Quinazoline derivatives

Abstract

In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof capable of suppressing splicing abnormalities that are one cause of the onset or progression of a disease. 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] Although originally an intron region, a splicing-promoting region may be newly formed due to a gene mutation, and as a result, a part of the intron region may be recognized as an exon, resulting in abnormal splicing. This abnormal splicing may cause various diseases.

[0004] One of the diseases caused by abnormal splicing is familial dysautonomia. Familial dysautonomia is a congenital, lethal, autosomal recessive genetic disease with disorders of sensory nerves and autonomic nerves due to abnormal neurodevelopment, degeneration and / or decline. Most FD patients have a single base substitution (IVS20+6T>C mutation) in the 20th intron of the IKBKAP (inhibitor ofκlight polypeptide gene enhancer in B-cells,kinasecomplex associated protein; inhibitor of B-cell κ light polypeptide gene enhancer, kinase complex associated protein) gene. It is believed that due to this mutation, abnormal splicing (exon skipping) in which the 20th exon is not incorporated into mRNA occurs mainly in the tissues of the nervous system, and the inability to produce normal IKBKAP protein is the cause of the disease.

[0005] The present inventors have developed a splicing reporter technology that expresses different fluorescent proteins such as GFP / RFP according to the selective use of exons, and constructed a splicing reporter that visualizes the splicing abnormality of IKBKAP, the causative gene of FD. In addition, the present inventors have also discovered a low molecular weight compound (2-chloro-6-(2-furanylmethyl)purine) that can clarify the pathological state of FD and correct abnormal splicing (for example, Patent Document 1). It was found that when the compound is administered to FD patient cells, the pathological state is improved, and FD, which is an autosomal recessive genetic disease, can also be treated with drugs.

[0006] In addition to FD, there are also known genetic diseases caused by various splicing abnormalities. Therefore, there is a demand for the development of new compounds that can suppress splicing abnormalities.

[0007] Prior art documents

[0008] Patent documents

[0009] Patent Document 1: WO2015 / 005491 Gazette

[0010] Non-patent documents

[0011] Non-patent Document 1: M.Ajiro et al., NATURE COMMUNICATIONS (2021) 12:4507 Summary of the invention

[0012] Problems to be solved by the invention

[0013] The present disclosure provides a compound or a pharmaceutically acceptable salt thereof that can suppress splicing abnormalities that are a cause of the onset or progression of a disease.

[0014] Means for solving the problems

[0015] In one aspect, the present disclosure relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[0016] [Chemical formula 1]

[0017]

[0018] In formula (I),

[0019] A is CH or N,

[0020] R 1 is a halogen atom,

[0021] R 2 and R 3 each independently selected from the group consisting of a hydrogen atom, -OR 4 , -O(CH 2 ) t R 5 and -O(CH 2 ) t C(O)R 5 and at least one of R 2 and R 3 is -OR 4 , -O(CH 2 ) t R 5 or -O(CH 2 ) t C(O)R5 , where t is 1, 2, 3 or 4,

[0022] R 4 is a hydrogen atom or C 1 -C 6 alkyl,

[0023] R 5 is selected from the group consisting of C 3 -C 6 cycloalkyl, a 4- to 10-membered heterocyclic group, -NR 6 R 7 and -OR 6 ; R 6 and R 7 are each independently a hydrogen atom or C 1 -C 3 alkyl,

[0024] Ar is selected from the group consisting of a 5- to 10-membered heteroaryl and a 6- to 12-membered aryl; the 5- to 10-membered heteroaryl and the 6- to 12-membered aryl may have one or more substituents.

[0025] In 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.

[0026] In another aspect, the present disclosure 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.

[0027] In another aspect, the present disclosure relates to a pharmaceutical composition for treating a genetic disease caused by splicing abnormality, comprising a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0028] In another aspect, the present disclosure relates to a method for treating a genetic disease caused by splicing abnormality, which comprises administering to a subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0029] In another aspect, the present disclosure relates to the use of a 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.

[0030] Advantages of the Invention

[0031] The present disclosure can provide a compound or a pharmaceutically acceptable salt thereof that can inhibit splicing abnormality, which is one of the causes of the onset or progression of a disease. Brief Description of the Drawings

[0032] Figure 1This is a diagram illustrating an example of the composition of a SPREADD reporter system for splicing mutations in the IKBKAP gene in familial dysautonomia. Detailed implementation mode

[0033] In the present disclosure, a "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.

[0034] In the present disclosure, "C 1 -C 6 alkyl" represents a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms. As C 1 -C 6 alkyl, in one or more embodiments, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl, etc.

[0035] In the present disclosure, "C 3 -C 6 cycloalkyl" represents a cyclic alkyl having 3 to 6 carbon atoms (saturated hydrocarbon group (ring)). As C 3 -C 6 cycloalkyl, in one or more embodiments, examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, etc.

[0036] In the present disclosure, a "4- to 10-membered heterocyclic group" represents a saturated or unsaturated monocyclic or polycyclic 4- to 10-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 4- to 10-membered 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.

[0037] As a heterocyclic group, in one or more embodiments, examples thereof 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, 1,1-dioxo-thietanyl, 1,4-oxathiane, morpholinyl, thiomorpholinyl, 1,4-dithiane, piperazinyl, 1,4-azathiane, oxepanyl, thiepanyl, azepanyl, isothiazolidinyl, 1,4-dioxepanyl, 1,4-oxathiepan-1-yl, 1,4-oxazepan-1-yl, 1,4-dithiepan-1-yl, 1,4-thiazepan-1-yl, 1,4-azaphosphorinane, 1,4-diazepane, 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 4- to 10-membered heterocyclic group, in one or more embodiments, oxetanyl, morpholinyl, thietanyl, 1,1-dioxo-thietanyl, 1,4-dioxanyl, etc. are preferred. In the present disclosure, "aryl group having 6 to 12 carbon atoms" refers to a monocyclic and polycyclic aromatic hydrocarbon ring system having 6 to 12 carbon atoms. As the aryl group having 6 to 12 carbon atoms, in one or more embodiments, aromatic hydrocarbon groups having 6 to 10 carbon atoms can be cited. As the aryl group having 6 to 12 carbon atoms, in one or more embodiments, phenyl, 1-naphthyl, 2-naphthyl, acenaphthylenyl, azulenyl, etc. can be cited.

[0038] As the 4- to 10-membered heterocyclic group, in one or more embodiments, oxetanyl, morpholinyl, thietanyl, 1,1-dioxo-thietanyl, 1,4-dioxanyl, etc. are preferred.

[0039] In the present disclosure, "aryl group having 6 to 12 carbon atoms" refers to a monocyclic and polycyclic aromatic hydrocarbon ring system having 6 to 12 carbon atoms. As the aryl group having 6 to 12 carbon atoms, in one or more embodiments, aromatic hydrocarbon groups having 6 to 10 carbon atoms can be cited. As the aryl group having 6 to 12 carbon atoms, in one or more embodiments, phenyl, 1-naphthyl, 2-naphthyl, acenaphthylenyl, azulenyl, etc. can be cited.

[0040] In the present disclosure, in one or more embodiments, the aryl having 6 to 12 members may be substituted with one or more substituents. As the substituents, in one or more embodiments, halogen atoms, -NO 2 , -CN, alkyl, aryl, heteroaryl, heterocyclic group, -(CH 2 ) p NR b R c , -NR b COR c , -NR b S(O) 2 R c , -(CH 2 ) p C(O)OR d , -C(O)NR b R c , -C(O)R d , -C(O)OR d and -OR d etc. The alkyl, aryl, heteroaryl and heterocyclic group may be substituted in one or more embodiments. R b , R c and R d are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms that may be substituted in one or more embodiments. P is an integer of 0, 1, 2 or 3.

[0041] In the present disclosure, "5- to 10-membered heteroaryl" means a 5- to 10-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 heteroaryl, in one or more embodiments, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, diazinylpyridyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, pyrazolo[3,4-b]pyridyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyridinyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, benzofuryl, isobenzofuryl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolinyl, quinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, and isobenzoxazinyl, etc. can be cited. As the 5- to 10-membered heteroaryl, in one or more embodiments, furyl, thienyl, 1,3-thiazolyl, pyridyl, 1,3-oxazolyl, and 1H-pyrrolyl, etc. are preferred.

[0042] In the present disclosure, the 5- to 10-membered heteroaryl can be substituted with one or more substituents in one or more embodiments. As the substituents, as described above.

[0043] The preferred substituents in the compounds of the present disclosure are described below.

[0044] R 1 Is preferably a chlorine atom in one or more embodiments.

[0045] R 2 and R 3 are each independently a hydrogen atom, -OR 4 , -O(CH 2 ) t R 5 or -O(CH 2 ) t C(O)R 5 , preferably a hydrogen atom, -OR 4 or -O(CH 2 ) t R 5 . R 4 is a hydrogen atom or C 1 -C 3 alkyl in one or more embodiments, preferably methyl, ethyl, propyl, or isopropyl. R5 is -NR in one or more embodiments 6 R 7 , -OH, methyl, cyclopropyl, oxetanyl, morpholinyl, 1,1 - dioxo - thietanyl or dioxolanyl, R 6 and R 7 are each independently a hydrogen atom or methyl. R 5 is amino, methylamino, dimethylamino, hydrogen atom, cyclopropyl, oxetanyl, morpholinyl, 1,1 - dioxo - thietanyl or dioxolanyl in one or more embodiments. t is 1 or 2 in one or more embodiments.

[0046] R 2 is a hydrogen atom, hydroxy, methoxy (-OCH 3 ), ethoxy, propoxy, isopropoxy, methoxyethoxy, cyclopropylmethoxy, 3 - oxetanylmethoxy, 3 - oxetanyl ethoxy, 2 - morpholinylethoxy, 2 - morpholinylpropoxy, 1,1 - dioxo - thietanylmethoxy, 1,1 - dioxo - thietanyl ethoxy, aminoethoxy, (methylamino) ethoxy, (dimethylamino) ethoxy, hydroxyethoxy, 1,4 - dioxolanylmethoxy, carboxyethoxy, methoxycarbonylethoxy or methoxycarbonylmethoxy in one or more embodiments.

[0047] R 3 is a hydrogen atom, methoxy (-OCH 3 ), ethoxy, aminoethoxy or (methylamino) ethoxy, preferably methoxy, in one or more embodiments.

[0048] Ar is a 5 - or 6 - membered heteroaryl in one or more embodiments, preferably furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl or pyridyl, more preferably furyl, thienyl or pyridyl, and even more preferably 2 - furyl.

[0049] In one or more embodiments of the compound of formula (I), Ar is 2 - furyl, R 2 is a hydrogen atom, -O(CH 2 ), 2 CH 3 , -OCH 2 R 5 or -O(CH 2 ), 2 R 5 , R 3 is methoxy, R 5 is -NR 6 R 7 , -OH or oxetanyl, R 6 and R 7Each is independently a hydrogen atom or a methyl group. In the compound represented by formula (I), preferably Ar is 2-furyl, and R 2 is a hydrogen atom, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a cyclopropylmethoxy group, a 3-oxetanylmethoxy group, an aminoethoxy group, a (methylamino)ethoxy group, a (dimethylamino)ethoxy group, a hydroxyethoxy group or a 1,4-dioxanyl methoxy group, and R 3 is a methoxy group. In the compound represented by formula (I), more preferably Ar is 2-furyl, and R 2 is a hydrogen atom, a propoxy group, an aminoethoxy group, a (methylamino)ethoxy group, a 3-oxetanylmethoxy group, a (dimethylamino)ethoxy group or a hydroxyethoxy group, and R 3 is a methoxy group.

[0050] As the 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.

[0051] 2-chloro-N-(furan-2-ylmethyl)-6,7-dimethoxyquinazolin-4-amine,

[0052] 2-chloro-6,7-dimethoxy-N-(thiophen-2-ylmethyl)quinazolin-4-amine,

[0053] 2-chloro-6,7-dimethoxy-N-(thiophen-3-ylmethyl)quinazolin-4-amine,

[0054] 2-chloro-6,7-dimethoxy-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine,

[0055] 2-chloro-6,7-dimethoxy-N-(pyridin-4-ylmethyl)quinazolin-4-amine,

[0056] 2-chloro-6,7-dimethoxy-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine,

[0057] 2-chloro-6,7-dimethoxy-N-(1H-pyrrol-3-ylmethyl)quinazolin-4-amine,

[0058] 2-chloro-N-(furan-3-ylmethyl)-6,7-dimethoxyquinazolin-4-amine,

[0059] 2-chloro-6,7-dimethoxy-N-(pyridin-2-ylmethyl)quinazolin-4-amine,

[0060] 2-chloro-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0061] 2-chloro-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine,

[0062] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxyquinolin-4-amine,

[0063] 2-Chloro-N-(furan-2-ylmethyl)-6-methoxyquinolin-4-amine,

[0064] 2-Chloro-6-ethoxy-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0065] 2-Chloro-6-ethoxy-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0066] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-propoxyquinazolin-4-amine,

[0067] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(propan-2-yloxy)quinazolin-4-amine, 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-amine, 2-Chloro-6-(cyclopropylmethoxy)-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0068] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(oxetan-3-ylmethoxy)quinazolin-4-amine,

[0069] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[2-(morpholin-4-yl)ethoxy]quinazolin-4-amine,

[0070] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine,

[0071] 2-Chloro-6-[2-(1,1-dioxidosulfolan-3-yl)ethoxy]-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0072] 6-(2-Aminoethoxy)-2-chloro-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0073] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[2-(methylamino)ethoxy]quinazolin-4-amine,

[0074] 2-Chloro-6-[2-(dimethylamino)ethoxy]-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0075] 2-({2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)ethanol,

[0076] 2-chloro-6-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0077] 3-({2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)propanoic acid,

[0078] methyl 3-({2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)propanoate,

[0079] methyl ({2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)acetate,

[0080] 7-(2-aminoethoxy)-2-chloro-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine, 2-chloro-4-[(furan-2-ylmethyl)amino]-6-methoxyquinazolin-7-ol,

[0081] 2-chloro-N-(furan-2-ylmethyl)-6-methoxy-7-[2-(methylamino)ethoxy]quinazolin-4-amine,

[0082] 2-chloro-7-ethoxy-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine.

[0083] 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. may be exemplified.

[0084] As "basic salts", in one or more embodiments, alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as magnesium salts and calcium salts; organic base salts such as N-methylmorpholine salts, triethylamine salts, tributylamine salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidine salts, pyridine salts, 4-pyrrolidinopyridine salts, and picolinate salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate salts, and aspartate salts may be exemplified. Preferably, they are alkali metal salts.

[0085] As "acid salts", in one or more embodiments, examples include hydrohalides such as hydrofluorides, hydrochlorides, hydrobromides, and hydroiodides; inorganic acid salts such as nitrates, perchlorates, sulfates, and phosphates; lower alkane sulfonates such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; aryl sulfonates such as benzenesulfonates and p-toluenesulfonates; organic acid salts such as acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, and maleates; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate salts, and aspartate salts, etc. Preferably, they are hydrohalides (especially hydrochlorides).

[0086] The pharmaceutically acceptable salts of the compounds of the present disclosure may include hydrates. Additionally, in the present disclosure, "salts of the compounds" may also include solvates that the compounds can form by absorbing other certain solvents.

[0087] The compounds of the present disclosure, their pharmaceutically acceptable salts, or their solvates may exist as various isomers such as geometric isomers, tautomers, rotational isomers, or optical isomers (enantiomers) and diastereomers like cis-forms, trans-forms, etc., depending on the types and combinations of substituents. Without particular limitation, the compounds of the present disclosure also include all these isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio. These mixtures of isomers can be separated by known separation methods.

[0088] 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.).

[0089] Compounds that are converted into the active ingredient of the pharmaceutical composition of the present disclosure, i.e., the compound represented by formula (I), under physiological conditions in the living body through reactions based on enzymes, gastric acid, etc., that is, compounds that are changed into the compound represented by formula (I) by oxidation, reduction, hydrolysis, etc. by enzymes or are changed into the compound represented by formula (I) by hydrolysis, etc. 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 that can be converted into an amino group, a hydroxyl group, a carboxyl group, etc. of a compound by hydrolysis or under physiological conditions. As the groups forming such prodrugs, they are the groups described in Prog. Med., Vol. 5, pages 2157 - 2161, 1985, etc.

[0090] As a prodrug, when an amino group is present in the compound represented by formula (I), examples of the compound include those obtained by acylating, alkylating or phosphorylating the amino group (such as those obtained by eicosanoylating, alanylylating, pentylaminocarbonylating, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylating, tetrahydrofuranylating, pyrrolidinomethylating, pivaloyloxymethylating or tert-butylating the amino group, etc.). When a hydroxyl group is present in the compound represented by formula (I), examples of the compound include those obtained by acylating, alkylating, phosphorylating or borylating the hydroxyl group (such as those obtained by acetylating, palmitoylating, propionylating, pivaloylating, succinylating, fumaroylating, alanylylating or dimethylaminomethylcarbonylating the hydroxyl group, etc.). In addition, when a carboxyl group is present in the compound represented by formula (I), examples of the compound include those obtained by esterifying or amidating the carboxyl group (such as those obtained by ethyl esterifying, phenyl esterifying, carboxymethyl esterifying, dimethylaminomethyl esterifying, pivaloyloxymethyl esterifying, ethoxycarbonyloxyethyl esterifying or methyl amidating the carboxyl group, etc.).

[0091] [Manufacturing Method]

[0092] Hereinafter, representative manufacturing methods of the compound represented by formula (I) 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 E. The manufacturing methods shown below are examples, and the present disclosure should not be construed as being limited to these examples.

[0093] Each compound of the following methods A to E 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, or an organic amine salt, sodium salt, potassium salt, etc.

[0094] The solvent used in the reactions of each step of the following methods A to E is not particularly limited as long as it does not hinder the reaction and partially dissolves the starting material. 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.

[0095] In one or more embodiments, examples of the aliphatic hydrocarbons include n-hexane, n-pentane, petroleum ether, cyclohexane, etc.

[0096] In one or more embodiments, examples of the aromatic hydrocarbons include benzene, toluene, xylene, etc.

[0097] As halogenated hydrocarbons, in one or more embodiments, examples include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene, etc.

[0098] As ethers, in one or more embodiments, examples include diethyl ether, diisopropyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, and diethylene glycol dimethyl ether, etc.

[0099] As ketones, in one or more embodiments, examples include acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone, etc.

[0100] As esters, in one or more embodiments, examples include ethyl acetate, propyl acetate, and butyl acetate, etc.

[0101] As nitriles, in one or more embodiments, examples include acetonitrile, propionitrile, butyronitrile, and isobutyronitrile, etc.

[0102] As carboxylic acids, in one or more embodiments, examples include acetic acid and propionic acid, etc.

[0103] As alcohols, in one or more embodiments, examples include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol, etc.

[0104] As amides, in one or more embodiments, examples include formamide, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and hexamethylphosphoric triamide, etc.

[0105] As sulfoxides, in one or more embodiments, examples include dimethyl sulfoxide (DMSO) and tetrahydrothiophene 1,1-dioxide, etc.

[0106] The base used in the reactions of each step of the following Method A to Method E 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 bicarbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal hydrides, alkali metal amides, alkali metal alkoxides, and organic amines, etc. can be mentioned. As the alkali metal carbonates, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be mentioned. As the alkali metal bicarbonates, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc. can be mentioned. As the alkali metal hydroxides, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. can be mentioned. As the alkaline earth metal hydroxides, calcium hydroxide, barium hydroxide, etc. can be mentioned. As the alkali metal hydrides, lithium hydride, sodium hydride, potassium hydride, etc. can be mentioned. As the alkali metal amides, lithium amide, sodium amide, potassium amide, etc. can be mentioned. As the organic amines, 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. can be mentioned.

[0107] [Method A]

[0108] [Chemical formula 2]

[0109]

[0110] Step A - 1 is the step of obtaining the compound shown by formula (I) from intermediate I. Step A - 1 can be carried out by heating in the presence of a solvent (such as acetonitrile, etc.) that is inert to the reaction and a base (such as triethylamine, etc.). In one or more embodiments, the reaction temperature is 0°C to 100°C, and the reaction time is 30 minutes to 24 hours.

[0111] In intermediate I and the compound of formula (I), X is a halogen atom such as a chlorine atom, and R 1 , R 2 and R 3 are the same as those in the above formula (I). In step A - 1 and the compound of formula (I), Ar is the same as that in the above formula (I).

[0112] [Method B]

[0113] [Chemical formula 3]

[0114]

[0115] Step B-1 is the step of obtaining the compound represented by formula (I) from intermediate II. Step B-1 can be carried out by heating in the presence of a solvent inert to the reaction (such as N-methyl-2-pyrrolidone (NMP), etc.) and a base (such as N,N-diisopropylethylamine, etc.). In one or more embodiments, the reaction temperature is 0°C to 140°C, and the reaction time is 30 minutes to 24 hours.

[0116] In intermediate II and the compound of formula (I), X is a halogen atom such as a chlorine atom, and R 1 , R 2 is the same as that in the above formula (I). In step B-1 and the compound of formula (I), Ar is the same as that in the above formula (I).

[0117] [Method C]

[0118] [Chemical formula 4]

[0119]

[0120] Step C-1 is the step of obtaining intermediate IV from intermediate III reported in Tetrahedron, 2005, 61, 9375-9380. Step C-1 can be carried out by reacting in the presence of a solvent inert to the reaction (such as acetonitrile, etc.). In one or more embodiments, the reaction temperature is 0°C to around room temperature, and the reaction time is 30 minutes to 24 hours.

[0121] Steps C-2 and C-3 are the steps of obtaining the compound represented by formula (I) from intermediate IV. Steps C-2 and C-3 can be carried out by reacting in the presence of a solvent inert to the reaction (such as N,N-dimethylformamide (DMF), toluene, methanol, etc.), a base (such as potassium carbonate), and a Mitsunobu reagent (such as cyanomethylenetributylphosphonium, etc.). In one or more embodiments, the reaction temperature is 0°C to around 100°C, and the reaction time is 30 minutes to 24 hours.

[0122] In step C-1, intermediate IV and the compound of formula (I), X is a halogen atom such as a chlorine atom. In intermediate IV and the compound of formula (I), Ar is the same as that in the above formula (I). In steps C-2 and C-3 and the compound of formula (I), R 8 is R in the above formula (I) 4 , -(CH 2 ) t R 5 or -(CH 2 ) t C(O)R 5 .

[0123] [Method D]

[0124] [Chemical Formula 5]

[0125]

[0126] Step D-1 is the step of obtaining intermediate VI from intermediate V. Step D-1 can be carried out by reacting in the presence of a solvent (such as tetrahydrofuran (THF), etc.) that is inert to the reaction and a base (such as triethylamine, etc.). In one or more embodiments, the reaction temperature is 0°C to 100°C, and the reaction time is 30 minutes to 24 hours.

[0127] Step D-2 is the step of obtaining intermediate VII from intermediate VI. Step D-1 can be carried out by reacting in a hydrogen atmosphere in a solvent (such as tetrahydrofuran (THF), etc.) that is inert to the reaction using a transition metal catalyst (such as Pd / alumina).

[0128] Steps D-3 and D-4 are the steps of obtaining the compound shown in formula (I) from intermediate VII. Steps D-3 and D-4 can be carried out by reacting in the presence of a solvent (such as toluene or DMF, etc.) that is inert to the reaction, a base (such as potassium carbonate), and a Mitsunobu reagent (such as cyanomethylenetributylphosphonium, etc.). In one or more embodiments, the reaction temperature is 0°C to around room temperature, and the reaction time is 30 minutes to 24 hours.

[0129] In intermediate VI, VII and the compound of formula (I), Ar is the same as that in the above formula (I). In steps D-3 and D-4 and the compound of formula (I), R 9 is -(CH 2 ) 2 NR 6 R 7 , R 6 and R 7 are each independently a hydrogen atom or a methyl group.

[0130] [Method E]

[0131] [Chemical Formula 6]

[0132]

[0133] Step E-1 is the step of obtaining the compound shown in formula (I) from intermediate VIII. Step E-1 can be carried out by reacting in the presence of a solvent (such as ethyl acetate, etc.) that is inert to the reaction and an acid (such as hydrochloric acid, etc.). In one or more embodiments, the reaction temperature is 0°C to room temperature, and the reaction time is 30 minutes to 24 hours.

[0134] In the intermediate VIII and the compound of formula (I), Ar is the same as in the above formula (I), and R 10 is methoxy, and R 11 is a hydrogen atom or a methyl group.

[0135] In one or more embodiments, the compound of the present disclosure or a pharmaceutically acceptable salt thereof has an effect of being able to inhibit 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.

[0136] 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 refers to a splicing mutation in which a normally recognized exon is no longer recognized (skips) due to a mutation in the exon or the surrounding intron sequence. A splice site selection mutation refers to a splicing mutation in which multiple 5' splice sites or 3' splice sites are generated due to a mutation in a splicing regulatory sequence in an exon region or an intron region. An intron retention mutation refers to 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 a 5' splice site or a 3' splice site, inducing intron retention. A pseudo-exon mutation refers to a splicing mutation in which a sequence that was originally an intron region is recognized as an exon due to a mutation.

[0137] Mutations other than those in the GU at positions +1 and +2 of the 5' splice site required for splicing and the AG at positions -1 and -2 of the 3' splice site in exon skipping mutations are assumed to be targets for splicing therapeutic drugs. As genetic diseases caused by splicing abnormalities based on exon skipping mutations, in one or more embodiments, familial dysautonomia, congenital long QT syndrome, Fabry disease, etc. can be cited.

[0138] Familial dysautonomia refers to a genetic disease caused by the following situation: at the 6th base of the intron downstream of the 20th exon of the IKBKAP gene, a single base substitution of T>C (IVS20+6T>C) causes exon 20 not to be recognized, exon skipping occurs, and as a result, the expression level of the gene product IKAP decreases and the modification of the tRNA encoding the recognition base is abnormal.

[0139] Congenital long QT syndrome is a genetic disease characterized by prolonged QT interval and coma and sudden death caused by polymorphic ventricular tachycardia, and it is considered that the cause lies in gene abnormalities of ion channel-related molecules. As the site of gene mutation, mutations in the exon region account for only about 70% of the whole, and research indicates that the remaining about 30% is related to mutations in the intron region. Hereditary congenital long QT syndrome includes Romano-Ward syndrome, which is autosomal dominant inheritance, and Jervell and Lange-Nielsen syndrome, which is autosomal recessive inheritance. Thirteen genotypes (LQT1-LQT13) have been reported for Romano-Ward syndrome, and two genotypes (JLN1 and JLN2) have been reported for Jervell and Lange-Nielsen syndrome. As pathogenic genes, KCNQ1 (LQT1, JLN1), KCNH2 (LQT2, JLN2), SCN5A (LQT3), ANK2 (LQT4), KCNE1 (LQT5), KCNE2 (LQT6), KCNJ2 (LQT7), CACNA1C (LQT8), CAV3 (LQT9), SCN4B (LQT10), AKAP-9 (LQT11), SNTA1 (LQT12), and KCNJ5 (LQT13) have been reported, among which mutations in the KCNQ1, KCNH2, and SCN5A genes are considered to have a high incidence of disease onset.

[0140] KCNQ1 (α subunit), KCNH2 (α subunit), KCNE1 (β subunit), and KCNE2 (β subunit) are genes encoding the α or β subunits of potassium channels. KCNQ1 encodes the α subunit of the voltage-gated potassium channel, and one KCNQ1 channel is formed by the aggregation of four KCNQ1 subunits.

[0141] As mutations in congenital long QT syndrome, in one or more embodiments, mutations in KCNQ1 (c.1032G>A), KCNH2, SCN5A, etc. can be cited.

[0142] [Pharmaceutical composition]

[0143] As 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. In one or more embodiments, the pharmaceutical composition of the present disclosure can be used to treat genetic diseases caused by splicing abnormalities.

[0144] As another aspect, the present disclosure also relates to a pharmaceutical composition for treating genetic diseases caused by splicing abnormalities, which contains the compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient.

[0145] As another aspect, the present disclosure also relates to a pharmaceutical composition for treating genetic diseases caused by splicing abnormalities, which uses the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0146] In one or more embodiments, the pharmaceutical composition of the present disclosure may contain the compound of the present disclosure or a pharmaceutically acceptable salt, and may also contain a pharmaceutically acceptable carrier, preservative, diluent, excipient or other pharmaceutically acceptable ingredients.

[0147] 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. 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.

[0148] In one or more embodiments, the pharmaceutical composition of the present disclosure can be formulated into a dosage form suitable for the administration method by applying known formulation techniques. As the administration method, in one or more embodiments, oral administration and parenteral administration, etc. can be cited. As the preparations for oral administration, in one or more embodiments, dosage forms such as tablets, capsules, granules, powders, pills, troches, syrups, liquids (such as solutions, suspensions), etc. can be cited. As the preparations for parenteral administration, in one or more embodiments, injections, aerosols, etc. can be cited. These preparations can be manufactured by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring and odor-masking agents, diluents, etc. in one or more embodiments.

[0149] As excipients, in one or more embodiments, starches such as starch, potato starch, corn starch, lactose, crystalline cellulose, calcium hydrogen phosphate, etc. can be cited. As lubricants, in one or more embodiments, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, paraffin wax, etc. can be cited. As binders, in one or more embodiments, polyvinylpyrrolidone, macrogol, and the same compounds as the excipients can be cited. As disintegrants, in one or more embodiments, the same compounds as the excipients and chemically modified starch-cellulose such as cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone can be cited. As stabilizers, in one or more embodiments, p-hydroxybenzoates such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalkonium chloride; phenols such as phenol, cresol; thimerosal; dehydroacetic acid; and sorbic acid can be cited. As flavoring and odor-masking agents, in one or more embodiments, commonly used sweeteners, acidulants, fragrances, etc. can be cited.

[0150] In the manufacture of oral liquid preparations, 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 adjusters or emulsifiers, etc. can also be used as needed. Oral liquid preparations can, in one or more embodiments, further contain solubilizers, wetting agents, suspending agents, sweeteners, flavoring agents, fragrances or preservatives.

[0151] Injectable preparations for parenteral administration can be sterile aqueous or non-aqueous liquid preparations, suspensions or emulsions. As aqueous solvents for injectable preparations, in one or more embodiments, distilled water or physiological saline can be used. As non-aqueous solvents for injectable preparations, in one or more embodiments, vegetable oils, alcohols or polysorbate 80 (pharmacopoeial name) can be used. As vegetable oils, propylene glycol, polyethylene glycol, olive oil, etc. can be cited. As alcohols, ethanol, etc. can be cited. Injectable preparations can, in one or more embodiments, further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or solubilizing aids. These preparations can, in one or more embodiments, be sterilized by filtration through a bacteria-retaining filter, incorporation of a bactericide or irradiation with radiation. In addition, a composition obtained by dissolving or suspending a sterile solid composition in sterile water or an injectable solvent immediately before use can also be used as these preparations.

[0152] The method of using the pharmaceutical composition of the present disclosure may vary depending on symptoms, age, administration method, etc. In one or more embodiments, the method of use may be intermittent or continuous oral, transdermal, submucosal, subcutaneous, intramuscular, intravenous, intracerebral, or intraperitoneal administration 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 an object (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 an object (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.

[0153] [Treatment method]

[0154] As another aspect, the present disclosure relates to a method for treating a genetic disease caused by splicing abnormality, which comprises administering to an object the compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0155] 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.

[0156] The present disclosure may relate to one or more of the following unrestricted embodiments.

[0157] [1] The compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[0158] [Chemical formula 7]

[0159]

[0160] In formula (I),

[0161] A is CH or N,

[0162] R 1 is a halogen atom,

[0163] R 2 and R 3 each independently is selected from the group consisting of a hydrogen atom, -OR 4 、-O(CH 2 ) t R 5and -O(CH 2 ) t C(O)R 5 group, where R 2 and R 3 at least one of them is -OR 4 、-O(CH 2 ) t R 5 or -O(CH 2 ) t C(O)R 5 , t is 1, 2, 3 or 4,

[0164] R 4 is a hydrogen atom or C 1 -C 6 alkyl group,

[0165] R 5 is selected from the group consisting of C 3 -C 6 cycloalkyl group, 4- to 10-membered heterocyclic group, -NR 6 R 7 and -OR 6 group, R 6 and R 7 are each independently a hydrogen atom or C 1 -C 3 alkyl group,

[0166] Ar is selected from the group consisting of 5- to 10-membered heteroaryl groups and 6- to 12-membered aryl groups. The 5- to 10-membered heteroaryl groups and 6- to 12-membered aryl groups may have one or more substituents.

[0167] [2] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein R 3 is methoxy.

[0168] [3] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein Ar is furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl or pyridyl.

[0169] [4] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of a hydrogen atom, -OR 4 、-O(CH 2 ) t R 5 and -O(CH 2 ) t C(O)R 5 group,

[0170] R 4 is C1 -C 3 alkyl

[0171] R 5 is -NR 6 R 7 , -OH, methyl, cyclopropyl, oxetanyl, morpholinyl, 1,1 - dioxo - thiolanyl or dioxolanyl,

[0172] R 6 and R 7 are each independently a hydrogen atom or methyl,

[0173] t is 1 or 2.

[0174] [5] The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof, wherein Ar is 2 - furyl,

[0175] R 2 is a hydrogen atom, -O(CH 2 ) 2 CH 3 , -OCH 2 R 5 or -O(CH 2 ) 2 R 5 ; R 5 is -NR 6 R 7 , -OH or oxetanyl; R 6 and R 7 are each independently a hydrogen atom or methyl,

[0176] R 3 is methoxy.

[0177] [6] Any compound selected from the following group or a pharmaceutically acceptable salt thereof.

[0178] 2 - chloro - N - (furan - 2 - ylmethyl) - 6,7 - dimethoxyquinazolin - 4 - amine,

[0179] 2 - chloro - 6,7 - dimethoxy - N - (thiophen - 2 - ylmethyl)quinazolin - 4 - amine,

[0180] 2 - chloro - 6,7 - dimethoxy - N - (thiophen - 3 - ylmethyl)quinazolin - 4 - amine,

[0181] 2 - chloro - 6,7 - dimethoxy - N - (1,3 - thiazol - 2 - ylmethyl)quinazolin - 4 - amine,

[0182] 2 - chloro - 6,7 - dimethoxy - N - (pyridin - 4 - ylmethyl)quinazolin - 4 - amine,

[0183] 2-Chloro-6,7-dimethoxy-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine,

[0184] 2-Chloro-6,7-dimethoxy-N-(1H-pyrrol-3-ylmethyl)quinazolin-4-amine,

[0185] 2-Chloro-N-(furan-3-ylmethyl)-6,7-dimethoxyquinazolin-4-amine,

[0186] 2-Chloro-6,7-dimethoxy-N-(pyridin-2-ylmethyl)quinazolin-4-amine,

[0187] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0188] 2-Chloro-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine,

[0189] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxyquinolin-4-amine,

[0190] 2-Chloro-N-(furan-2-ylmethyl)-6-methoxyquinolin-4-amine,

[0191] 2-Chloro-6-ethoxy-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0192] 2-Chloro-6-ethoxy-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0193] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-propoxyquinazolin-4-amine,

[0194] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(propan-2-yloxy)quinazolin-4-amine, 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-amine, 2-Chloro-6-(cyclopropylmethoxy)-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0195] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(oxetan-3-ylmethoxy)quinazolin-4-amine,

[0196] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[2-(morpholin-4-yl)ethoxy]quinazolin-4-amine,

[0197] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine,

[0198] 2-Chloro-6-[2-(1,1-dioxothietan-3-yl)ethoxy]-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0199] 6-(2-Aminoethoxy)-2-chloro-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0200] 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[2-(methylamino)ethoxy]quinazolin-4-amine,

[0201] 2-Chloro-6-[2-(dimethylamino)ethoxy]-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0202] 2-({2-Chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)ethanol,

[0203] 2-Chloro-6-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine,

[0204] 3-({2-Chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)propanoic acid,

[0205] Methyl 3-({2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)propanoate,

[0206] ({2-Chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)acetic acid methyl ester,

[0207] 7-(2-Aminoethoxy)-2-chloro-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine, 2-chloro-4-[(furan-2-ylmethyl)amino]-6-methoxyquinazolin-7-ol,

[0208] 2-Chloro-N-(furan-2-ylmethyl)-6-methoxy-7-[2-(methylamino)ethoxy]quinazolin-4-amine,

[0209] 2-Chloro-7-ethoxy-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine.

[0210] [7] A pharmaceutical composition comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof as an active ingredient.

[0211] [8] A pharmaceutical composition for treating genetic diseases caused by splicing abnormalities, comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof as an active ingredient.

[0212] [9] A pharmaceutical composition for treating genetic diseases caused by splicing abnormalities, comprising the compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0213] [Chemical formula 8]

[0214]

[0215] In formula (I),

[0216] A is CH or N,

[0217] R 1 is a halogen atom,

[0218] R 2 and R 3 each independently selected from the group consisting of a hydrogen atom, -OR 4 , -O(CH 2 ) t R 5 and -O(CH 2 ) t C(O)R 5 ; at least one of R 2 and R 3 is -OR 4 , -O(CH 2 ) t R 5 or -O(CH 2 ) t C(O)R 5 ; t is 1, 2, 3 or 4,

[0219] R 4 is a hydrogen atom or C 1 -C 6 alkyl,

[0220] R 5 is selected from the group consisting of C 3 -C 6 cycloalkyl, a 4- to 10-membered heterocyclic group, -NR 6 R 7 and -OR 6 ; R 6 and R 7Each independently is a hydrogen atom or C 1 -C 3 alkyl,

[0221] Ar is selected from the group consisting of 5- to 10-membered heteroaryl and 6- to 12-membered aryl, and the 5- to 10-membered heteroaryl and 6- to 12-membered aryl may have one or more substituents.

[0222]

[10] The pharmaceutical composition according to [9], wherein Ar is 2-furyl,

[0223] R 2 is a hydrogen atom, -O(CH 2 ) 2 CH 3 , -OCH 2 R 5 or -O(CH 2 ) 2 R 5 , R 5 is -NR 6 R 7 , -OH or oxetanyl, R 6 and R 7 each independently is a hydrogen atom or methyl,

[0224] R 3 is methoxy.

[0225]

[11] The pharmaceutical composition according to any one of [8] to

[10] , wherein the genetic disease caused by splicing abnormality is familial dysautonomia or congenital long QT syndrome.

[0226]

[12] A method for treating a genetic disease caused by splicing abnormality, which comprises administering to a subject the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of [7] to

[11] .

[0227]

[13] The method according to

[12] , wherein the genetic disease caused by splicing abnormality is familial dysautonomia or congenital long QT syndrome.

[0228]

[14] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for treating a genetic disease caused by splicing abnormality.

[0229]

[15] The use according to

[14] , wherein the genetic disease caused by splicing abnormality is familial dysautonomia or congenital long QT syndrome.

[0230] Examples

[0231] Hereinafter, examples are given to explain the present disclosure in more detail. However, the scope of the present disclosure is not limited to these, and these examples should not be construed restrictively in any sense. In addition, in this specification, reagents, solvents, and starting materials not specifically described can be easily obtained from commercially available sources.

[0232] 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 labels show significant peaks, including the chemical shift (expressed as relative ppm (δ) with tetramethylsilane as the reference substance), the number of protons, the 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, when applicable, the spin-coupling constant is expressed as a J value (unit: Hz).

[0233] 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 almost always coincides with the maximum UV absorption peak).

[0234] Silica gel column chromatography was carried out using commercially available pre-packed columns and an automatic separation and purification device (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 based on 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)" means silica gel whose surface has been chemically modified with a functional group having an amino group (for example, Purif-Pack (registered trademark, Shoko Scientific)-EX, NH series, etc.). In addition, in the examples, "silica gel column chromatography (C18)" means silica gel whose surface has been chemically modified with octadecyl (for example, SNAP Ultra C18 series, etc.).

[0235] (Example 1) 2-Chloro-N-(furan-2-ylmethyl)-6,7-dimethoxyquinazolin-4-amine

[0236] [Chemical formula 9]

[0237]

[0238] To a suspension of 2,4-dichloro-6,7-dimethoxyquinazoline (103 mg, 0.398 mmol) in acetonitrile (1.5 mL) were added furfurylamine (39.0 μL, 0.417 mmol) and triethylamine (67.0 μL, 0.417 mmol), and the mixture was stirred at 70 °C for 2.5 hours. After the reaction solution was naturally cooled to room temperature, water (7 mL) was added, and the insoluble matter was collected by filtration. Then, the solid was washed with a mixed solvent of acetonitrile / water (6 / 1) and dried to obtain the title compound (119 mg, yield 94%) as a white solid.

[0239] (Example 2) 2-Chloro-6,7-dimethoxy-N-(thiophen-2-ylmethyl)quinazolin-4-amine

[0240] [Chemical formula 10]

[0241]

[0242] Using 2,4-dichloro-6,7-dimethoxyquinazoline (203 mg, 0.784 mmol) and 2-thiophenemethylamine (82.4 μL, 0.823 mmol), the same procedure as in Example 1 was carried out, and thus the title compound was obtained as a pale yellow solid (237 mg, yield 90%).

[0243] (Example 3) 2-Chloro-6,7-dimethoxy-N-(thiophen-3-ylmethyl)quinazolin-4-amine

[0244] [Chemical formula 11]

[0245]

[0246] Using 2,4-dichloro-6,7-dimethoxyquinazoline (203 mg, 0.784 mmol) and 3-thiophenemethylamine (82.4 μL, 0.823 mmol), the same procedure as in Example 1 was carried out, and thus the title compound was obtained as a pale yellow solid (241 mg, yield 92%).

[0247] (Example 4) 2-Chloro-6,7-dimethoxy-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine

[0248] [Chemical formula 12]

[0249]

[0250] Using 2,4-dichloro-6,7-dimethoxyquinazoline (203 mg, 0.784 mmol) and 2-(aminomethyl)thiazole (78.1 μL, 0.824 mmol), the same procedure as in Example 1 was carried out, and thus the title compound was obtained as a pale yellow solid (229 mg, yield 87%).

[0251] (Example 5) 2-Chloro-6,7-dimethoxy-N-(pyridin-4-ylmethyl)quinazolin-4-amine

[0252] [Chemical formula 13]

[0253]

[0254] Using 2,4-dichloro-6,7-dimethoxyquinazoline (203 mg, 0.784 mmol) and 4-aminomethylpyridine (83.2 μL, 0.823 mmol), the same procedure as in Example 1 was carried out, and thus the title compound was obtained as a brown solid (225 mg, yield 87%).

[0255] (Example 6) 2-Chloro-6,7-dimethoxy-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine

[0256] [Chemical Formula 14]

[0257]

[0258] Using 2,4-dichloro-6,7-dimethoxyquinazoline (203 mg, 0.784 mmol) and 2-aminomethyl-oxazole hydrochloride (111 mg, 0.823 mmol), the same operation as in Example 1 was carried out, and thus the title compound (158 mg, yield 63%) was obtained as a light brown solid.

[0259] (Example 7) 2-Chloro-6,7-dimethoxy-N-(1H-pyrrol-3-ylmethyl)quinazolin-4-amine

[0260] [Chemical Formula 15]

[0261]

[0262] Using 2,4-dichloro-6,7-dimethoxyquinazoline (204 mg, 0.787 mmol) and (1H-pyrrol-3-yl)methylamine (72.3 μL, 0.827 mmol), the same operation as in Example 1 was carried out, and thus the title compound (208 mg, yield 83%) was obtained as a light brown solid.

[0263] (Example 8) 2-Chloro-N-(furan-3-ylmethyl)-6,7-dimethoxyquinazolin-4-amine

[0264] [Chemical Formula 16]

[0265]

[0266] Using 2,4-dichloro-6,7-dimethoxyquinazoline (203 mg, 0.784 mmol) and 3-(aminomethyl)furan hydrochloride (110 mg, 0.823 mmol), the same operation as in Example 1 was carried out, and thus the title compound (220 mg, yield 88%) was obtained as a light green solid.

[0267] (Example 9) 2-Chloro-6,7-dimethoxy-N-(pyridin-2-ylmethyl)quinazolin-4-amine

[0268] [Chemical Formula 17]

[0269]

[0270] Using 2,4-dichloro-6,7-dimethoxyquinazoline (204 mg, 0.787 mmol) and 2-aminomethylpyridine (83.6 μL, 0.827 mmol), the same procedure as in Example 1 was carried out, whereby the title compound was obtained as a pale white solid (231 mg, yield 89%).

[0271] (Example 10) 2-Chloro-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine

[0272] [Chemical Formula 18]

[0273]

[0274] Using 2,4-dichloro-7-methoxyquinazoline (118 mg, 0.515 mmol) and furfurylamine (48.0 μL, 0.515 mmol), the same procedure as in Example 1 was carried out, whereby the title compound was obtained as a pale white solid (149 mg, yield 100%).

[0275] (Example 11) 2-Chloro-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine

[0276] [Chemical Formula 19]

[0277]

[0278] Using 2,4-dichloro-6-methoxyquinazoline (101 mg, 0.441 mmol) and furfurylamine (43.0 μL, 0.463 mmol), the same procedure as in Example 1 was carried out, whereby the title compound was obtained as a white solid (127 mg, yield 99%).

[0279] (Example 12) 2-Chloro-N-(furan-2-ylmethyl)-7-methoxyquinolin-4-amine

[0280] [Chemical Formula 20]

[0281]

[0282] To a solution of 2,4-dichloro-7-methoxyquinoline (97.8 mg, 0.429 mmol) in NMP (1 mL) were added furfurylamine (44.0 μL, 0.472 mmol) and N,N-diisopropylethylamine (149 μL, 0.858 mmol), and the mixture was stirred at 120 °C for 11 h. After the reaction mixture was cooled to room temperature naturally, water (7 mL) was added and the mixture was extracted with ethyl acetate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 100 to 20 / 80) to give the title compound as a yellow solid (25.1 mg, yield 20%). 4-Chloro-N-(furan-2-ylmethyl)-7-methoxyquinolin-2-amine as a positional isomer was also obtained as a yellow solid (14.6 mg, yield 12%).

[0283] (Example 13) 2-Chloro-N-(furan-2-ylmethyl)-6-methoxyquinolin-4-amine

[0284] [Chemical formula 21]

[0285]

[0286] Using furfurylamine (42.0 μL, 0.455 mmol) for a solution of 2,4-dichloro-6-methoxyquinoline (94.4 mg, 0.414 mmol) in NMP (1 mL), the same procedure as in Example 12 was carried out to give the title compound as a yellow solid (19.5 mg, yield 16%).

[0287] (Example 14) 2-Chloro-6-ethoxy-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine

[0288] [Chemical formula 22]

[0289]

[0290] (Example 14-1) 2-Chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol

[0291] [Chemical formula 23]

[0292]

[0293] To a solution of 2,4-dichloro-7-methoxyquinazolin-6-yl acetate (8.00 g, 27.9 mmol) in acetonitrile (120 mL) reported by Tetrahedron, 2005, 61, 9375 - 9380 was added furfurylamine (27.1 g, 279 mmol), and the mixture was stirred at room temperature for 17 h. 5% Aqueous citric acid solution (550 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and air-dried. The obtained brown solid was purified by silica gel column chromatography (C18, water / methanol = 70 / 30 - 40 / 60) to give the title compound (8.22 g, 96% yield) as a white solid.

[0294] (Example 14-2) 2-Chloro-6-ethoxy-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine

[0295] [Chemical formula 24]

[0296]

[0297] To a solution of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (150 mg, 0.491 mmol) obtained in Example 14-1 in DMF (3 mL) were added potassium carbonate (136 mg, 0.981 mmol) and iodoethane (47.1 μL, 0.589 mmol), and the mixture was stirred at room temperature for 4 h. Water (30 mL) was added to the reaction mixture and stirred for 20 min, and then the precipitated solid was collected by filtration, washed with water, and dried to give the title compound (141 mg, 86% yield) as a yellowish-white solid.

[0298] (Example 15) 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-propoxyquinazolin-4-amine

[0299] [Chemical formula 25]

[0300]

[0301] To a solution of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (150 mg, 0.491 mmol) obtained in Example 14-1 in DMF (3 mL) were added potassium carbonate (136 mg, 0.981 mmol) and iodopropane (57.2 μL, 0.589 mmol), and the mixture was stirred at room temperature for 4 h. Water (30 mL) was added to the reaction mixture and stirred for 40 min, and then the precipitated solid was collected by filtration, washed with water, and dried to give the title compound (126 mg, 74% yield) as a yellowish-white solid.

[0302] (Example 16) 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(propan-2-yloxy)quinazolin-4-amine

[0303] [Chemical Formula 26]

[0304]

[0305] To a DMF solution (3 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (200 mg, 0.654 mmol) obtained in Example 14-1 was added potassium carbonate (181 mg, 1.31 mmol) and 2-iodopropane (78.1 μL, 0.786 mmol), and the mixture was stirred at room temperature for 22 hours. Water (30 mL) was added to the reaction solution and stirred, and the precipitated solid was collected by filtration, washed with water and dried, whereby the title compound (193 mg, yield 85%) was obtained as a white solid.

[0306] (Example 17) 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-amine

[0307] [Chemical Formula 27]

[0308]

[0309] To a DMF solution (3 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (200 mg, 0.654 mmol) obtained in Example 14-1 was added potassium carbonate (181 mg, 1.31 mmol) and 2-bromoethyl methyl ether (74.4 μL, 0.786 mmol), and the mixture was stirred at room temperature for 21 hours. Water (30 mL) was added to the reaction solution and stirred, and the precipitated solid was collected by filtration, washed with water and dried, whereby the title compound (211 mg, yield 89%) was obtained as a white solid.

[0310] (Example 18) 2-Chloro-6-(cyclopropylmethoxy)-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine

[0311] [Chemical Formula 28]

[0312]

[0313] To a solution of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (200 mg, 0.654 mmol) obtained in Example 14-1 in DMF (3 mL) were added potassium carbonate (181 mg, 1.31 mmol) and iodomethylcyclopropane (73.2 μL, 0.786 mmol), and the mixture was stirred at room temperature for 23 hours. Water (30 mL) was added to the reaction mixture and stirred, and the precipitated solid was collected by filtration, washed with water and dried to obtain the title compound (193 mg, yield 82%) as a white solid.

[0314] (Example 19) 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(oxetan-3-ylmethoxy)quinazolin-4-amine

[0315] [Chemical formula 29]

[0316]

[0317] To a solution of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (200 mg, 0.654 mmol) obtained in Example 14-1 in DMF (3 mL) were added potassium carbonate (181 mg, 1.31 mmol) and 3-bromomethyloxetane (75.6 μL, 0.786 mmol), and the mixture was stirred at room temperature for 24 hours. Water (30 mL) was added to the reaction mixture and stirred, and the precipitated solid was collected by filtration, washed with water and dried to obtain a crude pure product. It was purified by silica gel column chromatography (C18, water / methanol = 70 / 30 to 30 / 70) to obtain the title compound (163 mg, yield 66%) as a white solid.

[0318] (Example 20) 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[2-(morpholin-4-yl)ethoxy]quinazolin-4-amine

[0319] [Chemical formula 30]

[0320]

[0321] To a toluene solution (5 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (200 mg, 0.654 mmol) obtained in Example 14-1 was added 4-(2-hydroxyethyl)morpholine (160 μL, 1.31 mmol) and cyanomethylenetributylphosphorane (344 μL, 1.31 mmol), and the mixture was stirred at 80 °C for 3 hours. To the reaction solution were added 4-(2-hydroxyethyl)morpholine (40.0 μL, 0.327 mmol) and cyanomethylenetributylphosphorane (85.9 μL, 0.327 mmol), and the mixture was further stirred at 80 °C for 17 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (C18, 0.1% aqueous trifluoroacetic acid / methanol = 70 / 30 to 40 / 60). The fraction containing the target product was collected, neutralized with saturated aqueous sodium hydrogen carbonate, concentrated, the precipitated solid was collected by filtration, and dried to obtain the title compound (73.6 mg, yield 27%) as an off-white solid.

[0322] (Example 21) 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine

[0323] [Chemical formula 31]

[0324]

[0325] To a toluene solution (5 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (200 mg, 0.654 mmol) obtained in Example 14-1 was added 4-(3-hydroxypropyl)morpholine (182 μL, 1.31 mmol) and cyanomethylenetributylphosphorane (344 μL, 1.31 mmol), and the mixture was stirred at 80 °C for 3 hours. To the reaction solution were added 4-(3-hydroxypropyl)morpholine (45.4 μL, 0.327 mmol) and cyanomethylenetributylphosphorane (85.9 μL, 0.327 mmol), and the mixture was further stirred at 80 °C for 17 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (C18, 0.1% aqueous trifluoroacetic acid / methanol = 70 / 30 to 40 / 60). The fraction containing the target product was collected, neutralized with saturated aqueous sodium hydrogen carbonate, concentrated, 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 (NH, ethyl acetate) to obtain the title compound (76.2 mg, yield 27%) as an off-white solid.

[0326] (Example 22) 2-Chloro-6-[2-(1,1-dioxidosulfolan-3-yl)ethoxy]-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine

[0327] [Chemical Formula 32]

[0328]

[0329] To a DMF solution (3 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (150 mg, 0.491 mmol) obtained in Example 14-1 was added potassium carbonate (136 mg, 0.981 mmol) and 3-(2-bromoethyl)-1,1-dioxidosulfolane (126 mg, 0.591 mmol), and the mixture was stirred at room temperature for 24 hours. Water (30 mL) was added to the reaction solution and stirred for 30 minutes, and then the precipitated solid was collected by filtration, washed with water and dried, whereby the title compound (185 mg, yield 86%) was obtained as a pale yellow solid.

[0330] (Example 23) 6-(2-Aminoethoxy)-2-chloro-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine

[0331] [Chemical Formula 33]

[0332]

[0333] To a DMF solution (3 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (200 mg, 0.654 mmol) obtained in Example 14-1 was added potassium carbonate (181 mg, 1.31 mmol) and 2-(tert-butoxycarbonylamino)ethyl bromide (176 mg, 0.786 mmol), and the mixture was stirred at room temperature for 19 hours. Water (30 mL) was added to the reaction solution and stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4N Hydrochloric acid-ethyl acetate (8 mL) was added to an ethyl acetate solution (2 mL) of the obtained brown oil, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, water / methanol (1 / 1, 10 mL) was added to the obtained pale yellow solid to make a solution, and then neutralized with saturated aqueous sodium bicarbonate solution. After extraction 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 (C18, water / acetonitrile = 80 / 20 to 0 / 100) and then freeze-dried, whereby the title compound (107 mg, yield 47%) was obtained as a white solid.

[0334] (Example 24) 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[2-(methylamino)ethoxy]quinazolin-4-amine

[0335] [Chemical Formula 34]

[0336]

[0337] To a toluene solution (5 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (200 mg, 0.654 mmol) obtained in Example 14-1 were added tert-butyl (2-hydroxyethyl)(methyl)carbamate (172 mg, 0.982 mmol) and cyanomethylenetributylphosphorane (515 μL, 1.96 mmol), and the mixture was stirred at 80 °C for 2.5 hours. Cyanomethylenetributylphosphorane (515 μL, 1.96 mmol) was added to the reaction solution, and after further stirring at 80 °C for 1 hour, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (C18, water / methanol = 70 / 30 to 20 / 80) to obtain 247 mg of a pale yellow oil. To its methanol solution (5 mL) was added 4N hydrochloric acid-ethyl acetate (5 mL), and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium bicarbonate was added to the resulting white solid, and the mixture was extracted with ethyl acetate containing 10% THF, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (C18, water / methanol = 70 / 30 to 0 / 100), and the resulting crude purified product was purified again by silica gel column chromatography (C18, 0.1% aqueous trifluoroacetic acid / methanol = 80 / 20 to 40 / 60). The fractions containing the target product were concentrated, neutralized with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Water was added to a methanol solution of the resulting residue, and the precipitated solid was collected by filtration, washed with water, and dried to obtain the title compound (69.0 mg, yield 29%) as a slightly reddish-white solid.

[0338] (Example 25) 2-Chloro-6-[2-(dimethylamino)ethoxy]-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine

[0339] [Chemical Formula 35]

[0340]

[0341] To a solution of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (200 mg, 0.654 mmol) obtained in Example 14-1 in THF (4 mL) were added potassium carbonate (272 mg, 1.97 mmol) and 2-bromo-N,N-dimethylethylamine hydrobromide (183 mg, 0.786 mmol), and the mixture was stirred at room temperature for 3 hours. Potassium carbonate (91.0 mg, 0.658 mmol) and 2-bromo-N,N-dimethylethylamine hydrobromide (61.0 mg, 0.262 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hours. 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 sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH, ethyl acetate), and lyophilized to obtain the title compound (144 mg, yield 59%) as a white solid.

[0342] (Example 26) 2-({2-Chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)ethanol

[0343] [Chemical formula 36]

[0344]

[0345] To a solution of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (200 mg, 0.654 mmol) obtained in Example 14-1 in DMF (3 mL) were added potassium carbonate (181 mg, 1.31 mmol) and 2-bromoethanol (55.6 μL, 0.785 mmol), and the mixture was stirred at room temperature for 3 hours. 2-Bromoethanol (23.1 μL, 0.326 mmol) was added to the reaction mixture, and then potassium carbonate (181 mg, 1.31 mmol) and 2-bromoethanol (55.6 μL, 0.785 mmol) were added after 17 hours and 40 hours, and the mixture was stirred for a total of 44 hours. Water (100 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration. The resulting solid was purified by silica gel column chromatography (C18, water / methanol = 70 / 30 to 30 / 70) to obtain the title compound (133 mg, yield 58%) as a white solid.

[0346] (Example 27) 2-Chloro-6-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine

[0347] [Chemical formula 37]

[0348]

[0349] To a toluene solution (3 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (100 mg, 0.327 mmol) obtained in Example 14-1 were added (1,4-dioxan-2-yl)methanol (69.3 μL, 0.655 mmol) and cyanomethylenetributylphosphorane (172 μL, 0.654 mmol), and the mixture was stirred at 80 °C for 4 hours. Cyanomethylenetributylphosphorane (172 μL, 0.654 mmol) was added to the reaction mixture, and the mixture was further stirred at 80 °C for 3 hours. The reaction mixture was allowed to cool to room temperature naturally and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane = 50 / 50), and then purified by silica gel column chromatography (C18, water / methanol = 70 / 30 to 30 / 70) and silica gel column chromatography (ethyl acetate / hexane = 25 / 75 to 50 / 50), and again purified by silica gel column chromatography (C18, water / methanol = 70 / 30 to 30 / 70), whereby the title compound was obtained as a pale white solid (80.6 mg, yield 61%).

[0350] (Example 28) 3-({2-Chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)propanoic acid

[0351] [Chemical Formula 38]

[0352]

[0353] To a DMF solution (8 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (600 mg, 1.96 mmol) obtained in Example 14-1 were added potassium carbonate (814 mg, 5.89 mmol) and 3-bromopropanoic acid (360 mg, 2.36 mmol), and the mixture was stirred at room temperature for 16 hours. Potassium carbonate (271 mg, 1.96 mmol) and 3-bromopropanoic acid (300 mg, 1.96 mmol) were added to the reaction mixture, and the mixture was further stirred for 6 hours. Water (20 mL) and methanol (20 mL) were added to the reaction mixture and stirred for 16 hours, and then the reaction mixture was concentrated under reduced pressure. Citric acid was added to the resulting residue to adjust the pH to 4 - 5, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and 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 = 50 / 50 to 100 / 0), and the title compound was obtained as a white solid (213 mg, yield 29%).

[0354] (Example 29) Methyl 3-({2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)propanoate

[0355] [Chemical Formula 39]

[0356]

[0357] 3-({2-Chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)propanoic acid (100 mg, 0.265 mmol) obtained in Example 28 was added to a methanol solution (10 mL) of thionyl chloride (28.3 μL, 0.397 mmol) cooled to -18 °C, and the mixture was stirred for 10 minutes and then stirred at 50 °C for 1 hour. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. Methanol (3 mL) was added to the obtained residue, and saturated aqueous sodium bicarbonate solution was added, and the precipitated pale yellow solid was collected by filtration. The obtained crude purified product was purified by silica gel column chromatography (C18, water / methanol = 70 / 30 to 30 / 70) to obtain the title compound (73.2 mg, yield 71%) as a white solid.

[0358] (Example 30) Methyl ({2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)acetate

[0359] [Chemical Formula 40]

[0360]

[0361] Potassium carbonate (181 mg, 1.31 mmol) and methyl bromoacetate (72.3 μL, 0.786 mmol) were added to a DMF solution (3 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-ol (200 mg, 0.654 mmol) obtained in Example 14-1, and the mixture was stirred at room temperature for 4 hours. 5% Aqueous citric acid solution (30 mL) was added to the reaction solution, and the precipitated solid was collected by filtration. The obtained crude purified product was purified by silica gel column chromatography (C18, 0.1% aqueous trifluoroacetic acid solution / methanol = 70 / 30 to 30 / 70). Saturated aqueous sodium bicarbonate solution was added to the fraction of the target product for neutralization, and then concentrated. The precipitated solid was collected by filtration, washed with water and dried, thereby obtaining the title compound (161 mg, yield 65%) as a white solid.

[0362] (Example 31) 7-(2-Aminoethoxy)-2-chloro-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine

[0363] [Chemical Formula 41]

[0364]

[0365] (Example 31-1) 2-Chloro-4-[(furan-2-ylmethyl)amino]-6-methoxyquinazolin-7-ol

[0366] [Chemical Formula 42]

[0367]

[0368] To a solution of 7-(benzyloxy)-2,4-dichloro-6-methoxyquinazoline (8.50 g, 25.4 mmol) in THF (140 mL) were added furfurylamine (2.96 g, 30.5 mmol) and triethylamine (3.08 g, 30.4 mmol), and the mixture was stirred at 60 °C for 6 hours. Water (280 mL) was added to the reaction mixture, and the organic solvent was concentrated under reduced pressure. The precipitated solid was collected by filtration and dried to obtain 7-(benzyloxy)-2-chloro-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine (9.94 g, yield 99%) as a greenish-white solid. To a solution of the obtained 7-(benzyloxy)-2-chloro-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine (9.84 g, 24.9 mmol) in THF (200 mL) at 0 °C was added 10% Pd / alumina (2.46 g), and the mixture was stirred under a hydrogen atmosphere for 15 hours. The reaction mixture was filtered through diatomaceous earth, and the solid was washed with methanol and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 2 to ethyl acetate / hexane / THF = 4 / 5 / 1), and the obtained crude purified product was further purified by silica gel column chromatography (C18, water / methanol = 70 / 30 to 35 / 65) to obtain the title compound (5.17 g, yield 68%) as a pale yellow solid.

[0369] (Example 31-2) 7-(2-Aminoethoxy)-2-chloro-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine

[0370] [Chemical Formula 43]

[0371]

[0372] To a DMF solution (3 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-6-methoxyquinazolin-7-ol (200 mg, 0.654 mmol) obtained in Example 31-1 was added potassium carbonate (181 mg, 1.31 mmol) and 2-(tert-butoxycarbonylamino)ethyl bromide (176 mg, 0.785 mmol), and the mixture was stirred at room temperature for 24 hours. 5% Aqueous citric acid solution (30 mL) 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 sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (C18, water / methanol = 70 / 30 to 30 / 70) to obtain a yellow oil. To an ethyl acetate solution (2 mL) of the yellow oil obtained herein was added 4N hydrochloric acid-ethyl acetate (8 mL), and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (C18, 0.1% aqueous trifluoroacetic acid / methanol = 70 / 30 to 30 / 70). The fraction of the target product was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the resulting 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 dissolved in a mixed solvent of acetonitrile / water and freeze-dried to obtain the title compound (155 mg, yield 68%) as a white solid.

[0373] (Example 32) 2-Chloro-N-(furan-2-ylmethyl)-6-methoxy-7-[2-(methylamino)ethoxy]quinazolin-4-amine

[0374] [Chemical formula 44]

[0375]

[0376] To a toluene solution (5 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-6-methoxyquinazolin-7-ol (200 mg, 0.654 mmol) obtained in Example 31-1 were added (2-hydroxyethyl)(methyl)tert-butyl carbonate (172 mg, 0.982 mmol) and cyanomethylenetributylphosphorane (515 μL, 1.96 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 (C18, water / methanol = 70 / 30 to 20 / 80) to obtain a pale yellow solid. To a methanol solution (15 mL) of the obtained solid was added 4N hydrochloric acid-ethyl acetate (15 mL), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (C18, 0.1% aqueous trifluoroacetic acid / methanol = 80 / 20 to 50 / 50). After the fraction of the target product was concentrated under reduced pressure, it was freeze-dried. Water was added to the obtained pale yellow solid to make an aqueous solution, and saturated sodium bicarbonate aqueous solution was added for neutralization. The precipitated solid was collected by filtration and dried, whereby the title compound (164 mg, yield 69%) was obtained as an off-white solid.

[0377] (Example 33) 2-Chloro-7-ethoxy-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine

[0378] [Chemical formula 45]

[0379]

[0380] To a DMF solution (3 mL) of 2-chloro-4-[(furan-2-ylmethyl)amino]-6-methoxyquinazolin-7-ol (150 mg, 0.491 mmol) obtained in Example 31-1 were added potassium carbonate (136 mg, 0.984 mmol) and iodoethane (47.1 μL, 0.589 mmol), and the mixture was stirred at room temperature for 5 hours. Water (30 mL) was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water and dried, whereby the title compound (156 mg, yield 95%) was obtained as an off-white solid.

[0381] The structural formulas and physicochemical data of the compounds described in Examples 1 to 33 are shown below.

[0382] Table 1

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389] [Confirmation of the inhibitory effect on splicing abnormalities (exon skipping) caused by the IVS20+6T>C mutation]

[0390] Prepare the SPREADD reporter system for the splicing mutation of the IKBKAP gene in familial dysautonomia as shown in Figure 1 . In this reporter system, GFP is expressed under normal splicing, while RFP is expressed under abnormal splicing (exon skipping).

[0391] Contact the HeLa cells transfected with the prepared SPREADD reporter construct with the compounds shown in Table 2 below and culture them (concentrations: 22.86237 nM, 68.58711 nM, 205.7613 nM, 617.284 nM, 1851.852 nM, 5555.556 nM, 16666.67 nM, or 50000 nM). After 1 day, measure the fluorescence with an All-in-One Fluorescence Microscope BZ-X700 (Keyence), and quantify the IKBKAP-FD exon 20 encapsulation rate using the GFP / RFP ratio of the IKBKAP-FD reporter. The 50% effective concentration (EC 50 ) is shown in Table 2 below. Regarding EC 50 , the %GFP of 2-chloro-6-(2-furanylmethyl)purine at 20 μM is determined as 100%. The regression analysis for determining EC 50 is performed using GraphPad Prism 7.05.

[0392] Table 2

[0393]

[0394] The expression level of GFP of the above compounds is higher than that of RFP, and the inhibitory effect on abnormal splicing (exon skipping) caused by the IVS20 +6T>C mutation is confirmed.

[0395] Compounds with a higher inhibitory effect on abnormal splicing are obtained as shown in Table 2 compared to the known compound (2-chloro-6-(2-furanylmethyl)purine) that can correct abnormal splicing and treat FD.

Claims

1. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof: [Chemical formula 1] In formula (I), A is CH or N, R 1 is a halogen atom, R 2 and R 3 each independently selected from the group consisting of a hydrogen atom, -OR 4 , -O(CH 2 ) t R 5 and -O(CH 2 ) t C(O)R 5 wherein at least one of R 2 and R 3 is -OR 4 , -O(CH 2 ) t R 5 or -O(CH 2 ) t C(O)R 5 , and t is 1, 2, 3 or 4 R 4 is a hydrogen atom or a C 1 -C 6 alkyl group R 5 selected from the group consisting of C 3 -C 6 cycloalkyl, a 4- to 10-membered heterocyclic group, -NR 6 R 7 and -OR 6 and the group consisting of R 6 and R 7 each independently represents a hydrogen atom or a C 1 -C 3 alkyl group Ar is selected from the group consisting of 5- to 10-membered heteroaryl groups and 6- to 12-membered aryl groups, and the 5- to 10-membered heteroaryl groups and 6- to 12-membered aryl groups may have one or more substituents.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 3 is methoxy, i.e., -OCH 3 .

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Ar is furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl or pyridyl.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein, R 2 selected from the group consisting of a hydrogen atom, -OR 4 , -O(CH 2 ) t R 5 and -O(CH 2 ) t C(O)R 5 ; R 4 is C 1 -C 3 alkyl, R 5 is -NR 6 R 7 , -OH, methyl, cyclopropyl, oxetanyl, morpholinyl, 1,1-dioxo-thietanyl or dioxolanyl, R 6 and R 7 each independently represents a hydrogen atom or a methyl group, t is 1 or 2.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Ar is 2-furyl, R 2 is a hydrogen atom, -O(CH 2 ) 2 CH 3 , -OCH 2 R 5 or -O(CH 2 ) 2 R 5 , where R 5 is -NR 6 R 7 , -OH or oxetanyl, and R 6 and R 7 are each independently a hydrogen atom or a methyl group. R 3 is methoxy, i.e., -OCH 3 .

6. Any compound selected from the following group or a pharmaceutically acceptable salt thereof: 2-chloro-N-(furan-2-ylmethyl)-6,7-dimethoxyquinazolin-4-amine, 2-chloro-6,7-dimethoxy-N-(thiophen-2-ylmethyl)quinazolin-4-amine, 2-chloro-6,7-dimethoxy-N-(thiophen-3-ylmethyl)quinazolin-4-amine, 2-chloro-6,7-dimethoxy-N-(1,3-thiazol-2-ylmethyl)quinazolin-4-amine, 2-chloro-6,7-dimethoxy-N-(pyridin-4-ylmethyl)quinazolin-4-amine, 2-chloro-6,7-dimethoxy-N-(1,3-oxazol-2-ylmethyl)quinazolin-4-amine, 2-chloro-6,7-dimethoxy-N-(1H-pyrrol-3-ylmethyl)quinazolin-4-amine, 2-chloro-N-(furan-3-ylmethyl)-6,7-dimethoxyquinazolin-4-amine, 2-chloro-6,7-dimethoxy-N-(pyridin-2-ylmethyl)quinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-7-methoxyquinolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-6-methoxyquinolin-4-amine, 2-chloro-6-ethoxy-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine, 2-chloro-6-ethoxy-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-7-methoxy-6-propoxyquinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(propan-2-yloxy)quinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-amine, 2-chloro-6-(cyclopropylmethoxy)-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine, 2-chloro-N-(furan-2-ylmethyl)-7-methoxy-6-(oxetan-3-ylmethoxy)quinazolin-4-amine, 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[2-(morpholin-4-yl)ethoxy]quinazolin-4-amine, 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine, 2-Chloro-6-[2-(1,1-dioxothietan-3-yl)ethoxy]-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine, 6-(2-Aminoethoxy)-2-chloro-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine, 2-Chloro-N-(furan-2-ylmethyl)-7-methoxy-6-[2-(methylamino)ethoxy]quinazolin-4-amine, 2-Chloro-6-[2-(dimethylamino)ethoxy]-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine, 2-({2-Chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)ethanol, 2-Chloro-6-(1,4-dioxan-2-ylmethoxy)-N-(furan-2-ylmethyl)-7-methoxyquinazolin-4-amine, 3-({2-Chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)propanoic acid, Methyl 3-({2-Chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)propanoate, Methyl ({2-Chloro-4-[(furan-2-ylmethyl)amino]-7-methoxyquinazolin-6-yl}oxy)acetate, 7-(2-Aminoethoxy)-2-chloro-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine, 2-Chloro-4-[(furan-2-ylmethyl)amino]-6-methoxyquinazolin-7-ol, 2-Chloro-N-(furan-2-ylmethyl)-6-methoxy-7-[2-(methylamino)ethoxy]quinazolin-4-amine, 2-Chloro-7-ethoxy-N-(furan-2-ylmethyl)-6-methoxyquinazolin-4-amine.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.

8. A pharmaceutical composition for treating a genetic disease caused by splicing abnormality, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. A pharmaceutical composition for treating a genetic disease caused by splicing abnormality, comprising the compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical formula 2] In formula (I), A is CH or N, R 1 is a halogen atom, R 2 and R 3 each independently selected from the group consisting of a hydrogen atom, -OR 4 , -O(CH 2 ) t R 5 and -O(CH 2 ) t C(O)R 5 , at least one of R 2 and R 3 is -OR 4 , -O(CH 2 ) t R 5 or -O(CH 2 ) t C(O)R 5 , t is 1, 2, 3 or 4, R 4 is a hydrogen atom or a C 1 -C 6 alkyl group R 5 selected from the group consisting of C 3 -C 6 cycloalkyl, a 4- to 10-membered heterocyclic group, -NR 6 R 7 and -OR 6 and the group consisting of R 6 and R 7 each independently represents a hydrogen atom or a C 1 -C 3 alkyl group Ar is selected from the group consisting of 5- to 10-membered heteroaryl and 6- to 12-membered aryl, and the 5- to 10-membered heteroaryl and 6- to 12-membered aryl may have one or more substituents.

10. The pharmaceutical composition according to claim 9, wherein, Ar is 2-furyl, R 2 is a hydrogen atom, -O(CH 2 ) 2 CH 3 , -OCH 2 R 5 or -O(CH 2 ) 2 R 5 , where R 5 is -NR 6 R 7 , -OH or oxetanyl, and R 6 and R 7 are each independently a hydrogen atom or a methyl group, R 3 is methoxy, i.e., -OCH 3 .

11. The pharmaceutical composition according to claim 9 or 10, wherein, The genetic disease caused by splicing abnormality is familial dysautonomia or congenital long QT syndrome.

12. A method for treating a genetic disease caused by splicing abnormality, which comprises administering to a subject the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

13. The method according to claim 12, wherein, the genetic disease caused by splicing abnormality is familial dysautonomia or congenital long QT syndrome.

14. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in the manufacture of a pharmaceutical composition for treating a genetic disease caused by splicing abnormality.

15. The use according to claim 14, wherein, the genetic disease caused by splicing abnormality is familial dysautonomia or congenital long QT syndrome.

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