Dihydroquinazolinone derivative

Abstract

The present invention provides a compound that has DYRK-inhibiting activity and that is useful as a drug. Specifically, the present invention provides a dihydroquinazolinone derivative represented by formula (I) (in the formula, R1, R2, R3, R4, R5, and Q are as defined in the description), or a pharmaceutically acceptable salt thereof.

Description

Dihydroquinazolinone derivatives

[0001] The present invention relates to a pharmaceutical, particularly to a novel dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof having a DYRK inhibitory activity.

[0002] DYRK (dual-specificity tyrosine-phosphorylation regulated protein kinase) is a type of dual-specificity protein kinase that phosphorylates tyrosine, serine, and threonine. DYRK functions as a tyrosine kinase only in the case of autophosphorylation, but catalyzes the phosphorylation of exogenous substrates at serine or threonine residues. Five members of the DYRK family are known in humans: DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4 (Non-Patent Document 1). In this specification, "DYRK" refers to one or more of these DYRK family members (DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4). DYRK1A has been reported to be associated with many neuropsychiatric disorders. For example, in Alzheimer's disease patients, the expression of β-amyloid and DYRK1A expression are significantly correlated (Non-Patent Document 2). Furthermore, DYRK1A is speculated to be involved in the abnormal phosphorylation of tau protein (Tau), which is believed to be one of the causes of Alzheimer's disease (Non-Patent Document 3). Parkinson's disease is a neurodegenerative disease caused by the degeneration of dopamine neurons, which are important for motor function, and mitochondrial dysfunction is thought to be one of the causes (Non-Patent Document 4). Parkin, an enzyme involved in protein degradation, is known to metabolize abnormal mitochondria and suppress their abnormal accumulation, and DYRK1A has been reported to suppress the activity of this parkin protein (Non-Patent Document 5). The DYRK1A gene is located in the critical region for Down syndrome, and it has been reported that mice overexpressing DYRK1A exhibit abnormal neuropsychiatric functions and exhibit Down syndrome-like behavior (Non-Patent Document 6). It has also been reported that DYRK1A expression is elevated in the brains of Down's syndrome patients and Down's syndrome-like model mice (Non-Patent Document 7). These findings suggest that DYRK1A is involved in the onset of neurological symptoms in Down's syndrome patients (Non-Patent Document 8). Furthermore, it has been reported that early-onset Alzheimer's disease is frequently observed in Down's syndrome patients, indicating that DYRK1A is closely related to Alzheimer's disease (Non-Patent Document 8).Therefore, compounds that inhibit DYRK1A are believed to be useful in the treatment of neuropsychiatric disorders such as Alzheimer's disease, Down's syndrome, mental retardation, memory impairment, memory loss, and Parkinson's disease.

[0003] Recently, it has been reported that DYRK1A is highly expressed in brain tumors such as glioblastoma and that DYRK1A regulates the expression of epidermal growth factor receptor (EGFR) (Non-Patent Document 9). Therefore, compounds that inhibit DYRK1A are thought to suppress cancer cell proliferation in EGFR-dependent brain tumors and other tumors and be useful for the treatment of EGFR-dependent cancers. Furthermore, compounds that inhibit the family enzymes DYRK1B, DYRK2, and DYRK3 are also thought to have various pharmaceutical uses. For example, it has been reported that DYRK1B is highly expressed in cancer cells in the dormant phase (GO phase) and contributes to resistance to various chemotherapeutic agents (Non-Patent Document 10). It has also been reported that inhibition of DYRK1B promotes exit from the GO phase and improves sensitivity to chemotherapeutic agents (Non-Patent Document 11). Therefore, compounds that inhibit DYRK1B are thought to be useful in the treatment of pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, and lung cancer (Non-Patent Documents 11, 12, 13, 14, 15). DYRK2 has been suggested to regulate p53 and induce apoptosis in response to DNA damage (Non-Patent Document 16). Furthermore, compounds that inhibit DYRK3 have been reported to be useful in the treatment of sickle cell anemia and chronic kidney disease (Non-Patent Document 17). While compounds containing a benzothiazole ring have been reported as DYRK inhibitors (Patent Documents 1 to 5), no mention has been made of derivatives containing the dihydroquinazolinone skeleton of the present invention.

[0004] WO2021 / 153665 publication WO2022 / 059778 publication WO2022 / 059779 publication WO2023 / 008470 publication WO2023 / 008472 publication

[0005] BeckerW. et al. , J. Biol. Chem. , 1998, 273, 25893-25902 Kimura R. et al. , Hum. Mol. Genet. , 2007, 16, 15-23 Ryoo SR. et al. , J. Biol. Chem. , 2007, 282, 34850-34857 Narendra D. et al. , J. Cell. Biol. , 2008, 183, 795-803 Im E. , J. Neurochem. , 2015, 134, 756-768 Branchi I. et al. , J. Neuropathol. Exp. Neurol. , 2004, 63, 429-440 Dowjat WK. et al. , Neurosci. Lett. , 2007, 413, 77-81 Wegiel J. et al. , FEBS J. , 2011, 278, 236-245 Pozo N. et al. , J. Clin. Invest. , 2013, 123, 2475-2487. Deng X. et al. , Cancer Res. , 2006, 66, 4149-4158. Ewton DZ. et al. , Mol. Cancer Ther. , 2011, 10, 2104-2114. Deng X. et al. , Genes Cancer. , 2014, 5, 201-211 Yang C. et al. , Carcinogenesis. , 2010, 31, 552-558 Jin K. et al. , J. Biol. Chem. , 2009, 284, 22916-22925 Gao J et al. , Cancer Cell Int. 2013,13,2Taira N. et al. , Mol. Cell. , 2007, 25, 725-738 Bogacheva O. et al. , J. Biol. Chem. , 2008, 283, 36665-36675

[0006] An object of the present invention is to provide a novel compound that has a DYRK inhibitory effect and is useful as a pharmaceutical.

[0007] The object of the present invention is achieved by the following (1) to (19): (1) A compound of the following formula (I): (In the formula, R １ , R ２ , R ３ and R４ each independently represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an acyl group, an optionally substituted non-aromatic heterocyclic group, a halogen atom, a cyano group, an optionally substituted alkylsulfonyl group, a nitro group, an optionally substituted amino group, an optionally substituted phenyl group, or an optionally substituted heteroaryl group; R ５ represents a hydrogen atom or a lower alkyl group, and Q represents the following structure (a), (b), or (c): or a pharmaceutically acceptable salt thereof.

[0008] (2) The dihydroquinazolinone derivative or pharmaceutically acceptable salt thereof according to (1) above, wherein Q in formula (I) is structure (a). (3) The dihydroquinazolinone derivative or pharmaceutically acceptable salt thereof according to (1) above, wherein Q in formula (I) is structure (b). (4) The dihydroquinazolinone derivative or pharmaceutically acceptable salt thereof according to (1) above, wherein Q in formula (I) is structure (c). (5) The dihydroquinazolinone derivative or pharmaceutically acceptable salt thereof according to formula (I) above, wherein R ５ (6) The dihydroquinazolinone derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (4), wherein R is a hydrogen atom. １ , R ２ , R ３ and R ４ (7) The dihydroquinazolinone derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5) above, wherein R is independently a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted non-aromatic heterocyclic group, a halogen atom, an optionally substituted amino group, or an optionally substituted heteroaryl group. １ and R ３(8) The dihydroquinazolinone derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (6), wherein R is a hydrogen atom. ２ is a fluorine atom, and R ４ is an optionally substituted cycloalkenyl group, an optionally substituted non-aromatic heterocyclic group, an optionally substituted amino group or an optionally substituted heteroaryl group, or a dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any of the above (1) to (7).

[0009] (9) The compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof, selected from the following compound group: 1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-5-(2,5-dihydrofuran-3-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (Example 4), (RS)-1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-7-fluoro-5-(tetrahydrofuran-3-yl)-3,4-dihydroquinazolin-2(1H)-one (Example 5), 1-(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (Example 6), 1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-5-(3,6-dihydro-2H-pyran-4-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (Example 97), (RS)-1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-7-fluoro-5-(4-hydroxycyclohex-1-en-1-yl)-3,4-dihydroquinazolin-2(1H)-one (Example 100), 1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2(1H)-one (Example 101), 5-(3,4-dihydro-2H-pyran-6-yl)-1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (Example 104), (RS)-1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-7-fluoro-5-(tetrahydro-2H-pyran-3-yl)-3,4-dihydroquinazolin-2(1H)-one (Example 114),1-(7,8-Dihydrobenzofuro[4,5-d]thiazol-2-yl)-7-fluoro-5-(3-oxocyclopent-1-en-1-yl)-3,4-dihydroquinazolin-2(1H)-one (Example 115), 1-(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one sulfate (Example 127), and 1-(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one hydrochloride (Example 128). (10) A medicament comprising, as an active ingredient, the dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (9) above. (11) A pharmaceutical composition comprising, as an active ingredient, the dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (9) above. (12) A therapeutic and / or prophylactic agent for a disease involving DYRK, comprising, as an active ingredient, the dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (9) above. (13) The therapeutic and / or prophylactic agent according to (12) above, wherein the disease in which DYRK is involved is frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down's syndrome, depression, and mental retardation, memory impairment, memory loss, learning disability, intellectual disability, cognitive impairment, mild cognitive impairment, or progression of dementia symptoms associated therewith, or the treatment of or prevention of the onset of dementia, or brain tumor, pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, lung cancer, bone resorption disease, osteoporosis, sickle cell anemia, chronic kidney disease, or bone resorption disease. (14) A method for treating and / or preventing a disease in which DYRK is involved, comprising administering to a patient in need of treatment a therapeutically effective amount of the dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (9) above.(15) Use of the dihydroquinazolinone derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (9) above for the manufacture of an agent for treating and / or preventing a disease involving DYRK. (16) The dihydroquinazolinone derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (9) above for use in the treatment and / or prevention of a disease involving DYRK. (17) A pharmaceutical comprising a combination of the pharmaceutical according to (10) above and at least one or more drugs selected from drugs classified as anticancer drugs, antipsychotic drugs, antidementia drugs, antiepileptic drugs, antidepressants, gastrointestinal drugs, thyroid hormone drugs, or antithyroid drugs. (18) The pharmaceutical agent according to (10) above, for treating frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down's syndrome, depression and complications associated therewith, mental retardation, memory impairment, memory loss, learning disability, intellectual disability, cognitive impairment, mild cognitive impairment, progression of dementia symptoms or prevention of the onset of dementia, or for treating brain tumor, pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, lung cancer, bone resorption disease, osteoporosis, sickle cell anemia, chronic kidney disease or bone resorption disease, in combination with at least one or more drugs selected from drugs classified as anticancer drugs, antipsychotic drugs, antidementia drugs, antiepileptic drugs, antidepressants, gastrointestinal drugs, thyroid hormone drugs or antithyroid drugs. (19) A method for producing tert-butyl intermediate [2-amino-6-(dimethylamino)-4-fluorobenzyl]carbamate, comprising the following steps 1 to 6: Step 1 is a step for producing methyl 2-(bromomethyl)-5-fluoro-3-nitrobenzoate by reacting methyl 5-fluoro-2-methyl-3-nitrobenzoate with N-bromosuccinimide and 1,1'-azobis(cyclohexane-1-carbonitrile) in a solvent; and Step 2 is a step for producing methyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoate by reacting the methyl 2-(bromomethyl)-5-fluoro-3-nitrobenzoate with di-tert-butyl iminodicarboxylate and cesium carbonate in a solvent.The third step is a step of producing 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoic acid by reacting the methyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoate with sodium hydroxide in a solvent; the fourth step is a step of producing tert-butyl (tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)4-fluoro-6-nitrobenzyl)carbamate by reacting the methyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoate with tert-butyl alcohol, diphenylphosphoryl azide, and TEA in a solvent; and the fifth step is a step of producing tert-butyl (tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)4-fluoro-6-nitrobenzyl)carbamate by reacting the methyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoate with tert-butyl alcohol, diphenylphosphoryl azide, and TEA in a solvent. a production method in which the first step is a step of reacting tert-butyl (2-((tert-butoxycarbonyl)amino)4-fluoro-6-nitrobenzyl)carbamate with palladium-activated carbon and paraformaldehyde to produce tert-butyl (tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)-6-(dimethylamino)-4-fluorobenzyl)carbamate, and the sixth step is a step of reacting the tert-butyl (tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)-6-(dimethylamino)-4-fluorobenzyl)carbamate with hydrochloric acid in a solvent, followed by reaction with di-tert-butyl dicarbonate to produce tert-butyl [2-amino-6-(dimethylamino)-4-fluorobenzyl]carbamate.

[0010] The present inventors conducted extensive research to solve the above-mentioned problems, and as a result, discovered that the dihydroquinazolinone derivatives represented by the above formula (I) and pharmaceutically acceptable salts thereof have excellent DYRK inhibitory activity, thereby completing the present invention. The compounds provided by the present invention are useful as therapeutic agents for diseases known to be associated with abnormal cellular responses mediated by DYRK1A, such as psychiatric and neurological disorders such as Alzheimer's disease, Parkinson's disease, Down's syndrome, and depression, as well as the mental retardation, memory impairment, amnesia, learning disabilities, intellectual disability, cognitive impairment, mild cognitive impairment, and dementia symptom progression or preventive agents for the onset of dementia, and also as pharmaceutical agents (pharmaceutical compositions) for the prevention or treatment of tumors such as brain tumors. The compounds provided by the present invention are useful as DYRK1B inhibitors and as pharmaceutical agents (pharmaceutical compositions) for the prevention or treatment of tumors such as pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, and lung cancer. Furthermore, the compounds provided by the present invention are useful as pharmaceutical compositions for preventing or treating bone resorption diseases and osteoporosis because they regulate p53 and induce apoptosis in response to DNA damage in DYRK2. Furthermore, the compounds provided by the present invention are useful as DYRK3 inhibitors and as pharmaceutical compositions for preventing or treating sickle cell anemia, chronic kidney disease, bone resorption diseases, and osteoporosis. Furthermore, as DYRK inhibitors, they are useful as reagents for pathological imaging of the above-mentioned diseases, as well as for basic experiments and research. Furthermore, the compounds provided by the present invention are useful because they inhibit DYRK with high selectivity over other kinases and can reduce side effects caused by inhibiting other kinases. Examples of such other kinases include CLK (Cdc2-like kinase), and high selectivity for CLK can be expected to reduce bone marrow, immune, and gastrointestinal toxicity.

[0011] The present invention will be described in detail below. The dihydroquinazolinone derivative of the present invention is represented by the following formula (I): (In the formula, R １ , R ２ , R ３ and R ４each independently represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an acyl group, an optionally substituted non-aromatic heterocyclic group, a halogen atom, a cyano group, an optionally substituted alkylsulfonyl group, a nitro group, an optionally substituted amino group, an optionally substituted phenyl group, or an optionally substituted heteroaryl group; R ５ represents a hydrogen atom or a lower alkyl group, and Q represents the following structure (a), (b), or (c): It is a compound represented by the formula:

[0012] The term "lower alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms (C １ - ６ As the lower alkyl group, "C １ - ４ alkyl group," and more preferably "C １ - ３ Specific examples of the "lower alkyl group" include a methyl group, an ethyl group, an n-propyl group, a 1-methylethyl group, an n-butyl group, a tert-butyl group, a 1-methylpropyl group, a 2-methylpropyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a hexyl group, and the like.

[0013] The term "alkoxy group" refers to an oxy group substituted with the above-mentioned "lower alkyl group" or a 3- to 6-membered cyclic alkyl group. The "alkoxy group" is preferably "C １－６ An alkoxy group is preferred, and a C １－３Specific examples of the "alkoxy group" include a methoxy group, an ethoxy group, a propoxy group, a 1-methylethoxy group, a butoxy group, a 1,1-dimethylethoxy group, a 1-methylpropoxy group, a 2-methylpropoxy group, a pentyloxy group, a 1,1-dimethylpropoxy group, a 1,2-dimethylpropoxy group, a 1-methylbutoxy group, a 2-methylbutoxy group, a 4-methylpentyloxy group, a 3-methylpentyloxy group, a 2-methylpentyloxy group, a 1-methylpentyloxy group, a hexyloxy group, and a cyclopropyloxy group.

[0014] The term "alkenyl group" refers to a straight-chain or branched-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and 1 to 3 double bonds (C ２－６ As the "alkenyl group", preferably "C ２－５ alkenyl group," and more preferably "C ２－４ Specific examples of the "alkenyl group" include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, and a 2-methylallyl group.

[0015] The term "cycloalkyl group" refers to a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms. ３－７ A cycloalkyl group is preferred, and a C ３－６ Specific examples of the "cycloalkyl group" include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, and an adamantyl group.

[0016] The term "cycloalkenyl group" refers to a cyclic hydrocarbon group having 3 to 10 carbon atoms, including those having a partially unsaturated bond. The term "cycloalkenyl group" is preferably "C ３－７ A cycloalkenyl group is preferred, and a C ３－６Specific examples of the "cycloalkenyl group" include a cyclopentenyl group, a cyclohexenyl group, and a cycloheptenyl group. An "acyl group" is a group represented by -COR Ａ and R Ａ represents a hydrogen atom or a lower alkyl group.

[0017] The term "non-aromatic heterocyclic group" refers to a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom. The term "non-aromatic heterocyclic group" preferably refers to a 3- to 6-membered saturated heterocyclic group or a partially unsaturated heterocyclic group, more preferably a 5- or 6-membered heterocyclo group. Specific examples of the "non-aromatic heterocyclic group" include an epoxy group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a dihydropyridyl group, a dihydrofuranyl group, a dihydropyranyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, and the like. The term "amino group" refers to a group selected from the group consisting of -NR Ｄ R Ｅ where R Ｄ , R Ｅ are each independently a hydrogen atom or C １－３ It represents an alkyl group. Specific examples of the amino group include an amino group, a methylamino group, and a dimethylamino group.

[0018] The "halogen atom" refers to a chlorine atom (Cl), a bromine atom (Br), a fluorine atom (F) and an iodine atom (I), with a chlorine atom, a bromine atom and a fluorine atom being particularly preferred. The "alkylsulfonyl group" refers to a sulfonyl group substituted with the above-mentioned "lower alkyl group" or a 3- to 6-membered cyclic alkyl group. The "alkylsulfonyl group" is preferably a "C １ - ５ alkylsulfonyl group," and more preferably "C １ - ４ Specific examples of the "alkylsulfonyl group" include a methanesulfonyl group, an ethanesulfonyl group, and a propylsulfonyl group.

[0019] The term "heteroaryl group" refers to a 5- to 10-membered heteroaromatic ring group containing at least one heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom. The "heteroaryl group" is preferably a 5- to 8-membered heteroaryl group, more preferably a 5- or 6-membered heteroaryl group. Specific examples of the "heteroaryl group" include an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, a thienyl group, a furyl group, a pyrrole group, and a pyridyl group.

[0020] Unless otherwise specified, the "substituents" of an optionally substituted lower alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted non-aromatic heterocyclic group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted phenyl group, and an optionally substituted heteroaryl group may have one or more substituents of any type at any chemically possible positions, and when there are two or more substituents, the respective substituents may be the same or different.

[0021] Specific examples of the substituent include a halogen atom, a C alkyl group, an optionally substituted lower alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, and an optionally substituted alkylsulfonyl group. １－４ In addition to alkoxy groups, cyano groups, and hydroxy groups, morpholinyl groups, hydroxyethoxy groups, benzyloxy groups, and -NR Ｂ R Ｃ (R Ｂ , R Ｃ are independently selected from a lower alkyl group and a cyanomethyl group. Substituents for the optionally substituted cycloalkyl group, the optionally substituted cycloalkenyl group, the optionally substituted non-aromatic heterocyclic group, the optionally substituted phenyl group and the optionally substituted heteroaryl group include C １ - ３Alkyl group, halogen atom, C １－４ Examples of the substituted amino group include an alkoxy group, a cyano group, a hydroxy group, an oxo group, a hydroxyethyl group, and an ethoxycarbonyl group. Ｄ and / or R Ｅ is optionally substituted C １－３ It means that the C is an alkyl group. １－３ Examples of the substituent on the alkyl group include a halogen atom and a benzyloxy group.

[0022] Pharmaceutically acceptable salts of compound (I) of the present invention include inorganic acid salts with hydrochloric acid, sulfuric acid, carbonic acid, phosphoric acid, etc., and organic acid salts with fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. In addition, alkali metal salts with sodium, potassium, etc., alkaline earth metal salts with magnesium, calcium, etc., organic amine salts with lower alkylamines, lower alcoholamines, etc., basic amino acid salts with lysine, arginine, ornithine, etc., as well as ammonium salts, etc. Compound (I) of the present invention also includes various hydrates, solvates, and crystalline polymorphs. Compound (I) of the present invention can be used in combination with various isotopes (e.g., D, ３ H. １１ C. １３ C. １４ C. １３ N. １５ N. １５ O. ３５ S. １８ F. １２５ The compound (I) of the present invention may have isomers depending on the type of the substituent, for example. In this specification, the chemical structure of only one form of the isomer may be described, but the present invention also includes all isomers (geometric isomers, stereoisomers, tautomers, etc.) that can arise from the structure, and also includes all isomers alone or mixtures thereof.

[0023] Compound (I) of the present invention and its pharmaceutically acceptable salts can be prepared, for example, by the following methods. In the preparation methods shown below, if the defined groups are changed under the conditions of the method or are inappropriate for carrying out the method, the compound can be easily prepared by applying methods commonly used in organic synthetic chemistry, such as functional group protection and deprotection [T. W. Greene, Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, Inc., 1999]. Furthermore, the order of reaction steps such as introducing substituents can be changed as necessary. The meanings of the abbreviations and symbols used in the following description are as follows: DCM: Dichloromethane THF: Tetrahydrofuran DMF: N,N-dimethylformamide TEA: Triethylamine DMA: N,N-dimethylacetamide DMSO: Dimethyl sulfoxide CDI: 1,1'-carbonyldiimidazole DSC: N,N'-disuccinimidyl carbonate

[0024] [Method for Producing Compound (I) of the Present Invention] The compound of the present invention represented by formula (I) can be produced, for example, by Scheme 1. [Scheme 1] (In the formula, R １ , R ２ , R ３ , R ４ , R ５ and Q are as defined in (I) above, and PG represents a protecting group.

[0025] Compound (I) of the present invention can be produced by deprotecting the protecting group PG of compound (II) and then cyclizing the compound using a condensing agent. That is, compound (I) can be obtained by deprotecting the protecting group PG of compound (II) under conditions commonly used in organic chemistry to obtain an amine form, and then reacting the resulting amine with 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of a condensing agent such as CDI or DSC in a solvent. The solvent may be any solvent inert to the reaction, and is not particularly limited. Examples of suitable solvents include THF, DMF, and DMA, with DMF being preferred. The reaction can be carried out at a temperature ranging from 0°C to 100°C for several minutes to several days, but is preferably carried out at a temperature ranging from 0°C to 60°C for 10 minutes to 8 hours.

[0026] Compound (II) used as a starting material in Scheme 1 can be produced, for example, by the method shown in Scheme 2. [Scheme 2] (In the formula, R １ , R ２ , R ３ , R ４ , R ５ and Q are as defined in (I) above, and A is -CH ２ -, -O- or -CH ２ O-, and PG represents a protecting group.

[0027] Compound (II) can be produced by treating thiourea (III) with a brominating agent to cause cyclization. That is, (II) can be obtained by reacting thiourea (III) with a brominating agent in a solvent under conditions commonly used in organic chemistry. Any solvent inert to the reaction may be used, including, but not limited to, acetonitrile and DCM. The bromination reaction can be carried out, for example, by treating with a large excess of acetic acid and 0.5 to 2 molar equivalents, preferably 0.9 to 1.2 molar equivalents, of bromine. Alternatively, the reaction can be carried out using 1 to 20 molar equivalents, preferably 5 to 10 molar equivalents, of sodium bicarbonate and 0.5 to 2 molar equivalents, preferably 0.9 to 1.2 molar equivalents, of a brominating reagent such as benzyltrimethylammonium tribromide. The reaction can be carried out at a temperature ranging from -20°C to 70°C for several minutes to several days, but is preferably carried out at 10°C to room temperature for 30 minutes to 16 hours.

[0028] Thiourea (III) used as a starting material in Scheme 2 can be produced, for example, by the method shown in Scheme 3. [Scheme 3] (In the formula, R １ , R ２ , R ３ , R ４ and R ５ is the same as defined in (I) above, and A is -CH ２ -, -O- or -CH ２ O-, and PG represents a protecting group.

[0029] Thiourea (III) can be produced by reacting aniline (IV) with isothiocyanate (V). Specifically, thiourea (III) can be obtained by reacting isothiocyanate (V) with 0.5 to 5 molar equivalents, preferably 0.9 to 2 molar equivalents, of aniline (IV) in a solvent in the presence or absence of a base. Any solvent inert to the reaction may be used, and is not particularly limited. For example, ethanol can be used. If necessary, a base such as sodium ethoxide can be added to accelerate the reaction. The reaction can be carried out at a temperature ranging from -20°C to 70°C for several minutes to several days, but is preferably carried out at a temperature ranging from 0°C to 40°C for several hours to 24 hours.

[0030] Aniline (IV) and isothiocyanate (V), which are used as starting materials in Scheme 3, are commercially available or can be prepared by known methods or methods commonly used in organic synthetic chemistry. Compound (II), which is used as a starting material in Scheme 1, can also be prepared by the method shown in Scheme 4. [Scheme 4] (In the formula, R １ , R ２ , R ３ , R ４ , R ５ and Q are as defined in (I) above, and A is -CH ２ -, -O- or -CH ２ O-, and PG represents a protecting group.

[0031] Compound (II) can be produced by forming a thiazole ring from compound (VI) using Ullman-type condensation reaction conditions. That is, compound (II) can be obtained by cyclization in a solvent in the presence of a copper catalyst and a ligand, optionally with the addition of a base. As the copper catalyst, 0.01 to 1 molar equivalent, preferably 0.01 to 0.1 molar equivalent, of a copper salt such as copper(I) iodide can be used. As the ligand, 0.01 to 1 molar equivalent, preferably 0.05 to 0.5 molar equivalent, of a ligand such as 1,10-phenanthroline can be used. If necessary, a base such as potassium carbonate or cesium carbonate can be added to accelerate the reaction. Any solvent inert to the reaction may be used, and is not particularly limited. Examples of suitable solvents include, but are not limited to, THF. The reaction can be carried out at temperatures ranging from 0°C to reflux for several minutes to several days, but is preferably carried out at temperatures ranging from 0°C to 40°C for 16 hours.

[0032] Compound (VI) used as a starting material in Scheme 4 can be produced, for example, by the method shown in Scheme 5. [Scheme 5] (In the formula, R １ , R ２ , R ３ , R ４ and R ５ is the same as defined in (I) above, and A is -CH ２ -, -O- or -CH ２ O-, and PG represents a protecting group. Compound (VI) can be produced by reacting aniline (IV) with compound (VII).

[0033] That is, compound (VI) can be obtained by reacting compound (VII) with 0.5 to 5 molar equivalents, preferably 0.9 to 2 molar equivalents, of aniline (IV) in a solvent in the presence or absence of a base. The solvent may be any inert solvent, including, but not limited to, acetonitrile and DMSO. If necessary, a base can be added to accelerate the reaction. The reaction can be carried out at a temperature ranging from -20°C to 200°C for several minutes to several days, preferably at 0°C to 70°C for several hours to 3 days.

[0034] Compound (VII) used as a starting material in Scheme 5 is commercially available or can be produced by known methods or methods commonly used in organic synthetic chemistry. Compound (I) of the present invention having a desired functional group at a desired position can be obtained by appropriately combining the above methods and carrying out a method commonly used in organic synthetic chemistry (for example, a cross-coupling reaction such as the Mitsunobu reaction, the Sonogashira reaction, or the Suzuki-Miyaura reaction, a reaction to reduce an unsaturated bond, an amino group alkylation reaction, an acylation reaction, a carbamoylation reaction, a carbamate reaction, a reaction to oxidize an alkylthio group to a sulfoxide group or a sulfone group, an alkoxylation or carbamate reaction of a hydroxyl group, or a reaction to convert it to the opposite).

[0035] [Uses of Compound (I) of the Present Invention] The compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be prepared in the form of a conventional pharmaceutical preparation (pharmaceutical composition) suitable for oral, parenteral, or topical administration. Preparations for oral administration include solid preparations such as tablets, granules, powders, and capsules, as well as liquid preparations such as syrups. These preparations can be prepared by conventional methods. Solid preparations can be prepared using conventional pharmaceutical carriers such as lactose, starches such as cornstarch, crystalline cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, calcium carboxymethylcellulose, talc, magnesium stearate, and the like. Capsules can be prepared by encapsulating the granules or powder thus prepared. Syrups can be prepared by dissolving or suspending the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof in an aqueous solution containing sucrose, carboxymethylcellulose, or the like. Preparations for parenteral administration include injections such as intravenous infusions. Injection formulations can also be prepared by conventional methods and can be appropriately incorporated with isotonicity agents (e.g., mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose), stabilizers (e.g., sodium sulfite, albumin), and preservatives (e.g., benzyl alcohol, methyl p-hydroxybenzoate). The dose of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof can vary depending on the type and severity of the disease, the age, sex, and weight of the patient, the dosage form, etc., but is usually in the range of 1 mg to 1,000 mg per day for adults, and can be administered orally or parenterally in a single dose, or in two or three divided doses. Furthermore, the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be used as a DYRK inhibitor, as a reagent for pathological imaging of the above-mentioned diseases, or as a reagent for basic experiments and research.

[0036] The present invention will be explained in more detail below with reference to examples and test examples, but the present invention is not limited to these examples. 1 H-NMR) and liquid chromatography-mass spectrometry (LC-MS). 1 Unless otherwise specified, H-NMR was measured at 400 MHz, and exchangeable hydrogen may not be clearly observed depending on the compound and measurement conditions. Note that br means broad signal. The LC-MS system used was an ACQUITY UPLC H-Class PLUS system and an ACQUITY UPLC BEH system for liquid chromatography. A C18 column (130 Å, 1.7 um, 2.1 mm × 30 mm) was used, and the gradient mode (A solution: 0.1% formic acid aqueous solution, B solution: 0.1% formic acid acetonitrile solution, flow rate: 0.6 mL / min, 0.5 min; B solution 10%, 3 min; B solution 90%, 4 min; B solution 90%, detection UV: 220 nm and 254 nm, column temperature: 40 ° C.) or "Gradient mode 2" was used. Only when described, gradient mode 2 (A solution: 0.06% formic acid aqueous solution, B solution: 0.06% formic acid acetonitrile solution, flow rate: 0.8 mL / min, 0 min; B solution 2%, 1.3 min; B solution 96%, detection UV: 220 nm and 254 nm, column temperature: 40 ° C.) was used. Mass spectrometry was performed using an ACQUITY QDa detector, and mass was measured by electrospray ionization. For HPLC preparative chromatography, a commercially available ODS column was used, and unless otherwise noted, separation was performed in gradient mode using water / methanol or water / acetonitrile (containing formic acid) as the eluent. Furthermore, when the bond of a substituent at an optically active center is shown with a wavy line, it indicates a mixture of R and S isomers with respect to the stereochemistry of the substitution position. When the bond of a substituent at an optically active center is shown with a solid line, it indicates either the R or S isomer with respect to the substitution position. Each enantiomer was obtained as a single compound by optical resolution as appropriate.

[0037] Reference Example 1 Preparation of 5-bromo-4-isothiocyanato-2,3-dihydrobenzofuran 5-Bromobenzo[d][1,3]dioxol-4-amine (825 mg) was added to a chloroform solution (8.5 mL) of 1,1'-thiocarbonyldi-2(1H)-pyridone (940 mg, 4.39 mmol) at room temperature, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (928 mg). 1 H-NMR (CDCl3) δ 7.25 (1H, d, J = 8.5 Hz), 6.55 (1H, d, J = 8.5 Hz), 4.52 (2H, t, J = 8.8 Hz), 3.30 (2H, t, J = 8.8 Hz).

[0038] Reference Example 2 Preparation of 5-bromo-4-isothiocyanatobenzo[d][1,3]dioxole Using 5-bromobenzo[d][1,3]dioxol-4-amine (8.55 g, 39.58 mmol), the title compound was obtained in the same manner as in Reference Example 1 (yield 9.76 g). 1 H-NMR (DMSO-d6) δ 7.18 (1H, d, J = 8.4 Hz), 6.91 (1H, d, J = 8.4 Hz), 6.22 (2H, s).

[0039] Reference Example 3 Preparation of 6-bromo-5-isothiocyanato-2,3-dihydrobenzo[b][1,4]dioxine (Step 1) 6-Bromo-2,3-dihydrobenzo[b][1,4]dioxin (4 g, 18.6 mmol) was dissolved in anhydrous THF (186 mL) and cooled to −78°C. LDA (11.16 mL, 22.32 mmol, 2.0 M in THF / heptane / ethylbenzene) was added dropwise and the mixture was stirred at −78°C for 15 minutes. Crushed dry ice (50 g) was added to the reaction mixture, and the mixture was stirred at −78°C for 15 minutes. The mixture was then warmed to room temperature and further stirred overnight. 1M hydrochloric acid (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was extracted with 1M aqueous sodium hydroxide solution (100 mL). The resulting aqueous layer was acidified with concentrated hydrochloric acid and then extracted with chloroform. The organic layer was washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give 6-bromo-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (yield: 2.83 g). 1 H-NMR (DMSO-d6) δ 13.49 (s, 1H), 7.07 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 4.33 - 4.23 (m, 4H).

[0040] (Step 2) TEA (1.687 mL, 12.1 mmol) and diphenylphosphoryl azide (2.61 mL, 12.1 mmol) were added to a THF solution (27.5 mL) of 6-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylic acid (2.85 g, 11 mmol), and the mixture was stirred at room temperature for 3 hours. Water (3.96 mL) was added to the reaction mixture, and the mixture was stirred at 50°C for 3.5 hours. Insoluble matter was removed by filtration through Celite, and the filtrate was diluted with ethyl acetate (150 mL), washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give 6-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (yield 2.35 g). 1 H-NMR (CDCl3) δ 6.89 (d, J = 8.9 Hz, 1H), 6.24 (d, J = 8.9 Hz, 1H), 4.33 - 4.26 (m, 2H), 4.27 - 4.20 (m, 2H), 4.19 - 4.02 (m, 2H).

[0041] (Step 3) Using 6-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (2.35 g, 10.21 mmol), the title compound was obtained in the same manner as in Reference Example 1 (yield 1.95 g). 1 H-NMR (DMSO-d6) δ 7.14 (d, J = 8.9 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 4.45 - 4.38 (m, 2H), 4.34 - 4.27 (m, 2H).

[0042] Example 1 Preparation of 1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)-3,4-dihydroquinazolin-2(1H)-one (Step 1) 4-Isothiocyanato-2,3-dihydrobenzofuran (200 mg, 1.129 mmol) was added to a THF solution (11.3 mL) of tert-butyl (2-aminobenzyl)carbamate (376 mg, 1.69 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was washed with a mixed solvent of chloroform and hexane (1:3) and dried under reduced pressure to give tert-butyl {2-[3-(2,3-dihydrobenzofuran-4-yl)thioureido]benzyl}carbamate (yield: 368 mg). 1 H-NMR (CDCl3) δ 9.11 (s, 1H), 7.81 - 7.76 (m, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.39 - 7.23 (m, 3H), 7.19 - 7.10 (m, 1H), 6.90 (dd, J = 0.9, 8.1 Hz, 1H), 6.72 (dd, J = 0.8, 8.0 Hz, 1H), 5.15 (t, J = 6.3 Hz, 1H), 4.59 (t, J = 8.7 Hz, 2H), 4.13 (d, J = 6.3 Hz, 2H), 3.26 (t, J = 8.7 Hz, 2H), 1.31 (s, 9H).

[0043] (Step 2) To a chloroform solution (18.4 mL) of tert-butyl {2-[3-(2,3-dihydrobenzofuran-4-yl)thioureido]benzyl}carbamate (368 mg, 0.921 mmol) and sodium bicarbonate (774 mg, 9.21 mmol), benzyltrimethylammonium tribromide (323 mg, 0.829 mmol) was slowly added, and the mixture was stirred at room temperature for 1 hour. After filtering off insoluble matter, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to give tert-butyl {2-[(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)amino]benzyl}carbamate (220 mg). 1 H-NMR (CDCl3) δ 9.37 (s, 1H), 8.47 (s, 1H), 7.42 - 7.30 (m, 2H), 7.19 (dd, J = 1.7, 7.5 Hz, 1H), 7.09 - 7.00 (m, 1H), 6.69 (d, J = 8.3 Hz, 1H), 5.13 (s, 1H), 4.66 (t, J = 8.7 Hz, 2H), 4.34 (d, J = 6.8 Hz, 2H), 3.54 - 3.44 (m, 2H), 1.47 (s, 9H).

[0044] (Step 3) To a solution of tert-butyl {2-[(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)amino]benzyl}carbamate (220 mg, 0.553 mmol) in ethyl acetate (5.5 mL) was added 4 M hydrochloric acid-ethyl acetate solution (5 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with hexane, and the precipitated solid was collected by filtration. The resulting solid was dissolved in DMF (5 mL), and TEA (0.23 mL, 1.66 mmol) and DSC (142 mg, 0.553 mmol) were added, followed by stirring at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was dried under reduced pressure to give the title compound (yield 126 mg). 1H-NMR (DMSO-d6) δ 8.24 (t, J = 2.4 Hz, 1H), 7.76 - 7.68 (m, 1H), 7.62 (dd, J = 1.1, 8.4 Hz, 1H), 7.35 (dd, J = 1.5, 7.6 Hz, 1H), 7.30 (ddd, J = 1.6, 7.4, 8.2 Hz, 1H), 7.19 (td, J = 1.1, 7.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.37 (d, J = 2.3 Hz, 2H), 3.38 (t, J = 8.8 Hz, 2H). LCMS (m / z): 323.90 [M+H] + .

[0045] Example 2 Preparation of 1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)-7-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (Step 1) 1 M borane THF complex (5.37 mL, 5.37 mmol) was added dropwise to a THF solution (5 mL) of 2-amino-4-(trifluoromethyl)benzonitrile (0.5 g, 2.69 mmol) at 0°C, and the mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0°C, and methanol was added. The solvent was evaporated under reduced pressure to give 2-(aminomethyl)-5-(trifluoromethyl)aniline as a crude product (yield 0.5 g). 1 H-NMR (500 MHz, DMSO-d6) δ 7.23 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 5.56 (br. s, 2H), 3.66 (s, 2H), 3.38 (t, J = 5.6 Hz, 2H).

[0046] (Step 2) A THF solution (5 mL) of di-tert-butyl dicarbonate (0.3 mL, 1.31 mmol) was added to a THF solution (10 mL) of 2-(aminomethyl)-5-(trifluoromethyl)aniline (0.5 g, 2.63 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give tert-butyl [2-amino-4-(trifluoromethyl)benzyl]carbamate (yield 0.41 g). 1 H-NMR (DMSO-d6) δ 7.33 (t, J = 5.4 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 1.5 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 5.46 (br. s, 2H), 3.99 (d, J = 6.1 Hz, 2H), 1.39 (s, 9H). LCMS (m / z): 291.21 [M+H] + .

[0047] (Step 3) TEA (0.39 mL, 2.81 mmol) and 5-bromo-4-isothiocyanato-2,3-dihydrobenzofuran (Reference Example 1, 408 mg, 1.4 mmol) were added to a THF solution (10 mL) of tert-butyl [2-amino-4-(trifluoromethyl)benzyl]carbamate (360 mg, 1.4 mmol), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give tert-butyl {2-[3-(5-bromo-2,3-dihydrobenzofuran-4-yl)thioureido]-4-(trifluoromethyl)benzyl}carbamate (yield 425 mg). 1H-NMR (DMSO-d6) δ 9.70 (br. s, 1H), 9.47 (br. s, 1H), 7.64 (s, 2H), 7.52 - 7.34 (m, 3H), 6.71 (d, J = 8.3 Hz, 1H), 4.59 (t, J = 8.5 Hz, 2H), 4.22 (d, J = 4.8 Hz, 2H), 3.24 (t, J = 7.3 Hz, 2H), 1.37 (s, 9H). LCMS (m / z): 546.19 [M+H] + .

[0048] (Step 4) To a solution of tert-butyl {2-[3-(5-bromo-2,3-dihydrobenzofuran-4-yl)thioureido]-4-(trifluoromethyl)benzyl}carbamate (415 mg, 0.76 mmol) in acetonitrile (30 mL), cesium carbonate (493 mg, 1.52 mmol), 1,10-phenanthroline (27 mg, 0.15 mmol), and copper iodide (14 mg, 0.08 mmol) were added, and the mixture was stirred at 60°C for 3 hours. The reaction mixture was diluted with ethyl acetate, and insoluble matter was filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give tert-butyl {2-[(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)amino]-4-(trifluoromethyl)benzyl}carbamate (230 mg). 1 H-NMR (DMSO-d6) δ 10.06 (br. s, 1H), 8.62 (br. s, 1H), 7.52 - 7.34 (m, 4H), 6.66 - 6.57 (m, 1H), 4.59 (t, J = 8.5 Hz, 2H), 4.27 (d, J = 5.0 Hz, 2H), 3.28 - 3.26 (m, 2H), 1.41 (s, 9H). LCMS (m / z): 466.31 [M+H] + .

[0049] (Step 5) To a solution (5 mL) of tert-butyl {2-[(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)amino]-4-(trifluoromethyl)benzyl}carbamate (230 mg, 0.49 mmol) in ethyl acetate, 4 M hydrochloric acid-ethyl acetate solution (2 mL) was added and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was dissolved in DMF (3 mL). TEA (0.25 mL, 1.81 mmol) and DSC (154 mg, 0.60 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give the title compound (yield 90 mg). 1 H-NMR (DMSO-d6) δ 8.40 (s, 1H), 8.26 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.62 - 7.55 (m, 2H), 6.88 (d, J = 8.6 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.47 (s, 2H), 3.34 (t, J = 8.8 Hz, 2H). LCMS (m / z): 392.13 [M+H] + .

[0050] Example 3 Preparation of 1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-5-bromo-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (Step 1) N-Bromosuccinimide (10.65 g, 59.8 mmol) and benzoyl peroxide (1.035 g, 1.068 mmol) were added to a carbon tetrachloride solution (214 mL) of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (10 g, 42.7 mmol), and the mixture was stirred overnight at 80°C. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give 1-bromo-2-(bromomethyl)-5-fluoro-3-nitrobenzene (yield 13.3 g). 1 H-NMR (CDCl3) δ 7.70 - 7.62 (m, 2H), 4.85 (s, 2H).

[0051] (Step 2) Potassium phthalimide (7.87 g, 42.5 mmol) was added to a DMF solution (106 mL) of 1-bromo-2-(bromomethyl)-5-fluoro-3-nitrobenzene (13.3 g, 42.5 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was added to water (600 mL) with vigorous stirring, and the precipitated solid was collected by filtration. The obtained solid was washed with water and then dried under reduced pressure to give 2-(2-bromo-4-fluoro-6-nitrobenzyl)isoindoline-1,3-dione (yield 16.1 g). 1 H-NMR (CDCl3) δ 7.86 - 7.76 (m, 2H), 7.76 - 7.68 (m, 2H), 7.61 (ddd, J = 2.7, 7.5, 10.1 Hz, 2H), 5.30 (s, 2H).

[0052] (Step 3) Hydrazine monohydrate (7.89 mL, 162 mmol) was added to an ethanol solution (649 mL) of 2-(2-bromo-4-fluoro-6-nitrobenzyl)isoindoline-1,3-dione (12.3 g, 32.4 mmol), and the mixture was stirred overnight at 90° C. Insoluble matter formed in the reaction mixture was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain (2-bromo-4-fluoro-6-nitrophenyl)methanamine as a crude product (yield 7.92 g). 1H-NMR (CDCl3) δ 7.62 (dd, J = 7.3, 2.6 Hz, 1H), 7.53 (dd, J = 7.7, 2.6 Hz, 1H), 4.01 (s, 2H), 1.86 - 1.64 (m, br, 2H).

[0053] (Step 4) Diisopropylethylamine (5.83 ml, 33.4 mmol) and di-tert-butyl dicarbonate (7.75 ml, 33.4 mmol) were added to a THF solution (159 mL) of (2-bromo-4-fluoro-6-nitrophenyl)methanamine (7.92 g, 31.8 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to give tert-butyl (2-bromo-4-fluoro-6-nitrobenzyl)carbamate (yield 9.51 g). 1 H-NMR (CDCl3) δ 7.62 (dd, J = 7.3, 2.7 Hz, 1H), 7.54 (dd, J = 7.6, 2.7 Hz, 1H), 5.10 (s, br, 1H), 4.62 (d, J = 6.1 Hz, 2H), 1.43 (s, 9H).

[0054] (Step 5) To a solution (360 mL) of tert-butyl (2-bromo-4-fluoro-6-nitrobenzyl)carbamate (9.51 g, 27.2 mmol) in ethanol, water (176 mL), ammonium chloride (728 mg, 13.62 mmol), and iron powder (15.21 g, 272 mmol) were added, followed by stirring at 80°C for 2 hours. Insoluble matter was removed by filtration through Celite, and the mixture was concentrated under reduced pressure. The resulting residue was suspended and washed with water to give tert-butyl (2-amino-6-bromo-4-fluorobenzyl)carbamate (yield 8.43 g). 1 H-NMR (CDCl3) δ 6.64 (dd, J = 8.1, 2.5 Hz, 1H), 6.31 (dd, J = 10.4, 2.5 Hz, 1H), 5.11 (s, br, 1H), 4.93 (s, br, 2H), 4.37 (d, J = 6.8 Hz, 2H), 1.44 (s, 9H).

[0055] (Step 6) 5-Bromo-4-isothiocyanatobenzo[d][1,3]dioxole (Reference Example 2, 515 mg, 1.994 mmol) was added to a solution of tert-butyl (2-amino-6-bromo-4-fluorobenzyl)carbamate (700 mg, 2.193 mmol) in acetonitrile (20 mL), and the mixture was stirred at 50°C for 2 days. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was suspended and washed in a hexane-ethyl acetate mixed solvent, and the solid was dried under reduced pressure to give tert-butyl {2-bromo-6-[3-(5-bromobenzo[d][1,3]dioxol-4-yl)thioureido]-4-fluorobenzyl}carbamate (yield 930 mg). 1 H-NMR (DMSO-d6) δ 9.90 (s, 1H), 9.75 (s, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 9.9 Hz, 1H), 7.28 (s, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.10 (s, 2H), 4.12 - 4.04 (m, 2H), 1.28 (s, 9H).

[0056] (Step 7) To a solution of tert-butyl {2-bromo-6-[3-(5-bromobenzo[d][1,3]dioxol-4-yl)thioureido]-4-fluorobenzyl}carbamate (930 mg, 1.611 mmol) in THF (10 mL) were added potassium carbonate (445 mg, 3.22 mmol), 1,10-phenanthroline (29 mg, 0.161 mmol), and copper iodide (15 mg, 0.081 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to give tert-butyl [2-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-ylamino)-6-bromo-4-fluorobenzyl]carbamate (690 mg).1 H-NMR (DMSO-d6) δ 10.51 (s, 1H), 8.41 (d, J = 11.2 Hz, 1H), 7.72 (s, 1H), 7.37 - 7.30 (m, 2H), 6.89 (d, J = 8.3 Hz, 1H), 6.10 (s, 2H), 4.41 (d, J = 5.8 Hz, 2H), 1.41 (s, 9H).

[0057] (Step 8) To a 1,4-dioxane solution (20 mL) of tert-butyl {[2-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-ylamino)-6-bromo-4-fluorobenzyl]carbamate (690 mg, 1.39 mmol), 4 M hydrochloric acid-1,4-dioxane solution (20 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with hexane, and the precipitated solid was collected by filtration. The obtained solid was dissolved in DMF (20 mL), and TEA (1.938 mL, 13.9 mmol) and DSC (356 mg, 1.390 mmol) were added, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with water, and the precipitated solid was collected by filtration. The obtained solid was suspended and washed in a mixed solvent of methanol and diethyl ether, and then dried under reduced pressure to obtain the title compound (yield 540 mg). 1 H-NMR (DMSO-d6) δ 8.46 (t, J = 2.3 Hz, 1H), 7.63 (dd, J = 2.5, 11.0 Hz, 1H), 7.53 (dd, J = 2.5, 8.1 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.15 (s, 2H), 4.47 - 4.27 (m, 2H). LCMS (m / z): 423.89 [M+H] + .

[0058] Example 4 Preparation of 1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-5-(2,5-dihydrofuran-3-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one To a 1,4-dioxane solution (0.987 mL) of 1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-5-bromo-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (Example 3, 50 mg, 0.118 mmol), potassium carbonate (32.7 mg, 0.237 mmol), water (0.197 mL), tetrakis(triphenylphosphine)palladium(0) (13.68 mg, 0.012 mmol), and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46.4 mg, 0.237 mmol) were added and stirred at 100°C for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (yield 37 mg). 1 H-NMR (DMSO-d6) δ 8.42 - 8.36 (m, 1H), 7.58 (dd, J = 2.5, 10.8 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.10 (dd, J = 2.5, 9.5 Hz, 1H), 7.06 (d, LCMS (m / z): 412.07 [M+H] + .

[0059] Example 5 Preparation of (RS)-1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-7-fluoro-5-(tetrahydrofuran-3-yl)-3,4-dihydroquinazolin-2(1H)-one 1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-5-(2,5-dihydrofuran-3-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (Example 4, 38.8 mg, 0.094 mmol) was dissolved in an ethyl acetate / ethanol mixed solvent (1:1, 60 mL), and 10% palladium on activated carbon (150 mg, 0.141 mmol) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. Insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (yield 20.5 mg). 1H-NMR (DMSO-d6) δ 8.44 (t, J = 2.4 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.43 (dd, J = 10.8, 2.5 Hz, 1H), 7.09 - 7.01 (m, 2H), 6.13 (s, 2H), 4.42 - 4.35 (m, 2H), 4.01 - 3.90 (m, 2H), 3.84 - 3.75 (m, 1H), 3.70 - 3.63 (m, 1H), 3.62 - 3.53 (m, 1H), 2.37 - 2.25 (m, 1H), 1.97 - 1.85 (m, 1H).LCMS (m / z): 414.04 [M+H] + .

[0060] Example 6 Preparation of 1-(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (Step 1) Pyrrolidine (0.673 ml, 8.14 mmol) and N,N-dimethylformamide dimethyl acetal (1.982 ml, 14.8 mmol) were added to a DMF solution (12.67 mL) of 5-fluoro-N,N,2-trimethyl-3-nitroaniline (1.467 g, 7.4 mmol), and the mixture was stirred at 70°C in a sealed tube under a nitrogen atmosphere for 3 hours. The reaction mixtures obtained by repeating the same procedure three times were combined and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was dissolved in THF (79 mL), and TEA (6.19 ml, 44.4 mmol), sodium periodate (14.25 g, 66.6 mmol), and water (50 mL) were added, followed by stirring overnight at 50°C. Insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with a mixed solvent of ethyl acetate and hexane, washed successively with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to give 2-(dimethylamino)-4-fluoro-6-nitrobenzaldehyde (yield 1.2 g). 1 H-NMR (CDCl3) δ 10.07 (s, 1H), 6.95 (dd, J = 7.5, 2.3 Hz, 1H), 6.87 (dd, J = 10.9, 2.3 Hz, 1H), 2.98 (s, 6H).

[0061] (Step 2) Tetraethyl orthotitanate (1.581 ml, 7.54 mmol) and tert-butylsulfinamide (0.594 g, 4.9 mmol) were added to a THF solution (37.7 mL) of 2-(dimethylamino)-4-fluoro-6-nitrobenzaldehyde (0.8 g, 3.77 mmol), and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Under ice-cooling, saturated brine was added to the reaction mixture, followed by ethyl acetate at room temperature. After removing insoluble matter by filtration through Celite, the filtrate was concentrated, and the resulting residue was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was suspended and washed in water to give N-[2-(dimethylamino)-4-fluoro-6-nitrobenzylidene]-2-methylpropane-2-sulfinamide (yield: 929 mg). 1 H-NMR (CDCl3) δ 8.68 (d, J = 0.6 Hz, 1H), 6.89 (dd, J = 10.5, 2.4 Hz, 1H), 6.84 - 6.79 (m, 1H), 2.88 (s, 6H), 1.23 (s, 9H).

[0062] (Step 3) To a methanol solution (90 mL) of N-[2-(dimethylamino)-4-fluoro-6-nitrobenzylidene]-2-methylpropane-2-sulfinamide (0.928 g, 2.94 mmol), sodium borohydride (367 mg, 9.71 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 90 minutes. To complete the reaction, sodium borohydride (80 mg, 2.12 mmol) was added, and the mixture was stirred at room temperature for an additional 1 hour. The reaction mixture was concentrated under reduced pressure, and saturated brine was added to the resulting residue, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give N-[2-(dimethylamino)-4-fluoro-6-nitrobenzyl]-2-methylpropane-2-sulfinamide as a crude product (yield 986 mg). 1H-NMR (CDCl3) δ 7.24 (dd, J = 7.8, 2.6 Hz, 1H), 7.02 (dd, J = 9.9, 2.6 Hz, 1H), 4.58 (dd, J = 13.8, 5.7 Hz, 1H), 4.49 (dd, J = 13.8, 8.2 Hz, 1H), 4.08 - 3.99 (m, 1H), 2.77 (s, 6H), 1.17 (s, 9H).

[0063] (Step 4) To a 1,4-dioxane solution (8 mL) of N-[2-(dimethylamino)-4-fluoro-6-nitrobenzyl]-2-methylpropane-2-sulfinamide (crude product, 932 mg, 2.935 mmol), methanol (8 mL) and 4 M hydrochloric acid-1,4-dioxane solution (8 mL) were added and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting solid was dissolved in DMF (30 mL), and TEA (4.08 ml, 29.3 mmol) and di-tert-butyl dicarbonate (0.816 ml, 3.52 mmol) were added, followed by stirring at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give tert-butyl [2-(dimethylamino)-4-fluoro-6-nitrobenzyl]carbamate (yield 959 mg). 1 H-NMR (CDCl3) δ 7.23 (dd, J = 7.8, 2.6 Hz, 1H), 7.02 (dd, J = 10.0, 2.6 Hz, 1H), 5.29 (s, br, 1H), 4.52 (d, J = 6.1 Hz, 2H), 2.78 (s, 6H), 1.41 (s, 9H).

[0064] (Step 5) To a methanol solution (30 mL) of tert-butyl [2-(dimethylamino)-4-fluoro-6-nitrobenzyl]carbamate (918 mg, 2.93 mmol), a 1,4-dioxane suspension (1 mL) of 10% palladium-activated carbon (100 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After removing insoluble matter by filtration through Celite, the filtrate was concentrated under reduced pressure to give tert-butyl [2-amino-6-(dimethylamino)-4-fluorobenzyl]carbamate as a crude product (yield 829 mg). 1 H-NMR (CDCl3) δ 6.24 (dd, J = 10.7, 2.5 Hz, 1H), 6.13 (dd, J = 10.3, 2.5 Hz, 1H), 4.84 (s, br, 1H), 4.50 (s, br, 2H), 4.35 (d, J = 6.3 Hz, 2H), 2.60 (s, 6H), 1.44 (s, 9H).

[0065] (Step 6) Using 6-bromo-5-isothiocyanato-2,3-dihydrobenzo[b][1,4]dioxin (Reference Example 3, 180 mg, 0.66 mmol) and tert-butyl [2-amino-6-(dimethylamino)-4-fluorobenzyl]carbamate (170 mg, 0.6 mmol), tert-butyl {2-[3-(6-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)thioureido]-6-(dimethylamino)-4-fluorobenzyl}carbamate was obtained in the same manner as in Step 6 of Example 3 (yield 186 mg). 1 H-NMR (DMSO-d6) δ 9.47 (s, 1H), 9.15 (s, 1H), 7.12 (d, J = 8.9 Hz, 1H), 6.92 - 6.73 (m, 4H), 4.26 (q, J = 4.8 Hz, 4H), 4.17 - 4.03 (m, 2H), 2.63 (s, 6H), 1.33 (s, 9H).

[0066] (Step 7) Using tert-butyl {2-[3-(6-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)thioureido]-6-(dimethylamino)-4-fluorobenzyl}carbamate (186 mg, 0.335 mmol), tert-butyl {2-[(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)amino]-6-(dimethylamino)-4-fluorobenzyl}carbamate was obtained in the same manner as in Step 7 of Example 3 (yield 152 mg). 1 H-NMR (DMSO-d6) δ 10.12 (s, 1H), 8.16 (d, J = 11.3 Hz, 1H), 7.43 (s, 1H), 7.25 (d, J = 8.6 Hz, 1H), 6.81 - 6.68 (m, 2H), 4.36 (tt, J = 2.5, 5.2 Hz, 4H), 4.33 - 4.25 (m, 2H), 2.63 (s, 6H), 1.42 (s, 9H).

[0067] (Step 8) Using tert-butyl {2-[(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)amino]-6-(dimethylamino)-4-fluorobenzyl}carbamate (150 mg, 0.316 mmol), the title compound was obtained in the same manner as in Step 8 of Example 3 (yield 120 mg). 1 H-NMR (DMSO-d6) δ 8.29 - 8.18 (m, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.08 (dd, J = 2.4, 10.7 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.76 (dd, J = LCMS (m / z): 401.12 [M+H] + .

[0068] Alternative Preparation Method up to Step 5 of Example 6 (Step 1) N-Bromosuccinimide (41.7 g, 234 mmol) and 1,1'-azobis(cyclohexane-1-carbonitrile) (2.9 g, 11.7 mmol) were added to a chlorobenzene solution (325 mL) of methyl 5-fluoro-2-methyl-3-nitrobenzoate (25 g, 117 mmol), and the mixture was stirred at 110 °C for 5 hours. After cooling to room temperature, 5% aqueous sodium thiosulfate solution was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2-(bromomethyl)-5-fluoro-3-nitrobenzoate as a crude product (yield 42.7 g). 1 H-NMR (CDCl3) δ: 7.85 (dd, J = 8.2, 2.7 Hz, 1H), 7.71 (dd, J = 7.3, 3.1 Hz, 1H), 5.13 (s, 2H), 4.01 (s, 3H).

[0069] (Step 2) Di-tert-butyl iminodicarboxylate (25.4 g, 117 mmol) and cesium carbonate (76.2 g, 234 mmol) were added to a solution of methyl 2-(bromomethyl)-5-fluoro-3-nitrobenzoate (crude product, 42.7 g, 117 mmol) in acetonitrile (234 mL), and the mixture was stirred at 40°C to 50°C for 6 hours. After cooling to room temperature, Celite (50 g) was added to the reaction mixture, and insoluble matter was removed by Celite filtration and washed with ethyl acetate. The solvent was evaporated under reduced pressure to give methyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoate as a crude product (yield 61.1 g). 1 H-NMR (CDCl3) δ: 7.60-7.55 (m, 2H), 5.21 (s, 2H), 3.94 (s, 3H), 1.40 (s, 18H).

[0070] (Step 3) To a methanol / THF solution (120 mL / 120 mL) of methyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoate (crude product, 61.1 g, 97.4 mmol), 2M aqueous sodium hydroxide solution (97 mL) was added dropwise under ice cooling, and the mixture was stirred under ice cooling for 7 hours. After adding 2M aqueous hydrochloric acid solution (200 mL) dropwise under ice cooling, the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoic acid (yield 59.2 g). 1 H-NMR (DMSO-d6) δ: 9.18 (s, 1H), 7.67 (dd, J = 10.7, 2.7 Hz, 1H), 7.56 (dd, J = 8.2, 2.7 Hz, 1H), 4.84 (s, 2H), 1.33 (s, 18H).

[0071] (Step 4) 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoic acid (crude product, 59.2 g, 93.6 mmol) was azeotropically distilled three times with toluene (160 mL) and then dissolved in toluene (468 mL). tert-Butyl alcohol (44.4 mL, 468 mmol), diphenylphosphoryl azide (30.9 g, 112 mmol), and TEA (19.5 mL, 140 mmol) were added, and the mixture was stirred at 80°C for 4 hours. After cooling to room temperature, the reaction mixture was washed successively with 0.5 M aqueous hydrochloric acid, saturated sodium bicarbonate water, and water. The saturated sodium bicarbonate water layer and the aqueous layer were each filtered through Celite, washed with toluene, and then separated. The combined organic layers were concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give tert-butyl (tert-butoxycarbonyl) (2-((tert-butoxycarbonyl)amino) 4-fluoro-6-nitrobenzyl)carbamate (yield 27.7 g). 1H-NMR (DMSO-d6) δ: 9.18 (s, 1H), 7.67 (dd, J = 10.7, 2.7 Hz, 1H), 7.56 (dd, J = 8.2, 2.7 Hz, 1H), 4.84 (s, 2H), 1.46 (s, 9H), 1.33 (s, 18H).

[0072] (Step 5) To a solution of tert-butyl (tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)4-fluoro-6-nitrobenzyl)carbamate (7.0 g, 14.4 mmol) in acetic acid (140 mL), 10% palladium on activated carbon (3.50 g) and paraformaldehyde (2.16 g, 71.9 mmol) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. After insoluble matter was removed by filtration through Celite, the filtrate was concentrated under reduced pressure and azeotroped with toluene. The residue was dissolved in ethyl acetate, and insoluble matter was removed by filtration through Celite. The filtrate was concentrated under reduced pressure to give tert-butyl (tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)-6-(dimethylamino)-4-fluorobenzyl)carbamate as a crude product (yield 7.35 g). 1 H-NMR (CDCl3) δ: 8.19 (s, 1H), 7.49 (d, J = 10.4 Hz, 1H), 6.59 (dd, J = 10.1, 2.7 Hz, 1H), 4.82 (s, 2H), 2.57 (s, 6H), 1.51 (s, 9H), 1.43 (s, 18H).

[0073] (Step 6) A 4M hydrochloric acid-ethyl acetate solution (530 mL) was added to tert-butyl (tert-butoxycarbonyl) (2-((tert-butoxycarbonyl)amino)-6-(dimethylamino)-4-fluorobenzyl)carbamate (25.7 g, 53.1 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with hexane, and the precipitated solid was collected by filtration. Methanol (200 mL) and TEA (36.8 mL, 265.5 mmol) were added to the resulting solid, and the mixture was stirred at room temperature for 20 minutes. A methanol solution (12 mL) of di-tert-butyl dicarbonate (5.79 g, 26.5 mmol) was added, and the mixture was stirred for 1 hour, and then a methanol solution (10 mL) of di-tert-butyl dicarbonate (3.47 g, 15.9 mmol) was added, and the mixture was stirred for 1 hour. A methanol solution (10 mL) of di-tert-butyl dicarbonate (382 mg, 1.75 mmol) was further added, and the mixture was stirred for 1 hour, after which the solvent was evaporated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the layers were separated, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate). The resulting solid was suspended and washed in hexane and dried under reduced pressure to give tert-butyl [2-amino-6-(dimethylamino)-4-fluorobenzyl]carbamate (yield 11.8 g).

[0074] The following compounds of Examples 7 to 76 [Table 1-1], compounds of Examples 78 to 106 [Table 1-2], and compounds of Examples 108 to 126 [Table 1-3] were produced using the corresponding starting materials (commercially available products or compounds derived from commercially available compounds by known methods or methods similar thereto) according to the methods described in the above examples, and, where necessary, by appropriately combining methods commonly used in organic synthetic chemistry. The physicochemical data for each compound are shown in Table 2. In the table, when a bond of a substituent at an optically active center is shown with a wavy line, it indicates a mixture of R and S configurations with respect to the stereochemistry of that substitution position. When a bond of a substituent at an optically active center is shown with a solid line, it indicates either the R or S configuration at that substitution position. Each enantiomer was obtained as a single compound by optical resolution by supercritical fluid chromatography using a chiral column as appropriate.

[0075]

[0076] Example 77 Preparation of 1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)-7-fluoro-5-(1-methylpiperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one 1-(7,8-Dihydrobenzofuro[4,5-d]thiazol-2-yl)-7-fluoro-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (Example 65, 20 mg, 0.046 mmol) was dissolved in a methanol / THF mixed solvent (1:1, 200 mL), and 10% palladium-activated carbon (500 mg, 0.47 mmol) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. Insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, chloroform / methanol) to give the title compound (yield 2.5 mg). LCMS (m / z): 439.16 [M+H] + , Holding time: 1.9 minutes

[0077]

[0078] Example 107 Preparation of (RS)-1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)-7-fluoro-5-(tetrahydro-2H-pyran-2-yl)-3,4-dihydroquinazolin-2(1H)-one 5-(3,4-Dihydro-2H-pyran-6-yl)-1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (Example 104, 25 mg, 0.059 mmol) was dissolved in an ethanol / ethyl acetate mixed solvent (1:1, 60 mL), and 10% palladium-activated carbon (300 mg, 0.282 mmol) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. Insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (yield 3.85 mg). LCMS (m / z): 426.09 [M+H] + , Retention time: 2.96 minutes

[0079]

[0080] Example 127 Preparation of 1-(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one sulfate 1-(7,8-Dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (Example 6, 150 mg, 0.375 mmol) was dissolved in ethyl acetate (12 mL), and a solution of 98% sulfuric acid (37.5 mg, 0.375 mmol) in methanol (375 mg) was added dropwise, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to give the title compound as a white solid (yield 194 mg). 1 H-NMR (DMSO-d6) δ: 8.25-8.20 (m, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 10.4, 2.4 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.76 (dd, J = LCMS (m / z): 401.11 [M+H] + , retention time: 1.27 minutes (gradient mode 2)

[0081] Example 128 Preparation of 1-(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one hydrochloride 1-(7,8-Dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (Example 6, 150 mg, 0.375 mmol) was dissolved in ethyl acetate (12 mL), and 4 M hydrochloric acid-ethyl acetate solution (0.281 mL, 1.12 mmol) was added dropwise, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound as a white solid (yield 194 mg). 1 H-NMR (DMSO-d6) δ: 8.24 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.08 (dd, J = 10.4, 2.4 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.76 (dd, J = 11.0, 2.4 Hz, 1H), 5.10 (br s, 1H), 4.35-4.27 (m, 4H), 4.25-4.21 (m, 2H), 2.67 (s, 6H). LCMS (m / z): 401.13 [M+H] + , retention time: 1.29 minutes (gradient mode 2)

[0082]

[0083] Test Example 1 [Inhibition Test 1 of Activity Against DYRK Family (DYRK1A, DYRK1B, DYRK2, DYRK3)] (Method for Measuring Kinase Activity) Kinase activity was measured by the mobility shift assay (MSA) method using QuickScout Screening Assist™ MSA (a commercially available kit manufactured by Carna Biosciences). The FITC-labeled DYRKtide peptide included in the kit was used as the substrate for the kinase reaction. Assay buffer [20 mM HEPES, 0.01% Triton X-100™, 2 mM dithiothreitol, pH 7.5] was used, and the substrate (4 μM), MgCl ２ A substrate mixture of 20 mM DYRK1A and 200 μM DYRK1B, 40 μM DYRK2, and 20 μM DYRK3 was prepared. Kinases (DYRK1A, Carna Biosciences, Catalog No. 04-130; DYRK1B, Carna Biosciences, Catalog No. 04-131; DYRK2, Carna Biosciences, Catalog No. 04-132; DYRK3, Carna Biosciences, Catalog No. 04-133) were diluted with assay buffer to prepare enzyme solutions (DYRK1A, 0.2 ng / μL; DYRK1B, 0.08 ng / μL; DYRK2, 0.04 ng / μL; DYRK3, 0.25 ng / μL). A 10 mM DMSO solution of the test compound was further diluted with DMSO to 10 concentrations (0.00003 mM, 0.0001 mM, 0.0003 mM, 0.001 mM, 0.003 mM, 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, and 1 mM), and each was diluted 25-fold with assay buffer to prepare a drug solution (4% DMSO solution). Five μL of the drug solution or control solution (4% DMSO-assay buffer), 5 μL of the substrate mixture, and 10 μL of the enzyme solution were mixed in a well of a 384-well polypropylene plate and reacted at room temperature for 1 hour. The reaction was then terminated by adding 60 μL of the termination buffer provided with the kit. Then, the amounts of the substrate (S) and the phosphorylated substrate (P) in the reaction solution were measured using a LabChip EZ Reader II system (Caliper Life Sciences) according to the protocol of the assay kit.

[0084] (Method for evaluating inhibitory activity) The peak heights of the "substrate" and "phosphorylated substrate" were designated S and P, respectively, and a blank was measured by adding assay buffer instead of the enzyme solution. The inhibition rate (%) of the test compound was calculated according to the following formula: Inhibition rate (%) = (1-(C-A) / (B-A)) x 100, where A, B, and C represent P / (P+S) of the blank well, P / (P+S) of the control solution well, and P / (P+S) of the compound-added well, respectively. The IC ５０ The values ​​were calculated by regression analysis of the inhibition rate and the test compound concentration (logarithm). (Evaluation Results) The inhibitory activity of the representative compounds of the present invention against DYRK1A, DYRK1B, DYRK2, and DYRK3 is shown in Table 3. The kinase activity inhibitory effect was measured using the IC ５０ Values ​​of less than 0.01 μM are indicated by ***, values ​​of 0.01 μM or more and less than 0.1 μM are indicated by **, values ​​of 0.1 μM or more and less than 1 μM are indicated by *, and values ​​of 1 μM or more are indicated by - (ND: not measured).

[0085] This result indicates that the compound (I) of the present invention has a strong DYRK inhibitory activity.

[0086] Test Example 2 [Inhibition Test 2 of Activity Against DYRK Family (DYRK1A, DYRK1B, DYRK2, DYRK3)] Kinase inhibitory activity was measured using ADP-Glo™ Kinase Assay (a commercially available kit manufactured by Promega). DYRKtide was used as the substrate for the kinase reaction unless otherwise specified. A 10 mM DMSO solution of the test compound was further diluted with DMSO to 10 concentrations (0.00003 mM, 0.0001 mM, 0.0003 mM, 0.001 mM, 0.003 mM, 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, and 1 mM), and each was diluted 25-fold with assay buffer to prepare a drug solution. 2mM DYRKtide stock solution, 10mM ATP, 1M MgCl ２The enzyme solution was prepared by diluting the enzyme solution with assay buffer to a concentration four times the final concentration. Kinases (DYRK1A; Carna Biosciences, Catalog No. 04-130, DYRK1B; Carna Biosciences, Catalog No. 04-131, DYRK2; Carna Biosciences, Catalog No. 04-132, DYRK3; Carna Biosciences, Catalog No. 04-133) were diluted with assay buffer to a concentration two times the final concentration. Ten μL of the enzyme solution, 5 μL of the drug solution, and 5 μL of the substrate mixture were mixed in a well of a 384-well polystyrene plate and allowed to react at room temperature for 1 hour (final ATP concentrations: DYRK1A; 25 μM, DYRK1B; 25 μM, DYRK2; 10 μM, DYRK3; 5 μM). 20 μL of the ADP-Glo ​​Reagent (containing 10 mM Mg) included in the kit was added to each well and incubated at 25°C for 40 minutes. 40 μL of Kinase Detection Reagent was then added and incubated at 25°C for 40 minutes. Luciferase activity in each well was then measured using a microplate reader (Envision, Perkinelmer).

[0087] (Method of evaluating inhibitory activity) The luminescence intensity of the group without compound addition and with enzyme addition was set to 100%, and the luminescence intensity of the group without compound addition and with enzyme addition was set to 0%, and the IC was calculated by regression analysis of the inhibition rate calculated from the luminescence intensity at each compound concentration and the test compound concentration (logarithm). ５０ The inhibitory activity of the compounds of the present invention against DYRK1A, DYRK1B, DYRK2, and DYRK3 is shown in Table 4. The inhibitory effect on kinase activity was measured using the IC ５０ Values ​​less than 0.01 μM are indicated by ***, values ​​from 0.01 μM to less than 0.1 μM are indicated by **, values ​​from 0.1 μM to less than 1 μM are indicated by *, and values ​​of 1 μM or more are indicated by - (ND: not measured).

[0088] The compounds of Examples 2 and 23 to 36 were assayed using FITC-labeled DYRKtide instead of DYRKtide as the substrate. These results demonstrate that compound (I) of the present invention has strong DYRK inhibitory activity.

[0089] The compounds provided by the present invention are useful as preventive or therapeutic agents for diseases known to be associated with abnormal cellular responses mediated by DYRK1A, such as psychiatric and neurological disorders such as Alzheimer's disease, Parkinson's disease, Down's syndrome, mental retardation, memory impairment, amnesia, and depression, as well as cancers such as brain tumors. As inhibitors of DYRK1B, they are also useful as pharmaceutical compositions for preventing or treating cancers such as pancreatic cancer. Furthermore, the compounds provided by the present invention are useful as pharmaceutical compositions for preventing or treating bone resorption diseases and osteoporosis, since they regulate p53 and induce apoptosis in response to DNA damage in the case of DYRK2. As inhibitors of DYRK3, they are also useful as pharmaceutical compositions for preventing or treating sickle cell anemia, chronic kidney disease, bone resorption diseases, and osteoporosis. Furthermore, as DYRK inhibitors, they are useful as reagents for pathological imaging of the above-mentioned diseases, as well as for basic experimental and research purposes.

Claims

1. The following formula (I): (In the formula, R １ , R ２ , R ３ and R ４ each independently represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an acyl group, an optionally substituted non-aromatic heterocyclic group, a halogen atom, a cyano group, an optionally substituted alkylsulfonyl group, a nitro group, an optionally substituted amino group, an optionally substituted phenyl group, or an optionally substituted heteroaryl group; R ５ represents a hydrogen atom or a lower alkyl group, and Q represents the following structure (a), (b), or (c): or a pharmaceutically acceptable salt thereof.

2. The dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein in formula (I), Q is structure (a).

3. The dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein in formula (I), Q is structure (b).

4. The dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein in formula (I), Q is structure (c).

5. In formula (I), R ５ The dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein is a hydrogen atom.

6. In formula (I), R １ , R ２ , R ３ and R ４ are each independently a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted non-aromatic heterocyclic group, a halogen atom, an optionally substituted amino group, or an optionally substituted heteroaryl group, or a dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.

7. In formula (I), R １ and R ３ The dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein is a hydrogen atom.

8. In formula (I), R ２ is a fluorine atom, and R ４ is an optionally substituted cycloalkenyl group, an optionally substituted non-aromatic heterocyclic group, an optionally substituted amino group, or an optionally substituted heteroaryl group, or a dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from the following group of compounds: 1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-5-(2,5-dihydrofuran-3-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one, (RS)-1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-7-fluoro-5-(tetrahydrofuran-3-yl)-3,4-dihydroquinazolin-2(1H)-one, 1-(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one, 1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-5-(3,6-dihydro-2H-pyran-4-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one, (RS)-1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-7-fluoro-5-(4-hydroxycyclohex-1-en-1-yl)-3,4-dihydroquinazolin-2(1H)-one, 1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2(1H)-one, 5-(3,4-dihydro-2H-pyran-6-yl)-1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one, (RS)-1-([1,3]dioxolo[4',5':5,6]benzo[1,2-d]thiazol-7-yl)-7-fluoro-5-(tetrahydro-2H-pyran-3-yl)-3,4-dihydroquinazolin-2(1H)-one, 1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)-7-fluoro-5-(3-oxocyclopent-1-en-1-yl)-3,4-dihydroquinazolin-2(1H)-one, 1-(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,1-(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one sulfate, and 1-(7,8-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one hydrochloride.

10. A medicine containing, as an active ingredient, the dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9.

11. A pharmaceutical composition comprising, as an active ingredient, the dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9.

12. A therapeutic and / or preventive agent for a disease involving DYRK, comprising the dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 as an active ingredient.

13. The therapeutic and / or prophylactic agent according to claim 12, wherein the disease in which DYRK is involved is treatment of frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down's syndrome, depression, and associated mental retardation, memory impairment, memory loss, learning disability, intellectual disability, cognitive impairment, mild cognitive impairment, or progression of dementia symptoms or prevention of the onset of dementia, or brain tumor, pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, lung cancer, bone resorption disease, osteoporosis, sickle cell anemia, chronic kidney disease, or bone resorption disease.

14. A method for treating and / or preventing a disease in which DYRK is involved, comprising administering to a patient in need of treatment a therapeutically effective amount of a dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9.

15. Use of the dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 for the manufacture of an agent for treating and / or preventing a disease in which DYRK is involved.

16. A dihydroquinazolinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 for use in the treatment and / or prevention of a disease involving DYRK.

17. A medicine comprising a combination of the medicine according to claim 10 and at least one drug selected from the group consisting of anticancer drugs, antipsychotic drugs, antidementia drugs, antiepileptic drugs, antidepressants, gastrointestinal drugs, thyroid hormone drugs, and antithyroid drugs.

18. The pharmaceutical agent according to claim 10, for the treatment of frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down's syndrome, depression and complications associated therewith, mental retardation, memory impairment, memory loss, learning disability, intellectual disability, cognitive impairment, mild cognitive impairment, progression of dementia symptoms or prevention of the onset of dementia, or for the treatment of brain tumor, pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, lung cancer, bone resorption disease, osteoporosis, sickle cell anemia, chronic kidney disease or bone resorption disease, in combination with at least one or more drugs selected from drugs classified as anticancer agents, antipsychotic agents, antidementia agents, antiepileptic agents, antidepressants, gastrointestinal agents, thyroid hormone agents or antithyroid agents.

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