 3 and A 4 , any one of them is N.

[0120] In one or more embodiments, Ar is phenyl which can be substituted by 1 halogen atom, or 5- to 6-membered heteroaryl which can be substituted by 1 halogen atom. As the 5-membered heteroaryl, in one or more embodiments, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and oxadiazolyl etc. can be cited. As the 6-membered heteroaryl, in one or more embodiments, pyridyl and pyrimidinyl etc. can be cited. As Ar, in one or more embodiments, phenyl, fluorophenyl, furyl, fluorofuryl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyridyl, fluoropyridyl, and pyrimidinyl etc. can be cited.

[0121] R 1 is a chlorine atom or a bromine atom in one or more embodiments.

[0122] R 2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or C1-C2 alkoxy in one or more embodiments.

[0123] R 3 Among them, the heterocyclic group has 1 oxygen atom, 1 sulfur atom, 1 nitrogen atom, 1 oxygen atom and 1 nitrogen atom, 1 sulfur atom and 1 nitrogen atom, 2 oxygen atoms, or 2 nitrogen atoms in one or more embodiments.

[0124] R 3 Among them, as the heterocyclic group, in one or more embodiments, oxetanyl, tetrahydrofuryl, furyl, tetrahydropyranyl, dioxolanyl, and dioxanyl etc. can be cited.

[0125] R 3 Among them, as the heterocyclic group having an oxo group on the ring, in one or more embodiments, 2-oxooxazolidinyl, 2-oxooxazinyl, 3-oxomorpholinyl, 2-oxoazetidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxoimidazolidinyl, 2-oxo-1,3-dioxolanyl, 2-oxo-1,3-dioxolenyl, 1,1-dioxothietanyl, 1,1-dioxotetrahydrothienyl, and 1,1-dioxoisothiazolidinyl etc. can be cited.

[0126] R 3Among them, for a heterocyclic group that does not have an oxo group as a substituent on the ring, in one or more embodiments, oxazolyl, azetidinyl, pyrrolidinyl, dioxolanyl, dioxanyl, tetrahydrofuryl, pyranyl, furyl, and oxetanyl can be cited, etc.

[0127] R 3 The substituents of are selected from the following Group B in one or more embodiments.

[0128] Group B:

[0129] Fluorine atom; hydroxyl group; methyl, ethyl, isopropyl;

[0130] Fluoroethyl, difluoroethyl, trifluoromethyl; 2-hydroxyethyl, 2-hydroxy-2-methylpropyl; methoxy (-OCH3), difluoromethoxy (-OCHF2); methoxymethyl (-CH2OCH3), methoxyethyl (-C2H4OCH3); methoxyethoxyethyl (-C2H4OC2H4OCH3); methanesulfonyl (-S(O)2CH3); acetyl (-C(O)CH3); cyclopropylmethyl; phenyl; benzyl; oxetanyl; oxetanylmethyl; 2-amino-2-oxoethyl (-CH2C(O)NH2); propargyl; tert-butoxycarbonyl-2-aminoethoxyethyl (-C2H4OC2H4NHC(O)O(CH3)3); ethylaminocarbonyl (-C(O)NHCH2CH3); oxadiazolylmethyl;

[0131] Ethylene (bonded to the same carbon); methylenedioxy (bonded to the same carbon), ethylenedioxy (bonded to the same carbon); methylenoxymethyl (bonded to the same carbon)

[0132] In the present disclosure, as a preferred example of the compound represented by formula (I), in one or more embodiments, the compounds represented by formula (II), (III), (IV) or (V) or their pharmaceutically acceptable salts can be cited.

[0133] [Compound represented by formula (II)]

[0134] The present disclosure in another aspect relates to the compound represented by formula (II) or its pharmaceutically acceptable salt.

[0135] [Chemical formula 10]

[0136]

[0137] In formula (II),

[0138] Ar is furyl, phenyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl or oxadiazolyl, and furyl, phenyl and pyridyl may be substituted by one fluorine atom.

[0139] R 1 is a halogen atom.

[0140] R 4 , R 5 and R 6 are each independently 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.

[0141] R 3a is a hydrogen atom or any group selected from the following Group C.

[0142] Group C:

[0143] [Chemical formula 11]

[0144]

[0145] 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 (-C2H4OCH3), a methoxyethoxyethyl group (-C2H4OC2H4OCH3), a methanesulfonyl group (-S(O)2CH3), an acetyl group (-C(O)CH3), a cyclopropylmethyl group, a phenyl group, a benzyl group, an oxetanyl group, an oxetanylmethyl group, a 2-amino-2-oxoethyl group (-CH2C(O)NH2), a propargyl group (-CH2C≡CH), a tert-butoxycarbonyl-2-aminoethoxyethyl group (-C2H4OC2H4NHC(O)O(CH3)3), an ethylaminocarbonyl group (-C(O)NHCH2CH3) or an oxadiazolylmethyl group.

[0146] R Q2 , R Q3 and R Q4 are each independently a hydrogen atom, a fluorine atom, a hydroxy group, a methyl group or a trifluoromethyl group.

[0147] R Q5 and R Q6 are each independently a hydrogen atom, a fluorine atom, a hydroxy group, a methyl group, a methoxy group (-OCH3), a difluoromethoxy group (-OCHF2) or a methoxymethyl group.

[0148] R Q7is a hydrogen atom, a fluorine atom, a methyl group, or an ethyl group, or is ethylenedioxy (bonded to the same carbon) or methyloxymethyl (bonded to the same carbon).

[0149] [The compound represented by formula (III)]

[0150] In another aspect, the present disclosure relates to the compound represented by formula (III) or a pharmaceutically acceptable salt thereof.

[0151] [Chemical formula 12]

[0152]

[0153] In formula (III),

[0154] Ar is a furyl group or a phenyl group,

[0155] R 1 is a chlorine atom,

[0156] A 2 , A 3 and A 4 are each independently CH or N, and any one of A 2 , A 3 and A 4 is N, and R 3b is a hydrogen atom or any group selected from the following Group D.

[0157] Group D:

[0158] [Chemical formula 13]

[0159]

[0160] [The compound represented by formula (IV)]

[0161] In another aspect, the present disclosure relates to the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof.

[0162] [Chemical formula 14]

[0163]

[0164] In formula (IV),

[0165] Ar is a furyl group or a phenyl group,

[0166] R 1 is a chlorine atom,

[0167] R 3c is a hydrogen atom or any group selected from the following Group E.

[0168] Group E:

[0169] [Chemical Formula 15]

[0170]

[0171] R Q1 is a hydrogen atom, methyl group, acetyl group, methanesulfonyl group, fluoroethyl group or hydroxyethyl group,

[0172] R Q5 is a hydrogen atom or methyl group.

[0173] [Compound represented by formula (V)]

[0174] In another aspect, the present disclosure relates to a compound represented by formula (V) or a pharmaceutically acceptable salt thereof.

[0175] [Chemical Formula 16]

[0176]

[0177] In formula (V),

[0178] Ar is a furyl group or a phenyl group,

[0179] A 2 、A 3 and A 4 are each independently CH or N, and any one of A 2 、A 3 and A 4 is N, R 1 is a chlorine atom,

[0180] R 3d is a hydrogen atom or any group selected from the following Group F.

[0181] Group F:

[0182] [Chemical Formula 17]

[0183]

[0184] R Q1 is a hydrogen atom, methyl group, fluoroethyl group or hydroxyethyl group,

[0185] R Q5 is a hydrogen atom or methyl group.

[0186] In one or more embodiments, the compound represented by formula (V) preferably has A 2 and A 3 being CH, and A 4 being N. In one or more embodiments, the compound represented by formula (V) preferably has R 3d being the following group.

[0187] [Chemical Formula 18]

[0188]

[0189] As a compound of the present disclosure, in one or more embodiments, it is preferably any compound selected from the following group or a pharmaceutically acceptable salt thereof.

[0190] 2-chloro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine,

[0191] 2-chloro-N-(furan-2-ylmethyl)-8-methoxyquinolin-4-amine,

[0192] 2-chloro-7-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine,

[0193] 2-chloro-5-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine,

[0194] 2-bromo-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine,

[0195] 2-chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[3,4-d]pyrimidin-4-amine,

[0196] 2-chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[4,3-d]pyrimidin-4-amine,

[0197] 2-chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[3,2-d]pyrimidin-4-amine,

[0198] 2-chloro-6-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine,

[0199] 2-chloro-N-(furan-2-ylmethyl)-6,8-dimethoxyquinazolin-4-amine,

[0200] 2-chloro-N-(furan-2-ylmethyl)-7,8-dimethoxyquinazolin-4-amine,

[0201] 2-chloro-8-methoxy-N-(thiophen-2-ylmethyl)quinazolin-4-amine,

[0202] 2-chloro-8-methoxy-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine,

[0203] 2-chloro-8-methoxy-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine,

[0204] 2-Chloro-8-methoxy-N-(thiophen-3-ylmethyl)quinazolin-4-amine,

[0205] 2-Chloro-8-methoxy-N-(pyridin-4-ylmethyl)quinazolin-4-amine,

[0206] 2-Chloro-N-(2-fluorobenzyl)-8-methoxyquinazolin-4-amine,

[0207] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0208] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0209] (5R)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0210] (5S)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0211] 1-{3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-1-yl}ethanone,

[0212] 2-Chloro-N-(furan-2-ylmethyl)-8-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine,

[0213] 2-Chloro-8-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0214] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0215] 2-Chloro-8-[(2,2-difluorocyclobutyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0216] 2-Chloro-8-(1,4-dioxaspiro[4.4]nonan-7-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0217] 3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclopentanone,

[0218] 2-Chloro-8-(1,4-dioxaspiro[4.4]nonan-6-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0219] 2-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclopentanone,

[0220] 4-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0221] 3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclobutanol,

[0222] 2-Chloro-8-{[3-(difluoromethoxy)cyclobutyl]methoxy}-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0223] 5-[({2,6-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0224] (3S,5R)-5-[({2,6-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methylpyrrolidin-2-one,

[0225] 5-({[4-(Benzylamino)-2,6-dichloroquinazolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[0226] 5-[({2,7-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0227] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinolin-4-amine,

[0228] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0229] 5-({[4-(Benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[0230] 5-({[4-(Benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0231] 5-({[4-(Benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0232] 5-({[4-(Benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one, 2-chloro-N-(furan-2-ylmethyl)-8-(tetrahydrofuran-3-ylmethoxy)quinazolin-4-amine,

[0233] 2-chloro-N-(furan-2-ylmethyl)-8-(tetrahydro-2H-pyran-3-ylmethoxy)quinazolin-4-amine, 2-chloro-8-[(1-fluorocyclopropyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0234] 1-[2-({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)ethyl]imidazolidin-2-one,

[0235] 2-chloro-8-[(1,1-dioxotetrahydrothiophen-3-yl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0236] 7-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-6-oxa-4-azaspiro[2.4]heptan-5-one,

[0237] (3S,5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methylpyrrolidin-2-one,

[0238] 2-chloro-N-(furan-2-ylmethyl)-8-[(2-methyl-1,1-dioxo-1,2-thiazolidin-4-yl)methoxy]quinazolin-4-amine,

[0239] 2-chloro-8-(furan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0240] 3-[2-({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)ethyl]-1,3-oxazolidin-2-one,

[0241] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-dioxolan-2-one,

[0242] 2-chloro-8-[2-(1,4-dioxan-2-yl)ethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0243] 2-Chloro-N-(furan-2-ylmethyl)-8-[(3-methoxy-4,5-dihydro-1,2-oxazol-5-yl)methoxy]quinazolin-4-amine,

[0244] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]morpholin-3-one,

[0245] 1-Benzyl-4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]imidazolidin-2-one,

[0246] 2-Chloro-N-(furan-2-ylmethyl)-8-(2-oxaspiro[3.3]heptan-6-ylmethoxy)quinazolin-4-amine,

[0247] 2-Chloro-8-(cyclopentylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0248] 1-{3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]azetidin-1-yl}ethanone,

[0249] 2-Chloro-8-(furan-3-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0250] 2-Chloro-N-(furan-2-ylmethyl)-8-{[1-(trifluoromethyl)cyclobutyl]methoxy}quinazolin-4-amine,

[0251] 2-Chloro-8-(cyclohexylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0252] 2-Chloro-N-(furan-2-ylmethyl)-8-(tetrahydrofuran-2-ylmethoxy)quinazolin-4-amine,

[0253] 1-{2-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-1-yl}ethanone,

[0254] 4-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0255] 3-Benzyl-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0256] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-phenyl-1,3-oxazolidin-2-one,

[0257] (3S,5R)-5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-methylpyrrolidin-2-one

[0258] (3R,5R)-5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-methylpyrrolidin-2-one

[0259] 4-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)pyrrolidin-2-one

[0260] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-4,4-dimethyl-1,3-oxazolidin-2-one

[0261] 6-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazin-2-one

[0262] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-methylpyrrolidin-2-one

[0263] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-5-methyl-1,3-dioxol-2-one

[0264] 6-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]piperidin-2-one

[0265] (5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one

[0266] (5S)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one

[0267] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]azetidin-2-one

[0268] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-5-methylpyrrolidin-2-one

[0269] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-4-methyl-1,3-oxazolidin-2-one

[0270] 5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0271] 5-({[(4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one,

[0272] 5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0273] 5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0274] 5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0275] 1-{3-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]azetidin-1-yl}ethanone,

[0276] 4-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0277] 2-chloro-N-(furan-2-ylmethyl)-8-{[1-(methanesulfonyl)azetidin-3-yl]methoxy}quinolin-4-amine,

[0278] (3S,5R)-5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-3-methylpyrrolidin-2-one,

[0279] 2-chloro-N-(furan-2-ylmethyl)-8-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}quinolin-4-amine,

[0280] 1-{3-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-1-yl}ethanone,

[0281] (5R)-5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0282] (5S)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0283] (5R)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0284] (5S)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0285] 5-({[4-(Benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one,

[0286] 5-({[4-(Benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0287] 5-({[4-(Benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0288] (3S,5R)-5-({[4-(Benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-methylpyrrolidin-2-one,

[0289] 4-({[4-(Benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)pyrrolidin-2-one,

[0290] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)-1,5-naphthyridin-4-amine,

[0291] 5-[({6-Chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0292] 5-[({6-Chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0293] (3S,5R)-5-[({6-Chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-methylpyrrolidin-2-one,

[0294] 5-[({6-Chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0295] 5-([{6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0296] 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-1,3-oxazolidin-2-one,

[0297] 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[0298] (3S,5R)-5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-methylpyrrolidin-2-one,

[0299] 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0300] 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0301] 5-({[4-(benzylamino)-2-chloropyrido[3,2-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[0302] (5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(methoxymethyl)pyrrolidin-2-one,

[0303] 3-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0304] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-methylimidazolidin-2-one,

[0305] 5-[2-({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)ethyl]pyrrolidin-2-one,

[0306] 2-chloro-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0307] trans-4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclohexanol,

[0308] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1-methylimidazolidin-2-one,

[0309] 2-chloro-8-(cyclopropylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0310] 2-chloro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinazolin-4-amine, 2-chloro-8-(1,3-dioxolan-5-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-8-(cyclobutylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0311] 2-chloro-8-[(2S)-1,4-dioxolan-2-ylmethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0312] 2-chloro-8-[(2S)-1,4-dioxolan-2-ylmethoxy]-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0313] 2-chloro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinolin-4-amine,

[0314] 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-8-[(3,3-difluorocyclobutyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-[(1-methylcyclopropyl)methoxy]quinazolin-4-amine,

[0315] 2-chloro-N-(furan-2-ylmethyl)-8-(tetrahydro-2H-pyran-2-ylmethoxy)quinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-(oxetan-2-ylmethoxy)quinazolin-4-amine,

[0316] 2-chloro-8-[2-(1,1-dioxosulfolan-3-yl)ethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0317] 2-chloro-8-[(2R)-1,4-dioxolan-2-ylmethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0318] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-5-methyl-1,3-oxazolidin-2-one,

[0319] 2-chloro-8-[(2R)-1,4-dioxolan-2-ylmethoxy]-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0320] 2-chloro-8-(cyclopropylmethoxy)-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0321] 2-chloro-8-(cyclobutylmethoxy)-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0322] 2-chloro-7-fluoro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinazolin-4-amine,

[0323] 2-chloro-8-(cyclopropylmethoxy)-N-(furan-2-ylmethyl)quinolin-4-amine,

[0324] 2-chloro-8-[2-(1,1-dioxothietan-3-yl)ethoxy]-N-(furan-2-ylmethyl)quinolin-4-amine,

[0325] 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-2-ylmethyl)quinazolin-4-amine, 2-chloro-8-(1,4-dioxolan-2-ylmethoxy)-N-(thiophen-2-ylmethyl)quinazolin-4-amine, 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-3-ylmethyl)quinazolin-4-amine, 2-chloro-8-(1,4-dioxolan-2-ylmethoxy)-N-(thiophen-3-ylmethyl)quinazolin-4-amine,

[0326] 5-{[(2-chloro-4-{[(4-fluorofuran-2-yl)methyl]amino}quinazolin-8-yl)oxy]methyl}-1,3-oxazolidin-2-one,

[0327] 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,2-thiazol-5-ylmethyl)quinazolin-4-amine,

[0328] 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-oxazol-4-ylmethyl)quinazolin-4-amine,

[0329] 2-chloro-8-(1,4-dioxolan-2-ylmethoxy)-N-(1,2-oxazol-3-ylmethyl)quinazolin-4-amine,

[0330] 5-[({2-Chloro-4-[(1,3-oxazol-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0331] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine,

[0332] 5-[({2-Chloro-4-[(thiophen-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0333] 5-[({2-Chloro-4-[(thiophen-3-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0334] 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine,

[0335] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine,

[0336] 5-[({2-Chloro-4-[(1,3-thiazol-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0337] 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine,

[0338] 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(pyridin-4-ylmethyl)quinazolin-4-amine,

[0339] 5-[({2-Chloro-4-[(pyridin-4-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0340] 5-[({2-Chloro-4-[(pyrimidin-4-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0341] 5-[({2-Chloro-4-[(pyridin-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0342] 5-{[(2-Chloro-4-{[(3-fluoropyridin-4-yl)methyl]amino}quinazolin-8-yl)oxy]methyl}-1,3-oxazolidin-2-one,

[0343] 5-[({2-Chloro-4-[(2-fluorobenzyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0344] 5-[({2-Chloro-4-[(3-fluorobenzyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0345] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,2,4-oxadiazol-3-ylmethyl)quinazolin-4-amine,

[0346] 5-[({2-Chloro-4-[(1,2-thiazol-5-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0347] 5-[({2-Chloro-4-[(4-fluorobenzyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0348] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0349] (5S)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0350] (5R)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0351] 5-({[4-(Benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one,

[0352] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0353] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0354] 5-({[4-(Benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0355] 5-({[4-(Benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[0356] 5-({[4-(Benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0357] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,2-d]pyrimidin-4-amine,

[0358] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine,

[0359] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]pyrido[3,4-d]pyrimidin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0360] 5-({[4-(Benzylamino)-2-chloropyrido[3,4-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[0361] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]pyrido[4,3-d]pyrimidin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0362] 5-({[4-(Benzylamino)-2-chloropyrido[4,3-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[0363] 5-({[4-(Benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one,

[0364] 5-({[4-(Benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[0365] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-ethyl-1,3-oxazolidin-2-one,

[0366] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(propan-2-yl)-1,3-oxazolidin-2-one,

[0367] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0368] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(cyclopropylmethyl)-1,3-oxazolidin-2-one,

[0369] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2,2-difluoroethyl)-1,3-oxazolidin-2-one,

[0370] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0371] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(oxetan-3-yl)-1,3-oxazolidin-2-one,

[0372] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-hydroxy-2-methylpropyl)-1,3-oxazolidin-2-one,

[0373] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-N-ethyl-2-oxo-1,3-oxazolidine-3-carboxamide,

[0374] 4-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-(2-hydroxyethyl)pyrrolidin-2-one,

[0375] 4-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-(2-fluoroethyl)pyrrolidin-2-one,

[0376] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(prop-2-yn-1-yl)-1,3-oxazolidin-2-one,

[0377] tert-Butyl [2-(2-{5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}ethoxy)ethyl]carbamate,

[0378] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-[2-(2-methoxyethoxy)ethyl]-1,3-oxazolidin-2-one,

[0379] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(oxetan-3-ylmethyl)-1,3-oxazolidin-2-one,

[0380] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(1,2,4-oxadiazol-5-ylmethyl)-1,3-oxazolidin-2-one,

[0381] 2-{5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}acetamide,

[0382] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-methoxyethyl)-1,3-oxazolidin-2-one.

[0383] In the present disclosure, "pharmaceutically acceptable salts" refer to salts that can be used as drugs. In one or more embodiments, basic salts, acidic salts, etc. can be cited.

[0384] As "basic salts", in one or more embodiments, alkali metal salts such as sodium salts, potassium salts, and lithium salts can be cited; 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 picolinate salts; and amino acid salts such as glycinate salts, lysinate salts, arginate salts, ornithinate salts, glutamate salts, and aspartate salts, etc. Alkali metal salts are preferred.

[0385] As "acidic salts", in one or more embodiments, hydrohalic acid salts such as hydrofluoride salts, hydrochloride salts, hydrobromide salts, and hydroiodide salts can be cited; inorganic acid salts such as nitrate salts, perchlorate salts, sulfate salts, and phosphate salts; lower alkane sulfonate salts such as methanesulfonate salts, trifluoromethanesulfonate salts, and ethanesulfonate salts; aryl sulfonate salts such as benzenesulfonate salts and p-toluenesulfonate salts; organic acid salts such as acetate salts, malate salts, fumarate salts, succinate salts, citrate salts, ascorbate salts, tartrate salts, oxalate salts, and maleate salts; and amino acid salts such as glycinate salts, lysinate salts, arginate salts, ornithinate salts, glutamate salts, and aspartate salts, etc. Hydrohalic acid salts (especially hydrochloride salts) are preferred.

[0386] Pharmaceutically acceptable salts of the compounds of the present disclosure may include hydrates. Additionally, in the present disclosure, "salts of the compound" may also include solvates that the compound can form by absorbing some other solvent.

[0387] The compounds of the present disclosure, their pharmaceutically acceptable salts, or their solvates may exist as various isomers such as geometric isomers (e.g., cis - isomers, trans - isomers), tautomers, rotational isomers, or optical isomers (enantiomers) such as d - forms and l - forms, and diastereomers, depending on the type and combination of substituents. Without particular limitation, the compounds of the present disclosure also include all of these isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio. Mixtures of these isomers can be separated by known separation methods.

[0388] The compounds of the present disclosure also include labeled forms, that is, compounds in which one or more atoms of the compound are replaced with isotopes (e.g., 2 H, 3 H, 13 C, 14 C, 35 S, etc.).

[0389] Compounds that are converted into the active ingredients of the pharmaceutical compositions of the present disclosure, namely the compounds represented by formula (I), (II), (III), (IV), or (V), under physiological conditions in the living body through reactions based on enzymes, gastric acid, etc., that is, compounds that are changed into the compounds represented by formula (I), (II), (III), (IV), or (V) by oxidation, reduction, hydrolysis, etc. caused by enzymes or compounds that are changed into the compounds represented by formula (I), (II), (III), (IV), or (V) by hydrolysis, etc. caused by gastric acid, etc. are included in the present disclosure as "pharmaceutically acceptable prodrug compounds". In one or more embodiments, a prodrug refers to a compound having a group such as an amino group, a hydroxyl group, or a carboxyl group that can be converted into a compound by hydrolysis or under physiological conditions. As the group for forming such a prodrug, it is a group described in Prog. Med., Vol. 5, pp. 2157 - 2161, 1985, etc.

[0390] As a prodrug, in the case where an amino group is present in the compound represented by formula (I), (II), (III), (IV) or (V), examples of the compound obtained by acylating, alkylating or phosphorylating the amino group include compounds obtained by eicosanoylating, alanylylating, pentylaminocarbonylating, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylating, tetrahydrofuranylylating, pyrrolidinylmethylating, pivaloyloxymethylating or tert-butylating the amino group, etc. In the case where a hydroxyl group is present in the compound represented by formula (I), (II), (III), (IV) or (V), examples of the compound obtained by acylating, alkylating, phosphorylating or borylating the hydroxyl group include compounds obtained by acetylating, palmitoylating, propionylating, pivaloylating, succinylating, fumaroylating, alanylylating or dimethylaminomethylcarbonylating the hydroxyl group, etc. Further, in the case where a carboxyl group is present in the compound represented by formula (I), (II), (III), (IV) or (V), examples of the compound obtained by esterifying or amidating the carboxyl group include compounds obtained by ethyl esterifying, phenyl esterifying, carboxymethyl esterifying, dimethylaminomethyl esterifying, pivaloyloxymethyl esterifying, ethoxycarbonyloxyethyl esterifying or methyl amidating the carboxyl group, etc.

[0391] [Manufacturing method]

[0392] Hereinafter, representative manufacturing methods of the compound represented by formula (I), (II), (III), (IV) or (V) will be described. In one or more embodiments, the compounds of the present disclosure can be manufactured by any one of the following methods A to N. The manufacturing methods shown below are examples, and the present disclosure should not be construed as being limited to these examples.

[0393] Each compound of the following methods A to N can be separated and purified as various solvates such as a non-solvate, its salt or hydrate. The salt can be manufactured by a usual method. In one or more embodiments, examples of the salt include hydrochloride, sulfate, etc., or organic amine salts, sodium salts, potassium salts, etc.

[0394] The solvent used in the reactions of each step of the following methods A to N is not particularly limited as long as it does not hinder the reaction and partially dissolves the starting materials. In one or more embodiments, examples of the solvent include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, nitriles, carboxylic acids, alcohols, amides, sulfoxides, water, and mixtures thereof.

[0395] In one or more embodiments, examples of the aliphatic hydrocarbons include n-hexane, n-pentane, petroleum ether and cyclohexane, etc.

[0396] As aromatic hydrocarbons, in one or more embodiments, benzene, toluene, xylene, etc. can be cited.

[0397] As halogenated hydrocarbons, in one or more embodiments, dichloromethane (DCM, methylene chloride), chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, etc. can be cited.

[0398] As ethers, in one or more embodiments, diethyl ether, diisopropyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, diethylene glycol dimethyl ether, etc. can be cited.

[0399] As ketones, in one or more embodiments, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, etc. can be cited.

[0400] As esters, in one or more embodiments, ethyl acetate, propyl acetate, butyl acetate, etc. can be cited.

[0401] As nitriles, in one or more embodiments, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, etc. can be cited.

[0402] As carboxylic acids, in one or more embodiments, acetic acid, propionic acid, etc. can be cited.

[0403] As alcohols, in one or more embodiments, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, etc. can be cited.

[0404] As amides, in one or more embodiments, formamide, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, etc. can be cited.

[0405] As sulfoxides, in one or more embodiments, dimethyl sulfoxide (DMSO), 1,1-dioxotetrahydrothiophene, etc. can be cited.

[0406] The base used in the reactions of the respective steps of the following Method A to Method N is not particularly limited as long as it does not hinder the reaction. As the base, in one or more embodiments, alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal hydrides, alkali metal amides, alkali metal alkoxides, organic amines, etc. can be cited.

[0407] As alkali metal carbonates, in one or more embodiments, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be cited.

[0408] As alkali metal hydrogencarbonates, in one or more embodiments, lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc. may be cited.

[0409] As alkali metal hydroxides, in one or more embodiments, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. may be cited.

[0410] As alkaline earth metal hydroxides, in one or more embodiments, calcium hydroxide, barium hydroxide, etc. may be cited.

[0411] As alkali metal hydrides, in one or more embodiments, lithium hydride, sodium hydride, potassium hydride, etc. may be cited.

[0412] As alkali metal amides, in one or more embodiments, lithium amide, sodium amide, potassium amide, etc. may be cited.

[0413] As organic amines, in one or more embodiments, triethylamine (TEA), tributylamine, N,N - diisopropylethylamine (DIPEA), 1 - methylpiperidine, 4 - methylmorpholine, 4 - ethylmorpholine, pyridine, methylpyridine, 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, etc. may be cited.

[0414] [Method A]

[0415] Method A is an example of a method for producing the 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, A 4 and R 2 in the following intermediates and compounds are the same as those in formula (II) above, and R 3a’ is -(CH2) n -R 3a , R 3a and n are the same as those in formula (II) above.

[0416] [Chemical formula 19]

[0417]

[0418] (1) Step A - 1 is a step of obtaining intermediate A - III from intermediate A - I. The reaction conditions of step A - 1 are as described below.

[0419] [Reaction conditions]

[0420] Solvent: Acetic acid

[0421] Reaction temperature: Room temperature to 150 °C

[0422] Reaction time: 30 minutes to 24 hours

[0423] [Chemical formula 20]

[0424]

[0425] (2) Step A-2 is the step of obtaining intermediate A-II from intermediate A-I. The reaction conditions for step A-2 are as described below.

[0426] [Reaction conditions]

[0427] Solvent: Tetrahydrofuran

[0428] Condensing agent: 1,1'-Carbonyldiimidazole

[0429] Reaction temperature: 0 °C to 80 °C

[0430] Reaction time: 30 minutes to 24 hours

[0431] (3) Step A-3 is the 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.

[0432] [Reaction conditions a]

[0433] Solvent: Dimethylformamide

[0434] Base: Potassium carbonate

[0435] Reagent: 1,1'-Carbonyldiimidazole

[0436] Reaction temperature: Room temperature to 120 °C

[0437] Reaction time: 30 minutes to 24 hours

[0438] [Reaction conditions b]

[0439] Solvent: Tetrahydrofuran

[0440] Base: Lithium bis(trimethylsilyl)amide

[0441] Reagent: Triphosgene

[0442] Reaction temperature: 0 °C to 60 °C

[0443] Reaction time: 30 minutes to 24 hours

[0444] (4) Step A-4 is the step of obtaining intermediate A-IV from intermediate A-III. Step A-4 can be carried out, for example, under the following reaction conditions (where A 4 =CH).

[0445] [Reaction conditions]

[0446] Base: N,N-diethylaniline

[0447] Reaction temperature: room temperature to 120 °C

[0448] Reaction time: 30 minutes to 24 hours

[0449] (5) Step A-5 is the step of obtaining intermediate A-V from intermediate A-IV. Step A-5 can be carried out, for example, under the following reaction conditions (where A 4 =CH).

[0450] [Reaction conditions]

[0451] Solvent: dichloromethane

[0452] Reaction temperature: 0 °C to 40 °C

[0453] Reaction time: 30 minutes to 24 hours

[0454] (6) Step A-6 is the step of obtaining intermediate A-VI from intermediate A-V. Step A-6 can be carried out, for example, under the following reaction conditions (where A 4 =CH).

[0455] [Reaction conditions]

[0456] Solvent: acetonitrile

[0457] Base: triethylamine

[0458] Reaction temperature: room temperature to 80 °C

[0459] Reaction time: 30 minutes to 24 hours

[0460] (7) Step A-7 is the step of obtaining the compound represented by formula (II) from intermediate A-VI. The reaction conditions for step A-7 are as follows (where A in intermediate A-VI 4 =CH).

[0461] [Reaction conditions]

[0462] Solvent: toluene

[0463] Mitsunobu reagent: cyanomethylenetributylphosphonium

[0464] Reaction temperature: room temperature to 110 °C

[0465] Reaction time: 30 minutes to 24 hours

[0466] (8) Step A-8 is a step of obtaining the compound represented by formula (II) from intermediate A-VI. Step A-8 can be carried out, for example, under the following reaction conditions (wherein, when A in intermediate A-VI 4 =CH).

[0467] [Reaction conditions]

[0468] Solvent: Dimethylformamide

[0469] Base: Potassium carbonate

[0470] Reaction temperature: Room temperature to 100 °C

[0471] Reaction time: 30 minutes to 24 hours

[0472] [Method B]

[0473] Method B is an example of a method for producing intermediate B-IV of the compound represented by formula (II). Ar and R in the following intermediate 2 are the same as those in formula (II) above.

[0474] [Chemical formula 21]

[0475]

[0476] (1) Step B-1 is a step of obtaining intermediate B-II from intermediate B-I. The reaction conditions for step B-1 are as described below.

[0477] [Reaction conditions]

[0478] Protecting group (PG): tert-Butyldimethylsilyl

[0479] Protecting reagent: tert-Butyldimethylsilyl trifluoromethanesulfonate

[0480] Solvent: Dichloromethane

[0481] Base: 2,6-Dimethylpyridine

[0482] Reaction temperature: 0 °C to room temperature

[0483] Reaction time: 30 minutes to 24 hours

[0484] (2) Step B-2 is a step of obtaining intermediate B-III from intermediate B-II. The reaction conditions for step B-2 are as described below.

[0485] [Reaction conditions]

[0486] Solvent: Acetonitrile

[0487] Base: Triethylamine

[0488] Reaction temperature: Room temperature to 80 °C

[0489] (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 described below.

[0490] [Reaction conditions]

[0491] Reagent: Tetrabutylammonium fluoride

[0492] Solvent: Tetrahydrofuran

[0493] Reaction temperature: 0 °C to 80 °C

[0494] Reaction time: 30 minutes to 24 hours

[0495] [Method C]

[0496] Method C is an example of a method for manufacturing the compound represented by formula (II). R in the following intermediates and compounds 2 , R 3a and n are the same as those in formula (II) above, and R 3a’ is -(CH2) n -R 3a .

[0497] [Chemical formula 22]

[0498]

[0499] (1) Step C-1 is a step of obtaining intermediate C-II from intermediate C-I. The reaction conditions for step C-1 are as described below.

[0500] [Reaction conditions]

[0501] Solvent: Toluene

[0502] Reaction reagent: Bis(2-methoxymethyl)azodicarboxylate and triphenylphosphine

[0503] Reaction temperature: Room temperature to 110 °C

[0504] Reaction time: 30 minutes to 24 hours

[0505] (2) Step C-2 is a step of obtaining the compound represented by formula (II) from intermediate C-II. The reaction conditions for step C-2 are as described below.

[0506] [Reaction conditions]

[0507] Solvent: Acetonitrile

[0508] Base: Triethylamine

[0509] Reaction temperature: room temperature to 80 °C

[0510] Reaction time: 30 minutes to 24 hours

[0511] [Method D]

[0512] Method D is an example of the manufacturing method of the compound represented by formula (IV). Ar and R in the following intermediates and compounds 2 are the same as those in the above formula (IV), and R 3c’ is -(CH2) n -R 3c , R 3c and n are the same as those in the above formula (IV). X is a halogen atom such as a chlorine atom.

[0513] [Chemical formula 23]

[0514]

[0515] (1) Step D-1 is the step of obtaining intermediate D-II from intermediate D-I. The reaction conditions for step D-1 are as described below.

[0516] [Reaction conditions]

[0517] Reagent: boron tribromide

[0518] Solvent: dichloromethane

[0519] Reaction temperature: 0 °C to 40 °C

[0520] Reaction time: 30 minutes to 24 hours

[0521] (2) Step D-2 is the step of obtaining intermediate D-III from intermediate D-II. The reaction conditions for step D-2 are as described below.

[0522] [Reaction conditions]

[0523] Solvent: N-methylpyrrolidone

[0524] Base: N,N-diisopropylethylamine

[0525] Reaction temperature: room temperature to 120 °C

[0526] Reaction time: 30 minutes to 24 hours

[0527] (3) Step D-3 is the step of obtaining the compound represented by formula (IV) from intermediate D-III. The reaction conditions for step D-3 are as described below.

[0528] [Reaction conditions]

[0529] Solvent: toluene

[0530] Mitsunobu reagent: cyanomethylenetributylphosphonium

[0531] Reaction temperature: room temperature to 110 °C

[0532] Reaction time: 30 minutes to 24 hours

[0533] (4) Step D-4 is the step of obtaining the compound represented by formula (IV) from intermediate D-III. The reaction conditions for step D-4 are as described below.

[0534] [Reaction conditions]

[0535] Solvent: dimethylformamide

[0536] Base: potassium carbonate

[0537] Reaction temperature: room temperature to 100 °C

[0538] Reaction time: 30 minutes to 24 hours

[0539] [Method E]

[0540] Method E is an example of a method for producing intermediate E-III of the compound represented by formula (III). Ar in the following intermediates is the same as that in formula (III) above.

[0541] [Chemical formula 24]

[0542]

[0543] (1) Step E-1 is the step of obtaining intermediate E-II from intermediate E-I. The reaction conditions for step E-1 are as described below.

[0544] [Reaction conditions]

[0545] Base: N,N-diethylaniline

[0546] Reaction temperature: room temperature to 120 °C

[0547] (2) Step E-2 is the step of obtaining intermediate E-III from intermediate E-II. The reaction conditions for step E-2 are as described below.

[0548] [Reaction conditions]

[0549] Solvent: acetonitrile

[0550] Base: triethylamine

[0551] Reaction temperature: room temperature to 80 °C

[0552] Reaction time: 30 minutes to 24 hours

[0553] [Method F]

[0554] Method F is an example of a method for manufacturing the compound represented by formula (V). Ar in the following intermediates and compounds is the same as that in formula (V) above, and R 3d’ is -(CH2) n -R 3d R 3d and n are the same as those in formula (V) above.

[0555] [Chemical formula 25]

[0556]

[0557] (1) Step F-1 is a step of obtaining intermediate F-II from intermediate F-I. The reaction conditions for step F-1 are as described below.

[0558] [Reaction conditions]

[0559] Solvent: N-methylpyrrolidone

[0560] Base: N,N-diisopropylethylamine

[0561] Reaction temperature: room temperature to 120 °C

[0562] Reaction time: 30 minutes to 24 hours

[0563] (2) Step F-2 is a step of obtaining the compound represented by formula (V) from intermediate F-II. The reaction conditions for step F-2 are as described below.

[0564] [Reaction conditions]

[0565] Solvent: toluene

[0566] Mitsunobu reagent: cyanomethylenetributylphosphonium

[0567] Reaction temperature: room temperature to 110 °C

[0568] Reaction time: 30 minutes to 24 hours

[0569] [Method G]

[0570] Method G is an example of a method for manufacturing an intermediate of the compound represented by formula (V). Ar in the following intermediates is the same as that in formula (V) above.

[0571] [Chemical formula 26]

[0572]

[0573] (1) Step G-1 is a step of obtaining intermediate G-II from intermediate G-I. The reaction conditions for step G-1 are as described below.

[0574] Reaction conditions

[0575] Solvent: Tetrahydrofuran

[0576] Reaction reagent: Triphosgene

[0577] Reaction temperature: 0°C to 80°C

[0578] Reaction time: 30 minutes to 24 hours

[0579] (2) Step G-2 is the step of obtaining intermediate G-III from intermediate G-II. The reaction conditions of step G-2 are as described below.

[0580] [Reaction conditions

[0581] Solvent: Dimethylformamide

[0582] Reaction reagent: Diethyl malonate

[0583] Base: Sodium hydride

[0584] Reaction temperature: Room temperature to 80°C

[0585] Reaction time: 30 minutes to 24 hours

[0586] (3) Step G-3 is the step of obtaining intermediate G-IV from intermediate G-III. The reaction conditions of step G-3 are as described below.

[0587] [Reaction conditions

[0588] Solvent: Water

[0589] Base: Potassium hydroxide

[0590] Reaction temperature: Room temperature to 120°C

[0591] Reaction time: 30 minutes to 24 hours

[0592] (4) Step G-4 is the step of obtaining intermediate G-V from intermediate G-IV. The reaction conditions of step G-4 are as described below.

[0593] [Reaction conditions

[0594] Solvent: Tetrahydrofuran

[0595] Reaction reagent: N-Phenylbis(trifluoromethanesulfonimide)

[0596] Base: Triethylamine

[0597] Reaction temperature: Room temperature to 80°C

[0598] Reaction time: 30 minutes to 24 hours

[0599] (5) Step G-5 is the step of obtaining intermediate G-VI from intermediate G-V. The reaction conditions for step G-5 are as described below.

[0600] [Reaction Conditions]

[0601] Solvent: Acetonitrile

[0602] Reaction Temperature: Room temperature to 80 °C

[0603] Reaction Time: 30 minutes to 24 hours

[0604] (6) Step G-6 is the step of obtaining intermediate G-VII from intermediate G-VI. The reaction conditions for step G-6 are as described below.

[0605] [Reaction Conditions]

[0606] Base: N,N-Diethylaniline

[0607] Reaction Temperature: Room temperature to 110 °C

[0608] Reaction Time: 30 minutes to 24 hours

[0609] [Method H]

[0610] Method H is an example of a method for manufacturing an intermediate of the compound represented by formula (III). Ar in the following intermediate is the same as that in the above formula (III).

[0611] [Chemical Formula 27]

[0612]

[0613] (1) Step H-1 is the step of obtaining intermediate H-II from intermediate H-I. The reaction conditions for step H-1 are as described below.

[0614] [Reaction Conditions]

[0615] Base: N,N-Diisopropylethylamine

[0616] Reaction Temperature: Room temperature to 120 °C

[0617] Reaction Time: 30 minutes to 24 hours

[0618] (2) Step H-2 is the step of obtaining intermediate H-III from intermediate H-II. The reaction conditions for step H-2 are as described below.

[0619] [Reaction Conditions]

[0620] Solvent: Acetonitrile

[0621] Base: Triethylamine

[0622] Reaction temperature: room temperature to 80 °C

[0623] Reaction time: 30 minutes to 24 hours

[0624] [Method I]

[0625] Method I is an example of a method for manufacturing the compound represented by formula (I). Ar, A 1 , A 2 and A 4 in the following intermediates and compounds are the same as those in formula (I) above, R 3’ is -(CH2) n -R 3 , R 3 and n are the same as those in formula (I) above.

[0626] [Chemical formula 28]

[0627]

[0628] Step I-1 is a step of obtaining the compound represented by formula (I) from Intermediate I-I. The reaction conditions for Step I-1 are as described below.

[0629] [Reaction conditions]

[0630] Solvent: tetrahydrofuran

[0631] Base: sodium hydride

[0632] Reaction temperature: room temperature to 80 °C

[0633] Reaction time: 30 minutes to 24 hours

[0634] [Method J]

[0635] Method J is an example of a method for manufacturing an intermediate of the compound represented by formula (III). Ar in the following intermediate is the same as that in formula (III) above.

[0636] [Chemical formula 29]

[0637]

[0638] (1) Step J-1 is a step of obtaining Intermediate J-II from Intermediate J-I. The reaction conditions for Step J-1 are as described below.

[0639] [Reaction conditions]

[0640] Solvent: dimethyl sulfoxide

[0641] Reaction reagent: aqueous hydrogen peroxide

[0642] Base: potassium carbonate

[0643] Reaction temperature: 0 °C to 80 °C

[0644] Reaction time: 30 minutes to 24 hours

[0645] (2) Step J-2 is the step of obtaining intermediate J-III from intermediate J-II. The reaction conditions for step J-2 are as described below.

[0646] [Reaction conditions]

[0647] Solvent: 1,4-dioxane

[0648] Reaction reagent: triphosgene

[0649] Base: lithium bis(trimethylsilyl)amide

[0650] Reaction temperature: 0 °C to room temperature

[0651] Reaction time: 30 minutes to 24 hours

[0652] (3) Steps J-3_1) and 2) are the steps of obtaining intermediate J-IV from intermediate J-III. Step J-3_1) can be carried out, for example, under the following reaction conditions 1). Step J-3_2) can be carried out, for example, under the following reaction conditions 2).

[0653] [Reaction conditions 1)]

[0654] Base: N,N-diisopropylethylamine

[0655] Reaction temperature: room temperature to 120 °C

[0656] Reaction time: 30 minutes to 24 hours

[0657] [Reaction conditions 2)]

[0658] Solvent: tetrahydrofuran

[0659] Base: N,N-diisopropylethylamine

[0660] Reaction temperature: room temperature to 80 °C

[0661] Reaction time: 30 minutes to 24 hours

[0662] [K method]

[0663] The K method is an example of a method for manufacturing the compound represented by formula (III). Ar in the following intermediates and compounds is the same as that in the above formula (III), and R 3b’ is -(CH2) n -R 3b , R 3b and n are the same as those in the above formula (III).

[0664] [Chemical Formula 30]

[0665]

[0666] (1) Step K-1 is the step of obtaining intermediate K-II from intermediate K-I. The reaction conditions for step K-1 are as described below.

[0667] [Reaction Conditions]

[0668] Solvent: Tetrahydrofuran

[0669] Base: Sodium hydride

[0670] Reaction temperature: 0°C to 80°C

[0671] Reaction time: 30 minutes to 24 hours

[0672] (2) Step K-2 is the step of obtaining intermediate K-III from intermediate K-II. The reaction conditions for step K-2 are as described below.

[0673] [Reaction Conditions]

[0674] Solvent: Methanol

[0675] Reaction reagent: Ammonium acetate

[0676] Reaction temperature: Room temperature to 80°C

[0677] Reaction time: 30 minutes to 24 hours

[0678] (3) Step K-3 is the step of obtaining intermediate K-IV from intermediate K-III. The reaction conditions for step K~3 are as described below.

[0679] [Reaction Conditions]

[0680] Solvent: Tetrahydrofuran

[0681] Reaction reagent: Trichloroacetyl isocyanate

[0682] Reaction temperature: Room temperature to 80°C

[0683] Reaction time: 30 minutes to 24 hours

[0684] (4) Steps K-4_1) and 2) are the steps of obtaining the compound shown in formula (III) from intermediate K-I. Step K-4_1) can be carried out, for example, under the following reaction conditions 1). Step K-4_2) can be carried out, for example, under the following reaction conditions 2).

[0685] [Reaction Conditions 1)]

[0686] Base: N,N-Diisopropylethylamine

[0687] Reaction temperature: room temperature to 120 °C

[0688] Reaction time: 30 minutes to 24 hours

[0689] [Reaction condition 2)]

[0690] Solvent: tetrahydrofuran

[0691] Base: N,N - diisopropylethylamine

[0692] Reaction temperature: room temperature to 80 °C

[0693] Reaction time: 30 minutes to 24 hours

[0694] [L method]

[0695] The L method is an example of a method for manufacturing an intermediate of the compound represented by formula (III). Ar in the following intermediate is the same as that in the above formula (III).

[0696] [Chemical formula 31]

[0697]

[0698] Step L - 1 is a step of obtaining intermediate L - II from intermediate L - I. The reaction conditions of step L - 1 are as described below.

[0699] [Reaction conditions]

[0700] Solvent: tetrahydrofuran

[0701] Base: N,N - diisopropylethylamine

[0702] Reaction temperature: room temperature to 80 °C

[0703] Reaction time: 30 minutes to 24 hours

[0704] [M method]

[0705] The M method is an example of a method for manufacturing the compound represented by formula (V). Ar in the following intermediate and compound is the same as that in the above formula (V), and R 3d’ is -(CH2) n -R 3d and n are the same as those in the above formula (V). 3d

[0706] [Chemical formula 32]

[0707]

[0708] (1) Step M - 1 is a step of obtaining intermediate M - II from intermediate M - I. The reaction conditions of step M - 1 are as described below.​

[0709] [Reaction conditions]

[0710] Solvent: acetic anhydride

[0711] Base: pyridine

[0712] Reaction temperature: room temperature to 100 °C

[0713] Reaction time: 30 minutes to 24 hours

[0714] (2) Step M-2 is the step of obtaining intermediate M-III from intermediate M-II. The reaction conditions of step M-2 are as described below.

[0715] [Reaction conditions]

[0716] Solvent: tetrahydrofuran

[0717] Base: potassium bis(trimethylsilyl)amide

[0718] Reaction temperature: -78 °C to 60 °C

[0719] Reaction time: 30 minutes to 48 hours

[0720] (3) Step M-3 is the step of obtaining intermediate M-IV from intermediate M-III. The reaction conditions of step M-3 are as described below.

[0721] [Reaction conditions]

[0722] Solvent: tetrahydrofuran

[0723] Reaction reagent: N-phenylbis(trifluoromethanesulfonimide)

[0724] Base: triethylamine

[0725] Reaction temperature: room temperature to 80 °C

[0726] Reaction time: 30 minutes to 24 hours

[0727] (4) Step M-4 is the step of obtaining intermediate M-V from intermediate M-IV. The reaction conditions of step M~4 are as described below.

[0728] [Reaction conditions]

[0729] Solvent: 1,4-dioxane

[0730] Reaction temperature: room temperature to 100 °C

[0731] Reaction time: 30 minutes to 24 hours

[0732] (5) Step M-5 is a step of obtaining the compound represented by formula (V) from intermediate M-V. The reaction conditions for step M-5 are as described below.

[0733] [Reaction conditions]

[0734] Solvent: 1,4-dioxane

[0735] Base: N,N-diethylaniline

[0736] Reaction temperature: room temperature to 110 °C

[0737] Reaction time: 30 minutes to 24 hours

[0738] [Method N]

[0739] Method N is an example of a method for producing the compound represented by formula (I’). The compound represented by formula (I’) is an example of the compound represented by formula (I). In the following intermediates and compounds, Ar, A 1 , A 2 , A 3 and A 4 are the same as those in the above formula (I), R Q1 is the same as that in the above formula (II), and W is an oxygen atom, -NH-, or -CH-.

[0740] [Chemical formula 33]

[0741]

[0742] Step N-1 is a step of obtaining the compound represented by formula (I’) from intermediate N-I. The reaction conditions for step N-1 are as described below.

[0743] [Reaction conditions]

[0744] Solvent: tetrahydrofuran, dimethylformamide

[0745] Base: potassium tert-butoxide

[0746] Reaction temperature: 0 °C to 80 °C

[0747] Reaction time: 30 minutes to 24 hours

[0748] In one or more embodiments, the compound of the present disclosure or a pharmaceutically acceptable salt thereof has an effect of inhibiting splicing abnormalities that are a cause of the onset or progression of genetic diseases. In one or more embodiments, the compound of the present disclosure or a pharmaceutically acceptable salt thereof can be used to treat genetic diseases caused by splicing abnormalities.

[0749] In the present disclosure, as "genetic diseases caused by splicing abnormalities", in one or more embodiments, genetic diseases caused by splicing abnormalities based on exon skipping mutations, genetic diseases caused by splicing abnormalities based on splice site selection mutations, genetic diseases caused by splicing abnormalities based on intron retention mutations, and genetic diseases caused by splicing abnormalities based on pseudo-exon mutations can be cited. An exon skipping mutation is a splicing mutation in which an exon that is normally recognized becomes unrecognized (skips) due to a mutation in the exon or the surrounding intron sequence. A splice site selection mutation is a splicing mutation that produces multiple 5' splice sites or 3' splice sites due to a mutation in a splicing regulatory sequence in an exon region or an intron region. An intron retention mutation is a splicing mutation in which the recognition of an intron region becomes incomplete due to a mutation in an exon or an intron region around the 5' splice site or the 3' splice site, inducing intron retention. A pseudo-exon mutation is a splicing mutation in which a sequence that was originally an intron region is recognized as an exon due to a mutation.

[0750] As genetic diseases caused by splicing abnormalities, in one or more embodiments, Fabry disease etc. can be cited. Fabry disease is a disease in which glycosphingolipids such as globotriaosylceramide (Gb3) accumulate in the lysosomes of cells due to the deficiency of GLA enzyme, which is one of the lysosomal hydrolases, and as a result, various symptoms related to various organs such as the heart and other circulatory organs and the kidneys occur.

[0751] As one of the causes of cardiac mutant Fabry disease, a single base substitution (IVS4+919G>A mutation) within the fourth intron of the α-galactosidase (GLA) gene has been reported. The IVS4+919G>A mutation causes alternative splicing in the transcription of the GLA gene, and as a result, the deficiency of lysosomal GLA enzyme occurs. It has been reported that in adult Chinese Taiwanese with this IVS4+919G>A mutation, a large number of cardiovascular abnormalities etc. have been confirmed. In addition, it has been reported that when screening based on GLA enzyme activity is performed in newborns in Chinese Taiwan, among newborns with low GLA enzyme activity in plasma and the presence of a causative mutation of Fabry disease, about 70-80% have the IVS4+919G>A mutation (Lin H-Y, et al., Circ Cardiovasc Genet 2(5)450-456 2009, Hwu W-L et al., Hum Mutat 30(10)1397-1405 2009).

[0752] Aberrant splicing, which is a cause of Fabry disease, results from a mutation in the gene to be spliced in one or more embodiments, and in one or more embodiments, is splicing that occurs in the pre-mRNA of the mutant GLA gene with the IVS4+919G>A mutation (splicing abnormality based on a pseudo-exon type mutation).

[0753] [Pharmaceutical composition]

[0754] As another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present disclosure can be used for treating a genetic disease caused by splicing abnormality in one or more embodiments.

[0755] As another aspect, the present disclosure also relates to a pharmaceutical composition for treating a genetic disease caused by splicing abnormality, comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient.

[0756] As another aspect, the present disclosure also relates to a pharmaceutical composition for treating a genetic disease caused by splicing abnormality, comprising a compound represented by the above formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0757] The pharmaceutical composition of the present disclosure can contain a compound of the present disclosure or a pharmaceutically acceptable salt in one or more embodiments, and can also contain a pharmaceutically acceptable carrier, preservative, diluent, excipient or other pharmaceutically acceptable ingredients.

[0758] In the pharmaceutical composition of the present disclosure, the content ratio of the compound of the present disclosure or a pharmaceutically acceptable salt as an active ingredient can be appropriately determined according to differences in dosage form, administration method, carrier, etc. in one or more embodiments. The pharmaceutical composition of the present disclosure can be manufactured by a conventional method by adding the compound of the present disclosure in a proportion of 0.01 to 100% (w / w) or 0.1 to 95% (w / w) based on the total amount of the preparation.

[0759] In one or more embodiments, the pharmaceutical composition of the present disclosure can be formulated into a dosage form suitable for the mode of administration using well-known formulation techniques. As the mode of administration, in one or more embodiments, oral administration and parenteral administration can be mentioned. As the preparations for oral administration, in one or more embodiments, dosage forms such as tablets, capsules, granules, powders, pills, troches, syrups, and liquids (such as solutions and suspensions) can be mentioned. As the preparations for parenteral administration, in one or more embodiments, injections, aerosols, etc. can be mentioned. These preparations can be manufactured by well-known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring and odor-masking agents, and diluents in one or more embodiments.

[0760] As excipients, in one or more embodiments, starches such as starch, potato starch, and corn starch, lactose, crystalline cellulose, calcium hydrogen phosphate, etc. can be mentioned. As lubricants, in one or more embodiments, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, paraffin wax, etc. can be mentioned. As binders, in one or more embodiments, polyvinylpyrrolidone, macrogol, and the same compounds as excipients can be mentioned. As disintegrants, in one or more embodiments, the same compounds as excipients and chemically modified starch-cellulose such as cross-linked carboxymethylcellulose sodium, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone can be mentioned. As stabilizers, in one or more embodiments, p-hydroxybenzoic acid esters such as methyl p-hydroxybenzoate and propyl p-hydroxybenzoate; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid can be mentioned. As flavoring and odor-masking agents, in one or more embodiments, commonly used sweeteners, acidulants, fragrances, etc. can be mentioned.

[0761] In the manufacture of liquids for oral administration, in one or more embodiments, as solvents, ethanol, phenol, chlorocresol, purified water, or distilled water, etc. can be used, and surfactants, preservatives, isotonic agents, pH regulators, or emulsifiers, etc. can also be used as needed. The liquids for oral administration can also contain solubilizers, wetting agents, suspending agents, sweeteners, flavoring agents, fragrances, or preservatives in one or more embodiments.

[0762] Injectables for parenteral administration may be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As an aqueous solvent for injectables, in one or more embodiments, it may be distilled water or physiological saline. As a non-aqueous solvent for injectables, in one or more embodiments, it may be vegetable oil, alcohols or polysorbate 80 (pharmacopoeial name). As vegetable oil, propylene glycol, polyethylene glycol, olive oil, etc. may be cited. As alcohols, ethanol, etc. may be cited. The injectable may, in one or more embodiments, further contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers or solubilizing aids. These preparations may, in one or more embodiments, be sterilized by filtering through a bacteria-retaining filter, incorporating a bactericide or irradiating with radiation. Alternatively, a composition obtained by dissolving or suspending a sterile solid composition in sterile water or a solvent for injection immediately before use may also be used as these preparations.

[0763] The method of using the pharmaceutical composition of the present disclosure may vary depending on symptoms, age, administration method, etc. The method of use may, in one or more embodiments, be carried out orally, transdermally, submucosally, subcutaneously, intramuscularly, intravascularly, intracranially or intraperitoneally intermittently or continuously in such a manner that the in vivo concentration of the above-mentioned compound as the active ingredient reaches any value between 100 pM and 1 mM. As an unrestricted embodiment, in the case of oral administration, for a subject (if human, an adult), when converted to the compound represented by formula (I), 0.01 mg / kg body weight to 2000 mg / kg body weight, 0.1 mg / kg body weight to 500 mg / kg body weight, or 0.1 mg / kg body weight to 100 mg / kg body weight may be administered once to multiple times per day according to symptoms. As an unrestricted embodiment, in the case of intravenous administration, for a subject (if human, an adult), 0.001 mg / kg body weight to 50 mg / kg body weight or 0.01 mg / kg body weight to 50 mg / kg body weight may be administered once to multiple times per day according to symptoms.

[0764] [Treatment method]

[0765] As another aspect, the present disclosure relates to a method for treating a genetic disease caused by splicing abnormality, which comprises the step of administering to a subject the compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0766] As another aspect, the present disclosure also relates to the use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for treating a genetic disease caused by splicing abnormality.

[0767] The present disclosure may relate to one or more of the following unrestricted embodiments.

[0768] [1] The compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[0769] [Chemical formula 34]

[0770]

[0771] In formula (I),

[0772] A 1 、A 2 、A 3 and A 4 are each independently CH or N,

[0773] Ar is a 6- to 12-membered aryl group or a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring. The 6- to 12-membered aryl group and the 5- to 6-membered heteroaryl group may be substituted with one or more halogen atoms,

[0774] n is 1 or 2,

[0775] R 1 is a halogen atom,

[0776] R 2 is a hydrogen atom, a halogen atom, or a C1-C4 alkoxy group,

[0777] R 3 is a hydrogen atom, a C3-C6 cycloalkyl group, or a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.

[0778] R 3 The C3-C6 cycloalkyl group and the 4- to 6-membered heterocyclic group in

[0779] Group A:

[0780] Halogen atom,

[0781] Hydroxyl group,

[0782] C1-C4 alkyl group that may be substituted with a halogen atom,

[0783] C1-C6 hydroxyalkyl group that may be substituted with a halogen atom,

[0784] C1-C2 alkoxy group that may be substituted with a halogen atom,

[0785] C2-C6 alkoxyalkyl group that may be substituted with a halogen atom,

[0786] C3-C6 alkoxyalkoxyalkyl group that may be substituted with a halogen atom,

[0787] C1-C2 alkylsulfonyl which may be substituted by a halogen atom,

[0788] acetyl (-C(O)CH3),

[0789] cyclopropylmethyl,

[0790] phenyl which may be substituted by a halogen atom,

[0791] phenyl C1-C3 alkyl which may be substituted by a halogen atom,

[0792] 3- to 5-membered heterocyclic group having 1 or 2 oxygen atoms,

[0793] 3- to 5-membered heterocyclic group-C1-C3 alkyl having 1 or 2 oxygen atoms,

[0794] aminooxy C1-C3 alkyl,

[0795] C2-C4 alkynyl which may be substituted by a halogen atom,

[0796] protected amino C2-C6 (alkoxyalkyl),

[0797] C1-C3 alkylaminocarbonyl,

[0798] 5-membered heteroaryl C1-C3 alkyl,

[0799] C2-C4 alkylene (bonded to the same carbon),

[0800] C1-C4 alkylenedioxy (bonded to the same carbon),

[0801] C1-C4 alkoxy-C1-C4 alkyl (bonded to the same carbon).

[0802] [2] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein R 3 The substituents of the C3-C6 cycloalkyl and 4- to 6-membered heterocyclic group in are selected from the following Group B:

[0803] Group B:

[0804] fluorine atom,

[0805] hydroxyl group,

[0806] methyl, ethyl, isopropyl,

[0807] fluoroethyl, difluoroethyl, trifluoromethyl,

[0808] hydroxyethyl, 2-hydroxy-2-methylpropyl,

[0809] Methoxy (-OCH3), difluoromethoxy (-OCHF2),

[0810] Methoxymethyl (-CH2OCH3), methoxyethyl (-C2H4OCH3),

[0811] Methoxyethoxyethyl (-C2H4OC2H4OCH3),

[0812] Methylsulfonyl (-S(O)2CH3),

[0813] Acetyl (-C(O)CH3),

[0814] Cyclopropylmethyl,

[0815] Phenyl,

[0816] Benzyl,

[0817] Oxetanyl,

[0818] Oxetanylmethyl,

[0819] 2-Amino-2-oxoethyl (-CH2C(O)NH2),

[0820] Propargyl,

[0821] tert-Butoxycarbonyl-2-aminoethoxyethyl (-C2H4OC2H4NHC(O)O(CH3)3), ethylaminocarbonyl (-C(O)NHCH2CH3),

[0822] Oxadiazolylmethyl,

[0823] Ethylene (bonded to the same carbon),

[0824] Methylenedioxy (bonded to the same carbon), ethylenedioxy (bonded to the same carbon),

[0825] Methyleneoxymethyl (bonded to the same carbon).

[0826] [3] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein A 1 is N or CH, A 2 , A 3 and A 4 0 or 1 of which is N.

[0827] [4] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl which may be substituted by 1 halogen atom or 5- to 6-membered heteroaryl which may be substituted by 1 halogen atom,

[0828] The 5-membered heteroaryl is selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl and oxadiazolyl.

[0829] The 6-membered heteroaryl is pyridyl or pyrimidinyl.

[0830] [5] The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof, wherein the halogen atom is fluorine or chlorine.

[0831] [6] The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, wherein R 1 is a chlorine atom or a bromine atom.

[0832] [7] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom and a C1-C2 alkoxy group.

[0833] [8] The compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof, wherein R 3 in the heterocyclic 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.

[0834] [9] The compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof, wherein R 3 in the heterocyclic group is selected from the group consisting of oxetanyl, tetrahydrofuryl, furyl, tetrahydropyranyl, dioxolanyl and dioxanyl.

[0835]

[10] The compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof, wherein R 3 in the heterocyclic group having an oxo group on the ring is selected from the group consisting of 2-oxooxazolidinyl, 2-oxooxazinyl, 3-oxomorpholinyl, 2-oxoazetidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxoimidazolidinyl, 2-oxo-1,3-dioxolanyl, 2-oxo-1,3-dioxolenyl, 1,1-dioxothietanyl, 1,1-dioxotetrahydrothienyl and 1,1-dioxoisothiazolidinyl.

[0836]

[11] The compound according to any one of [1] to

[10] or a pharmaceutically acceptable salt thereof, wherein R 3Among them, the heterocyclic group without an oxo group as a substituent on the ring is selected from the group consisting of oxazolyl, azetidinyl, pyrrolidinyl, dioxolanyl, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, and oxetanyl.

[0837]

[12] A compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof.

[0838] [Chemical formula 35]

[0839]

[0840] In formula (II),

[0841] Ar is furanyl, phenyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, or oxadiazolyl, and furanyl, phenyl, and pyridyl may be substituted by one fluorine atom.

[0842] R 1 is a halogen atom.

[0843] R 4 、R 5 and R 6 are each independently 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.

[0844] R 3a is a hydrogen atom or any group selected from the following Group C.

[0845] Group C:

[0846] [Chemical formula 36]

[0847]

[0848] 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 (-C2H4OCH3), a methoxyethoxyethyl group (-C2H4OC2H4OCH3), a methanesulfonyl group (-S(O)2CH3), an acetyl group (-C(O)CH3), a cyclopropylmethyl group, a phenyl group, a benzyl group, an oxetanyl group, an oxetanylmethyl group, a 2-amino-2-oxoethyl group (-CH2C(O)NH2), a propargyl group (-CH2C≡CH), a tert-butoxycarbonyl-2-aminoethoxyethyl group (-C2H4OC2H4NHC(O)O(CH3)3), an ethylaminocarbonyl group (-C(O)NHCH2CH3), or an oxadiazolylmethyl group.

[0849] RQ2 , R Q3 and R Q4 are each independently a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group or a trifluoromethyl group,

[0850] R Q5 and R Q6 are each independently a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group, a methoxy group (-OCH3), a difluoromethoxy group (-OCHF2) or a methoxymethyl group,

[0851] R Q7 is a hydrogen atom, a fluorine atom, a methyl group or an ethyl group, or is an ethylenedioxy group (bonded to the same carbon) or a methyleneoxymethyl group (bonded to the same carbon).

[0852]

[13] A compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof.

[0853] [Chemical formula 37]

[0854]

[0855] In formula (III),

[0856] Ar is a furyl group or a phenyl group,

[0857] R 1 is a chlorine atom,

[0858] A 2 、A 3 and A 4 are each independently CH or N, and any one of A 2 、A 3 and A 4 is N, and R 3b is a hydrogen atom or any group selected from the following Group D.

[0859] Group D:

[0860] [Chemical formula 38]

[0861]

[0862]

[14] A compound represented by the following formula (IV) or a pharmaceutically acceptable salt thereof.

[0863] [Chemical formula 39]

[0864]

[0865] In formula (IV),

[0866] Ar is a furyl group or a phenyl group,

[0867] R1 is a chlorine atom,

[0868] R 3c is a hydrogen atom or any group selected from the following Group E.

[0869] Group E:

[0870] [Chemical formula 40]

[0871]

[0872] R Q1 is a hydrogen atom, methyl group, methanesulfonyl group (-S(O)2CH3), acetyl group (-C(O)CH3), fluoroethyl group or hydroxyethyl group,

[0873] R Q5 is a hydrogen atom or methyl group.

[0874]

[15] The compound represented by the following formula (V) or a pharmaceutically acceptable salt thereof.

[0875] [Chemical formula 41]

[0876]

[0877] In formula (V),

[0878] Ar is a furyl group or a phenyl group,

[0879] R 1 is a chlorine atom,

[0880] A 2 、A 3 and A 4 are each independently CH or N, and any one of A 2 、A 3 and A 4 is N, R 3d is a hydrogen atom or any group selected from the following Group F.

[0881] Group F:

[0882] [Chemical formula 42]

[0883]

[0884] R Q1 is a hydrogen atom, methyl group, fluoroethyl group or hydroxyethyl group,

[0885] R Q5 is a hydrogen atom or methyl group.

[0886]

[16] Any compound selected from the following group or a pharmaceutically acceptable salt thereof.

[0887] 2-Chloro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine,

[0888] 2-Chloro-N-(furan-2-ylmethyl)-8-methoxyquinolin-4-amine,

[0889] 2-Chloro-7-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine,

[0890] 2-Chloro-5-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine,

[0891] 2-Bromo-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine,

[0892] 2-Chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[3,4-d]pyrimidin-4-amine,

[0893] 2-Chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[4,3-d]pyrimidin-4-amine,

[0894] 2-Chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[3,2-d]pyrimidin-4-amine,

[0895] 2-Chloro-6-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine,

[0896] 2-Chloro-N-(furan-2-ylmethyl)-6,8-dimethoxyquinazolin-4-amine,

[0897] 2-Chloro-N-(furan-2-ylmethyl)-7,8-dimethoxyquinazolin-4-amine,

[0898] 2-Chloro-8-methoxy-N-(thiophen-2-ylmethyl)quinazolin-4-amine,

[0899] 2-Chloro-8-methoxy-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine,

[0900] 2-Chloro-8-methoxy-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine,

[0901] 2-Chloro-8-methoxy-N-(thiophen-3-ylmethyl)quinazolin-4-amine,

[0902] 2-Chloro-8-methoxy-N-(pyridin-4-ylmethyl)quinazolin-4-amine,

[0903] 2-Chloro-N-(2-fluorobenzyl)-8-methoxyquinazolin-4-amine,

[0904] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0905] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0906] (5R)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0907] (5S)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0908] 1-{3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-1-yl}ethanone,

[0909] 2-Chloro-N-(furan-2-ylmethyl)-8-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine,

[0910] 2-Chloro-8-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0911] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0912] 2-Chloro-8-[(2,2-difluorocyclobutyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0913] 2-Chloro-8-(1,4-dioxaspiro[4.4]nonan-7-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0914] 3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclopentanone,

[0915] 2-Chloro-8-(1,4-dioxaspiro[4.4]nonan-6-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0916] 2-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclopentanone,

[0917] 4-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0918] 3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclobutanol,

[0919] 2-Chloro-8-{[3-(difluoromethoxy)cyclobutyl]methoxy}-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0920] 5-[({2,6-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0921] (3S,5R)-5-[({2,6-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methylpyrrolidin-2-one,

[0922] 5-({[4-(Benzylamino)-2,6-dichloroquinazolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[0923] 5-[({2,7-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0924] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinolin-4-amine,

[0925] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0926] 5-({[4-(Benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[0927] 5-({[4-(Benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0928] 5-({[4-(Benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0929] 5-({[4-(benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one, 2-chloro-N-(furan-2-ylmethyl)-8-(tetrahydrofuran-3-ylmethoxy)quinazolin-4-amine,

[0930] 2-chloro-N-(furan-2-ylmethyl)-8-(tetrahydro-2H-pyran-3-ylmethoxy)quinazolin-4-amine,

[0931] 2-chloro-8-[(1-fluorocyclopropyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0932] 1-[2-({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)ethyl]imidazolidin-2-one,

[0933] 2-chloro-8-[(1,1-dioxidotetrahydrothiophen-3-yl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0934] 7-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-6-oxa-4-azaspiro[2.4]heptan-5-one,

[0935] (3S,5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-3-methylpyrrolidin-2-one,

[0936] 2-chloro-N-(furan-2-ylmethyl)-8-[(2-methyl-1,1-dioxid-1,2-thiazolidin-4-yl)methoxy]quinazolin-4-amine,

[0937] 2-chloro-8-(furan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0938] 3-[2-({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)ethyl]-1,3-oxazolidin-2-one,

[0939] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1,3-dioxolan-2-one,

[0940] 2-chloro-8-[2-(1,4-dioxan-2-yl)ethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0941] 2-Chloro-N-(furan-2-ylmethyl)-8-[(3-methoxy-4,5-dihydro-1,2-oxazol-5-yl)methoxy]quinazolin-4-amine,

[0942] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]morpholin-3-one,

[0943] 1-Benzyl-4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]imidazolidin-2-one,

[0944] 2-Chloro-N-(furan-2-ylmethyl)-8-(2-oxaspiro[3.3]heptan-6-ylmethoxy)quinazolin-4-amine,

[0945] 2-Chloro-8-(cyclopentylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0946] 1-{3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]azetidin-1-yl}ethanone,

[0947] 2-Chloro-8-(furan-3-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0948] 2-Chloro-N-(furan-2-ylmethyl)-8-{[1-(trifluoromethyl)cyclobutyl]methoxy}quinazolin-4-amine,

[0949] 2-Chloro-8-(cyclohexylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[0950] 2-Chloro-N-(furan-2-ylmethyl)-8-(tetrahydrofuran-2-ylmethoxy)quinazolin-4-amine,

[0951] 1-{2-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-1-yl}ethanone,

[0952] 4-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0953] 3-Benzyl-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0954] 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-phenyl-1,3-oxazolidin-2-one,

[0955] (3S,5R)-5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-methylpyrrolidin-2-one

[0956] (3R,5R)-5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-methylpyrrolidin-2-one

[0957] 4-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)pyrrolidin-2-one

[0958] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-4,4-dimethyl-1,3-oxazolidin-2-one

[0959] 6-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazin-2-one

[0960] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-methylpyrrolidin-2-one

[0961] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-5-methyl-1,3-dioxol-2-one

[0962] 6-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]piperidin-2-one

[0963] (5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one

[0964] (5S)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one

[0965] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]azetidin-2-one

[0966] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-5-methylpyrrolidin-2-one

[0967] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-4-methyl-1,3-oxazolidin-2-one

[0968] 5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0969] 5-({[(4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one,

[0970] 5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0971] 5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0972] 5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0973] 1-{3-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]azetidin-1-yl}ethanone,

[0974] 4-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0975] 2-chloro-N-(furan-2-ylmethyl)-8-{[1-(methanesulfonyl)azetidin-3-yl]methoxy}quinolin-4-amine,

[0976] (3S,5R)-5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-3-methylpyrrolidin-2-one,

[0977] 2-chloro-N-(furan-2-ylmethyl)-8-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}quinolin-4-amine,

[0978] 1-{3-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-1-yl}ethanone,

[0979] (5R)-5-([({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0980] (5S)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0981] (5R)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0982] (5S)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[0983] 5-({[4-(Benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one,

[0984] 5-({[4-(Benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0985] 5-({[4-(Benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0986] (3S,5R)-5-({[4-(Benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-methylpyrrolidin-2-one,

[0987] 4-({[4-(Benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)pyrrolidin-2-one,

[0988] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)-1,5-naphthyridin-4-amine,

[0989] 5-[({6-Chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[0990] 5-[({6-Chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[0991] (3S,5R)-5-[({6-Chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-methylpyrrolidin-2-one,

[0992] 5-[({6-Chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0993] 5-([{6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0994] 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-1,3-oxazolidin-2-one,

[0995] 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[0996] (3S,5R)-5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-methylpyrrolidin-2-one,

[0997] 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[0998] 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[0999] 5-({[4-(benzylamino)-2-chloropyrido[3,2-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[1000] (5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(methoxymethyl)pyrrolidin-2-one,

[1001] 3-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one,

[1002] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-methylimidazolidin-2-one,

[1003] 5-[2-({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)ethyl]pyrrolidin-2-one,

[1004] 2-chloro-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[1005] trans-4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclohexanol,

[1006] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1-methylimidazolidin-2-one,

[1007] 2-chloro-8-(cyclopropylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[1008] 2-chloro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinazolin-4-amine, 2-chloro-8-(1,3-dioxolan-5-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-8-(cyclobutylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine,

[1009] 2-chloro-8-[(2S)-1,4-dioxolan-2-ylmethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[1010] 2-chloro-8-[(2S)-1,4-dioxolan-2-ylmethoxy]-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine,

[1011] 2-chloro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinolin-4-amine,

[1012] 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-8-[(3,3-difluorocyclobutyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-[(1-methylcyclopropyl)methoxy]quinazolin-4-amine,

[1013] 2-chloro-N-(furan-2-ylmethyl)-8-(tetrahydro-2H-pyran-2-ylmethoxy)quinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-(oxetan-2-ylmethoxy)quinazolin-4-amine,

[1014] 2-chloro-8-[2-(1,1-dioxosulfolan-3-yl)ethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[1015] 2-chloro-8-[(2R)-1,4-dioxolan-2-ylmethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine,

[1016] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-5-methyl-1,3-oxazolidin-2-one,

[1017] 2-chloro-8-[(2R)-1,4-dioxolan-2-ylmethoxy]-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine,

[1018] 2-chloro-8-(cyclopropylmethoxy)-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine,

[1019] 2-chloro-8-(cyclobutylmethoxy)-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine,

[1020] 2-chloro-7-fluoro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinazolin-4-amine,

[1021] 2-chloro-8-(cyclopropylmethoxy)-N-(furan-2-ylmethyl)quinolin-4-amine,

[1022] 2-chloro-8-[2-(1,1-dioxothietan-3-yl)ethoxy]-N-(furan-2-ylmethyl)quinolin-4-amine,

[1023] 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-2-ylmethyl)quinazolin-4-amine, 2-chloro-8-(1,4-dioxolan-2-ylmethoxy)-N-(thiophen-2-ylmethyl)quinazolin-4-amine, 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-3-ylmethyl)quinazolin-4-amine, 2-chloro-8-(1,4-dioxolan-2-ylmethoxy)-N-(thiophen-3-ylmethyl)quinazolin-4-amine,

[1024] 5-{[(2-chloro-4-{[(4-fluorofuran-2-yl)methyl]amino}quinazolin-8-yl)oxy]methyl}-1,3-oxazolidin-2-one,

[1025] 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,2-thiazol-5-ylmethyl)quinazolin-4-amine,

[1026] 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-oxazol-4-ylmethyl)quinazolin-4-amine,

[1027] 2-chloro-8-(1,4-dioxolan-2-ylmethoxy)-N-(1,2-oxazol-3-ylmethyl)quinazolin-4-amine,

[1028] 5-[({2-Chloro-4-[(1,3-oxazol-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[1029] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine,

[1030] 5-[({2-Chloro-4-[(thiophen-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[1031] 5-[({2-Chloro-4-[(thiophen-3-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[1032] 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine,

[1033] 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine,

[1034] 5-[({2-Chloro-4-[(1,3-thiazol-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[1035] 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine,

[1036] 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(pyridin-4-ylmethyl)quinazolin-4-amine,

[1037] 5-[({2-Chloro-4-[(pyridin-4-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[1038] 5-[({2-Chloro-4-[(pyrimidin-4-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[1039] 5-[({2-Chloro-4-[(pyridin-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[1040] 5-{[(2-Chloro-4-{[(3-fluoropyridin-4-yl)methyl]amino}quinazolin-8-yl)oxy]methyl}-1,3-oxazolidin-2-one,

[1041] 5-[({2-chloro-4-[(2-fluorobenzyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[1042] 5-[({2-chloro-4-[(3-fluorobenzyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[1043] 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,2,4-oxadiazol-3-ylmethyl)quinazolin-4-amine,

[1044] 5-[({2-chloro-4-[(1,2-thiazol-5-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[1045] 5-[({2-chloro-4-[(4-fluorobenzyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one,

[1046] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[1047] (5S)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[1048] (5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[1049] 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one,

[1050] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[1051] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[1052] 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[1053] 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[1054] 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[1055] 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,2-d]pyrimidin-4-amine,

[1056] 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine,

[1057] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]pyrido[3,4-d]pyrimidin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[1058] 5-({[4-(benzylamino)-2-chloropyrido[3,4-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[1059] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]pyrido[4,3-d]pyrimidin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one,

[1060] 5-({[4-(benzylamino)-2-chloropyrido[4,3-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[1061] 5-({[4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one,

[1062] 5-({[4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one,

[1063] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-ethyl-1,3-oxazolidin-2-one,

[1064] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(propan-2-yl)-1,3-oxazolidin-2-one,

[1065] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one,

[1066] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(cyclopropylmethyl)-1,3-oxazolidin-2-one,

[1067] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2,2-difluoroethyl)-1,3-oxazolidin-2-one,

[1068] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one,

[1069] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(oxetan-3-yl)-1,3-oxazolidin-2-one,

[1070] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-hydroxy-2-methylpropyl)-1,3-oxazolidin-2-one,

[1071] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-N-ethyl-2-oxo-1,3-oxazolidine-3-carboxamide,

[1072] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-(2-hydroxyethyl)pyrrolidin-2-one,

[1073] 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-(2-fluoroethyl)pyrrolidin-2-one,

[1074] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(prop-2-yn-1-yl)-1,3-oxazolidin-2-one,

[1075] [2-(2-{5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}ethoxy)ethyl]carbamic acid tert-butyl ester,

[1076] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-[2-(2-methoxyethoxy)ethyl]-1,3-oxazolidin-2-one,

[1077] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(oxetan-3-ylmethyl)-1,3-oxazolidin-2-one,

[1078] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(1,2,4-oxadiazol-5-ylmethyl)-1,3-oxazolidin-2-one,

[1079] 2-{5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}acetamide,

[1080] 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-methoxyethyl)-1,3-oxazolidin-2-one.

[1081]

[17] A pharmaceutical composition comprising, as an active ingredient, the compound according to any one of [1] to

[16] or a pharmaceutically acceptable salt thereof

[1082]

[18] A pharmaceutical composition for treating a genetic disease caused by splicing abnormality, comprising, as an active ingredient, the compound according to any one of [1] to

[16] or a pharmaceutically acceptable salt thereof.

[1083]

[19] The pharmaceutical composition according to

[18] , wherein the splicing abnormality is caused by the α-galactosidase gene IVS4+919G>A mutation.

[1084]

[20] The pharmaceutical composition according to

[18] or

[19] , wherein the genetic disease caused by splicing abnormality is Fabry disease.

[1085]

[21] A method for treating a genetic disease caused by splicing abnormality, comprising the step of administering to a subject the compound according to any one of [1] to

[16] or a pharmaceutically acceptable salt thereof.

[1086]

[22] The method according to

[21] , wherein the genetic disease caused by splicing abnormality is Fabry disease.

[1087] Use of the compound according to any one of

[23] [1] to

[16] or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for treating a genetic disease caused by splicing abnormality.

[1088]

[24] The use according to

[23] , wherein the genetic disease caused by splicing abnormality is Fabry disease.

[1089] Examples

[1090] Hereinafter, examples are given to explain the present disclosure in more detail. However, the scope of the present disclosure is not limited thereto, and these examples should not be construed in a limiting sense in any way. In addition, in this specification, reagents, solvents, and starting materials not specifically described can be easily obtained from commercially available sources.

[1091] Proton nuclear magnetic resonance spectroscopy (1H-NMR) was measured using a 400 MHz nuclear magnetic resonance apparatus manufactured by JEOL Ltd., a 400 MHz nuclear magnetic resonance apparatus manufactured by Varian Inc., or a 400 MHz nuclear magnetic resonance apparatus manufactured by Bruker Corporation. The spectral data markers show significant peaks, including chemical shift (expressed as relative ppm (δ) with tetramethylsilane as the reference substance), number of protons, multiplicity of peak splitting (expressed as s: singlet; d: doublet; t: triplet; q: quartet; quint.: quintet; m: multiplet; br: broad; br s: broad singlet, etc.), and in cases where it can be clearly shown, the spin coupling constant is expressed as J value (unit: Hz).

[1092] Mass spectrometry (MS m / z) was measured using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). The mass spectrometry data show the maximum ionization peak after passing through a reversed-phase high-performance liquid chromatography column (Agilent system; column: Develosil Combi-RP-5, 2.0×50 mm, Cadenza CD-C18, 3.0×75 mm, or ZORBAX SB-C18, 1.8 μm, 2.1×50 mm; solvent: acetonitrile / water system containing 0.1% formic acid, or acetonitrile / water system containing 0.01% trifluoroacetic acid), which is almost always consistent with the maximum UV absorption peak.

[1093] Silica gel column chromatography was carried out using commercially available pre-packed columns and an automatic separation and purification device (such as SP1 manufactured by BIOTAGE, EPCLC-W-Prep2XY manufactured by Yamazen Corporation, Purif-α2 manufactured by Shoko Science Co., Ltd., etc.), and only the types of various solvents used as the mobile phase were described. Elution was carried out under the observation of thin-layer chromatography (TLC). As the TLC plate, silica gel 60F254 or 60NH2F254S manufactured by Merck, NH2 silica gel 60F254 plate manufactured by Wako Pure Chemical Industries, Ltd., or CHROMATOREX NH TLC manufactured by Fuji Silysia Chemical Ltd. was used. As the developing solvent, the mobile phase used in column chromatography was used, and as the detection method, a UV detector or a coloring reagent was used. It should be noted that in the examples, "silica gel column chromatography (NH)" refers to silica gel whose surface has been chemically modified with a functional group having an amino group (such as Purif-Pack (registered trademark, Shoko Scientific)-EX, NH series, etc.).

[1094] (Example 1) 2-Chloro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine

[1095] [Chemical formula 43]

[1096]

[1097] To a suspension of 2,4-dichloro-8-methoxyquinazoline (102 mg, 0.445 mmol) in acetonitrile (1.5 mL) were added furfurylamine (44.0 μL, 0.468 mmol) and triethylamine (75.0 μL, 0.534 mmol), and the mixture was stirred at 60 °C for 7 hours. After the reaction solution was naturally cooled to room temperature, water (6 mL) was added to the reaction solution, and the solid was collected by filtration. The obtained crude purified product was washed with water and then dried to obtain the title compound (120 mg, yield 93%) as a white solid.

[1098] (Example 2) 2-Chloro-N-(furan-2-ylmethyl)-8-methoxyquinolin-4-amine

[1099] [Chemical formula 44]

[1100]

[1101] Using 2,4-dichloro-8-methoxyquinoline (214 mg, 0.938 mmol), furfurylamine (96.0 μL, 1.03 mmol), and NMP (1.5 mL) as a solvent instead of DMF as described in J. Mol. Structure, 2017, 1131, 51 - 72, the same operation as in Example 1 was carried out, and thus the title compound was obtained as a pale brown solid (82.1 mg, yield 30%).

[1102] (Example 3) 2-Chloro-7-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine

[1103] [Chemical formula 45]

[1104]

[1105] (Example 3-1) 7-Fluoro-8-methoxyquinazoline-2,4(1H,3H)-dione

[1106] [Chemical formula 46]

[1107]

[1108] A mixture of 2-amino-3-methoxy-4-fluorobenzoic acid (400 mg, 2.16 mmol), urea (1.00 g, 21.6 mmol), and acetic acid (3 mL) was stirred at 150 °C for 0.5 h. After the reaction solution was naturally cooled to room temperature, water (50 mL) was added to make a suspension, and then the solid was collected by filtration, washed with water, and dried. Thus, the title compound was obtained as a white solid (320 mg, yield 70%).

[1109] (Example 3-2) 2,4-Dichloro-7-fluoro-8-methoxyquinazoline

[1110] [Chemical formula 47]

[1111]

[1112] 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 μL, 2.28 mmol) was stirred at 100 °C for 3 h. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 - 10 / 90), and the title compound was obtained as a white solid (280 mg, yield 74%).

[1113] (Example 3-3) 2-Chloro-7-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine

[1114] [Chemical Formula 48]

[1115]

[1116] To a suspension of 2,4-dichloro-7-fluoro-8-methoxyquinazoline (280 mg, 1.134 mmol) obtained in Example 3-2 in NMP (4 mL) were added furfurylamine (0.120 mL, 11.2 mmol) and N,N-diisopropylamine (300 μL, 1.70 mmol), and the mixture was stirred using microwave at 120 °C for 1 hour. Water (10 mL) was added to the reaction mixture, and after extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 100 / 0) to give the title compound as a white solid (226 mg, yield 65%).

[1117] (Example 4) 2-Chloro-5-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine

[1118] [Chemical Formula 49]

[1119]

[1120] (Example 4-1) 2-Amino-6-fluoro-3-methoxybenzamide

[1121] [Chemical Formula 50]

[1122]

[1123] To a suspension of 6-fluoro-3-methoxy-2-nitrobenzonitrile (3.93 g, 22.0 mmol), iron(II) phthalocyanine (62.9 mg, 0.111 mmol), and iron(II) sulfate heptahydrate (29.1 mg, 0.105 mmol) in ethanol (60 mL) / water (60 mL) described in WO2009 / 060209 was added hydrazine monohydrate, and the mixture was stirred at 120 °C for 8.5 hours. After the reaction mixture was naturally cooled to room temperature, saturated brine (100 mL) was added thereto, and after extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 40 / 60) to give the title compound as a pale yellow solid (2.04 g, yield 55%).

[1124] (Example 4-2) 5-Fluoro-8-methoxyquinazoline-2,4(1H,3H)-dione

[1125] [Chemical Formula 51]

[1126]

[1127] To a DMF solution (30 mL) of 2-amino-6-fluoro-3-methoxybenzamide (2.04 g, 11.1 mmol) obtained in Example 4-1 was added potassium carbonate (3.39 g, 24.5 mmol) and 1,1'-carbonyldiimidazole (3.66 g, 22.6 mmol), and the mixture was stirred at 90 °C for 4 hours. Water (200 mL) was added to the reaction solution, and after washing with ethyl acetate, 2 M hydrochloric acid was added while stirring the aqueous layer under ice-cooling for neutralization. The precipitated solid was collected by filtration, washed with water, and dried to obtain the title compound (1.67 g, yield 72%) as a white solid.

[1128] (Example 4-3) 2,4-Dichloro-5-fluoro-8-methoxyquinazoline

[1129] [Chemical Formula 52]

[1130]

[1131] A mixture of 5-fluoro-8-methoxyquinazoline-2,4(1H,3H)-dione (156 mg, 0.742 mmol), phosphoryl chloride (855 mg, 5.58 mmol), and N,N-diethylaniline (238 μL, 1.48 mmol) obtained in Example 4-2 was stirred at 100 °C for 8 hours. In the middle, N,N-diethylaniline was added additionally after 3 hours (60.0 μL, 0.371 mmol) and 5.5 hours (25.0 μL, 0.148 mmol) from the start of the reaction. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. Toluene was added to the obtained residue, and it was concentrated again under reduced pressure. Chloroform (3 mL) was added to the obtained residue, and saturated aqueous sodium bicarbonate solution was added dropwise to the obtained suspension while stirring until pH = 5. After extraction with chloroform, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 100 - 20 / 80) to obtain the title compound (155 mg, yield 85%) as a pale yellow solid.

[1132] (Example 4-4) 2-Chloro-5-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine

[1133] [Chemical Formula 53]

[1134]

[1135] To a solution of 2,4-dichloro-5-fluoro-8-methoxyquinazoline (71.4 mg, 0.289 mmol) in acetonitrile (1.5 mL) obtained in Example 4-3 were added furfurylamine (32.0 μL, 0.347 mmol) and triethylamine (61.0 μL, 0.434 mmol), and the mixture was stirred at 60 °C for 2 hours. After the reaction solution was naturally cooled to room temperature, water (4 mL) was added, and the insoluble matter was collected by filtration, washed with water and dried to obtain a crude purified product. The obtained crude purified product was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 35 / 65) to obtain the title compound (62.6 mg, yield 70%) as a white solid.

[1136] (Example 5) 2-Bromo-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine

[1137] [Chemical formula 54]

[1138]

[1139] To a solution of 2,4-dibromo-8-methoxyquinazoline (200 mg, 0.629 mmol) in NMP (10 mL) were added furfurylamine (64.0 μL, 0.692 mmol) and N,N-diisopropylethylamine (160 μL, 0.943 mmol), and the mixture was stirred at 120 °C for 0.5 hour. After the reaction solution was naturally cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 100 / 0) to obtain the title compound (168 mg, yield 80%) as a white solid.

[1140] (Example 6) 2-Chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[3,4-d]pyrimidin-4-amine

[1141] [Chemical formula 55]

[1142]

[1143] To a toluene solution (5 mL) of 8-methoxypyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 1.04 mmol) and N,N-diisopropylethylamine (404 μL, 2.32 mmol) described in Bioorg. Med. Chem. Lett., 2013, 23, 5923 - 5930 was added phosphoryl chloride (194 μL, 2.09 mmol), and the mixture was stirred at 80 °C for 2 h. The reaction solution was concentrated under reduced pressure to obtain a yellow oil. After adding THF (5 mL) to make a solution, furfurylamine (114 μL, 1.24 mmol) was added, and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated, and the obtained residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25 mm×10 μm, elution solvent: 0.225% formic acid aqueous solution / acetonitrile = 79 / 21 - 49 / 51) to obtain the title compound as a yellow solid (25.1 mg, yield 8%).

[1144] (Example 7) 2-Chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[4,3-d]pyrimidin-4-amine

[1145] [Chemical formula 56]

[1146]

[1147] (Example 7-1) 4-Amino-5-methoxypyridine-3-carboxamide

[1148] [Chemical formula 57]

[1149]

[1150] To a DMSO solution (10 mL) of 4-amino-5-methoxypyridine-3-carbonitrile (900 mg, 6.03 mmol) was added 30% aqueous hydrogen peroxide (10 mL, 104 mmol) and potassium carbonate (1.70 g, 12.3 mmol) under ice-cooling, and the mixture was stirred at room temperature for 12 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The remaining aqueous layer was neutralized with 3M hydrochloric acid and concentrated under reduced pressure. Methanol was added to the obtained white solid, and after filtering off the solid, the methanol was concentrated under reduced pressure. The residue obtained by concentrating the organic layer was combined with the residue obtained by concentrating the methanol and purified by silica gel column chromatography (methanol / DCM = 1 / 40 - 1 / 10) to obtain the title compound as a white solid (720 mg, yield 72%).

[1151] (Example 7-2) 8-Methoxypyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione

[1152] [Chemical Formula 58]

[1153]

[1154] Under ice-cooling, 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. After stirring at 15 °C for 1 hour, a 1,4-dioxane solution (3 mL) of triphosgene (1.20 g, 4.04 mmol) was added to the reaction solution under ice-cooling, and the mixture was stirred at 0 °C to 15 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: Shim-pack C18 150×25 mm×10 μm, elution solvent: 0.1% aqueous trifluoroacetic acid / acetonitrile = 99 / 1 to 75 / 25) to obtain the title compound (125 mg, yield 23%) as a white solid.

[1155] (Example 7-3) 2-Chloro-N-(furan-2-ylmethyl)pyrido[4,3-d]pyrimidin-4-amine

[1156] [Chemical Formula 59]

[1157]

[1158] A mixture of 8-methoxypyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.518 mmol), phosphoryl chloride (10.0 mL, 108 mmol) and N,N-diisopropylethylamine (0.900 mL, 5.17 mmol) obtained in Example 7-2 was stirred at 100 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the operation of adding toluene to the resulting residue and concentrating under reduced pressure was repeated 3 times. To a THF solution (5 mL) of the resulting residue, furfurylamine (51.9 μL, 0.566 mmol) and N,N-diisopropylethylamine (333 μL, 1.91 mmol) were added, and the mixture was stirred at 15 °C for 1 hour. The reaction solution was concentrated under reduced pressure, water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25 mm×10 μm, elution solvent: 0.225% aqueous formic acid / acetonitrile = 79 / 21 to 49 / 51) to obtain the title compound (28.0 mg, yield 19%) as a yellow solid.

[1159] (Example 8) 2-Chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[3,2-d]pyrimidin-4-amine

[1160] [Chemical Formula 60]

[1161]

[1162] To a solution of 2,4-dichloro-8-methoxypyrido[3,2-d]pyrimidine (119 mg, 0.517 mmol) in THF (5 mL) described in WO2020 / 081636 was added furfurylamine (56.6 μL, 0.618 mmol) and N,N-diisopropylethylamine (189 μL, 1.08 mmol), and the mixture was stirred at room temperature for 4 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25 mm×10 μm, elution solvent: 0.225% aqueous formic acid / acetonitrile = 62 / 38 to 32 / 68) to obtain the title compound as a yellow solid (30.3 mg, yield 20%).

[1163] The structural formulas and physicochemical data of the compounds described in Examples 1 to 8 are shown below.

[1164] Table 1

[1165]

[1166]

[1167]

[1168] The compounds of Examples 9 to 17 shown below were prepared according to the procedures described in Examples 1 to 4 described above.

[1169] Table 2

[1170]

[1171]

[1172]

[1173] (Example 18) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine

[1174] [Chemical Formula 61]

[1175]

[1176] (Example 18-1) 2,4-Dichloroquinazolin-8-ol

[1177] [Chemical Formula 62]

[1178]

[1179] To a suspension of aluminum chloride (30.4 mg, 228 mmol) in dichloromethane (120 mL) under ice-cooling was added a solution of 2,4-dichloro-8-methoxyquinazoline (8.71 g, 38.0 mmol) in dichloromethane (90 mL). After stirring for 30 minutes, the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice in a beaker for quenching, and then concentrated hydrochloric acid (20 mL) was added and stirred. The reaction solution was extracted with dichloromethane, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10% - 20%), and the obtained crude pure product was purified again by column chromatography (ethyl acetate / hexane = 2% - 15%) to obtain the title compound (5.02 g, yield 62%) as a pale yellow solid.

[1180] (Example 18-2) 2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol

[1181] [Chemical Formula 63]

[1182]

[1183] To a mixture of 2,4-dichloroquinazolin-8-ol (1.01 g, 4.70 mmol) obtained in Example 18-1 and acetonitrile (25 mL) were added furfurylamine (0.478 mL, 5.17 mmol) and triethylamine (1.30 mL, 9.39 mmol), and the mixture was stirred at 60 °C for 2 hours. After the reaction solution was naturally cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 - 25 / 75) to obtain the title compound (1.14 g, yield 88%) as a yellow solid.

[1184] (Example 18-3) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine

[1185] [Chemical Formula 64]

[1186]

[1187] To 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 was added (1,4-dioxan-2-yl)methanol (86.4 μL, 0.816 mmol) and cyanomethylene tributylphosphorane (429 μL, 1.63 mmol), and the mixture was stirred at 80 °C for 2 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 34 / 66 to 66 / 34) to obtain the title compound (87.1 mg, yield 43%) as a white solid.

[1188] (Example 19) 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one

[1189] [Chemical formula 65]

[1190]

[1191] 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 was added 5-(hydroxymethyl)-1,3-oxazolidin-2-one (32.5 mg, 0.277 mmol) and cyanomethylene tributylphosphorane (73.0 μL, 0.277 mmol), and the mixture was stirred at 80 °C for 4 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20 / 80 to 100 / 0) to obtain the title compound (42.4 mg, yield 82%) as a white solid.

[1192] (Example 20) (5R)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one

[1193] [Chemical formula 66]

[1194]

[1195] 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 were added (5R)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (44.1 mg, 0.376 mmol) and cyanomethylenetributylphosphorane (123 μL, 0.470 mmol), and the mixture was stirred at 80 °C for 2 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20 / 80 to 100 / 0). The resulting solid was made into a suspension in a mixed solvent of ethyl acetate / hexane (50 / 50), and the solid was collected by filtration and dried to obtain the title compound (48.0 mg, yield 55%) as a white solid.

[1196] (Example 21) (5S)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one

[1197] [Chemical Formula 67]

[1198]

[1199] 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 were added (5S)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (46.5 mg, 0.397 mmol) and cyanomethylenetributylphosphorane (126 μL, 0.480 mmol), and the mixture was stirred at 80 °C for 2 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20 / 80 to 100 / 0). The resulting solid was made into a suspension in a mixed solvent of ethyl acetate / hexane (50 / 50), and the solid was collected by filtration and dried to obtain the title compound (59.5 mg, yield 66%) as a white solid.

[1200] (Example 22) 1-{3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-1-yl}ethanone

[1201] [Chemical Formula 68]

[1202]

[1203] 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 were added 1-[3-(hydroxymethyl)pyrrolidin-1-yl]ethan-1-one (46.2 mg, 0.323 mmol) and cyanomethylenetributylphosphorane (113 μL, 0.430 mmol), and the mixture was stirred at 80 °C for 1 hour. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate = 0 / 100 to 10 / 90) to obtain the title compound (84.4 mg, yield 98%) as a yellow solid.

[1204] (Example 23) 2-Chloro-N-(furan-2-ylmethyl)-8-{[1-(methylsulfonyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine

[1205] [Chemical Formula 69]

[1206]

[1207] To a toluene solution (1 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (40.8 mg, 0.148 mmol) obtained in Example 18-2 were added (1-methylsulfonylpyrrolidin-3-yl)methanol (40.9 mg, 0.228 mmol) and cyanomethylenetributylphosphorane (58.0 μL, 0.222 mmol), and the mixture was stirred at 80 °C for 1 hour. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography (NH, ethyl acetate / hexane = 30 / 70 to 75 / 25), and the resulting crude purified product was purified by silica gel column chromatography (ethyl acetate / hexane = 30 / 70 to 75 / 25) to obtain the title compound (50.7 mg, yield 78%) as a yellow solid.

[1208] (Example 24) 2-Chloro-8-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine

[1209] [Chemical Formula 70]

[1210]

[1211] To a toluene solution (0.5 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (22.3 mg, 0.0809 mmol) obtained in Example 18-2 was added (2,2-dimethyl-1,3-dioxan-5-yl)methanol (16.1 mg, 0.110 mmol) and cyanomethylene tributylphosphorane (46.0 μL, 0.162 mmol), and the mixture was stirred at 80 °C for 4.5 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 40 / 60) to obtain the title compound (32.7 mg, yield 100%) as a pale yellow solid.

[1212] (Example 25) 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one

[1213] [Chemical formula 71]

[1214]

[1215] 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 was added 5-(hydroxymethyl)pyrrolidin-2-one (33.0 mg, 0.287 mmol) and cyanomethylene tributylphosphorane (96.0 μL, 0.365 mmol), and the mixture was stirred at 80 °C for 1.5 hours. After the reaction solution was naturally cooled to room temperature, 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 light brown solid.

[1216] (Example 26) 2-Chloro-8-[(2,2-difluorocyclobutyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine

[1217] [Chemical formula 72]

[1218]

[1219] To a toluene solution (1 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (40.0 mg, 0.145 mmol) obtained in Example 18-2 was added (2,2-difluorocyclobutyl)methanol (20.0 mg, 0.160 mmol) and cyanomethylenetributylphosphorane (76.0 μL, 0.290 mmol), and the mixture was stirred at 80 °C for 0.5 hour. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 30 / 70) to obtain the title compound (51.0 mg, yield 93%) as a white solid.

[1220] (Example 27) 2-Chloro-8-(1,4-dioxaspiro[4.4]nonan-7-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine

[1221] [Chemical formula 73]

[1222]

[1223] 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 was added 1,4-dioxaspiro[4,4]nonan-8-ylmethanol (90.0 mg, 0.569 mmol) and cyanomethylenetributylphosphorane (220 mg, 0.912 mmol), and the mixture was stirred at 80 °C for 12 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 μm, elution solvent: 0.05% aqueous ammonia / acetonitrile = 57 / 43 to 27 / 73) to obtain the title compound (97.0 mg, yield 64%) as a white solid.

[1224] (Example 28) 3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclopentanone

[1225] [Chemical formula 74]

[1226]

[1227] To a solution of 2-chloro-8-(1,4-dioxaspiro[4.4]nonan-7-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine (75.0 mg, 0.180 mmol) obtained in Example 27 in acetone (5 mL) / water (2 mL) was added p-toluenesulfonic acid (32.0 mg, 0.186 mmol), and the mixture was stirred at room temperature for 1 hour. After distilling off acetone under reduced pressure, water (20 mL) was added to the residue, and after extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to preparative HPLC (column: Shim-pack C18 150×25 mm×10 μm, elution solvent: 0.225% aqueous formic acid / acetonitrile = 67 / 33 to 37 / 63) for rough purification and then purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 μm, elution solvent: 0.05% aqueous ammonia / acetonitrile = 70 / 30 to 43 / 57), whereby the title compound was obtained as a yellow solid (41.1 mg, yield 61%).

[1228] (Example 29) 2-Chloro-8-(1,4-dioxaspiro[4.4]nonan-6-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine

[1229] [Chemical formula 75]

[1230]

[1231] 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, the same procedure as in Example 18-3 was carried out, whereby the title compound was obtained as a yellow solid (170 mg, yield 75%).

[1232] (Example 30) 2-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclopentanone

[1233] [Chemical formula 76]

[1234]

[1235] To a solution of 2-chloro-8-(1,4-dioxaspiro[4.4]nonan-6-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine (90.0 mg, 0.216 mmol) obtained in Example 29 in acetone (5 mL) / water (2 mL) was added p-toluenesulfonic acid monohydrate (45.0 mg, 0.237 mmol), and the mixture was stirred at room temperature for 1 hour. After distilling off acetone under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25 mm×10 μm, elution solvent: 0.225% aqueous formic acid / acetonitrile = 62 / 38 to 32 / 68), whereby the title compound was obtained as a white solid (50.3 mg, yield 60%).

[1236] (Example 31) 4-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one

[1237] [Chemical Formula 77]

[1238]

[1239] Using 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (37.1 mg, 0.135 mmol) obtained in Example 18-2 and 4-(hydroxymethyl)pyrrolidin-2-one (31.5 mg, 0.269 mmol), the same operation as in Example 18-3 was carried out, whereby the title compound was obtained as a pale white solid (42.0 mg, yield 84%).

[1240] (Example 32) 3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclobutanol

[1241] [Chemical Formula 78]

[1242]

[1243] Using 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (102 mg, 0.369 mmol) obtained in Example 18-2 and 3-(hydroxymethyl)cyclobutan-1-ol (38.4 mg, 0.376 mmol), the same operation as in Example 18-3 was carried out, whereby the title compound was obtained as a yellow solid (22.5 mg, yield 17%).

[1244] (Example 33) 2-Chloro-8-{[3-(difluoromethoxy)cyclobutyl]methoxy}-N-(furan-2-ylmethyl)quinazolin-4-amine

[1245] [Chemical Formula 79]

[1246]

[1247] To a solution of 3-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclobutanol (16.0 mg, 0.0445 mmol) and copper(I) iodide (1.70 mg, 0.00889 mmol) in acetonitrile (1 mL) obtained in Example 32, a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (7.00 μL, 0.0667 mmol) in acetonitrile (0.5 mL) was added dropwise little by little at 50 °C, and the mixture was stirred at 50 °C for 1.5 hours. After concentrating the reaction solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10 / 90 to 35 / 65) to obtain the title compound (6.10 mg, yield 33%) as a yellow solid.

[1248] (Example 34) 5-[({2,6-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one

[1249] [Chemical Formula 80]

[1250]

[1251] (Example 34-1) 2-Amino-5-chloro-3-methoxybenzamide

[1252] [Chemical Formula 81]

[1253]

[1254] To a solution of 2-amino-5-chloro-3-methoxybenzoic acid (2.92 g, 14.5 mmol) in THF (60 mL) under ice-cooling, 1,1'-carbonyldiimidazole (2.82 g, 17.4 mmol) was added, and then the mixture was stirred at room temperature for 3 hours. 28% aqueous ammonia solution (4.84 mL, 72.4 mmol) was added to the reaction solution and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, water (50 mL) was added to the obtained residue, and the solid was collected by filtration. Diethyl ether was added to the obtained solid for slurry purification, whereby the title compound (2.33 g, yield 80%) was obtained as a pale white solid.

[1255] (Example 34-2) 6-Chloro-8-methoxyquinazoline-2,4(1H,3H)-dione

[1256] [Chemical Formula 82]

[1257]

[1258] Under ice-cooling, 1.11 M lithium bis(trimethylsilyl)amide (26.0 mL, 28.7 mmol) was added to a THF solution (70 mL) of 2-amino-5-chloro-3-methoxybenzamide (2.30 g, 11.5 mmol) obtained in Example 34-1. After stirring at the same temperature for 15 minutes, a THF solution (12 mL) of triphosgene (3.57 g, 12.0 mmol) was added to the reaction solution and stirred for 30 minutes, and then stirred at room temperature for 2 hours. After the reaction solution was cooled under ice-cooling, water (30 mL) was added. After the organic solvent was concentrated under reduced pressure, the solid was collected by filtration, washed with water and dried to obtain a crude pure product. Ethyl acetate / hexane (2 / 1) mixed solvent was added to the obtained crude pure product to form a suspension, which was stirred for 1 hour, and then the solid was collected by filtration to obtain the title compound (2.12 g, yield 82%) as a light brown solid.

[1259] (Example 34-3) 2,4,6-Trichloro-8-methoxyquinazoline

[1260] [Chemical Formula 83]

[1261]

[1262] A mixture of 6-chloro-8-methoxyquinazoline-2,4(1H,3H)-dione (2.08 g, 9.18 mmol), phosphoryl chloride (10.0 g, 65.2 mmol) and N,N-diethylaniline (2.95 mL, 18.4 mmol) obtained in Example 34-2 was stirred at 100 °C for 4 hours. After the reaction solution was naturally cooled to room temperature, the operation of adding toluene and concentrating under reduced pressure was repeated 3 times. Chloroform (50 mL) was added to the obtained residue. While stirring vigorously, saturated aqueous sodium bicarbonate solution was added until the pH reached 5-6, and then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 - 18 / 82) to obtain the title compound (1.57 g, yield 65%) as a pale yellow solid.

[1263] (Example 34-4) 2,4,6-Trichloroquinazolin-8-ol

[1264] [Chemical Formula 84]

[1265]

[1266] Using 2,4,6-trichloro-8-methoxyquinazoline (1.57 g, 5.96 mmol) obtained in Example 34-3 and aluminum chloride (4.77 g, 35.7 mmol), the same operation as in Example 18-1 was carried out, and thus the title compound was obtained as a pale yellow solid (1.45 g, yield 98%).

[1267] (Example 34-5) 2,6-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol

[1268] [Chemical formula 85]

[1269]

[1270] Using 2,4,6-trichloroquinazolin-8-ol (509 mg, 2.04 mmol) obtained in Example 34-4 and furfurylamine (208 μL, 2.24 mmol), the same operation as in Example 18-2 was carried out, and thus the title compound was obtained as a yellow solid (512 mg, yield 81%).

[1271] (Example 34-6) 5-[({2,6-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one

[1272] [Chemical formula 86]

[1273]

[1274] 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, and thus the title compound was obtained as a white solid (58.3 mg, yield 84%).

[1275] (Example 35) (3S,5R)-5-[({2,6-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methylpyrrolidin-2-one

[1276] [Chemical formula 87]

[1277]

[1278] 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, and thus the title compound was obtained as a white solid (24.1 mg, yield 39%).

[1279] (Example 36) 5-({[4-(benzylamino)-2,6-dichloroquinazolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1280] [Chemical Formula 88]

[1281]

[1282] (Example 36-1) 4-(benzylamino)-2,6-dichloroquinazolin-8-ol

[1283] [Chemical Formula 89]

[1284]

[1285] Using 2,4,6-trichloroquinazolin-8-ol (240 mg, 0.962 mmol) obtained in Example 34-4 and benzylamine (116 μL, 1.06 mmol), the same operation as in Example 18-2 was carried out, and thus the title compound was obtained as a pale yellow solid (218 mg, yield 71%).

[1286] (Example 36-2) 5-({[4-(benzylamino)-2,6-dichloroquinazolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1287] [Chemical Formula 90]

[1288]

[1289] 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, and thus the title compound was obtained as a white solid (58.7 mg, yield 81%).

[1290] (Example 37) 5-[({2,7-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one

[1291] [Chemical Formula 91]

[1292]

[1293] (Example 37-1) 2-Amino-4-chloro-3-methoxybenzamide

[1294] [Chemical Formula 92]

[1295]

[1296] Using 2-amino-4-chloro-3-methoxybenzoic acid (1.21 g, 6.00 mmol), the same operation as in Example 34-1 was carried out, and thus the title compound was obtained as a brown solid (1.06 g, yield 88%).

[1297] (Example 37-2) 7-Chloro-8-methoxyquinazoline-2,4(1H,3H)-dione

[1298] [Chemical Formula 93]

[1299]

[1300] Using the 2-amino-4-chloro-3-methoxybenzamide (1.06 g, 5.28 mmol) obtained in Example 37-1, the same operation as in Example 34-2 was carried out, and thus the title compound was obtained as a light brown solid (0.950 g, yield 79%).

[1301] (Example 37-3) 2,4,7-Trichloro-8-methoxyquinazoline

[1302] [Chemical Formula 94]

[1303]

[1304] Using the 7-chloro-8-methoxyquinazoline-2,4(1H,3H)-dione (950 mg, 4.19 mmol) obtained in Example 37-2, the same operation as in Example 34-3 was carried out, and thus the title compound was obtained as a white solid (297 mg, yield 27%).

[1305] (Example 37-4) 2,4,7-Trichloroquinazolin-8-ol

[1306] [Chemical Formula 95]

[1307]

[1308] Using 2,4,7-trichloro-8-methoxyquinazoline (103 mg, 0.391 mmol) obtained in Example 37-3, the same operation as in Example 34-4 was carried out, whereby the title compound (98.4 mg, yield 100%) was obtained.

[1309] (Example 37-5) 2,7-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol

[1310] [Chemical formula 96]

[1311]

[1312] Using 2,4,7-trichloroquinazolin-8-ol (97.5 mg, 0.391 mmol) obtained in Example 37-4, the same operation as in Example 34-5 was carried out, whereby the title compound (103 mg, yield 85%) was obtained as a pale white solid.

[1313] (Example 37-6) 5-[({2,7-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one

[1314] [Chemical formula 97]

[1315]

[1316] Using 2,7-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (43.5 mg, 0.140 mmol) and 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (27.6 mg, 0.210 mmol) obtained in Example 37-5, the same operation as in Example 18-3 was carried out, whereby the title compound (51.0 mg, yield 86%) was obtained as a white solid.

[1317] (Example 38) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinolin-4-amine

[1318] [Chemical formula 98]

[1319]

[1320] (Example 38-1) 2,4-Dichloroquinolin-8-ol

[1321] [Chemical formula 99]

[1322]

[1323] To a solution of 2,4-dichloro-8-methoxyquinoline (154 mg, 0.675 mmol) in DCM (5 mL) described in J.Mol.Structure, 2017, 1131, 51 - 72, 1 M boron tribromide - DCM (1.35 mL, 1.35 mmol) was added. After stirring at the same temperature for 5 hours, it was stirred at room temperature for 18 hours. The reaction solution was cooled in ice, water (2 mL) was added, and then it was concentrated under reduced pressure. Water was added to the obtained residue, the solid was collected by filtration, washed with water and then dried, whereby the title compound (143 mg, yield 99%) was obtained as a pale yellow solid.

[1324] (Example 38 - 2) 2 - chloro - 4 - [(furan - 2 - ylmethyl)amino]quinolin - 8 - ol

[1325] [Chemical formula 100]

[1326]

[1327] To a solution of 2,4 - dichloroquinolin - 8 - ol (6.01 g, 28.1 mmol) obtained in Example 38 - 1 in NMP (112 mL), furfurylamine (5.20 mL, 56.2 mmol) and N,N - diisopropylethylamine (12.2 mL, 70.0 mmol) were added, and it was stirred at 120 °C for 19 hours. After the reaction solution was naturally cooled to room temperature, water (200 mL) was added and it was extracted with ethyl acetate. The organic layer was washed with water, then washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was roughly purified by silica gel column chromatography (methanol / DCM = 0 / 100 - 10 / 90), and then purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 - 50 / 50), whereby the title compound (4.94 g, yield 64%) was obtained as a pale yellow solid. Additionally, the positional isomer 4 - chloro - 2 - [(furan - 2 - ylmethyl)amino]quinolin - 8 - ol (1.38 g, yield 18%) of the title compound was obtained as a white solid.

[1328] (Example 38 - 3) 2 - chloro - 8 - (1,4 - dioxan - 2 - ylmethoxy)-N - (furan - 2 - ylmethyl)quinolin - 4 - amine

[1329] [Chemical formula 101]

[1330]

[1331] Using 2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-ol (150 mg, 0.546 mmol) obtained in Example 38-2 and (1,4-dioxan-2-yl)methanol (86.7 μL, 0.819 mmol), the same operation as in Example 18-3 was carried out, and thus the title compound was obtained as a white solid (167 mg, yield 81%).

[1332] (Example 39) 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one

[1333] [Chemical Formula 102]

[1334]

[1335] Using 2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-ol (90.7 mg, 0.330 mmol) obtained in Example 38-2 and 5-(hydroxymethyl)-1,3-oxazolidin-2-one (79.1 mg, 0.675 mmol), the same operation as in Example 18-3 was carried out, and thus the title compound was obtained as a white solid (65.3 mg, yield 53%).

[1336] (Example 40) 5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1337] [Chemical Formula 103]

[1338]

[1339] (Example 40-1) 4-(benzylamino)-2-chloroquinazolin-8-ol

[1340] [Chemical Formula 104]

[1341]

[1342] To a mixture of 2,4-dichloroquinazolin-8-ol (156 mg, 0.725 mmol) obtained in Example 18-1 and acetonitrile (3 mL) was added benzylamine (83.0 μL, 0.759 mmol) and triethylamine (200 μL, 1.44 mmol), and the mixture was stirred at 60 °C for one and a half hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 30 / 70), and the title compound was obtained as a white solid (158 mg, yield 76%).

[1343] (Example 40-2) 5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1344] [Chemical Formula 105]

[1345]

[1346] To a toluene solution (2 mL) of 4-(benzylamino)-2-chloroquinazolin-8-ol (122 mg, 0.427 mmol) obtained in Example 40-1, 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (103 mg, 0.785 mmol) and cyanomethylenetributylphosphorane (224 μL, 0.853 mmol) were added, and the mixture was stirred at 80 °C for one and a half hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 50 / 50 to 100 / 0) to obtain the title compound as a white solid (137 mg, yield 80%).

[1347] (Example 41) 5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one

[1348] [Chemical Formula 106]

[1349]

[1350] (Example 41-1) 5-[(benzyloxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one

[1351] [Chemical Formula 107]

[1352]

[1353] To a solution of 5-[(benzyloxy)methyl]-1,3-oxazolidin-2-one (1.13 g, 5.45 mmol) in THF (10 mL) described in WO20008 / 044700 were added potassium tert-butoxide (0.931 mg, 8.30 mmol), 1-bromo-2-fluoroethane (0.831 g, 6.54 mmol) and tetrabutylammonium iodide (TBAI) (0.201 g, 0.545 mmol), and the mixture was stirred at 60 °C for 5 h. After the reaction mixture was naturally cooled to room temperature, water (1 mL) was added, and the mixture was concentrated under reduced pressure. Ethyl acetate (20 mL) was added to the resulting residue, and the mixture was washed with water, then with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 50 / 50) to obtain the title compound (0.908 g, yield 66%) as a yellow oil.

[1354] (Example 41-2) 3-(2-Fluoroethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one

[1355] [Chemical formula 108]

[1356]

[1357] To a solution of 5-[(benzyloxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one (907 mg, 3.58 mmol) obtained in Example 41-1 in ethanol (7 mL) was added 20% palladium hydroxide on carbon (90.0 mg), and the mixture was stirred under a hydrogen atmosphere for 8 h. The reaction mixture was filtered and concentrated under reduced pressure. Toluene was added to the resulting residue, and the mixture was concentrated again under reduced pressure to obtain the title compound (568 mg, yield 97%) as a colorless oil.

[1358] (Example 41-3) 5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one

[1359] [Chemical formula 109]

[1360]

[1361] Using 4-(benzylamino)-2-chloroquinazolin-8-ol (40.0 mg, 0.140 mmol) obtained in Example 40-1 and 3-(2-fluoroethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (40.0 mg, 0.245 mmol) obtained in Example 41-2, the same procedure as in Example 18-3 was carried out to obtain the title compound (46.2 mg, yield 77%) as a pale yellow solid.

[1362] (Example 42) 5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one

[1363] [Chemical Formula 110]

[1364]

[1365] (Example 42-1) 5-[(benzyloxy)methyl]-3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1,3-oxazolidin-2-one

[1366] [Chemical Formula 111]

[1367]

[1368] 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, the same operation as in Example 41-1 was carried out to obtain the title compound (1.26 g, yield 63%) as a yellow oil.

[1369] (Example 42-2) 3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one

[1370] [Chemical Formula 112]

[1371]

[1372] Using 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, the same operation as in Example 41-2 was carried out to obtain the title compound (0.948 g, yield 100%) as a colorless oil.

[1373] (Example 42-3) 5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one

[1374] [Chemical Formula 113]

[1375]

[1376] Using 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, the same operation as in Example 18-3 was carried out, and thus 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) was obtained as a brown oil [MS(m / z): 543 (M) + . The obtained 5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1,3-oxazolidin-2-one was dissolved in THF (2 mL), 1M TBAF-THF (92.0 μL, 0.0920 mmol) was added thereto, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the resulting suspension was washed with water, and then the precipitated solid was collected by filtration, washed with water, ethyl acetate and hexane, and then dried, and thus the title compound (11.9 mg, yield: 45%) was obtained as a white solid.

[1377] (Example 43) 5-({[4-(benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1378] [Chemical formula 114]

[1379]

[1380] (Example 43-1) 4-(benzylamino)-2-chloroquinolin-8-ol

[1381] [Chemical formula 115]

[1382]

[1383] To a solution of 2,4-dichloroquinolin-8-ol (300 mg, 1.40 mmol) obtained in Example 38-1 in NMP (3.5 mL) were added benzylamine (306 μL, 2.80 mmol) and N,N-diisopropylethylamine (488 μL, 2.80 mmol), and the mixture was stirred at 120 °C for 9 hours. After the reaction mixture was naturally cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 50 / 50) to obtain the title compound (268 mg, yield 67%) as a pale yellow solid. Additionally, the positional isomer 2-(benzylamino)-4-chloroquinolin-8-ol (102 mg, yield 26%) of the title compound was obtained as a pale yellow solid.

[1384] (Example 43-2) 5-({[4-(benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1385] [Chemical Formula 116]

[1386]

[1387] To a toluene solution (2 mL) of 4-(benzylamino)-2-chloroquinolin-8-ol (136 mg, 0.478 mmol) obtained in Example 43-1 were added 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (100 mg, 0.763 mmol) and cyanomethylenetributylphosphorane (251 μL, 0.956 mmol), and the mixture was stirred at 80 °C for 2 hours. After the reaction mixture was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 100 / 0) to obtain the title compound (107 mg, yield 56%) as a white solid.

[1388] The structural formulas and physical and chemical data of the compounds described in Examples 18 to 43 are shown below.

[1389] Table 3

[1390]

[1391]

[1392]

[1393]

[1394]

[1395]

[1396]

[1397]

[1398]

[1399] The compounds of Examples 44 to 103 shown below were prepared according to the procedures described in Examples 18 to 43 described above.

[1400] Table 4

[1401]

[1402]

[1403]

[1404]

[1405]

[1406]

[1407]

[1408]

[1409]

[1410]

[1411]

[1412]

[1413]

[1414] (Example 104) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)-1,5-naphthyridin-4-amine

[1415] [Chemical Formula 117]

[1416]

[1417] (Example 104-1) 6-Chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-ol

[1418] [Chemical Formula 118]

[1419]

[1420] To a solution of 6,8-dichloro-1,5-naphthyridin-4-ol (200 mg, 0.930 mmol) in NMP (3.7 mL) as described in WO2017 / 055306, furfurylamine (172 μL, 1.86 mmol) and N,N-diisopropylethylamine (410 μL, 2.35 mmol) were added, and the mixture was stirred at 120 °C for 17 hours. After the reaction mixture was naturally cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (5 mL) and methanol (2 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 20 minutes. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (131 mg, yield 51%) as a gray solid.

[1421] (Example 104-2) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)-1,5-naphthyridin-4-amine

[1422] [Chemical formula 119]

[1423]

[1424] Using 6-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 μL, 0.420 mmol), the same operation as in Example 18-3 was carried out to obtain the title compound (36.0 mg, yield 37%) as a white solid.

[1425] (Example 105) 5-[({6-Chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-1,3-oxazolidin-2-one

[1426] [Chemical formula 120]

[1427]

[1428] Using 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), the same operation as in Example 18-3 was carried out to obtain the title compound (20.2 mg, yield 23%) as a white solid.

[1429] (Example 106) 5-[({6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one

[1430] [Chemical Formula 121]

[1431]

[1432] Using 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), the same operation as in Example 18-3 was carried out, and thus the title compound was obtained as a white solid (21.9 mg, yield 10%).

[1433] (Example 107) (3S,5R)-5-[({6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-methylpyrrolidin-2-one

[1434] [Chemical Formula 122]

[1435]

[1436] Using 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), the same operation as in Example 18-3 was carried out, and thus the title compound was obtained as a light brown solid (52.5 mg, yield 71%).

[1437] (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

[1438] [Chemical Formula 123]

[1439]

[1440] Using 6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-ol (59.9 mg, 0.217 mmol) obtained in Example 104-1 and 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, and thus crude 3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-[({6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-1,3-oxazolidin-2-one (164 mg) was obtained as a brown oil [MS(m / z): 533 (M) + . The obtained 3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-[({6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-1,3-oxazolidin-2-one was dissolved in THF (1.5 mL), 1 M TBAF-THF (434 μL, 0.434 mmol) was added, and the same operation as in Example 42-3 was carried out, and thus the title compound (33.9 mg, yield 37%) was obtained as a white solid.

[1441] (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

[1442] [Chemical Formula 124]

[1443]

[1444] Using 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, the same operation as in Example 18-3 was carried out, and thus the title compound (54.3 mg, yield 77%) was obtained as a light brown solid.

[1445] (Example 110) 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-1,3-oxazolidin-2-one

[1446] [Chemical Formula 125]

[1447]

[1448] (Example 110-1) 8-(Benzylamino)-6-chloro-1,5-naphthyridin-4-ol

[1449] [Chemical Formula 126]

[1450]

[1451] To a solution of 6,8-dichloro-1,5-naphthyridin-4-ol (582 mg, 2.71 mmol) in NMP (11 mL) described in WO2017 / 055306, benzylamine (591 μL, 5.49 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.90 mmol) were added, and the mixture was stirred at 120 °C for 7 hours. After the reaction solution was naturally cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The precipitated solid was collected by filtration in the extract and dried under reduced pressure to obtain the title compound (409 mg, yield 53%) as a white solid.

[1452] (Example 110-2) 5-({[8-(Benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-1,3-oxazolidin-2-one

[1453] [Chemical Formula 127]

[1454]

[1455] Using 8-(benzylamino)-6-chloro-1,5-naphthyridin-4-ol (150 mg, 0.525 mmol) obtained in Example 110-1 and 5-(hydroxymethyl)-1,3-oxazolidin-2-one (104 mg, 0.888 mmol), the same operation as in Example 18-3 was carried out to obtain the title compound (75.4 mg, yield 37%) as a white solid.

[1456] (Example 111) 5-({[8-(Benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1457] [Chemical Formula 128]

[1458]

[1459] Using 8-(benzylamino)-6-chloro-1,5-naphthyridin-4-ol (150 mg, 0.525 mmol) obtained in Example 110-1 and 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (107 mg, 0.816 mmol), the same operation as in Example 18-3 was carried out to obtain the title compound (38.4 mg, yield 18%) as a white solid.

[1460] (Example 112) (3S,5R)-5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-methylpyrrolidin-2-one

[1461] [Chemical Formula 129]

[1462]

[1463] Using 8-(benzylamino)-6-chloro-1,5-naphthyridin-4-ol (47.6 mg, 0.167 mmol) obtained in Example 110-1 and (3S,5R)-5-(hydroxymethyl)-3-methylpyrrolidin-2-one (32.3 mg, 0.250 mmol), the same operation as in Example 18-3 was carried out, and thus the title compound (46.1 mg, yield 70%) was obtained as a light brown solid.

[1464] (Example 113) 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one

[1465] [Chemical Formula 130]

[1466]

[1467] 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, and thus crude 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1,3-oxazolidin-2-one (47.6 mg) [MS (m / z): 543 (M) + was obtained as a brown oil. The obtained 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1,3-oxazolidin-2-one was dissolved in THF (2 mL), 1M TBAF-THF (131 μL, 0.131 mmol) was added, and the same operation as in Example 42-3 was carried out, and thus the title compound (18.1 mg, yield 20%) was obtained as a white solid.

[1468] (Example 114) 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one

[1469] [Chemical Formula 131]

[1470]

[1471] 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, and thus the title compound (49.5 mg, yield 81%) was obtained as a pale white solid.

[1472] (Example 115) 5-({[4-(benzylamino)-2-chloropyrido[3,2-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1473] [Chemical Formula 132]

[1474]

[1475] (Example 115-1) 2,4-dichloropyrido[3,2-d]pyrimidin-8-ol

[1476] [Chemical Formula 133]

[1477]

[1478] To a solution of 8-methoxy-1H-pyrido[3,2-d]pyrimidine-2,4-dione (286 mg, 1.48 mmol) in phosphorus oxychloride (2.11 mL, 23.0 mmol) described in WO2020 / 081636, N,N-diethylaniline (950 μL, 5.92 mmol) was added, and the mixture was stirred at 100 °C for seven and a half hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 100 / 0) to obtain crude 2,4-dichloro-8-methoxypyrido[3,2-d]pyrimidine (42.6 mg) [MS (m / z): 230 (M) +. To a solution of 2,4-dichloro-8-methoxypyrido[3,2-d]pyrimidine (20.7 mg, 90.0 μmol) in dichloromethane (1.8 mL) was added aluminum chloride (56.0 mg, 0.420 mmol) under ice-cooling, and the mixture was stirred at room temperature for 11 hours. 1N Hydrochloric acid was added to the reaction solution under ice-cooling, and the mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (8.10 mg, yield 42%) as a white solid.

[1479] (Example 115-2) 5-({[4-(Benzylamino)-2-chloropyrido[3,2-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1480] [Chemical formula 134]

[1481]

[1482] 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) were added benzylamine (29 μL, 0.25 mmol) and triethylamine (75 μL, 0.541 mmol), and the mixture was stirred at 80 °C for two and a half hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. Ethyl acetate (3.0 mL) was added to the obtained residue and stirred. The precipitated solid was collected by filtration and dried to obtain the crude 4-(benzylamino)-2-chloropyrido[3,2-d]pyrimidin-8-ol (61.2 mg) as a yellow solid [MS (m / z): 287 (M+H) + . To a toluene solution (1 mL) of the obtained 4-(benzylamino)-2-chloropyrido[3,2-d]pyrimidin-8-ol (50.0 mg, 0.174 mmol) were added 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (37.5 mg, 0.286 mmol) and cyanomethylenetributylphosphorane (92 μL, 0.350 mmol), and the mixture was stirred at 80 °C for 2 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 50 / 50 to 100 / 0) to obtain the title compound (17.2 mg, yield 25%) as a pale yellow solid.

[1483] The structural formulas and physical and chemical data of the compounds described in Examples 104 to 115 are shown below.

[1484] Table 5

[1485]

[1486]

[1487]

[1488] (Example 116) (5R)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(methoxymethyl)pyrrolidin-2-one

[1489] [Chemical Formula 135]

[1490]

[1491] To a THF solution (1 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (33.1 mg, 0.120 mmol) and (5R)-5-(hydroxymethyl)-3-(methoxymethyl)pyrrolidin-2-one (21.6 mg, 0.136 mmol) obtained in Example 18-2 were added triphenylphosphine (44.8 mg, 0.170 mmol) and diisopropyl azodicarboxylate (33.8 μL, 0.174 mmol), and the mixture was stirred at room temperature for 5.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 50 / 50 to 100 / 0, ethyl acetate / methanol = 100 / 0 to 95 / 5) to obtain the title compound (16.2 mg, yield 33%) as a yellow solid.

[1492] (Example 117) 3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one

[1493] [Chemical Formula 136]

[1494]

[1495] To a solution of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (67.6 mg, 0.245 mmol) obtained in Example 18-2 in THF (2.0 mL) were added 3-(hydroxymethyl)pyrrolidin-2-one (55.7 mg, 0.484 mmol), triphenylphosphine (164 mg, 0.626 mmol), and 40% diethyl azodicarboxylate-toluene (250 μL, 0.550 mmol), and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 5 / 95 to 100 / 0; methanol / dichloromethane = 2 / 98 to 5 / 95). Ethyl acetate / hexane = 2 / 1 (6 mL) was added to the resulting residue, and the precipitated solid was collected by filtration to obtain the title compound (29.0 mg, yield 32%) as a white solid.

[1496] The structural formulas and physicochemical data of the compounds described in Examples 116 and 117 are shown below.

[1497] Table 6

[1498]

[1499] The compounds of Examples 118 to 122 shown below were prepared according to the procedures described in Examples 116 and 117 described above.

[1500] Table 7

[1501]

[1502] (Example 123) 2-Chloro-8-(cyclopropylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine

[1503] [Chemical Formula 137]

[1504]

[1505] To a solution of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (64.5 mg, 0.234 mmol) obtained in Example 18-2 in DMF (0.3 mL) were added potassium carbonate (64.7 mg, 0.468 mmol) and (bromomethyl)cyclopropane (27.2 μL, 0.281 mmol), and the mixture was stirred at room temperature for 21 hours. Water (5 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried to obtain the title compound (75.1 mg, yield 97%) as a light brown solid.

[1506] (Example 124) 2-Chloro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinazolin-4-amine

[1507] [Chemical Formula 138]

[1508]

[1509] To a DMF solution (0.3 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (59.1 mg, 0.214 mmol) obtained in Example 18-2 were added potassium carbonate (59.3 mg, 0.429 mmol) and 3-(bromomethyl)oxetane (38.8 mg, 0.257 mmol), and the mixture was stirred at room temperature for 23 hours. Water (5 mL) was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water, and dried to obtain the title compound (73.0 mg, yield 99%) as a pale white solid.

[1510] (Example 125) 2-Chloro-8-(1,3-dioxolan-5-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine

[1511] [Chemical Formula 139]

[1512]

[1513] To a DMF solution (0.5 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (20.8 mg, 0.0754 mmol) obtained in Example 18-2 were added potassium carbonate (21.8 mg, 0.158 mmol) and 3-(bromomethyl)-1,3-dioxolane (18.1 mg, 0.100 mmol), and the mixture was stirred at 60 °C for 4 hours. Water (5 mL) was added to the reaction solution, and after extraction with ethyl acetate, the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 70 / 30) to obtain the title compound (23.7 mg, yield 84%) as a white solid.

[1514] (Example 126) 2-Chloro-8-(cyclobutylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine

[1515] [Chemical Formula 140]

[1516]

[1517] To a DMF solution (0.5 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (50.0 mg, 0.181 mmol) obtained in Example 18-2 was added potassium carbonate (50.0 mg, 0.363 mmol) and bromomethylcyclobutane (40.0 μL, 0.363 mmol), and the mixture was stirred at 80 °C for 1 hour. Water was added to the reaction solution, and after extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 40 / 60) to obtain the title compound (45.0 mg, yield 72%) as a white solid.

[1518] (Example 127) 2-Chloro-8-[(2S)-1,4-dioxan-2-ylmethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine

[1519] [Chemical formula 141]

[1520]

[1521] 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 was added potassium carbonate (70.0 mg, 0.506 mmol), and the mixture was stirred at 90 °C for 0.5 hour. After the reaction solution was naturally cooled to room temperature, a DMF solution (3 mL) of [(2S)-1,4-dioxan-2-yl]methyl 4-methylbenzenesulfonate (90.0 mg, 0.333 mmol) was added, and the mixture was stirred at 90 °C for 12 hours. Water (20 mL) was added to the reaction solution and after extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 50) to obtain the title compound (39.5 mg, yield 29%) as a white solid.

[1522] (Example 128) 2-Chloro-8-[(2S)-1,4-dioxan-2-ylmethoxy]-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine

[1523] [Chemical formula 142]

[1524]

[1525] (Example 128-1) 2,4-Dichloroquinazolin-8-ol

[1526] [Chemical formula 143]

[1527]

[1528] Using 2,4-dichloro-7-fluoro-8-methoxyquinazoline (300 mg, 1.21 mmol) obtained in Example 3-2 and aluminum chloride (1.30 g, 9.75 mmol), the same operation as in Example 18-1 was carried out, and thus the title compound was obtained as a white solid (283 mg, yield 100%).

[1529] (Example 128-2) 2-Chloro-7-fluoro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol

[1530] [Chemical Formula 144]

[1531]

[1532] To a THF solution (5 mL) of 2,4-dichloro-7-fluoroquinazolin-8-ol (300 mg, 1.29 mmol) obtained in Example 128-1 were added diisopropylethylamine (500 μL, 2.87 mmol) and furfurylamine (132 μL, 1.44 mmol), 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 obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 17 / 83) to obtain the title compound as a yellow solid (320 mg, yield 85%).

[1533] (Example 128-3) 2-Chloro-8-[(2S)-1,4-dioxan-2-ylmethoxy]-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine

[1534] [Chemical Formula 145]

[1535]

[1536] Using 2-chloro-7-fluoro-4-[(furan-2-ylmethyl)amino]quinazolin-8-ol (150 mg, 0.511 mmol) obtained in Example 128-2 and [(2R)-1,4-dioxan-2-yl]methyl 4-methylbenzenesulfonate (150 mg, 0.551 mmol), the same operation as in Example 127 was carried out, and thus the title compound was obtained as a white solid (114 mg, yield 54%).

[1537] (Example 129) 2-Chloro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinolin-4-amine

[1538] [Chemical Formula 146]

[1539]

[1540] Using 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 μL, 0.612 mmol), the same operation as in Example 125 was carried out, and thus the title compound was obtained as a white solid (88.0 mg, yield 50%).

[1541] The structural formulas and physicochemical data of the compounds described in Examples 123 to 129 are shown below.

[1542] Table 8

[1543]

[1544]

[1545] The compounds of Examples 130 to 143 shown below were prepared according to the procedures described in Examples 123 to 129 described above.

[1546] Table 9

[1547]

[1548]

[1549]

[1550]

[1551] (Example 144) 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-2-ylmethyl)quinazolin-4-amine

[1552] [Chemical formula 147]

[1553]

[1554] (Example 144-1) 2-Chloro-4-[(thiophen-2-ylmethyl)amino]quinazolin-8-ol

[1555] [Chemical formula 148]

[1556]

[1557] To a solution of 2,4-dichloroquinazolin-8-ol (120 mg, 0.558 mmol) obtained in Example 18-1 in acetonitrile (4 mL) were added triethylamine (0.154 mL, 1.12 mmol) and thiophene-2-methylamine (0.070 mL, 0.670 mmol), and the mixture was stirred at 60 °C for 1 hour. Water (10 mL) was added to the reaction mixture, and after extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 25 / 75) to give the title compound (89.0 mg, yield 55%) as a white solid.

[1558] (Example 144-2) 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-2-ylmethyl)quinazolin-4-amine

[1559] [Chemical formula 149]

[1560]

[1561] To a solution of 2-chloro-4-[(thiophen-2-ylmethyl)amino]quinazolin-8-ol (40.0 mg, 0.137 mmol) obtained in Example 144-1 in DMF (2 mL) were added potassium carbonate (30.0 mg, 0.206 mmol) and 2-(bromomethyl)-1,1-difluorocyclopropane (26.0 mg, 0.151 mmol), and the mixture was stirred at 90 °C for 1 hour. After the reaction mixture was allowed to cool to room temperature naturally, water (5 mL) was added to the reaction mixture, and after extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 40 / 60) to give the title compound (23.0 mg, yield 44%) as a pale yellow solid.

[1562] (Example 145) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(thiophen-2-ylmethyl)quinazolin-4-amine

[1563] [Chemical formula 150]

[1564]

[1565] To a solution of 2-chloro-4-[(thiophen-2-ylmethyl)amino]quinazolin-8-ol (69.0 mg, 0.237 mmol) obtained in Example 144-1 in DMF (2 mL) were added potassium carbonate (50.0 mg, 0.355 mmol) and 1,4-dioxan-2-ylmethyl 4-methylbenzenesulfonate (77.0 mg, 0.284 mmol), and the mixture was stirred at 90 °C for 4 hours. After the reaction mixture was naturally cooled to room temperature, water (10 mL) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 100 / 0) to obtain the title compound (67.0 mg, yield: 72%) as a pale yellow solid.

[1566] (Example 146) 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-3-ylmethyl)quinazolin-4-amine

[1567] [Chemical formula 151]

[1568]

[1569] (Example 146-1) 2-Chloro-4-[(thiophen-3-ylmethyl)amino]quinazolin-8-ol

[1570] [Chemical formula 152]

[1571]

[1572] To a solution of 2,4-dichloroquinazolin-8-ol (120 mg, 0.558 mmol) obtained in Example 18-1 in acetonitrile (4 mL) were added triethylamine (0.154 mL, 1.12 mmol) and 3-thiophenemethylamine (60.0 μL, 0.614 mmol), and the mixture was stirred at 60 °C for 0.5 hour. After the reaction mixture was naturally cooled to room temperature, water (10 mL) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 15 / 85) to obtain the title compound (98.0 mg, yield: 60%) as a white solid.

[1573] (Example 146-2) 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-3-ylmethyl)quinazolin-4-amine

[1574] [Chemical formula 153]

[1575]

[1576] To a solution of 2-chloro-4-[(thiophen-3-ylmethyl)amino]quinazolin-8-ol (40.0 mg, 0.137 mmol) obtained in Example 146-1 in DMF (2 mL) were added potassium carbonate (30.0 mg, 0.206 mmol) and 2-(bromomethyl)-1,1-difluorocyclopropane (26.0 mg, 0.151 mmol), and the mixture was stirred at 90 °C for 2 hours. After the reaction solution was naturally cooled to room temperature, water (5 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 25 / 75) to obtain the title compound (46.0 mg, yield 88%) as a white solid.

[1577] (Example 147) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(thiophen-3-ylmethyl)quinazolin-4-amine

[1578] [Chemical formula 154]

[1579]

[1580] To a solution of 2-chloro-4-[(thiophen-3-ylmethyl)amino]quinazolin-8-ol (81.0 mg, 0.278 mmol) obtained in Example 146-1 in DMF (2 mL) were added potassium carbonate (58.0 mg, 0.416 mmol) and 1,4-dioxan-2-ylmethyl 4-methylbenzenesulfonate (91.0 mg, 0.333 mmol), and the mixture was stirred at 90 °C for 3 hours. After the reaction solution was naturally cooled to room temperature, water (10 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 100 / 0) to obtain the title compound (52.0 mg, yield 48%) as a light brown solid.

[1581] (Example 148) 5-{[(2-Chloro-4-{[(4-fluorofuran-2-yl)methyl]amino}quinazolin-8-yl)oxy]methyl}-1,3-oxazolidin-2-one

[1582] [Chemical formula 155]

[1583]

[1584] (Example 148-1) 2-[(4-Fluorofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione

[1585] [Chemical formula 156]

[1586]

[1587] 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 were added triphenylphosphine (359 mg, 1.37 mmol) and 40% diethyl azodicarboxylate-toluene (580 μL, 1.30 mmol), and the mixture was stirred at room temperature for 5 hours. After adding water to the reaction solution, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 40 / 60) to obtain the title compound (110 mg, yield 50%) as a white solid.

[1588] (Example 148-2) 2-Chloro-4-{[(4-fluorofuran-2-yl)methyl]amino}quinazolin-8-ol

[1589] [Chemical formula 157]

[1590]

[1591] To an ethanol solution (4.0 mL) of 2-[(4-fluorofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (110 mg, 0.449 mmol) obtained in Example 148-1 was added hydrazine monohydrate (29.0 μL, 0.598 mmol), and the mixture was stirred at 80 °C for 5.5 hours. After the reaction solution was naturally cooled to room temperature, dichloromethane was added, diluted, and the insoluble matter was filtered out and washed with dichloromethane. The filtrate and washings were washed with 1N aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain crude 4-fluoro-2-furanmethanamine (39.2 mg, yield 76%) as a white solid. To a mixture of the obtained 4-fluoro-2-furanmethanamine (39.2 mg, 0.341 mmol) and acetonitrile (25 mL) were added 2,4-dichloroquinazolin-8-ol (75.0 mg, 0.349 mmol) and triethylamine (90.0 μL, 0.649 mmol) obtained in Example 18-1, and the mixture was stirred at 60 °C for 2 hours. Triethylamine (45.0 μL, 0.325 mmol) was added to the reaction solution, and the mixture was stirred at 60 °C for 2 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 15 / 85) to obtain the title compound (21.0 mg, yield 21%) as a colorless oil.

[1592] (Example 148-3) 5-{[(2-chloro-4-{[(4-fluorofuran-2-yl)methyl]amino}quinazolin-8-yl)oxy]methyl}-1,3-oxazolidin-2-one

[1593] [Chemical Formula 158]

[1594]

[1595] 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.

[1596] (Example 149) 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,2-thiazol-5-ylmethyl)quinazolin-4-amine

[1597] [Chemical Formula 159]

[1598]

[1599] (Example 149-1) 8-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dichloroquinazoline

[1600] [Chemical Formula 160]

[1601]

[1602] To a suspension of 2,4-dichloroquinazolin-8-ol (2.55 g, 11.9 mmol) obtained in Example 18-1 in DCM (25 mL) under ice-cooling, 2,6-dimethylpyridine (2.76 mL, 23.7 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (4.09 mL, 17.8 mmol) were added, and after stirring for 2 hours, the mixture was stirred at room temperature for 3 hours. After cooling the reaction solution under ice-cooling, water (15 mL) was added and the mixture was extracted with DCM, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 6 / 94) to obtain the title compound (3.54 g, yield 91%) as a pale yellow solid.

[1603] (Example 149-2) 8-{[tert-butyl(dimethyl)silyl]oxy}-2-chloro-N-(1,2-thiazol-5-ylmethyl)quinazolin-4-amine

[1604] [Chemical Formula 161]

[1605]

[1606] To a solution of 8-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dichloroquinazoline (180 mg, 0.547 mmol) obtained in Example 149-1 in acetonitrile (1 mL) were added (1,2-thiazol-5-yl)methanamine hydrochloride (90.0 mg, 0.601 mmol) and triethylamine (0.170 mL, 1.20 mmol), and the mixture was stirred at 60 °C for 1 hour. After the reaction mixture was naturally cooled to room temperature, water (5 mL) was added, and the precipitated solid was collected by filtration and then dried to obtain the title compound (180 mg, yield 94%) as a pale yellow solid.

[1607] (Example 149-3) 2-Chloro-4-[(1,2-thiazol-5-ylmethyl)amino]quinazolin-8-ol

[1608] [Chemical Formula 162]

[1609]

[1610] To a solution of 8-{[tert-butyl(dimethyl)silyl]oxy}-2-chloro-N-(1,2-thiazol-5-ylmethyl)quinazolin-4-amine (209 mg, 514 mmol) obtained in Example 149-2 in THF (1 mL) was added 1 M TBAF-THF (0.616 mL, 0.616 mmol), and the mixture was stirred at room temperature for 16 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 100 / 0) to obtain the title compound (114 mg, yield 76%) as a white solid.

[1611] (Example 149-4) 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,2-thiazol-5-ylmethyl)quinazolin-4-amine

[1612] [Chemical Formula 163]

[1613]

[1614] To a solution of 2-chloro-4-[(1,2-thiazol-5-ylmethyl)amino]quinazolin-8-ol (40.0 mg, 0.137 mmol) obtained in Example 149-3 in DMF (1 mL) were added 2-(bromomethyl)-1,1-difluorocyclopropane (26.0 mg, 0.150 mmol) and potassium carbonate (28.0 mg, 0.205 mmol), and the mixture was stirred at 90 °C for 1 hour. After the reaction mixture was naturally cooled to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 100 / 0) to obtain the title compound (48.0 mg, yield 92%) as a pale yellow solid.

[1615] (Example 150) 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-oxazol-4-ylmethyl)quinazolin-4-amine

[1616] [Chemical formula 164]

[1617]

[1618] (Example 150-1) 8-{[tert-Butyl(dimethyl)silyl]oxy}-2-chloro-N-(1,3-oxazol-4-ylmethyl)quinazolin-4-amine

[1619] [Chemical formula 165]

[1620]

[1621] 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), the same operation as in Example 149-2 was carried out, and thus the title compound (184 mg, yield 86%) was obtained as a white solid.

[1622] (Example 150-2) 2-Chloro-4-[(1,3-oxazol-4-ylmethyl)amino]quinazolin-8-ol

[1623] [Chemical formula 166]

[1624]

[1625] 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, the same operation as in Example 149-3 was carried out, whereby the title compound was obtained as a white solid (110 mg, yield 84%).

[1626] (Example 150-3) 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-oxazol-4-ylmethyl)quinazolin-4-amine

[1627] [Chemical Formula 167]

[1628]

[1629] Using 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), the same operation as in Example 149-4 was carried out, whereby the title compound was obtained as a white solid (33.0 mg, yield 62%).

[1630] (Example 151) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,2-oxazol-3-ylmethyl)quinazolin-4-amine

[1631] [Chemical Formula 168]

[1632]

[1633] (Example 151-1) 8-{[tert-butyl(dimethyl)silyl]oxy}-2-chloro-N-(1,2-oxazol-3-ylmethyl)quinazolin-4-amine

[1634] [Chemical Formula 169]

[1635]

[1636] Using 8-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dichloroquinazoline (180 mg, 0.547 mmol) obtained in Example 149-1 and isoxazol-3-ylmethylamine (60.0 mg, 0.601 mmol), the same operation as in Example 149-2 was carried out, whereby the title compound was obtained as a white solid (195 mg, yield 91%).

[1637] (Example 151-2) 2-Chloro-4-[(1,2-oxazol-3-ylmethyl)amino]quinazolin-8-ol

[1638] [Chemical Formula 170]

[1639]

[1640] 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, the same operation as in Example 149-3 was carried out, and thus the title compound was obtained as a white solid (87.0 mg, yield 63%).

[1641] (Example 151-3) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,2-oxazol-3-ylmethyl)quinazolin-4-amine

[1642] [Chemical Formula 171]

[1643]

[1644] 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), the same operation as in Example 149-4 was carried out, and thus the title compound was obtained as a pale yellow solid (12.0 mg, yield 22%).

[1645] (Example 152) 5-[({2-Chloro-4-[(1,3-oxazol-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one

[1646] [Chemical Formula 172]

[1647]

[1648] (Example 152-1) 8-{[tert-butyl(dimethyl)silyl]oxy}-2-chloro-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine

[1649] [Chemical Formula 173]

[1650]

[1651] To a solution of 8-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dichloroquinazoline (99.4 mg, 0.302 mmol) in NMP (1.5 mL) obtained in Example 149-1 was added oxazol-2-yl-methanamine hydrochloride (52.1 mg, 0.387 mmol) and N,N-diisopropylethylamine (106 μL, 0.609 mmol), and the mixture was stirred at 120 °C for 1 hour. After the reaction solution was naturally cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 100 / 0) to obtain the title compound (94.3 mg, yield 80%) as a white solid.

[1652] (Example 152-2) 2-Chloro-4-[(1,3-oxazol-2-ylmethyl)amino]quinazolin-8-ol

[1653] [Chemical formula 174]

[1654]

[1655] 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, the same operation as in Example 149-3 was carried out to obtain the title compound (59.6 mg, yield 89%) as a white solid.

[1656] (Example 152-3) 5-[({2-Chloro-4-[(1,3-oxazol-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one

[1657] [Chemical formula 175]

[1658]

[1659] Using 2-Chloro-4-[(1,3-oxazol-2-ylmethyl)amino]quinazolin-8-ol (75.6 mg, 0.273 mmol) and 5-(hydroxymethyl)-1,3-oxazolidin-2-one (46.7 mg, 0.399 mmol) obtained in Example 152-2, 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.

[1660] (Example 153) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine

[1661] [Chemical Formula 176]

[1662]

[1663] (Example 153-1) 2,4-Dichloro-8-(1,4-dioxan-2-ylmethoxy)quinazoline

[1664] [Chemical Formula 177]

[1665]

[1666] To a toluene solution (2 mL) of 2,4-dichloroquinazolin-8-ol (50.0 mg, 0.233 mmol) obtained in Example 18-1 were added (1,4-dioxan-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), and the mixture was stirred at 90 °C for 40 minutes. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 50 / 50) to obtain the title compound (19.0 mg, yield 26%).

[1667] (Example 153-2) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine

[1668] [Chemical Formula 178]

[1669]

[1670] To an acetonitrile solution (1 mL) of 2,4-dichloro-8-(1,4-dioxan-2-ylmethoxy)quinazoline (52.0 mg, 0.165 mmol) obtained in Example 153-1 were added triethylamine (0.060 mL, 0.413 mmol) and oxazol-2-ylmethylamine hydrochloride (25.0 mg, 0.182 mmol), and the mixture was stirred at 60 °C for 4 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 100 / 0) to obtain the title compound as a white solid (32.0 mg, yield 51%).

[1671] The structural formulas and physicochemical data of the compounds described in Examples 144 to 153 are shown below.

[1672] Table 10

[1673]

[1674]

[1675]

[1676]

[1677]

[1678] The compounds of Examples 154 to 169 shown below were prepared according to the procedures described in Examples 144 to 153 described above.

[1679] Table 11

[1680]

[1681]

[1682]

[1683]

[1684]

[1685] (Example 170) 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one

[1686] [Chemical Formula 179]

[1687]

[1688] (Example 170-1) 8-Methoxy-2H-pyrido[3,4-d][1,3]oxazine-2,4(1H)-dione

[1689] [Chemical Formula 180]

[1690]

[1691] To a suspension of 3-amino-2-methoxy-isonicotinic acid (1.00 g, 5.96 mmol) in THF (30 mL) was slowly added triphosgene (1.73 g, 5.84 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, diethyl ether (30 mL) was added to the resulting residue, and the insoluble matter was collected by filtration to obtain the title compound as a cream-colored solid (1.09 g, yield 94%).

[1692] (Example 170-2) Ethyl 4-hydroxy-8-methoxy-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate

[1693] [Chemical Formula 181]

[1694]

[1695] At room temperature, a DMF suspension (25 mL) of 55% sodium hydride (dispersed in liquid paraffin) (320 mg, 7.30 mmol) was added with a DMF mixture (25 mL) of the 8-methoxy-2H-pyrido[3,4-d][1,3]oxazin-2,4(1H)-dione (1.09 g, 5.61 mmol) obtained in Example 170-1 and diethyl malonate (8.51 mL, 56.0 mmol), and the mixture was stirred at 160 °C for 4 hours. After the reaction solution was naturally cooled to room temperature, 1 M hydrochloric acid (13 mL) was added to make the reaction solution acidic, and it was extracted with ethyl acetate. After the organic layer was washed with saturated brine, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Diethyl ether (200 mL) was added to the obtained residue, and the insoluble matter was collected by filtration, and thus the title compound was obtained as a cream-colored solid (902 mg, yield 61%).

[1696] (Example 170-3) 4-Hydroxy-8-methoxy-1,7-naphthyridin-2(1H)-one

[1697] [Chemical Formula 182]

[1698]

[1699] Ethyl 4-hydroxy-8-methoxy-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate (900 mg, 3.41 mmol) obtained in Example 170-2 and an aqueous solution (19 mL) of potassium hydroxide (712 mg, 12.7 mmol) were stirred at 120 °C for 16 hours. After the reaction solution was naturally cooled to room temperature, 1 M hydrochloric acid (14 mL) was added to make the reaction solution acidic, and it was stirred at 0 °C for 30 minutes. The precipitated solid was collected by filtration, and thus the title compound was obtained as a white solid (595 mg, yield 91%).

[1700] (Example 170-4) 8-Methoxy-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl trifluoromethanesulfonate

[1701] [Chemical Formula 183]

[1702]

[1703] To a THF solution (2 mL) of 4-hydroxy-8-methoxy-1,7-naphthyridin-2(1H)-one (199 mg, 1.04 mmol) and triethylamine (0.430 mL, 3.11 mmol) obtained in Example 170-3 was added N-phenylbis(trifluoromethanesulfonimide) (445 mg, 1.24 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, chloroform (2 mL) was added to the resulting residue, and the insoluble matter was collected by filtration to obtain the title compound (174 mg) as a white solid. Additionally, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 25 / 75 to 50 / 50) to obtain the title compound (129 mg, overall yield 90%) as a white solid.

[1704] (Example 170-5) 4-[(Furan-2-ylmethyl)amino]-8-methoxy-1,7-naphthyridin-2(1H)-one

[1705] [Chemical formula 184]

[1706]

[1707] To a suspension of 8-methoxy-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl trifluoromethanesulfonate (958 mg, 2.95 mmol) obtained in Example 170-4 in acetonitrile (15 mL) was added furfurylamine (820 μL, 8.86 mmol), and the mixture was stirred at 60 °C for 6 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure until the liquid volume became approximately half, and the solid was collected by filtration. The resulting crude purified product was washed with ice-cold acetonitrile and then dried to obtain the title compound (547 mg, yield 68%) as a light brown solid.

[1708] (Example 170-6) 2,8-Dichloro-N-(furan-2-ylmethyl)-1,7-naphthyridin-4-amine

[1709] [Chemical formula 185]

[1710]

[1711] To a mixture of 4-[(furan-2-ylmethyl)amino]-8-methoxy-1,7-naphthyridin-2(1H)-one (537 mg, 1.98 mmol) obtained in Example 170-5 and phosphoryl chloride (16.8 g, 109 mmol) was added N,N-diethylaniline (635 μL, 3.96 mmol). After stirring at 90 °C for 3 hours, it was stirred at 100 °C for 9 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure, and the operation of adding toluene to the obtained residue and concentrating was repeated twice. To the obtained residue was added chloroform (10 mL), and while stirring vigorously, saturated aqueous sodium bicarbonate solution was added for neutralization, followed by extraction with chloroform and concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane = 0 / 100 - 40 / 60) to obtain the title compound (401 mg, yield 69%) as a light brown solid.

[1712] (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

[1713] [Chemical formula 186]

[1714]

[1715] To a THF solution (5 mL) of 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (106 mg, 0.808 mmol) at room temperature was added 55% sodium hydride (dispersed in liquid paraffin) (47.0 mg, 1.08 mmol), and it was stirred for 1 hour. To this was added a THF solution (3 mL) of 2,8-dichloro-N-(furan-2-ylmethyl)-1,7-naphthyridin-4-amine (198 mg, 0.673 mmol) obtained in Example 170-6, and it was stirred at 60 °C for 7 hours. To this reaction solution was added a mixture of 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (98.2 mg, 0.749 mmol) and 55% sodium hydride (dispersed in liquid paraffin) (34.0 mg, 0.779 mmol) in THF (3 mL) prepared by stirring for 1 hour in advance, and it was further stirred at 60 °C for 7 hours. After adding water (5 mL) to the reaction solution under ice-cooling, it was extracted with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10 / 90 - 100 / 0) to obtain the title compound (131 mg, yield 50%) as a white solid.

[1716] (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

[1717] [Chemical Formula 187]

[1718]

[1719] To a solution of 2,8-dichloro-N-(furan-2-ylmethyl)-1,7-naphthyridin-4-amine (213 mg, 0.724 mmol) obtained in Example 170-6 in acetonitrile (7.2 mL) were added (5S)-5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (123 mg, 0.941 mmol) and cesium carbonate (472 mg, 1.45 mmol), and the mixture was treated in a microwave reactor at 110 °C for 2.5 hours. After the reaction solution was naturally cooled to room temperature, ethyl acetate (8 mL) was added to the reaction solution, the insoluble matter was filtered off, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH ， Ethyl acetate / hexane = 20 / 80 to 100 / 0) and then purified again by silica gel column chromatography (ethyl acetate / hexane = 20 / 80 to 100 / 0) to obtain the title compound (184 mg, yield 65%) as a white solid. It should be noted that the title compound can also be obtained by separating 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. [Analysis conditions] Column: DAICEL CHIRALPAK IC (4.6 × 150 mm), elution solvent: hexane / ethanol = 55 / 45, flow rate: 1.00 mL / min, retention time: 4.92 min.

[1720] (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

[1721] [Chemical Formula 188]

[1722]

[1723] Using 2,8-dichloro-N-(furan-2-ylmethyl)-1,7-naphthyridin-4-amine (210 mg, 0.714 mmol) and (5R)-5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (122 mg, 0.928 mmol) obtained in Example 170-6, the same operation as in Example 171 was carried out, and thus the title compound was obtained as a white solid (171 mg, yield 62%). It should be noted that the title compound can also be obtained by separating 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. [Analysis conditions] Column: DAICEL CHIRALPAK IC (4.6×150 mm), elution solvent: hexane / ethanol = 55 / 45, flow rate: 1.00 mL / min, retention time: 6.36 min.

[1724] (Example 173) 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one

[1725] [Chemical formula 189]

[1726]

[1727] (Example 173-1) 4-(benzylamino)-8-methoxy-1,7-naphthyridin-2(1H)-one

[1728] [Chemical formula 190]

[1729]

[1730] Using 8-methoxy-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl trifluoromethanesulfonate (1.09 g, 3.36 mmol) and benzylamine (1.10 mL, 10.1 mmol) obtained in Example 170-4, the same operation as in Example 170-5 was carried out, and thus the title compound was obtained as a white solid (0.610 g, yield 65%).

[1731] (Example 173-2) N-benzyl-2,8-dichloro-1,7-naphthyridin-4-amine

[1732] [Chemical formula 191]

[1733]

[1734] Using 4-(benzylamino)-8-methoxy-1,7-naphthyridin-2(1H)-one (610 mg, 2.17 mmol) obtained in Example 173-1, the same operation as in Example 170-6 was carried out, and thus the title compound was obtained as a white solid (610 mg, yield 93%).

[1735] (Example 173-3) 5-({[4-(Benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one

[1736] [Chemical formula 192]

[1737]

[1738] 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, and thus crude 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-(4-methoxybenzyl)-1,3-oxazolidin-2-one (58.4 mg) was obtained as a colorless solid [MS (m / z): 505 (M+H) + . The trifluoroacetic acid solution (1 mL) of the obtained 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-(4-methoxybenzyl)-1,3-oxazolidin-2-one (50.2 mg, 0.0994 mmol) was stirred at 60 °C for 46 hours, and then trifluoroacetic acid (0.5 mL) was added and further stirred for 18 hours. The reaction solution was concentrated under reduced pressure to form a dichloromethane solution, neutralized with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and then with ethyl acetate, and all the organic layers were concentrated under reduced pressure. The obtained residue was roughly purified by silica gel column chromatography (ethyl acetate / hexane = 20 / 80 to 100 / 0), and then purified again by silica gel column chromatography (NH, ethyl acetate / hexane = 50 / 50 to 100 / 0), and the title compound was obtained as a colorless solid (13.5 mg, yield 35%).

[1739] (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

[1740] [Chemical formula 193]

[1741]

[1742] Using 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, the same operation as in Example 171 was carried out, and thus the title compound was obtained as a colorless solid (85.1 mg, yield 70%).

[1743] (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

[1744] [Chemical formula 194]

[1745]

[1746] (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

[1747] [Chemical formula 195]

[1748]

[1749] 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}ethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (60.6 mg, 0.220 mmol) obtained in Example 42-2, the same operation as in Example 170-7 was carried out, and the title compound was obtained as a colorless solid (12.9 mg, yield 15%).

[1750] (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

[1751] [Chemical formula 196]

[1752]

[1753] To a solution 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) in THF (0.6 mL) was added 1 M TBAF-THF (36.0 μL, 0.0360 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate = 0 / 100 to 7 / 93) to obtain the title compound (7.10 mg, yield 72%) as a white solid.

[1754] (Example 176) 5-({[4-(Benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one

[1755] [Chemical formula 197]

[1756]

[1757] Using N-benzyl-2,8-dichloro-1,7-naphthyridin-4-amine (94.6 mg, 0.311 mmol) obtained in Example 173-2 and 3-(2-fluoroethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (76.1 mg, 0.467 mmol) obtained in Example 41-2, the same operation as in Example 170-7 was carried out to obtain the title compound (58.6 mg, yield 44%) as a white solid.

[1758] (Example 177) 5-({[4-(Benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1759] [Chemical formula 198]

[1760]

[1761] Using N-benzyl-2,8-dichloro-1,7-naphthyridin-4-amine (201 mg, 0.661 mmol) obtained in Example 173-2 and 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (104 mg, 0.793 mmol), the same operation as in Example 170-7 was carried out, and thus the title compound (167 mg, yield 63%) was obtained as a white solid.

[1762] (Example 178) 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one

[1763] [Chemical Formula 199]

[1764]

[1765] (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

[1766] [Chemical Formula 200]

[1767]

[1768] Using N-benzyl-2,8-dichloro-1,7-naphthyridin-4-amine (109 mg, 0.358 mmol) obtained in Example 173-2 and 3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (148 mg, 0.538 mmol) obtained in Example 42-2, the same operation as in Example 170-7 was carried out to obtain the title compound (59.9 mg, yield 31%) as a white solid.

[1769] (Example 178-2) 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one

[1770] [Chemical Formula 201]

[1771]

[1772] 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, the same operation as in Example 175-2 was carried out to obtain the title compound (25.6 mg, yield 55%) as a white solid.

[1773] (Example 179) 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,2-d]pyrimidin-4-amine

[1774] [Chemical Formula 202]

[1775]

[1776] (Example 179-1) 2,8-Dichloro-N-(furan-2-ylmethyl)pyrido[3,2-d]pyrimidin-4-amine

[1777] [Chemical Formula 203]

[1778]

[1779] To a solution of 8-methoxy-1H-pyrido[3,2-d]pyrimidine-2,4-dione (182 mg, 0.512 mmol) described in WO2020 / 081636 in phosphoryl chloride (2.72 mL, 29.7 mmol) was added N,N-diisopropylethylamine (384 μL, 2.21 mmol), and the mixture was stirred at 110 °C for 3 hours. N,N-Diisopropylethylamine (178 μL, 1.02 mmol) was added to the reaction solution, and the mixture was stirred at 110 °C for 1 hour. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 40 / 60) to obtain crude 2,4,8-trichloropyrido[3,2-d]pyrimidine (34.8 mg) as a white solid [MS (m / z): 234 (M) + . To a mixture of the obtained 2,4,8-trichloropyrido[3,2-d]pyrimidine and acetonitrile (2 mL) were added furfurylamine (14 μL, 0.151 mmol) and triethylamine (39.0 μL, 0.281 mmol), and the mixture was stirred at 60 °C for 1 hour. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 30 / 70) to obtain the title compound (39.5 mg, yield 90%).

[1780] (Example 179-2) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,2-d]pyrimidin-4-amine

[1781] [Chemical Formula 204]

[1782]

[1783] To a solution of 2,8-dichloro-N-(furan-2-ylmethyl)pyrido[3,2-d]pyrimidin-4-amine (35.5 mg, 0.120 mmol) obtained in Example 179-1 in THF (1 mL) were added (1,4-dioxan-2-yl)methanol (14.0 μL, 0.127 mmol) and 55% sodium hydride (dispersed in liquid paraffin) (5.3 mg, 0.120 mmol), and the mixture was stirred at 65 °C for 4 hours. Further, (1,4-dioxan-2-yl)methanol (14.0 μL, 0.127 mmol) and 55% sodium hydride (dispersed in liquid paraffin) (4.40 mg, 0.100 mmol) were added to the reaction solution, and the mixture was stirred at 65 °C for 4 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10 / 90 to 50 / 50) to obtain the title compound (3.90 mg, yield 9%) as a white solid. In addition, the isomer of the title compound, 8-chloro-2-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,2-d]pyrimidin-4-amine (5.40 mg, yield 12%) was obtained as a white solid.

[1784] (Example 180) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine

[1785] [Chemical formula 205]

[1786]

[1787] (Example 180-1) 2,4,8-Trichloropyrido[3,4-d]pyrimidine

[1788] [Chemical formula 206]

[1789]

[1790] To a mixture of 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) described in Bioorg. Med. Chem. Lett., 2013, 23, 5923 - 5930 was added N,N-diethylaniline (259 μL, 1.61 mmol), and the mixture was stirred at 100 °C for 7 hours. After the reaction solution was naturally cooled to room temperature, the solvent was removed by distillation under reduced pressure, and the resulting residue was azeotroped with toluene. The residue was dissolved in chloroform, neutralized with saturated aqueous sodium bicarbonate at 0 °C, and then extracted with chloroform. The extract was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 - 20 / 80) to obtain the title compound (101 mg, yield 53%) as a brown solid.

[1791] (Example 180-2) 2,8-Dichloro-N-(furan-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine

[1792] [Chemical formula 207]

[1793]

[1794] To a solution of 2,4,8-trichloropyrido[3,4-d]pyrimidine (45.1 mg, 0.192 mmol) obtained in Example 180-1 in acetonitrile (1.5 mL) were added furfurylamine (21.2 μL, 0.238 mmol) and triethylamine (58.0 μL, 0.418 mmol), and the mixture was stirred at 60 °C for 2 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10 / 90 - 50 / 50) to obtain the title compound (55.9 mg, yield 98%) as a yellow solid.

[1795] (Example 180-3) 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine

[1796] [Chemical formula 208]

[1797]

[1798] To a solution of (1,4-dioxan-2-yl)methanol (15.7 mg, 0.133 mmol) in THF (1 mL) was added 55% sodium hydride (dispersed in liquid paraffin) (4.90 mg, 0.112 mmol), and the mixture was stirred at room temperature for 1 hour. 2,8-Dichloro-N-(furan-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine (29.6 mg, 0.100 mmol) obtained in Example 180-2 was added to the reaction solution, and the mixture was stirred at 65 °C for 18 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20 / 80 to 50 / 50) to obtain the title compound (6.00 mg, yield 16%) as a pale yellow solid.

[1799] (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

[1800] [Chemical Formula 209]

[1801]

[1802] Using 2,8-dichloro-N-(furan-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine (108 mg, 0.366 mmol) obtained in Example 180-2 and 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (144 mg, 1.10 mmol), the same procedure as in Example 180-3 was carried out to obtain the title compound (20.1 mg, yield 14%) as a white solid.

[1803] (Example 182) 5-({[4-(benzylamino)-2-chloropyrido[3,4-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1804] [Chemical Formula 210]

[1805]

[1806] (Example 182-1) N-Benzyl-2,8-dichloropyrido[3,4-d]pyrimidin-4-amine

[1807] [Chemical Formula 211]

[1808]

[1809] Using 2,4,8-trichloropyrido[3,4-d]pyrimidine (47.1 mg, 0.201 mmol) obtained in Example 180-1 and benzylamine (24.0 μL, 0.221 mmol), the same operation as in Example 180-2 was carried out, and thus the title compound was obtained as a white solid (60.9 mg, yield 99%).

[1810] (Example 182-2) 5-({[4-(benzylamino)-2-chloropyrido[3,4-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1811] [Chemical formula 212]

[1812]

[1813] Using N-benzyl-2,8-dichloropyrido[3,4-d]pyrimidin-4-amine (56.8 mg, 0.186 mmol) obtained in Example 182-1 and 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (29.3 mg, 0.223 mmol), the same operation as in Example 180-3 was carried out, and thus the title compound was obtained as a white solid (11.2 mg, yield 15%).

[1814] The structural formulas and physical and chemical data of the compounds described in Examples 170 to 182 are shown below.

[1815] Table 12

[1816]

[1817]

[1818]

[1819]

[1820]

[1821]

[1822] (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

[1823] [Chemical formula 213]

[1824]

[1825] (Example 183-1) Methyl 4-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]-3-oxobutanoate

[1826] [Chemical formula 214]

[1827]

[1828] To a solution of 5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one (671 mg, 5.12 mmol) in THF (17 mL) was added 55% sodium hydride (dispersed in liquid paraffin) (421 mg, 9.65 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a solution of methyl 4-chloroacetoacetate (500 μL, 4.33 mmol) in THF (17 mL), and the mixture was stirred at room temperature for 7 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (407 mg, yield 38%) as a yellow oil.

[1829] (Example 183-2) Methyl 4-amino-5-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]pyridine-3-carboxylate

[1830] [Chemical formula 215]

[1831]

[1832] To a solution of 3-methyl-5-nitropyrimidin-4-one (21.3 mg, 0.137 mmol) described in WO2018 / 125961 in methanol (1 mL) were added methyl 4-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]-3-oxobutanoate (44.8 mg, 0.183 mmol) obtained in Example 183-1 and ammonium acetate (30.0 mg, 0.183 mmol), and the mixture was stirred at 70 °C for 8.5 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (100% ethyl acetate) to give the title compound (30.3 mg, yield 78%) as a yellow oil.

[1833] (Example 183-3) 8-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione

[1834] [Chemical formula 216]

[1835]

[1836] To a 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 in THF (1 mL) was added trichloroacetyl isocyanate (20.0 μL, 0.169 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the resulting residue was added 7M ammonia water (2 mL), and the mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure, ethyl acetate (2 mL) was added and stirred, and the precipitated solid was collected by filtration to obtain the title compound (20.6 mg, yield 65%) as a white solid.

[1837] (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

[1838] [Chemical formula 217]

[1839]

[1840] 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 in phosphoryl chloride (1.64 mL, 17.9 mmol) was added N,N-diisopropylethylamine (330 μL, 1.90 mmol), and the mixture was stirred at 115 °C for 1 hour. The solvent was distilled off under reduced pressure, NMP (1.5 mL) was added to the resulting residue, and then furfurylamine (70.0 μL, 0.757 mmol) and N,N-diisopropylethylamine (66.0 μL, 0.379 mmol) were added under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol / ethyl acetate = 0 / 100 to 90 / 10) to obtain the title compound (4.00 mg, yield 5%) as a pale yellow solid.

[1841] (Example 184) 5-({[4-(benzylamino)-2-chloropyrido[4,3-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1842] [Chemical formula 218]

[1843]

[1844] 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 μL, 2.50 mmol), the same operation as in Example 183-4 was carried out, and thus the title compound was obtained as a white solid (9.80 mg, yield 4%).

[1845] The structural formulas and physicochemical data of the compounds described in Examples 183 and 184 are shown below.

[1846] Table 13

[1847]

[1848] (Example 185) 5-({[4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one

[1849] [Chemical formula 219]

[1850]

[1851] (Example 185-1) Methyl 4-{[3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy}-3-oxobutyrate

[1852] [Chemical formula 220]

[1853]

[1854] Using 5-(hydroxymethyl)-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one (434 mg, 1.83 mmol) described in WO2014 / 085413 and methyl 4-chloroacetoacetate (211 μL, 1.83 mmol), the same operation as in Example 183-1 was carried out, and thus the title compound was obtained as a colorless oil (203 mg, yield 32%).

[1855] (Example 185-2) Methyl 4-amino-5-{[3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy}pyridine-3-carboxylate

[1856] [Chemical formula 221]

[1857]

[1858] Using methyl 4-{[3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy}-3-oxobutyrate (203 mg, 0.578 mmol) obtained in Example 185-1 and 3-methyl-5-nitropyrimidin-4-one (80.0 mg, 0.516 mmol), the same operation as in Example 183-2 was carried out, and thus the title compound was obtained as a yellow oil (115 mg, yield 58%).

[1859] (Example 185-3) Methyl 4-(diacetylamino)-5-{[3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy}pyridine-3-carboxylate

[1860] [Chemical formula 222]

[1861]

[1862] A mixture of methyl 4-amino-5-{[3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy}pyridine-3-carboxylate (115 mg, 0.297 mmol), pyridine (24.0 μL, 0.297 mmol) and acetic anhydride (1 mL) obtained in Example 185-2 was stirred at 100 °C for 9 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100 / 0 to 97 / 3), and the title compound was obtained as a pale yellow oily substance (125 mg, yield 89%).

[1863] (Example 185-4) 4-Hydroxy-8-{[3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy}-1,6-naphthyridin-2(1H)-one

[1864] [Chemical formula 223]

[1865]

[1866] To a solution of methyl 4-(diacetylamino)-5-{[3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy}pyridine-3-carboxylate (123 mg, 0.261 mmol) obtained in Example 185-3 in THF (2 mL) at -78 °C, 1 M potassium bis(trimethylsilyl)amide-THF (0.530 mL, 0.530 mmol) was added dropwise, and the mixture was stirred for 2.5 hours while slowly warming to room temperature. Methanol was added to the reaction solution, and it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100 / 0 to 75 / 25), and the title compound was obtained as a light brown solid (37.4 mg, yield 36%).

[1867] (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

[1868] [Chemical formula 224]

[1869]

[1870] 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 μL, 0.270 mmol) in THF (1 mL) were added N-phenylbis(trifluoromethanesulfonimide) (40.2 mg, 0.113 mmol) and a small amount of DMF, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 100 / 0) to obtain the crude title compound (54.5 mg, yield 114%) containing a trace amount of DMF as a pale yellow solid.

[1871] (Example 185-6) 4-(Benzylamino)-8-{[(3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl)methoxy]-1,6-naphthyridin-2(1H)-one

[1872] [Chemical formula 225]

[1873]

[1874] To a solution 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 in 1,4-dioxane (1 mL) was added benzylamine (87.6 μL, 0.801 mmol), and the mixture was stirred at 80 °C for 2 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain the crude title compound (14.2 mg, yield 36%) as a pale yellow solid.

[1875] (Example 185-7) 5-({[(4-(Benzylamino)-2-chloro-1,6-naphthyridin-8-yl)oxy]methyl}-1,3-oxazolidin-2-one

[1876] [Chemical Formula 226]

[1877]

[1878] To a solution of 4-(benzylamino)-8-{[3-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-5-yl]methoxy}-1,6-naphthyridin-2(1H)-one (10.9 mg, 0.0224 mmol) in 1,4-dioxane (1 mL) obtained in Example 185-6 were added phosphorus oxychloride (24.5 mg, 0.159 mmol) and N,N-diethylaniline (8.0 μL, 0.0448 mmol), and the mixture was stirred at 80 °C for 1.5 hours. Phosphorus oxychloride (43.0 mg, 0.280 mmol) was added, and the mixture was further stirred at 80 °C for 2.5 hours. After the reaction solution was naturally cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100 / 0 to 85 / 15) to obtain crude 5-({[4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy}methyl)-3-(4-methoxybenzyl)-1,3-oxazolidin-2-one (15.2 mg) [MS (m / z): 505 (M+H) + . The obtained 5-({[4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy}methyl)-3-(4-methoxybenzyl)-1,3-oxazolidin-2-one was stirred in trifluoroacetic acid (0.8 mL) at 80 °C for 1.5 hours. After further stirring at 100 °C for 7 hours, the reaction solution was naturally cooled to room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC (column: Develosil Combi-RP-5 100×28 mm×5 μm, elution solvent: 0.1% aqueous formic acid / acetonitrile = 77 / 23 to 50 / 50) to obtain the title compound (1.64 mg, yield 14%) as a white solid.

[1879] (Example 186) 5-({[4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1880] [Chemical Formula 227]

[1881]

[1882] (Example 186-1) Methyl 4-(diacetylamino)-5-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]pyridine-3-carboxylate

[1883] [Chemical Formula 228]

[1884]

[1885] 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), pyridine (12.0 μL, 0.151 mmol), and acetic anhydride (1 mL) obtained in Example 183-2 was stirred at 100 °C for 8.5 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100 / 0 to 91 / 9) to obtain the title compound (56.4 mg, yield 100%) as a pale yellow oily substance.

[1886] (Example 186-2) 8-[(3-Methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]-2-oxo-1,2-dihydro-1,6-naphthyridine-4-yl trifluoromethanesulfonate

[1887] [Chemical formula 229]

[1888]

[1889] To a solution of methyl 4-(diacetylamino)-5-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]pyridine-3-carboxylate (49.3 mg, 0.135 mmol) obtained in Example 186-1 in THF (1 mL) at -78 °C was added dropwise 1 M potassium bis(trimethylsilyl)amide-THF (0.270 mL, 0.270 mmol), and the mixture was stirred overnight while slowly warming to room temperature. 1 M hydrochloric acid (290 μL, 0.290 mmol) was added to the reaction solution, and it was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Develosil Combi-RP-5 100×28 mm×5 μm, elution solvent: 0.1% aqueous formic acid / acetonitrile = 100 / 0 to 79 / 21) to obtain crude 4-hydroxy-8-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]-1,6-naphthyridin-2(1H)-one (9.10 mg) [MS (m / z): 293 (M+H) +To a solution of the obtained 4-hydroxy-8-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]-1,6-naphthyridin-2(1H)-one and triethylamine (13.0 μL, 0.0938 mmol) in THF (3 mL) was added N-phenylbis(trifluoromethanesulfonimide) (13.3 mg, 0.0372 mmol) and a small amount of DMF, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain the crude title compound (14.4 mg, yield 110%) containing a trace amount of DMF as a white solid.

[1890] (Example 186-3) 5-({[4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one

[1891] [Chemical formula 230]

[1892]

[1893] 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) were added benzylamine (16.0 μL, 0.143 mmol) and N,N-diisopropylethylamine (7.50 μL, 0.0429 mmol), and the mixture was stirred at 50 °C for 40 minutes. After the reaction solution was naturally cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100 / 0 to 75 / 25) to obtain crude 4-(benzylamino)-8-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methoxy]-1,6-naphthyridin-2(1H)-one (8.50 mg) [MS (m / z): 381 (M+H) +To a solution of 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 (2 mL) were added phosphorus oxychloride (35.0 mg, 0.228 mmol) and N,N-diethylaniline (13.6 μL, 0.0783 mmol), and the mixture was stirred at 80 °C for 1 hour. Phosphorus oxychloride (52.0 mg, 0.339 mmol) was added, and the mixture was further stirred at 80 °C for 3 hours. After the reaction mixture was allowed to cool to room temperature naturally, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative HPLC (column: Develosil Combi-RP-5 100×28 mm×5 μm, elution solvent: 0.1% aqueous formic acid / acetonitrile = 75 / 25 to 47 / 53) to obtain the title compound (3.30 mg, yield 21%) as a pale yellow solid.

[1894] The structural formulas and physicochemical data of the compounds described in Examples 185 and 186 are shown below.

[1895] Table 14

[1896]

[1897]

[1898] (Example 187) 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-ethyl-1,3-oxazolidin-2-one

[1899] [Chemical formula 231]

[1900]

[1901] To a mixed solution of 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one (13.4 mg, 0.0358 mmol), obtained in Example 19, in THF (0.3 mL) / DMF (0.1 mL) was added potassium tert-butoxide (9.10 mg, 0.0811 mmol) and iodoethane (10.0 μL, 0.125 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 5.5 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20 / 80 to 85 / 15) to obtain the title compound (8.30 mg, yield 58%) as a white solid.

[1902] (Example 188) 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(propan-2-yl)-1,3-oxazolidin-2-one

[1903] [Chemical Formula 232]

[1904]

[1905] To a mixed solution of THF (0.6 mL) / DMF (0.2 mL) 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 under ice-cooling was added potassium tert-butoxide (22.8 mg, 0.203 mmol) and 2-iodopropane (19.0 μL, 0.183 mmol). After stirring at the same temperature for 3 hours, it was stirred at room temperature for 4 hours. Potassium tert-butoxide (22.8 mg, 0.203 mmol) and 2-iodopropane (19.0 μL, 0.183 mmol) were added to the reaction solution again, and it was stirred at 60 °C for 4 hours. After the reaction solution was naturally cooled to room temperature, water (5 mL) was added to the reaction solution, and after extraction with ethyl acetate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 70 / 30) to obtain the title compound (15.8 mg, yield 41%) as a white solid.

[1906] (Example 189) 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one

[1907] [Chemical Formula 233]

[1908]

[1909] 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 (29.4 mg, 0.0784 mmol) and TBAI (14.7 mg, 0.0398 mmol) obtained in Example 19 were added potassium tert-butoxide (19.1 mg, 0.170 mmol) and 1-bromo-2-fluoromethane (18.0 μL, 0.157 mmol), and it was stirred at room temperature for 1 hour. Water (6 mL) was added to the reaction solution, and after extraction with ethyl acetate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20 / 80 to 80 / 20) to obtain the title compound (26.9 mg, yield 82%) as a white solid.

[1910] (Example 190) 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(cyclopropylmethyl)-1,3-oxazolidin-2-one

[1911] [Chemical Formula 234]

[1912]

[1913] 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 (31.5 mg, 0.0840 mmol) and TBAI (15.8 mg, 0.0428 mmol) obtained in Example 19 were added potassium tert-butoxide (21.2 mg, 0.189 mmol) and (bromomethyl)cyclopropane (16.0 μL, 0.168 mmol), and the mixture was stirred at room temperature for 1 hour. Water (6 mL) was added to the reaction solution, and after extraction with ethyl acetate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20 / 80 to 70 / 30) to obtain the title compound (28.0 mg, yield 78%) as a white solid.

[1914] (Example 191) 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2,2-difluoroethyl)-1,3-oxazolidin-2-one

[1915] [Chemical Formula 235]

[1916]

[1917] To a DMF solution (0.5 mL) of 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one (31.2 mg, 0.0832 mmol) obtained in Example 19 were added potassium tert-butoxide (22.4 mg, 0.200 mmol) and 2-iodo-1,1-difluoroethane (35.3 mg, 0.184 mmol), and the mixture was stirred at room temperature for 3.5 hours. Water (6 mL) was added to the reaction solution, and after extraction with ethyl acetate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20 / 80 to 80 / 20) to obtain the title compound (19.1 mg, yield 52%) as a white solid.

[1918] (Example 192) 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one

[1919] [Chemical Formula 236]

[1920]

[1921] (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

[1922] [Chemical Formula 237]

[1923]

[1924] Under ice-cooling, potassium tert-butoxide (31.3 mg, 0.279 mmol) and (2-bromoethoxy)tert-butyldimethylsilane (39.0 μL, 0.179 mmol) were added to a mixed solution of 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one (55.9 mg, 0.149 mmol) obtained in Example 19 in THF (0.8 mL) / DMF (0.2 mL), and the mixture was stirred at the same temperature for 3 hours. After adding TBAI (27.6 mg, 0.0746 mmol) to the reaction solution and stirring for 2 hours, the mixture was stirred at room temperature for 2 hours. After adding potassium tert-butoxide (31.3 mg, 0.279 mmol) and (2-bromoethoxy)tert-butyldimethylsilane (39.0 μL, 0.179 mmol) to the reaction solution and further stirring for 37 hours, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 70 / 30) to obtain the title compound (35.8 mg, yield 45%) as a pale yellow solid.

[1925] (Example 192-2) 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one

[1926] [Chemical Formula 238]

[1927]

[1928] To a solution 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) in THF (1 mL) was added 1 M TBAF-THF (98.0 μL, 0.0980 mmol), and the mixture was stirred at room temperature for 2.5 h. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / ethyl acetate = 0 / 100 to 10 / 90) to give the title compound as a white solid (21.1 mg, yield 77%).

[1929] (Example 193) 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(oxetan-3-yl)-1,3-oxazolidin-2-one

[1930] [Chemical formula 239]

[1931]

[1932] To a solution 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) in DMF (0.4 mL) obtained in Example 19 were added cesium carbonate (67.5 mg, 0.207 mmol) and 3-iodooxetane (32.1 mg, 0.174 mmol), and the mixture was stirred at room temperature for 3 h and then at 60 °C for 17.5 h. After the reaction mixture was naturally cooled to room temperature, water (6 mL) was added, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 50 / 50 to 100 / 0) to give the title compound as a white solid (7.10 mg, yield 15%).

[1933] (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

[1934] [Chemical formula 240]

[1935]

[1936] To a mixed solution of 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one (29.6 mg, 0.0790 mmol) obtained in Example 19 in DMF (0.5 mL) were added potassium tert-butoxide (19.1 mg, 0.170 mmol) and isobutene oxide (15.0 μL, 0.158 mmol), and the mixture was stirred at room temperature for 3 hours. Isobutene oxide (57.0 μL, 0.632 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 17 hours. Water (6 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 50 / 50 to 90 / 10) and then purified by silica gel column chromatography (NH, methanol / ethyl acetate = 0 / 100 to 2 / 98) to obtain the title compound (12.1 mg, yield 34%) as a white solid.

[1937] (Example 195) 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-N-ethyl-2-oxo-1,3-oxazolidine-3-carboxamide

[1938] [Chemical formula 241]

[1939]

[1940] 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 were added 1,4-diazabicyclo[2.2.2]octane (23.2 mg, 0.207 mmol) and ethyl isocyanate (17.0 μL, 0.207 mmol), and the mixture was stirred at room temperature for 9 hours. Water (9 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane = 30 / 70 to 90 / 10) to obtain the title compound (18.7 mg, yield 41%) as a colorless solid.

[1941] (Example 196) 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-(2-hydroxyethyl)pyrrolidin-2-one

[1942] [Chemical formula 242]

[1943]

[1944] 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) as a colorless solid [MS(m / z): 531(M) + . To a THF solution (1.5 mL) of the obtained 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, 0.0975 mmol) was added 1M TBAF-THF (147 μL, 0.147 mmol), and the mixture was stirred at room temperature for 1 hour. Water (7 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. To the obtained residue was added a mixed solvent of diethyl ether / hexane (3 / 1), and the solid was collected by filtration to obtain the title compound (31.2 mg, yield 77%) as a white solid.

[1945] (Example 197) 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-(2-fluoroethyl)pyrrolidin-2-one

[1946] [Chemical Formula 243]

[1947]

[1948] 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, the same operation as in Example 189 was carried out to obtain the title compound (20.4 mg, yield 45%) as a white solid.

[1949] The structural formulas and physicochemical data of the compounds described in Examples 187 to 197 are shown below.

[1950] Table 15

[1951]

[1952]

[1953]

[1954] The compounds of Examples 198 to 204 shown below were manufactured according to the procedures described in Examples 189 to 197 described above.

[1955] Table 16

[1956]

[1957]

[1958] [Measurement of Activity Value]

[1959] The HeLa cell line was inoculated into a 24-well plate (Corning) (2 × 10 5 cells / well) with DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin (Nacalai Tesque). The next day, the GLA splicing reporter vector ( Figure 1 ) was transfected by Lipofectamine 2000 (Thermo Fisher Scientific). The medium was changed 5 hours after transfection, and the evaluation compounds prepared in the above examples dissolved at 10 mM in DMSO were added at 0.1% by volume (final concentration: 10 μM for the evaluation compound and 0.1% for DMSO). In addition, a group containing only DMSO without the evaluation compound was used as a negative control, and a group of 10 μM of a known splicing control compound (2-chloro-6-(2-furanylmethyl)purine) was used as a positive control as an index for activity evaluation. 16 hours after adding the compounds, the cells on the plate were fixed by treatment with 4% paraformaldehyde at room temperature for 15 minutes. After replacing the fixing solution with phosphate-buffered saline, the fluorescence intensities of GFP (GLA splicing: exon 4 + exon 5) and RFP (GLA splicing: exon 4 + pseudo-exon (Ψ) + exon 5) were measured using a BZ-X700 fluorescence microscope (Keyence), and the ratio (GFP signal / RFP signal) was measured. Then, the fluorescence ratio at the time of treatment with 10 μM of the known compound (positive control) was set to 1, and the activity value (GLA_Signal_REC10_2) of each evaluation compound was quantified.

[1960] The results obtained are shown in the table below.

[1961] Table 17

[1962]

[1963]

[1964] [Evaluation System for Splicing Abnormality Caused by GLA IVS4+919G>A Mutation in Fabry Disease]

[1965] The region of GLA exon 4 to exon 5 (nt 7272-9215 in the GLA gene sequence) with a normal IVS4 or IVS4+919G>A mutation cloned downstream of the cytomegalovirus (CMV) immediate early gene promoter, which is disclosed in WO2018 / 151326 and is used to study the effect of splicing operation compounds on splicing abnormalities caused by the GLA IVS4+919G>A mutation, was used to prepare vectors pAM1 (normal type) and pAM2 (919G>A mutant type) as an evaluation system. By introducing these vectors into cultured cells, splicing abnormalities (introduction of pseudoexons) in Fabry disease patient cells can be reproduced, and the efficacy of compounds can be determined.

Claims

1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: [Chemical formula 1] 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 selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring, and the 6- to 12-membered aryl group and the 5- to 6-membered heteroaryl group may be substituted by one or more halogen atoms, n is 1 or 2, R 1 is a halogen atom, R 2 is a hydrogen atom, a halogen atom or a C1-C4 alkoxy group, R 3 is a hydrogen atom, a C3-C6 cycloalkyl group, or a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring R 3 The C3-C6 cycloalkyl group and 4- to 6-membered heterocyclic group in 3 may have one or two oxo groups (=O) on the ring, and / or may be substituted with one or two substituents selected from the following Group A: Group A: Halogen atom, Hydroxyl group, C1-C4 alkyl group that may be substituted by a halogen atom, C1-C6 hydroxyalkyl group that may be substituted by a halogen atom, C1-C2 alkoxy group that may be substituted by a halogen atom, C2-C6 alkoxyalkyl group that may be substituted by a halogen atom, C3-C6 alkoxyalkoxyalkyl group that may be substituted by a halogen atom, C1-C2 alkylsulfonyl group that may be substituted by a halogen atom, Acetyl group (-C(O)CH3), Cyclopropylmethyl, Phenyl group that may be substituted by a halogen atom, Phenyl C1-C3 alkyl group that may be substituted by a halogen atom, 3- to 5-membered heterocyclic group having 1 or 2 oxygen atoms, 3- to 5-membered heterocyclic group having 1 or 2 oxygen atoms - C1-C3 alkyl group, Aminooxy C1-C3 alkyl group, C2-C4 alkynyl group that may be substituted by a halogen atom, Amino group that may be protected - C2-C6 (alkoxyalkyl), C1-C3 alkylaminocarbonyl, 5-membered heteroaryl C1-C3 alkyl group, C2-C4 alkylene (bonded to the same carbon), C1-C4 alkylenedioxy (bonded to the same carbon), C1-C4 alkoxy - C1-C4 alkyl group (bonded to the same carbon).

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 3 The substituents of the C3-C6 cycloalkyl group and the 4- to 6-membered heterocyclic group in Group B: Fluorine atom, Hydroxyl group, Methyl, ethyl, isopropyl, Fluoroethyl, difluoroethyl, trifluoromethyl, Hydroxyethyl, 2-hydroxy-2-methylpropyl, Methoxy (-OCH3), difluoromethoxy (-OCHF2), Methoxymethyl (-CH2OCH3), methoxyethyl (-C2H4OCH3), Methoxyethoxyethyl (-C2H4OC2H4OCH3), Methanesulfonyl group (-S(O)2CH3), Acetyl group (-C(O)CH3), Cyclopropylmethyl, Phenyl group, Benzyl group, Oxetanyl group, Oxetanylmethyl group, 2-amino-2-oxoethyl (-CH2C(O)NH2), Propargyl group, tert-Butoxycarbonyl-2-aminoethoxyethyl (-C2H4OC2H4NHC(O)O(CH3)3), ethylaminocarbonyl (-C(O)NHCH2CH3), Oxadiazolylmethyl group, Ethylene group (bonded to the same carbon), Methylenedioxy (bonded to the same carbon), ethylenedioxy (bonded to the same carbon), Methyleneoxymethyl (bonded to the same carbon).

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, A 1 is N or CH, A 2 , A 3 and A 4 and 0 or 1 of them is N.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Ar is a phenyl group that may be substituted by one halogen atom or a 5- to 6-membered heteroaryl group that may be substituted by one halogen atom, The 5-membered heteroaryl is selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl and oxadiazolyl, The 6-membered heteroaryl is pyridyl or pyrimidinyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, The halogen atom is fluorine or chlorine.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 1 is a chlorine atom or a bromine atom.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 2 is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, and a C1-C2 alkoxy group.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 3 in which the heterocyclic 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.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 3 In the formula, the heterocyclic group is selected from the group consisting of oxetanyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, dioxolanyl, and dioxanyl.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 3 Among them, the heterocyclic group having an oxo group on the ring is selected from the group consisting of 2-oxooxazolidinyl, 2-oxooxazinyl, 3-oxomorpholinyl, 2-oxoazetidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxoimidazolidinyl, 2-oxo-1,3-dioxolanyl, 2-oxo-1,3-dioxolenyl, 1,1-dioxothietanyl, 1,1-dioxotetrahydrothienyl, and 1,1-dioxoisothiazolidinyl.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 3 Among them, the heterocyclic group having no oxo group as a substituent on the ring is selected from the group consisting of oxazolyl, azetidinyl, pyrrolidinyl, dioxolanyl, dioxanyl, tetrahydrofuryl, tetrahydropyranyl, furyl, and oxetanyl.

12. The compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof: [Chemical formula 2] In formula (II), Ar is furyl, phenyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl or oxadiazolyl, and furyl, phenyl and pyridyl may be substituted by one fluorine atom, R 1 is a halogen atom, R 4 、R 5 and R 6 each independently represents 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 the following Group C: Group C: [Chemical formula 3] 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 (-C2H4OCH3), a methoxyethoxyethyl group (-C2H4OC2H4OCH3), a mesyl group (-S(O)2CH3), an acetyl group (-C(O)CH3), a cyclopropylmethyl group, a phenyl group, a benzyl group, an oxetanyl group, an oxetanylmethyl group, a 2-amino-2-oxoethyl group (-CH2C(O)NH2), a propargyl group (-CH2C≡CH), a tert-butoxycarbonyl-2-aminoethoxyethyl group (-C2H4OC2H4NHC(O)O(CH3)3), an ethylaminocarbonyl group (-C(O)NHCH2CH3) or an oxadiazolylmethyl group, R Q2 、R Q3 and R Q4 each independently represents a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group or a trifluoromethyl group, R Q5 and R Q6 each independently represents a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group, a methoxy group (-OCH3), a difluoromethoxy group (-OCHF2), or a methoxymethyl group, R Q7 is a hydrogen atom, a fluorine atom, a methyl group, or an ethyl group, or is ethylenedioxy (bonded to the same carbon) or methyloxymethyl (bonded to the same carbon).

13. The compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof: [Chemical formula 4] In formula (III), Ar is furyl or phenyl, R 1 is a chlorine atom, A 2 , A 3 and A 4 are independently CH or N, A 2 , A 3 and A 4 Any one of is N, R 3b is a hydrogen atom or any one of the groups selected from the following Group D: Group D: [Chemical formula 5] 14. The compound represented by the following formula (IV) or a pharmaceutically acceptable salt thereof: [Chemical formula 6] In formula (IV), Ar is furyl or phenyl, R 1 is a chlorine atom, R 3c is a hydrogen atom or any one of the groups selected from the following group E: Group E: [Chemical formula 7] R Q1 is a hydrogen atom, a methyl group, a mesyl group (-S(O)2CH3), an acetyl group (-C(O)CH3), a fluoroethyl group or a hydroxyethyl group, R Q5 is a hydrogen atom or a methyl group.

15. The compound represented by the following formula (V) or a pharmaceutically acceptable salt thereof: [Chemical formula 8] In formula (V), Ar is furyl or phenyl, R 1 is a chlorine atom, A 2 , A 3 and A 4 are each independently CH or N, and A 2 , A 3 and A 4 Any one of is N, R 3d is a hydrogen atom or any one of the following groups selected from Group F: Group F: [Chemical formula 9] 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.

16. Any compound selected from the following group or a pharmaceutically 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[4,3-d]pyrimidin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-methoxypyrido[3,2-d]pyrimidin-4-amine, 2-chloro-6-fluoro-N-(furan-2-ylmethyl)-8-methoxyquinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-6,8-dimethoxyquinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-7,8-dimethoxyquinazolin-4-amine, 2-chloro-8-methoxy-N-(thiophen-2-ylmethyl)quinazolin-4-amine, 2-Chloro-8-methoxy-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine, 2-Chloro-8-methoxy-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine, 2-Chloro-8-methoxy-N-(thiophen-3-ylmethyl)quinazolin-4-amine, 2-Chloro-8-methoxy-N-(pyridin-4-ylmethyl)quinazolin-4-amine, 2-Chloro-N-(2-fluorobenzyl)-8-methoxyquinazolin-4-amine, 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine, 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, (5R)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, (5S)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 1-{3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-1-yl}ethanone, 2-Chloro-N-(furan-2-ylmethyl)-8-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine, 2-Chloro-8-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine, 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one, 2-Chloro-8-[(2,2-difluorocyclobutyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-Chloro-8-(1,4-dioxaspiro[4.4]nonan-7-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine, 3-[({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, 2-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclopentanone, 4-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one, 3-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclobutanol, 2-Chloro-8-{[3-(difluoromethoxy)cyclobutyl]methoxy}-N-(furan-2-ylmethyl)quinazolin-4-amine, 5-[({2,6-Dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one, (3S,5R)-5-[({2,6-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methylpyrrolidin-2-one, 5-({[4-(benzylamino)-2,6-dichloroquinazolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one, 5-[({2,7-dichloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one, 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinolin-4-amine, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one, 5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one, 5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one, 5-({[4-(benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one, 2-chloro-N-(furan-2-ylmethyl)-8-(tetrahydrofuran-3-ylmethoxy)quinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-(tetrahydro-2H-pyran-3-ylmethoxy)quinazolin-4-amine, 2-chloro-8-[(1-fluorocyclopropyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine, 1-[2-({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)ethyl]imidazolidin-2-one, 2-chloro-8-[(1,1-dioxotetrahydrothiophen-3-yl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine, 7-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-6-oxa-4-azaspiro[2.4]heptan-5-one, (3S,5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methylpyrrolidin-2-one, 2-chloro-N-(furan-2-ylmethyl)-8-[(2-methyl-1,1-dioxo-1,2-thiazolidin-4-yl)methoxy]quinazolin-4-amine, 2-chloro-8-(furan-2-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine, 3-[2-({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)ethyl]-1,3-oxazolidin-2-one, 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-dioxolan-2-one, 2-chloro-8-[2-(1,4-dioxan-2-yl)ethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-[(3-methoxy-4,5-dihydro-1,2-oxazol-5-yl)methoxy]quinazolin-4-amine, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]morpholin-3-one, 1-benzyl-4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]imidazolidin-2-one, 2-chloro-N-(furan-2-ylmethyl)-8-(2-oxaspiro[3.3]heptan-6-ylmethoxy)quinazolin-4-amine, 2-chloro-8-(cyclopentylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine, 1-{3-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]azetidin-1-yl}ethanone, 2-chloro-8-(furan-3-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-{[1-(trifluoromethyl)cyclobutyl]methoxy}quinazolin-4-amine, 2-chloro-8-(cyclohexylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-(tetrahydrofuran-2-ylmethoxy)quinazolin-4-amine, 1-{2-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-1-yl}ethanone, 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 3-benzyl-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-phenyl-1,3-oxazolidin-2-one, (3S,5R)-5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-methylpyrrolidin-2-one, (3R,5R)-5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-3-methylpyrrolidin-2-one, 4-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)pyrrolidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-4,4-dimethyl-1,3-oxazolidin-2-one, 6-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazinan-2-one, 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-methylpyrrolidin-2-one, 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-5-methyl-1,3-dioxolane-2-one, 6-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]piperidin-2-one, (5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one, (5S)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one, 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]azetidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-5-methylpyrrolidin-2-one, 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-4-methyl-1,3-oxazinan-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-methyl-1,3-oxazinan-2-one, 5-({[4-(benzylamino)-2-chloroquinazolin-8-yl]oxy}methyl)-1,3-oxazinan-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazinan-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazinan-2-one, 1-{3-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]azetidin-1-yl}ethanone, 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one, 2-chloro-N-(furan-2-ylmethyl)-8-{[1-(methanesulfonyl)azetidin-3-yl]methoxy}quinolin-4-amine, (3S,5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-3-methylpyrrolidin-2-one, 2-chloro-N-(furan-2-ylmethyl)-8-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}quinolin-4-amine, 1-{3-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-1-yl}ethanone (5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one (5S)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one (5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one (5S)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]pyrrolidin-2-one 5-({[4-(benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one 5-({[4-(benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one 5-({[4-(benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one (3S,5R)-5-({[4-(benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)-3-methylpyrrolidin-2-one 4-({[4-(benzylamino)-2-chloroquinolin-8-yl]oxy}methyl)pyrrolidin-2-one 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)-1,5-naphthyridin-4-amine 5-[({6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-1,3-oxazolidin-2-one 5-[({6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one (3S,5R)-5-[({6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-methylpyrrolidin-2-one 5-[({6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one 5-[({6-chloro-8-[(furan-2-ylmethyl)amino]-1,5-naphthyridin-4-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-1,3-oxazolidin-2-one 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one (3S,5R)-5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-methylpyrrolidin-2-one 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one 5-({[8-(benzylamino)-6-chloro-1,5-naphthyridin-4-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one 5-({[4-(benzylamino)-2-chloropyrido[3,2-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one (5R)-5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(methoxymethyl)pyrrolidin-2-one 3-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]pyrrolidin-2-one 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-methylimidazolidin-2-one 5-[2-({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)ethyl]pyrrolidin-2-one 2-chloro-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine trans-4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]cyclohexanol 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinolin-8-yl}oxy)methyl]-1-methylimidazolidin-2-one 2-chloro-8-(cyclopropylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine 2-chloro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinazolin-4-amine, 2-chloro-8-(1,3-dioxolan-5-ylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-8-(cyclobutylmethoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine 2-chloro-8-[(2S)-1,4-dioxan-2-ylmethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine 2-chloro-8-[(2S)-1,4-dioxan-2-ylmethoxy]-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine 2-chloro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinolin-4-amine 2-chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-8-[(3,3-difluorocyclobutyl)methoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-8-[(1-methylcyclopropyl)methoxy]quinazolin-4-amine 2-chloro-N-(furan-2-ylmethyl)-8-(tetrahydro-2H-pyran-2-ylmethoxy)quinazolin-4-amine 2-Chloro-N-(furan-2-ylmethyl)-8-(oxetan-2-ylmethoxy)quinazolin-4-amine 2-Chloro-8-[2-(1,1-dioxothietan-3-yl)ethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine 2-Chloro-8-[(2R)-1,4-dioxan-2-ylmethoxy]-N-(furan-2-ylmethyl)quinazolin-4-amine 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-5-methyl-1,3-oxazolidin-2-one 2-Chloro-8-[(2R)-1,4-dioxan-2-ylmethoxy]-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine 2-Chloro-8-(cyclopropylmethoxy)-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine 2-Chloro-8-(cyclobutylmethoxy)-7-fluoro-N-(furan-2-ylmethyl)quinazolin-4-amine 2-Chloro-7-fluoro-N-(furan-2-ylmethyl)-8-(oxetan-3-ylmethoxy)quinazolin-4-amine 2-Chloro-8-(cyclopropylmethoxy)-N-(furan-2-ylmethyl)quinolin-4-amine 2-Chloro-8-[2-(1,1-dioxothietan-3-yl)ethoxy]-N-(furan-2-ylmethyl)quinolin-4-amine 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-2-ylmethyl)quinazolin-4-amine 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(thiophen-2-ylmethyl)quinazolin-4-amine 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(thiophen-3-ylmethyl)quinazolin-4-amine 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(thiophen-3-ylmethyl)quinazolin-4-amine 5-{[(2-Chloro-4-{[(4-fluorofuran-2-yl)methyl]amino}quinazolin-8-yl)oxy]methyl}-1,3-oxazolidin-2-one 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,2-thiazol-5-ylmethyl)quinazolin-4-amine 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-oxazol-4-ylmethyl)quinazolin-4-amine 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,2-oxazol-3-ylmethyl)quinazolin-4-amine 5-[({2-Chloro-4-[(1,3-oxazol-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine 5-[({2-Chloro-4-[(thiophen-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one 5-[({2-Chloro-4-[(thiophen-3-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine, 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine, 5-[({2-Chloro-4-[(1,3-thiazol-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine, 2-Chloro-8-[(2,2-difluorocyclopropyl)methoxy]-N-(pyridin-4-ylmethyl)quinazolin-4-amine, 5-[({2-Chloro-4-[(pyridin-4-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 5-[({2-Chloro-4-[(pyrimidin-4-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 5-[({2-Chloro-4-[(pyridin-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 5-{[(2-Chloro-4-{[(3-fluoropyridin-4-yl)methyl]amino}quinazolin-8-yl)oxy]methyl}-1,3-oxazolidin-2-one, 5-[({2-Chloro-4-[(2-fluorobenzyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 5-[({2-Chloro-4-[(3-fluorobenzyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 2-Chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(1,2,4-oxadiazol-3-ylmethyl)quinazolin-4-amine, 5-[({2-Chloro-4-[(1,2-thiazol-5-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 5-[({2-Chloro-4-[(4-fluorobenzyl)amino]quinazolin-8-yl}oxy)methyl]-1,3-oxazolidin-2-one, 5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one, (5S)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one, (5R)-5-[({2-Chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one, 5-({[4-(Benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]-1,7-naphthyridin-8-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one, 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-(2-fluoroethyl)-1,3-oxazolidin-2-one, 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one, 5-({[4-(benzylamino)-2-chloro-1,7-naphthyridin-8-yl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one, 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,2-d]pyrimidin-4-amine, 2-chloro-8-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)pyrido[3,4-d]pyrimidin-4-amine, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]pyrido[3,4-d]pyrimidin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one, 5-({[4-(benzylamino)-2-chloropyrido[3,4-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]pyrido[4,3-d]pyrimidin-8-yl}oxy)methyl]-3-methyl-1,3-oxazolidin-2-one, 5-({[4-(benzylamino)-2-chloropyrido[4,3-d]pyrimidin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one, 5-({[4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy}methyl)-1,3-oxazolidin-2-one, 5-({[4-(benzylamino)-2-chloro-1,6-naphthyridin-8-yl]oxy}methyl)-3-methyl-1,3-oxazolidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-ethyl-1,3-oxazolidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(propan-2-yl)-1,3-oxazolidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-fluoroethyl)-1,3-oxazolidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(cyclopropylmethyl)-1,3-oxazolidin-2-one, 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2,2-difluoroethyl)-1,3-oxazolidin-2-one 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-hydroxyethyl)-1,3-oxazolidin-2-one 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(oxetan-3-yl)-1,3-oxazolidin-2-one 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-hydroxy-2-methylpropyl)-1,3-oxazolidin-2-one 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-N-ethyl-2-oxo-1,3-oxazolidine-3-carboxamide 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-(2-hydroxyethyl)pyrrolidin-2-one 4-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-1-(2-fluoroethyl)pyrrolidin-2-one 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(prop-2-yn-1-yl)-1,3-oxazolidin-2-one tert-butyl [2-(2-{5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}ethoxy)ethyl]carbamate 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-[2-(2-methoxyethoxy)ethyl]-1,3-oxazolidin-2-one 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(oxetan-3-ylmethyl)-1,3-oxazolidin-2-one 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(1,2,4-oxadiazol-5-ylmethyl)-1,3-oxazolidin-2-one 2-{5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}acetamide 5-[({2-chloro-4-[(furan-2-ylmethyl)amino]quinazolin-8-yl}oxy)methyl]-3-(2-methoxyethyl)-1,3-oxazolidin-2-one 17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient.

18. A pharmaceutical composition for treating genetic diseases caused by splicing abnormalities, which contains the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient.

19. The pharmaceutical composition according to claim 18, wherein the splicing abnormality is caused by the α-galactosidase gene IVS4+919G>A mutation.

20. The pharmaceutical composition according to claim 18, wherein the genetic disease caused by the splicing abnormality is Fabry disease.

21. A method for treating a genetic disease caused by splicing abnormalities, which comprises the step of administering to a subject the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

22. The method according to claim 21, wherein the genetic disease caused by the splicing abnormality is Fabry disease.

23. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for treating genetic diseases caused by splicing abnormalities.

24. The use according to claim 23, wherein, The genetic disease caused by the splicing abnormality is Fabry disease.

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