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

TITLE OF THE INVENTION: DIHYDROQUINAZOLINONE DERIVATIVE TECHNICAL FIELD

[0001] The present invention relates to a medicament, especially a novel dihydroquinazolinone derivative having a DYRK inhibitory activity or a pharmaceutically acceptable salt thereof. BACKGROUND ART

[0002] DYRK (Dual-specificity tYrosine-phosphorylation Regulated protein Kinase) is one of the bispecific protein kinases that phosphorylate tyrosine, serine, and threonine. DYRK functions as a tyrosine kinase only in the case of autophosphorylation and catalyzes the phosphorylation of serine or threonine residues on exogenous substrates. Five members of the DYRK family are known in humans: DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4 (Nonpatent Document 1). In the present description, "DYRK" means one or more of these DYRK family members (DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4). It has been widely reported that DYRK1A is associated with neuropsychiatric diseases. For example, in patients with Alzheimer's disease, the expression of P-amyloid is significantly consistent with that of DYRK1A (Nonpatent Document 2), and it is speculated that DYRK1A is involved in abnormal phosphorylation of a tau protein (Tau), which is considered to contribute to the onset of Alzheimer's disease (Nonpatent Document 3). In addition, Parkinson's disease is a neurodegenerative disease caused by the degeneration of dopamine neurons, which are important for motor function, and one of the causes is considered to be mitochondrial dysfunction (Nonpatent Document 4). An enzyme involved in protein degradation called Parkin is known to metabolize abnormal mitochondria and suppress abnormal accumulation, but DYRK1A has been reported to suppress the activity of this parkin protein (Nonpatent Document 5). The gene for DYRK1A is located in the Down syndrome critical region, and it has been reported that mice overexpressing DYRK1A exhibit neuropsychiatric dysfunction and show Down syndrome-like features (Nonpatent Document 6). It has also been reported that DYRK1A expression is increased in the brains of patients with Down syndrome and Down syndrome-like model mice (Nonpatent Document 7). These reports suggest that DYRK1A is involved in the onset of neurological symptoms in patients with Down syndrome (Nonpatent Document 8). In addition, it has been reported that early-onset Alzheimer's disease occurs frequently in patients with Down syndrome, thus indicating that DYRK1A is closely related to Alzheimer's disease (Nonpatent Document 8). Therefore, compounds inhibiting DYRK1A are considered useful for treating neuropsychiatric diseases such as Alzheimer's disease, Down 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 regulates the expression of epidermal growth factor receptor (EGFR) (Nonpatent Document 9). Therefore, compounds inhibiting DYRK1A are considered useful for treating EGFR-dependent cancers by suppressing the proliferation of cancer cells in EGFR-dependent brain tumors and other tumors. Compounds inhibiting the family enzymes DYRK1B, DYRK2, and DYRK3 are also considered to have various pharmaceutical applications. For example, it has been reported that DYRK1B is highly expressed in quiescent (G0- phase) cancer cells and contributes to resistance to various chemotherapeutic agents (Nonpatent Document 10). It has also been reported that inhibition of DYRK1B promotes withdrawal from the G0-phase and enhances sensitivity to chemotherapeutic agents (Nonpatent Document 11). Therefore, compounds inhibiting DYRK1B are considered useful for treating pancreatic cancer, ovarian cancer, osteosarcoma, colorectal cancer, and lung cancer (Nonpatent Documents 11, 12, 13, 14, and 15). It is suggested that DYRK2 controls p53 to induce apoptosis in response to DNA damages (Nonpatent Document 16). Furthermore, it has been reported that compounds inhibiting DYRK3 are useful for treating sickle cell anemia and chronic renal disease (Nonpatent Document 17). Compounds that inhibit DYRK, such as compounds containing a benzothiazole ring, have been reported (Patent Documents 1 to 5).  However, derivatives containing the dihydroquinazolinone scaffold of the present invention have not been disclosed therein. CITATION LIST PATENT DOCUMENT

[0004] Patent Document 1: WO 2021 / 153665 pamphlet Patent Document 2: WO 2022 / 059778 pamphlet Patent Document 3: WO 2022 / 059779 pamphlet Patent Document 4: WO 2023 / 008470 pamphlet Patent Document 5: WO 2023 / 008472 pamphlet NONPATENT DOCUMENT

[0005] Nonpatent Document 1: Becker W. et al., J. Biol. Chem., 1998, 273, 25893-25902 Nonpatent Document 2: Kimura R. et al., Hum. Mol. Genet., 2007, 16, 15-23 Nonpatent Document 3: Ryoo SR. et al., J. Biol. Chem., 2007, 282, 34850-34857 Nonpatent Document 4: Narendra D. et al., J. Cell. Biol., 2008, 183, 795-803 Nonpatent Document 5: Im E., J. Neurochem., 2015, 134, 756 768 Nonpatent Document 6: Branchi I. et al., J. Neuropathol. Exp. Neurol., 2004, 63, 429-440 Nonpatent Document 7: Dowjat WK. et al., Neurosci. Lett., 2007, 413, 77-81 Nonpatent Document 8: Wegiel J. et al., FEBS J., 2011, 278, 236-245 Nonpatent Document 9: Pozo N. et al., J. Clin. Invest., 2013, 123, 2475-2487. Nonpatent Document 10: Deng X. et al., Cancer Res., 2006, 66, 4149-4158. Nonpatent Document 11: Ewton DZ. et al., Mol. Cancer Ther., 2011, 10, 2104-2114. Nonpatent Document 12: Deng X. et al., Genes Cancer., 2014, 201-211 Nonpatent Document 13: Yang C. et al., Carcinogenesis., 2010, 31, 552-558 Nonpatent Document 14: Jin K. et al., J. Biol. Chem., 2009, 284, 22916-22925 Nonpatent Document 15: Gao J et al., Cancer Cell Int. 2013, 13, 2 Nonpatent Document 16: Taira N. et al., Mol. Cell., 2007, 25, 725-738 Nonpatent Document 17: Bogacheva O. et al., J. Biol. Chem., 2008, 283, 36665-36675 SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0006] An object of the present invention is to provide a novel compound that has a DYRK inhibitory activity and is useful as a medicament. MEANS TO SOLVE THE PROBLEMS

[0007] The object of the present invention is achieved by the following (1) to (19). (1) A dihydroquinazolinone derivative represented by the following formula (I): (wherein R1, R2 , R3, and R4 each independently represent a hydrogen atom, an optionally substituted lower alkyl group, 5    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 nonaromatic heterocyclic group, a halogen atom, a cyano group, an 10    optionally substituted alkylsulfonyl group, a nitro group, an optionally substituted amino group, an optionally substituted phenyl group, or an optionally substituted heteroaryl group; R5 represents a hydrogen atom or a lower alkyl group; 15    and Q represents the following structure (a),  (b), or (c)) (b) or a pharmaceutically acceptable salt thereof.

[0008] (2) The dihydroquinazolinone derivative according to the above (1) or a pharmaceutically acceptable salt thereof, wherein Q is the structure (a) in the above formula (I). (3) The dihydroquinazolinone derivative according to the above (1) or a pharmaceutically acceptable salt thereof, wherein Q is the structure (b) in the above formula (I). (4) The dihydroquinazolinone derivative according to the above (1) or a pharmaceutically acceptable salt thereof, wherein Q is the structure (c) in the above formula (I). (5) The dihydroquinazolinone derivative according to any one of the above (1) to (4) or a pharmaceutically acceptable salt thereof, wherein R5 is a hydrogen atom in the above formula (I). (6) The dihydroquinazolinone derivative according to any one of the above (1) to (5) or a pharmaceutically acceptable salt thereof, wherein R1, R2 , R3, and R4 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 nonaromatic heterocyclic group, a halogen atom, an optionally substituted amino group, or an optionally substituted heteroaryl group in the above formula (I). (7) The dihydroquinazolinone derivative according to any one of the above (1) to (6) or a pharmaceutically acceptable salt thereof, wherein R1 and R3 are each a hydrogen atom in the above formula (I). (8) The dihydroquinazolinone derivative according to any one of the above (1) to (7) or a pharmaceutically acceptable salt thereof, wherein R2 is a fluorine atom, and R4 is an optionally substituted cycloalkenyl group, an optionally substituted nonaromatic heterocyclic group, an optionally substituted amino group, or an optionally substituted heteroaryl group in the above formula (I).

[0009] (9) The compound according to any one of (1) to (8) selected from the following compound group or a pharmaceutically acceptable salt thereof: 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 the dihydroquinazolinone derivative according to any one of the above (1) to (9) or a pharmaceutically acceptable salt thereof as an active ingredient. (11) A pharmaceutical composition comprising the dihydroquinazolinone derivative according to any one of the above (1) to (9) or a pharmaceutically acceptable salt thereof as an active ingredient. (12) A therapeutic agent and / or a prophylactic agent for a disease involving DYRK, comprising the dihydroquinazolinone derivative according to any one of the above (1) to (9) or a pharmaceutically acceptable salt thereof as an active ingredient. (13) The therapeutic agent and / or the prophylactic agent according to the above (12), wherein the disease involving DYRK is frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down syndrome, depression, and their associated mental retardation, memory impairment, memory loss, learning disability, intellectual disability, cognitive dysfunction, mild cognitive impairment, treatment of dementia symptom progression or prevention of dementia onset, or brain tumor, pancreatic cancer, ovarian cancer, osteosarcoma, colorectal cancer, lung cancer, bone resorption disease, osteoporosis, sickle cell anemia, chronic renal disease, or bone resorption disease. (14) A method for treating and / or preventing a disease involving DYRK, comprising administering a therapeutically effective amount of the dihydroquinazolinone derivative according to any one of the above (1) to (9) or a pharmaceutically acceptable salt thereof to a patient in need of treatment. (15) Use of the dihydroquinazolinone derivative according to any one of the above (1) to (9) or a pharmaceutically acceptable salt thereof, for producing a therapeutic agent and / or a prophylactic agent for a disease involving DYRK. (16) The dihydroquinazolinone derivative according to any one of the above (1) to (9) or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease involving DYRK. (17) A medicament comprising a combination of the medicament according to the above (10), and at least one or more agents selected from agents classified into an anticancer agent, an antipsychotic drug, an antidementia drug, an antiepileptic drug, an antidepressant drug, a gastrointestinal drug, a thyroid hormone drug, or an antithyroid drug. (18) The medicament according to the above (10), for treating frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down syndrome, depression, and their associated complication, mental retardation, memory impairment, memory loss, learning disability, intellectual disability, cognitive dysfunction, mild cognitive impairment, treatment of dementia symptom progression or prevention of dementia onset, or brain tumor, pancreatic cancer, ovarian cancer, osteosarcoma, colorectal cancer, lung cancer, bone resorption disease, osteoporosis, sickle cell anemia, chronic renal disease, or bone resorption disease, in combination with at least one or more agents selected from agents classified into an anticancer agent, an antipsychotic drug, an antidementia drug, an antiepileptic drug, an antidepressant drug, a gastrointestinal drug, a thyroid hormone drug, or an antithyroid drug. (19) A method for producing an intermediate tert-butyl [2- amino-6-(dimethylamino)-4-fluorobenzyl]carbamate comprising the following Steps 1 to 6, wherein Step 1 is a step in which methyl 5-fluoro-2-methyl-3-nitrobenzoate is reacted with N-bromosuccinimide and 1,1'-azobis(cyclohexane-1-carbonitrile) in a solvent to produce methyl 2-(bromomethyl)-5-fluoro-3-nitrobenzoate, Step 2 is a step in which the above methyl 2- (bromomethyl)-5-fluoro-3-nitrobenzoate is reacted with ditert-butyl iminodicarboxylate and cesium carbonate in a solvent to produce methyl 2-((bis(tert- butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoate, Step 3 is a step in which the above methyl 2- ((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoate is reacted with sodium hydroxide in a solvent to produce 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoic acid, Step 4 is a step in which the above 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoic acid is reacted with tert-butylalcohol, diphenylphosphoryl azide, and TEA in a solvent to produce tert-butyl (tertbutoxycarbonyl) (2-((tert-butoxycarbonyl)amino)4-fluoro-6-nitrobenzyl)carbamate, Step 5 is a step in which the above tert-butyl (tertbutoxycarbonyl) (2-((tert-butoxycarbonyl)amino)4-fluoro-6-nitrobenzyl)carbamate is reacted with palladium-activated carbon and paraformaldehyde in a solvent to produce tertbutyl (tert-butoxycarbonyl) (2-((tert-butoxycarbonyl)amino)-6-(dimethylamino)-4-fluorobenzyl)carbamate, and Step 6 is a step in which the above tert-butyl (tertbutoxycarbonyl) (2-((tert-butoxycarbonyl)amino)-6-(dimethylamino)-4-fluorobenzyl)carbamate is reacted with hydrochloric acid in a solvent, and then reacted with ditert-butyl dicarbonate to produce tert-butyl [2-amino-6- (dimethylamino)-4-fluorobenzyl]carbamate. EFFECT OF INVENTION

[0010] The present inventors have carried out various studies in order to solve the above problems and as a result, have found that the dihydroquinazolinone derivative represented by the above formula (1) and a pharmaceutically acceptable salt thereof have an excellent DYRK inhibitory activity, and have completed the present invention. The compound provided by the present invention is useful as a pharmaceutical (pharmaceutical composition) for prevention or treatment of a disease known to be associated with a DYRK1A-mediated abnormal cellular response, such as a psychiatric or neurologic disease such as Alzheimer's disease, Parkinson's disease, Down syndrome, or depression, and their associated mental retardation, memory impairment, memory loss, learning disability, intellectual disability, cognitive dysfunction, mild cognitive impairment, or a therapeutic drug for dementia symptom progression or a prophylactic drug for dementia onset, or further a tumor such as brain tumor. The compound provided by the present invention is, as an inhibitor of DYRK1B, useful as a pharmaceutical (pharmaceutical composition) for prevention or treatment of a tumor such as pancreatic cancer, ovarian cancer, osteosarcoma, colorectal cancer, or lung cancer. Further, the compound provided by the present invention is useful as a pharmaceutical (pharmaceutical composition) for prevention or treatment of bone resorption disease and osteoporosis because DYRK2 controls p53 in response to DNA damage and induces apoptosis. In addition, the compound provided by the present invention is, as an inhibitor of DYRK3, useful as a pharmaceutical (pharmaceutical composition) for prevention or treatment of sickle cell anemia, chronic renal disease, bone resorption disease, and osteoporosis. In addition, the compound provided by the present invention is, as a compound that inhibits DYRK, useful as a reagent for pathological imaging or a reagent for a basic experiment or for research related to the above diseases. Further, the compound provided by the present invention is useful because it inhibits DYRK with high selectivity relative to other kinases and can thereby reduce side effects caused by the inhibition of other kinases. Examples of such other kinases include CLK (Cdc2-like kinase), and if the compound exhibits high selectivity relative to CLK, it is expected to reduce bone marrow, immune, and gastrointestinal toxicities. BEST MODE FOR CARRYING OUT THE INVENTION

[0011] Hereinafter, the present invention is described in detail. The dihydroquinazolinone derivative of the present invention is a compound represented by the following formula (I): (wherein: R1, R2 , R3, and R4 each independently represent 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 nonaromatic 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; R5 represents a hydrogen atom or a lower alkyl group; and Q represents the following structure (a),  (b), or (c))

[0012] (b) The term "lower alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atom(s) (C1 -6 alkyl group). The lower alkyl group is preferably a "C1 -4 alkyl group", and more preferably a "C1- 3 alkyl group". Specific examples of "lower alkyl group" include a methyl group, an ethyl group, a n-propyl group, a 1-methylethyl group, a n-butyl group, a tert-butyl group, a 1-methylpropyl group, a 2-methylpropyl group, a 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, and a hexyl group.

[0013] The term "alkoxy group" means an oxy group substituted with the above "lower alkyl group" or a 3 to 6 membered cyclic alkyl group. The "alkoxy group" is preferably a "C1-6 alkoxy group", and more preferably a "C1-3 alkoxy group". Specific examples of "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" means a linear or branched unsaturated hydrocarbon group having 1 to 3 double bond(s) and 2 to 6 carbon atoms (C2-6 alkenyl group). The "alkenyl group" is preferably a "C2-5 alkenyl group", and more preferably a "C2-4 alkenyl group". Specific examples of "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" means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms. The "cycloalkyl group" is preferably a "C3-7 cycloalkyl group", and more preferably a "C3-6 cycloalkyl group". Specific examples of "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" means a cyclic hydrocarbon group having 3 to 10 carbon atoms and unsaturated bond(s). The "cycloalkenyl group" is preferably a "C3-7 cycloalkenyl group", and more preferably a "C3-6 cycloalkenyl group". Specific examples of "cycloalkenyl group" include a cyclopentenyl group, a cyclohexenyl group, and a cycloheptenyl group. The "acyl group" is represented by -CORA, wherein RA represents a hydrogen atom or a lower alkyl group.

[0017] The term "nonaromatic heterocyclic group" means a 3 to 8 membered saturated or partially unsaturated monocyclic heterocyclic group containing at least one heteroatom selected from the group of a nitrogen atom, a sulfur atom, and an oxygen atom. The "nonaromatic heterocyclic group" is preferably a 3 to 6 membered saturated heterocyclic group and partially unsaturated heterocyclic group, and more preferably a 5 or 6 membered heterocyclo group. Specific examples of "nonaromatic 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, and a thiomorpholinyl group. The "amino group" means -NRDRE, wherein RD and RE each independently represent a hydrogen atom or a C1-3 alkyl group. Specific examples of said amino group include -NH2, a methylamino group, and a dimethylamino group.

[0018] The term "halogen atom" refers to a chlorine atom (Cl), a bromine atom (Br), a fluorine atom (F), and an iodine atom (I), and especially a chlorine atom, a bromine atom, and a fluorine atom are preferable. The term "alkylsulfonyl group" means a sulfonyl group substituted with the above "lower alkyl group" or a 3 to 6 membered cyclic alkyl group. The "alkylsulfonyl group" is preferably a "C1 -5 alkylsulfonyl group", and more preferably a "C1 -4 alkylsulfonyl group". Specific examples of "alkylsulfonyl group" include a methanesulfonyl group, an ethanesulfonyl group, and a propylsulfonyl group.

[0019] The term "heteroaryl group" means a 5 to 10 membered heterocyclic aromatic group containing at least one heteroatom selected from the group of a nitrogen atom, a sulfur atom, and an oxygen atom. The "heteroaryl group" is preferably a 5 to 8 membered heteroaryl group, and more preferably a 5 or 6 membered heteroaryl group. Specific examples of "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] Regarding the "substituent" 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 nonaromatic heterocyclic group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted phenyl group, or an optionally substituted heteroaryl group, unless otherwise specified, one or more substituents of any kind may be present at any chemically possible position, and if there are two or more substituents, each substituent may be identical to or different from each other.

[0021] Specific examples of substituent of an optionally substituted lower alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, and an optionally substituted alkylsulfonyl group include a halogen atom, a C1-4 alkoxy group, a cyano group, and a hydroxy group, as well as a morpholinyl group, a hydroxyethoxy group, a benzyloxy group, and -NRB RC (wherein RB and RC are independently selected from a lower alkyl group and a cyanomethyl group). Examples of substituent of an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted nonaromatic heterocyclic group, an optionally substituted phenyl group, and an optionally substituted heteroaryl group include a C1-3 alkyl group, a halogen atom, a C1-4 alkoxy group, a cyano group, a hydroxy group, an oxo group, a hydroxyethyl group, and an ethoxycarbonyl group. An optionally substituted amino group means that RD and / or RE are / is an optionally substituted C1-3 alkyl group, and examples of substituent of said C1-3 alkyl group include a halogen atom and a benzyloxy group.

[0022] Also, examples of pharmaceutically acceptable salt of the compound (I) of the present invention include inorganic acid salts with hydrochloric acid, sulfuric acid, carbonic acid, phosphoric acid, or the like, and organic acid salts with fumaric acid, maleic acid, methanesulfonic acid, p- toluenesulfonic acid, or the like. Further, the present invention also encompasses alkaline metal salts with sodium, potassium, or the like, alkaline earth metal salts with magnesium, calcium, or the like, organic amine salts with lower alkylamine, lower alcoholamine, or the like, and basic amino acid salts with lysine, arginine, ornithine, or the like, as well as ammonium salt, and the like. The compound (I) of the present invention also encompasses various hydrates, solvates, and crystal polymorphs. The compound (I) of the present invention is optionally substituted with isotope(s) (for example D, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 35S, 18F, or 125I). The compound (I) of the present invention may have isomer(s), for example, depending on the type of substituent. The present description may describe the chemical structure of only one form of these isomers, but the present invention encompasses all isomers that may arise structurally (such as geometric isomers, stereoisomers, and tautomers), and also encompasses both individual isomers and mixtures thereof.

[0023] The compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be produced, for example, by the following methods. Note that in the production methods described below, if a defined group changes under the conditions of the methods or is unsuitable for carrying out the methods, the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be readily produced by using 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 the introduction of substituents, can also be altered as needed. The meanings of the abbreviations and symbols used in the following explanation are as follows. DCM: dichloromethane THF: tetrahydrofuran DMF: N,N-dimethylformamide TEA: triethylamine DMA: N,N-dimethylacetamide DMSO: dimethylsulfoxide CDI: 1,1’-carbonyldiimidazole DSC: N,N’-disuccinimidyl carbonate

[0024] [Production method of the compound (I) of the present invention] The compound of the present invention represented by formula (I) can be produced according to, for example, Scheme 1. [Scheme 1] (wherein R1 , R2 , R3, R4, R5, and Q are the same as defined in the above (I), and PG represents a protecting group.)

[0025] The compound (I) of the present invention can be produced by deprotecting the protecting group PG of the compound (II) and then cyclizing the product using a condensing agent. Namely, the compound (I) can be produced by deprotecting the protecting group PG of the compound (II) under conditions commonly used in organic chemistry to produce an amine compound, and reacting the amine compound with 1 to 10 molar equivalent(s), preferably 1 to 5 molar equivalent(s) of a condensing agent such as CDI and DSC in a solvent. The solvent may be any as long as it is inert to the reaction. The solvent is not specifically limited, but, for example, THF, DMF, DMA, or the like may be used, and preferably DMF may be used. The reaction can be carried out at a temperature range of 0°C to 100°C for several minutes to several days, but it can be preferably carried out at 0°C to 60°C for 10 minutes to 8 hours.

[0026] The compound (II), which is used as a starting material of Scheme 1, can be produced according to, for example, the method shown in Scheme 2. [Scheme 2] (wherein R1 , R2 , R3, R4, R5, and Q are the same as defined in the above (I), A represents -CH2 -, -O-, or -CH2 O-, and PG represents a protecting group.)

[0027] The compound (II) can be produced by treating the thiourea (III) with a brominating agent to cyclize it. Namely, the compound (II) can be produced by reacting the thiourea (III) with a brominating agent in a solvent under conditions commonly used in organic chemistry. The solvent may be any as long as it is inert to the reaction. The solvent is not specifically limited, but, for example, acetonitrile, DCM, or the like may be used. The bromination reaction can be carried out by, for example, a treatment with a large excess of acetic acid and 0.5 to 2 molar equivalent(s), preferably 0.9 to 1.2 molar equivalent(s) of bromine. Also as other bromination conditions, the reaction can also be carried out by a treatment with 1 to 20 molar equivalent(s), preferably 5 to 10 molar equivalents of sodium hydrogen carbonate, and 0.5 to 2 molar equivalent(s), preferably 0.9 to 1.2 molar equivalent(s) of a bromination reagent such as benzyltrimethylammonium tribromide. The reaction can be carried out at a temperature range of -20°C to 70°C for several minutes to several days, but it can be preferably carried out at 10°C to room temperature for 30 minutes to 16 hours.

[0028] The thiourea (III), which is used as a starting material of Scheme 2, can be produced according to, for example, the method shown in Scheme 3. [Scheme 3] PG      ozy^NCS hN          ^—a H2N    )-R5               ( V ) ( IV ) (wherein R1, R2, R3, R4, and R5 the above (I), A represents -CH represents a protecting group.) n x H o^n nh vR5 v- A  H )=( Ry^R4 ( III ) are the same as defined in 2-, -O-, or -CH2 O-, and PG

[0029] The thiourea (III) can be produced by reacting the aniline (IV) with the isothiocyanate (V). Namely, the thiourea (III) can be produced by reacting the isothiocyanate (V) with 0.5 to 5 molar equivalent(s), preferably 0.9 to 2 molar equivalent(s) of the aniline (IV) in a solvent in the presence or absence of a base. The solvent may be any as long as it is inert to the reaction. The solvent is not specifically limited, but, for example, ethanol or the like may be used. If necessary, a base such as sodium ethoxide may be added to accelerate the reaction. The reaction can be carried out at a temperature range of - 20°C to 70°C for several minutes to several days, but it can be preferably carried out at 0°C to 40°C for several hours to 24 hours.

[0030] The aniline (IV) and the isothiocyanate (V), which are used as starting materials of Scheme 3, can be obtained as commercially available products, or can be produced according to known methods or methods commonly used in organic synthetic chemistry. The compound (II), which is used as a starting material of Scheme 1, can also be produced according to, for example, the method shown in Scheme 4. [Scheme 4] (wherein R1 , R2 , R3, R4, R5, and Q are the same as defined in the above (I), A represents -CH2 -, -O-, or -CH2 O-, and PG represents a protecting group.)

[0031] The compound (II) can be produced by subjecting the compound (VI) to thiazole ring formation using reaction conditions of an Ullmann-type condensation conditions. Namely, the compound (II) can be produced by cyclization in a solvent in the presence of a copper catalyst and a ligand, if necessary with the addition of a base.  As the copper catalyst, 0.01 to 1 molar equivalent(s), preferably 0.01 to 0.1 molar equivalents of a copper salt such as copper(I) iodide may be used, and as the ligand, 0.01 to 1 molar equivalent(s), preferably 0.05 to 0.5 molar equivalents of a ligand such as 1,10-phenanthroline may be used. If necessary, a base such as potassium carbonate and cesium carbonate may be added to accelerate the reaction. The solvent may be any as long as it is inert to the reaction. The solvent is not specifically limited, but, for example, THF or the like may be used. The reaction can be carried out at a temperature range of 0°C to reflux temperature for several minutes to several days, but it can be preferably carried out at 0°C to 40°C for 16 hours.

[0032] The compound (VI), which is used as a starting material in Scheme 4, can be produced according to, for example, the method shown in Scheme 5. [Scheme 5] ( VII ) ( IV )                                                                                 ( VI ) (wherein R1 , R2 , R3, R4, and R5 are the same as defined in the above (I), A represents -CH2 -, -O-, or -CH2 O-, and PG represents a protecting group.) The compound (VI) can be produced by reacting the aniline (IV) with the compound (VII).

[0033] Namely, the compound (VI) can be produced by reacting the compound (VII) with 0.5 to 5 molar equivalent(s), preferably 0.9 to 2 molar equivalent(s) of the aniline (IV) in a solvent in the presence or absence of a base. The solvent may be any as long as it is inert to the reaction. The solvent is not specifically limited, but, for example, acetonitrile, DMSO, or the like may be used. If necessary, a base may be added to accelerate the reaction. The reaction can be carried out at a temperature range of -20°C to 200°C for several minutes to several days, but it can be preferably carried out at 0°C to 70°C for several hours to 3 days.

[0034] The compound (VII), which is used as a starting material of Scheme 5, can be obtained as a commercially available product, or can be produced according to known methods or methods commonly used in organic synthetic chemistry. Further, the above methods may be appropriately combined, and methods commonly used in organic synthetic chemistry (for example, cross-coupling reactions such as the Mitsunobu reaction, Sonogashira reaction, and Suzuki- Miyaura reaction; reactions for reducing unsaturated bonds; alkylation reaction, acylation reaction, carbamoylation reaction, and carbamation reaction of amino groups; oxidation reactions of alkylthio groups to sulfoxide groups or sulfone groups; and conversion reactions of hydroxyl groups to alkoxy groups or carbamate groups, or the reverse) may be carried out to produce the compound (I) of the present invention having a desired functional group at a desired position.

[0035] [Use of compound (I) of the present invention] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof of the present invention can be prepared in the form of a conventional pharmaceutical formulation (pharmaceutical composition), which is suitable for oral administration, parenteral administration, or local administration. Formulations for oral administration include solid formulations such as tablets, granules, powders, and capsules; and liquid formulations such as syrups. These formulations can be prepared by a conventional method. The solid formulations can be prepared by using conventional pharmaceutical carriers, for example, lactose; starches such as corn starch; crystalline celluloses such as microcrystalline cellulose; and hydroxypropyl cellulose, calcium carboxymethyl cellulose, talc, and magnesium stearate. Capsules can be prepared by encapsulating thus prepared granules or powders. Syrups can be prepared by dissolving or suspending the compound represented by formula (I) or a pharmaceutically acceptable salt thereof of the present invention in an aqueous solution containing sucrose, carboxymethyl cellulose, and the like. Formulations for parenteral administration include injections such as formulations for drip infusion. Injection formulations can also be prepared by a conventional method and can be appropriately incorporated into isotonic agents (for example, mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, and mannose), stabilizers (for example, sodium sulfite and albumin), and antiseptics (for example, benzyl alcohol and methyl p-oxybenzoate). The dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof of the present invention can vary depending on types and severity of disease; age, sex, and body weight of the patient; dosage form, and the like, and is usually within a range from 1 mg to 1,000 mg per day for adults. The compound or a pharmaceutically acceptable salt thereof can be administered once a day, or dividedly administered twice or three times a day through an oral or parenteral route. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof of the present invention, as a DYRK inhibitor, can also be used as a reagent for pathological imaging or a reagent for a basic experiment or for research related to the above diseases. EXAMPLES

[0036] The present invention will be more specifically described below by way of Examples, Test Examples, and the like, but the present invention is not limited to these Examples. Identification of the compound was carried out by hydrogen nuclear magnetic resonance spectrum (1H-NMR) and liquid chromatography / mass spectrometry (LC-MS).  1H-NMR was measured at 400 MHz unless otherwise specified, and exchangeable hydrogen may not be clearly observed depending on the compound and measurement conditions. The sign "br" means a broad signal (broad). LC-MS system was carried out by using an ACQUITY UPLC H-Class PLUS system and an ACQUITY UPLC BEH C18 column (130 A, 1.7 um, 2.1 mm x 30 mm) as liquid chromatography in a gradient mode (Solution A: 0.1% formic acid in water, Solution B: 0.1% formic acid in acetonitrile, Flow rate: 0.6 mL / min, 0.5 min; Solution B 10%, 3 min; Solution B 90%, 4 min; Solution B 90%, Detection UV: 220 nm and 254 nm, Column temperature: 40°C) or Gradient mode 2 (Solution A: 0.06% formic acid in water, Solution B: 0.06% formic acid in acetonitrile, Flow rate: 0.8 mL / min, 0 min; Solution B 2%, 1.3 min; Solution B 96%, Detection UV: 220 nm and 254 nm, Column temperature: 40°C) only when specified as "Gradient mode 2" to measure a retention time, and mass spectrometry was carried out by using an ACQUITY QDa detector according to an electrospray ionization method to measure a mass. HPLC preparative chromatography was carried out by using a commercially available ODS column in a gradient mode using water / methanol or water / acetonitrile (containing formic acid) as eluents, unless otherwise specified. When the bond of the substituent at an optically active center of a compound is indicated by a wavy line, it indicates that the compound is a mixture of R and S forms with respect to the stereochemistry at a substitution position thereof; and when the bond of the substituent at an optically active center is indicated by a solid line, it indicates that the compound is an R or S form for a substitution position thereof. Each enantiomer was obtained appropriately as a single compound by optical resolution.

[0037] Reference Example 1 Production of 5-bromo-4-isothiocyanate-2,3-dihydrobenzofuran Br qV^NCS To a solution of 1,1’-thiocarbonyldi-2(1H)-pyridone (940 mg, 4.39 mmol) in chloroform (8.5 mL) was added 5-bromobenzo[d][1,3]dioxol-4-amine (825 mg) at room temperature, and the resulting mixture was stirred at room temperature for 5 hours. To the reaction mixture was added water, and the resulting mixture was subjected to extraction with chloroform. The resulting organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (928 mg). 1H-NMR (CDCI3 ) 6 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 Production of 5-bromo-4-isothiocyanatebenzo[d][1,3]dioxole Br O^y^NCS 5-Bromobenzo[d][1,3]dioxol-4-amine (8.55 g, 39.58 mmol) was used in a similar reaction to the method described in the Reference Example 1 to give the title compound (yield: 9.76 g). 1H-NMR (DMSO-d6) 6 7.18 (1H, d, J = 8.4 Hz), 6.91 (1H, d, J = 8.4 Hz), 6.22 (2H, s).

[0039] Reference Example 3 Production of 6-bromo-5-isothiocyanate-2,3- dihydrobenzo[b][1,4]dioxin (Step 1) 6-Bromo-2,3-dihydrobenzo[b][1,4]dioxin (4 g, 18.6 mmol) was dissolved in dehydrated THF (186 mL), cooled to -78°C, then LDA (11.16 mL, 22.32 mmol, 2.0 M in THF / heptane / ethylbenzene) was added dropwise thereto, and the resulting mixture was stirred at -78°C for 15 minutes. Crushed dry ice (50 g) was added to the reaction mixture, the resulting mixture was stirred at -78°C for 15 minutes, then warmed to room temperature, and additionally stirred overnight. To the reaction mixture was added 1 M hydrochloric acid (200 mL), and the resulting mixture was subjected to extraction with ethyl acetate. The resulting organic layer was subjected to extraction with 1 M aqueous solution of sodium hydroxide (100 mL), to the resulting aqueous layer was added concentrated hydrochloric acid to acidize it, and then the resulting mixture was subjected to extraction with chloroform. The resulting organic layer was washed with a saturated brine 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-carboxylic acid (yield: 2.83 g). 1H-NMR (DMSO-d6) 5 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) To a solution of 6-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylic acid (2.85 g, 11 mmol) in THF (27.5 mL) were added TEA (1.687 mL, 12.1 mmol) and diphenylphosphoryl azide (2.61 mL, 12.1 mmol), and the resulting mixture was stirred at room temperature for 3 hours.  To the reaction mixture was added water (3.96 mL), and the resulting mixture was stirred at 50°C for 3.5 hours.  The resulting insoluble matters were removed by Celite filtration, the resulting filtrate was diluted with ethyl acetate (150 mL), washed with a saturated brine 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). 1H-NMR (CDCl3) 5 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) 6-Bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (2.35 g, 10.21 mmol) was used in a similar reaction to the method described in the Reference Example 1 to give the title compound (yield: 1.95 g). 1H-NMR (DMSO-d6) 5 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 Production of 1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)-3,4-dihydroquinazolin-2(1H)-one (Step 1) To a solution of tert-butyl (2-aminobenzyl)carbamate (376 mg, 1.69 mmol) in THF (11.3 mL) was added 4-isothiocyanate-2,3-dihydrobenzofuran (200 mg, 1.129 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, subjected to extraction with ethyl acetate, then the resulting organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, then 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). 1H-NMR (CDCI3 ) 5 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 solution of tert-butyl {2-[3-(2,3-dihydrobenzofuran-4-yl)thioureido]benzyl}carbamate (368 mg, 0.921 mmol) and sodium hydrogen carbonate (774 mg, 9.21 mmol) in chloroform (18.4 mL) was slowly added benzyltrimethylammonium tribromide (323 mg, 0.829 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The resulting insoluble matters were filtered, then the resulting 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). 1H-NMR (CDCl3) 5 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 a 4 M solution of hydrochloric acid in ethyl acetate (5 mL), and the resulting 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), TEA (0.23 mL,1.66 mmol) and DSC (142 mg, 0.553 mmol) were added thereto, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, subjected to extraction with ethyl acetate, then the resulting organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and then the resulting solid was dried under reduced pressure to give the title compound (yield: 126 mg). 1H-NMR (DMSO-d6) 5 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 Production of 1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)- 7-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (Step 1) To a solution of 2-amino-4-(trifluoromethyl)benzonitrile (0.5 g, 2.69 mmol) in THF (5 mL) was added dropwise a 1 M borane-THF complex (5.37 mL, 5.37 mmol) at 0°C, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0°C, and methanol was added thereto. The solvent was distilled away under reduced pressure to give 2-(aminomethyl)-5-(trifluoromethyl)aniline as a crude product (yield: 0.5 g). 1H-NMR (500 MHz, DMSO-d6) 5 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) To a solution of 2-(aminomethyl)-5-(trifluoromethyl)aniline (0.5 g, 2.63 mmol) in THF (10 mL) was added a solution of di-tert-butyl dicarbonate (0.3 mL, 1.31 mmol) in THF (5 mL), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, subjected to extraction with ethyl acetate, then the resulting organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away 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). 1H-NMR (DMSO-d6) 6 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) To a solution of tert-butyl [2-amino-4-(trifluoromethyl)benzyl]carbamate (360 mg, 1.4 mmol) in THF (10 mL) were added TEA (0.39 mL, 2.81 mmol) and 5-bromo-4- isothiocyanate-2,3-dihydrobenzofuran (Reference Example 1, 408 mg, 1.4 mmol), and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with water, subjected to extraction with ethyl acetate, then the resulting organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and then 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) 5 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) were added cesium carbonate (493 mg, 1.52 mmol), 1,10-phenanthroline (27 mg, 0.15 mmol), and copper iodide (14 mg, 0.08 mmol), and the resulting mixture was stirred at 60°C for 3 hours. The reaction mixture was diluted with ethyl acetate, and the resulting insoluble matters were subjected to Celite filtration. The resulting filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give tertbutyl {2-[(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)amino]-4-(trifluoromethyl)benzyl}carbamate (230 mg). 1H-NMR (DMSO-d6) 5 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 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 (5 mL) was added a 4 M solution of hydrochloric acid in ethyl acetate (2 mL), and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, then 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 thereto, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, subjected to extraction with ethyl acetate, then the resulting organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and then the resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give the title compound (yield: 90 mg). 1H-NMR (DMSO-d6) 5 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 Production 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 F (Step 1) To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (10 g, 42.7 mmol) in carbon tetrachloride (214 mL) were added N-bromosuccinimide (10.65 g, 59.8 mmol) and benzoyl peroxide (1.035 g, 1.068 mmol), and the resulting mixture was stirred at 80°C overnight. The reaction mixture was diluted with water, subjected to extraction with chloroform, then the resulting organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and then 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). 1H-NMR (CDCI3) 6 7.70 - 7.62  (m, 2H), 4.85 (s, 2H).

[0051] (Step 2) To a solution of 1-bromo-2-(bromomethyl)-5-fluoro-3- nitrobenzene (13.3 g, 42.5 mmol) in DMF (106 mL) was added phthalimide potassium salt (7.87 g, 42.5 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was added to water (600 mL) with vigorously stirring, and the precipitated solid was collected by filtration. The resulting 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). 1H-NMR (CDCl3) 6 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) To a solution of 2-(2-bromo-4-fluoro-6-nitrobenzyl)isoindoline-1,3-dione (12.3 g, 32.4 mmol) in ethanol (649 mL) was added hydrazine monohydrate (7.89 mL, 162 mmol), and the resulting mixture was stirred at 90°C overnight. The resulting insoluble matters in the reaction mixture were removed by filtration, and the resulting filtrate was concentrated under reduced pressure to give (2-bromo-4-fluoro-6-nitrophenyl)methaneamine as a crude product (yield: 7.92 g). 1H-NMR (CDCls) 5 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) To a solution of (2-bromo-4-fluoro-6-nitrophenyl)methaneamine (7.92 g, 31.8 mmol) in THF (159 mL) were added diisopropylethylamine (5.83 ml, 33.4 mmol) and di-tert-butyl dicarbonate (7.75 mL, 33.4 mmol), and the resulting mixture was stirred at room temperature overnight. 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). 1H-NMR (CDCI3) 6 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 of tert-butyl (2-bromo-4-fluoro-6-nitrobenzyl)carbamate (9.51 g, 27.2 mmol) in ethanol (360 mL) were added water (176 mL), ammonium chloride (728 mg, 13.62 mmol), and iron powder (15.21 g, 272 mmol), and the resulting mixture was stirred at 80°C for 2 hours. The resulting insoluble matters were removed by Celite filtration, and the resultant was concentrated under reduced pressure. The resulting residue was washed by suspending in water to give tert-butyl (2-amino-6-bromo-4-fluorobenzyl)carbamate (yield: 8.43 g). 1H-NMR (CDCl3) 6 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) To a solution of tert-butyl (2-amino-6-bromo-4-fluorobenzyl)carbamate (700 mg, 2.193 mmol) in acetonitrile (20 mL) was added 5-bromo-4- isothiocyanatebenzo[d][1,3]dioxole (Reference Example 2, 515 mg, 1.994 mmol), and the resulting mixture was stirred at 50°C for 2 days. The reaction mixture was diluted with ethyl acetate, sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, then the resulting residue was washed by suspending in a mixed solvent of hexane and ethyl acetate, and the resulting 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). 1H-NMR (DMSO-d6) 6 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 resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, sequentially washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and then 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). 1H-NMR (DMSO-d6) 5 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 solution 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) in 1,4-dioxane (20 mL) was added a 4 M solution of hydrochloric acid in 1,4-dioxane (20 mL), and the resulting 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 (20 mL), TEA (1.938 mL, 13.9 mmol) and DSC (356 mg, 1.390 mmol) were added thereto, and the resulting 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 resulting solid was washed by suspending in a mixed solvent of methanol and diethyl ether, and dried under reduced pressure to give the title compound (yield: 540 mg). 1H-NMR (DMSO-d6) 5 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 Production 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 O S    / —NH To a solution 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) in 1,4-dioxane (0.987 mL) were added 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), and the resulting mixture was stirred at 100°C for 1 hour. The reaction mixture was diluted with water, subjected to extraction with ethyl acetate, then the resulting organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and then the resulting residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (yield: 37 mg). 1H-NMR (DMSO-d6) 5 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, J = 8.3 Hz, 1H), 6.16 - 6.09 (m, 3H), 4.93 - 4.85 (m, 2H), 4.85 - 4.77  (m, 2H), 4.42 - 4.37 (m, 2H). LCMS (m / z): 412.07 [M+H]+ .

[0059] Example 5 Production 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 O O O F 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 a mixed solvent of ethyl acetate / ethanol (1:1, 60 mL), 10% palladium-activated carbon (150 mg, 0.141 mmol) was added thereto, and the resulting mixture was stirred under hydrogen atmosphere at room temperature overnight. The resulting insoluble matters were removed by Celite filtration, and the resulting 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) 6 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 Production 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) To a solution of 5-fluoro-N,N,2-trimethyl-3- nitroaniline (1.467 g, 7.4 mmol) in DMF (12.67 mL) were added pyrrolidine (0.673 ml, 8.14 mmol) and N,N-dimethylformamide dimethyl acetal (1.982 ml, 14.8 mmol), and the resulting mixture was stirred under nitrogen atmosphere in a sealed tube at 70°C for 3 hours.  The same procedure was repeated three times, the resulting reaction mixtures were combined, and concentrated under reduced pressure.  The resulting residue was diluted with ethyl acetate, then sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, then the resulting residue was dissolved in THF (79 mL), TEA (6.19 ml, 44.4 mmol), sodium periodate (14.25 g, 66.6 mmol), and water (50 mL) were added thereto, and the resulting mixture was stirred at 50°C overnight. The resulting insoluble matters were removed by Celite filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was diluted with a mixed solvent of ethyl acetate and hexane, sequentially washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium hydrogen carbonate, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and then 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). 1H-NMR (CDCI3) 5 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) To a solution of 2-(dimethylamino)-4-fluoro-6-nitrobenzaldehyde (0.8 g, 3.77 mmol) in THF (37.7 mL) were added tetraethyl orthotitanate (1.581 ml, 7.54 mmol) and tert-butylsulfinamide (0.594 g, 4.9 mmol), and the resulting mixture was stirred under nitrogen atmosphere at room temperature overnight. To the reaction mixture was added saturated brine under ice-cooling, and then ethyl acetate was added thereto at room temperature. The resulting insoluble matters were removed by Celite filtration, then the resulting filtrate was concentrated, and the resulting residue was subjected to extraction with ethyl acetate. The resulting organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the resulting solid was washed by suspending in water to give N-[2- (dimethylamino)-4-fluoro-6-nitrobenzylidene]-2-methylpropane-2-sulfinamide (yield: 929 mg). 1H-NMR (CDCl3) 5 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 solution of N-[2-(dimethylamino)-4-fluoro-6-nitrobenzylidene]-2-methylpropane-2-sulfinamide (0.928 g, 2.94 mmol) in methanol (90 mL) was added sodium borohydride (367 mg, 9.71 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 90 minutes. Then, in order to complete the reaction, sodium borohydride (80 mg, 2.12 mmol) was additionally added thereto, and the resulting mixture was stirred at room temperature for additional 1 hour. The reaction mixture was concentrated under reduced pressure, to the resulting residue was added saturated brine, and the resulting mixture was subjected to extraction with ethyl acetate. The resulting organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate.  The solvent was distilled away 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 (CDCI3 ) 5 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 solution of N-[2-(dimethylamino)-4-fluoro-6-nitrobenzyl]-2-methylpropane-2-sulfinamide (crude product, 932 mg, 2.935 mmol) in 1,4-dioxane (8 mL) were added methanol (8 mL) and a 4 M solution of hydrochloric acid in 1,4-dioxane (8 mL), and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, then the resulting solid was dissolved in DMF (30 mL), TEA (4.08 ml, 29.3 mmol) and di-tert-butyl dicarbonate (0.816 ml, 3.52 mmol) were added thereto, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, subjected to extraction with ethyl acetate, then the resulting organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and then 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). 1H-NMR (CDCI3) 5 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 solution of tert-butyl [2-(dimethylamino)-4-fluoro-6-nitrobenzyl]carbamate (918 mg, 2.93 mmol) in methanol (30 mL) was added a suspension of 10% palladium-activated carbon (100 mg) in 1,4-dioxane (1 mL), and the resulting mixture was stirred under hydrogen atmosphere at room temperature overnight. The resulting insoluble matters were removed by Celite filtration, and then the resulting filtrate was concentrated under reduced pressure to give tert-butyl [2-amino-6-(dimethylamino)-4-fluorobenzyl]carbamate as a crude product (yield: 829 mg). 1H-NMR (CDCI3) 5 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) 6-Bromo-5-isothiocyanate-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) were used in a similar reaction to the method described in the Step 6 of Example 3 to give tert-butyl {2-[3-(6-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)thioureido]-6-(dimethylamino)-4-fluorobenzyl}carbamate (yield: 186 mg). 1H-NMR (DMSO-d6) 6 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) 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) was used in a similar reaction to the method described in the Step 7 of Example 3 to give 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 (yield: 152 mg). 1 H-NMR (DMSO-d6 ) 6 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) 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) was used in a similar reaction to the method described in the Step 8 of Example 3 to give the title compound (yield: 120 mg). 1H-NMR (DMSO-d6) 6 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 = 2.4, 11.0 Hz, 1H), 4.40 - 4.26 (m, 4H), 4.24 (d, J = 2.4 Hz, 2H), 2.68 (s, 6H). LCMS (m / z): 401.12  [M+H]+ .

[0068] Alternative production method up to Step 5 in Example 6 (Step 1) To a solution of methyl 5-fluoro-2-methyl-3-nitrobenzoate (25 g, 117 mmol) in chlorobenzene (325 mL) were added N-bromosuccinimide (41.7 g, 234 mmol) and 1,1'-azobis(cyclohexane-1-carbonitrile) (2.9 g, 11.7 mmol), and the resulting mixture was stirred at 110°C for 5 hours. After cooled to room temperature, to the reaction mixture was added a 5% aqueous solution of sodium thiosulfate, and the resulting mixture was subjected to extraction with chloroform. The resulting organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to give methyl 2-(bromomethyl)-5-fluoro-3-nitrobenzoate as a crude product (yield: 42.7 g). 1H-NMR (CDCl3) 6: 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) To a solution of methyl 2-(bromomethyl)-5-fluoro-3-nitrobenzoate (crude product, 42.7 g, 117 mmol) in acetonitrile (234 mL) were added di-tert-butyl iminodicarboxylate (25.4 g, 117 mmol) and cesium carbonate (76.2 g, 234 mmol), and the resulting mixture was stirred at 40°C to 50°C for 6 hours. After cooled to room temperature, to the reaction mixture was added Celite (50 g), the resulting insoluble matters were removed by Celite filtration, and the resultant was washed with ethyl acetate. The solvent was distilled away under reduced pressure to give methyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoate as a crude product (yield: 61.1 g). 1H-NMR (CDCI3) 5: 7.60—7.55 (m, 2H), 5.21 (s, 2H), 3.94 (s, 3H), 1.40 (s, 18H).

[0070] (Step 3) To a solution of methyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-fluoro-3-nitrobenzoate (crude product, 61.1 g, 97.4 mmol) in methanol / THF (120 mL / 120 mL) was added dropwise a 2 M aqueous solution of sodium hydroxide (97 mL) under ice-cooling, and the resulting mixture was stirred under ice-cooling for 7 hours. A 2 M aqueous solution of hydrochloric acid (200mL) was added dropwise thereto under ice-cooling, and then the resulting mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure to give 2-((bis(tert-butoxycarbonyl)amino)methyl)- 5-fluoro-3-nitrobenzoic acid as a crude product (yield: 59.2 g). 1H-NMR (DMSO-d6) 5: 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 subjected to azeotropic evaporation with toluene (160 mL) three times, and then dissolved in toluene (468 mL). Tertbutylalcohol (44.4 mL, 468 mmol), diphenylphosphoryl azide (30.9 g, 112 mmol), and TEA (19.5 mL, 140 mmol) were added thereto, and the resulting mixture was stirred at 80°C for 4 hours. After cooled to room temperature, the reaction mixture was sequentially washed with a 0.5 M aqueous solution of hydrochloric acid, saturated sodium hydrogen carbonate water, and water. The resulting saturated aqueous sodium hydrogen carbonate layer and aqueous layer were each subjected to Celite filtration, washed with toluene, and then separated. The combined organic layer was concentrated under reduced pressure, and then 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) 5: 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) were added 10% palladium-activated carbon (3.50 g) and paraformaldehyde (2.16 g, 71.9 mmol), and the resulting mixture was stirred under hydrogen atmosphere at room temperature for 4 hours. The resulting insoluble matters were removed by Celite filtration, then the resulting filtrate was concentrated under reduced pressure, and subjected to azeotropic evaporation with toluene. The resulting residue was dissolved in ethyl acetate, the resulting insoluble matters were removed by Celite filtration, and the resulting 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). 1H-NMR (CDCI3 ) 6: 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) To tert-butyl (tert-butoxycarbonyl) (2-((tert-butoxycarbonyl)amino)-6-(dimethylamino)-4-fluorobenzyl)carbamate (25.7 g, 53.1 mmol) was added a 4 M solution of hydrochloric acid in ethyl acetate (530 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with hexane, and the precipitated solid was collected by filtration. To the resulting solid were added methanol (200 mL) and TEA (36.8 mL, 265.5 mmol), and the resulting mixture was stirred at room temperature for 20 minutes. A solution of di-tert-butyl dicarbonate (5.79 g, 26.5 mmol) in methanol (12 mL) was added thereto, the resulting mixture was stirred for 1 hour, then a solution of di-tert-butyl dicarbonate (3.47 g, 15.9 mmol) in methanol (10 mL) was added thereto, and the resulting mixture was stirred for 1 hour. Additionally, a solution of di-tert-butyl dicarbonate (382 mg, 1.75 mmol) in methanol (10 mL) was added thereto, the resulting mixture was stirred for 1 hour, and then solvent was distilled away under reduced pressure. To the resulting residue were added ethyl acetate and saturated sodium hydrogen carbonate water to separate the mixture, and extraction with ethyl acetate was carried out. The resulting organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate). The resulting solid was washed by suspending in hexane, and dried under reduced pressure to give tert-butyl [2-amino-6- (dimethylamino)-4-fluorobenzyl]carbamate (yield: 11.8 g).

[0074] Each of the following compounds of Examples 7 to 76 in [Table 1-1], compounds of Examples 78 to 106 in [Table 12], and compounds of Examples 108 to 126 in [Table 1-3] was produced by using a corresponding starting material (a commercially available product, or a compound derivatized from a commercially available compound by known methods or equivalent methods thereof), according to the above methods in Examples, if necessary, by appropriately combining methods commonly used in organic synthetic chemistry. Further, the physicochemical data of each compound is shown in [Table 2]. In the tables, when the bond of the substituent at an optically active center of a compound is indicated by a wavy line, it indicates that the compound is a mixture of R and S forms with respect to the stereochemistry at a substitution position thereof; and 5    when the bond of the substituent at an optically active center is indicated by a solid line, it indicates that the compound is an R or S form for a substitution position thereof. Each enantiomer was obtained appropriately as a single compound by optical resolution by supercritical 10    fluid chromatography using a chiral column.

[0075] [Table 1-1] Example Structural formula Compound name 7 0 y—NH Jf T / >-N ) M \__1        c A—F 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-fluoro-3,4-dihydroquinazolin -2(1H)-one 8 0 y—NH fj T N ) N-O 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-8-methyl-3,4-dihydroquinazolin -2(1H)-one 9 XXX 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-3,4-dihydroquinazolin -2(1H)-one 10 0 y—NH If T / >-N > °C / N o F 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-6-fluoro-3,4-dihydroquinazolin -2(1H)-one 11 O y—NH —oz 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-methoxy-3,4- dihydroquinazolin -2(1H)-one 12 0 y—NH 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-methyl-3,4-dihydroquinazolin -2(1H)-one 13 z^cn xxx 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-6-methyl-3,4-dihydroquinazolin -2(1H)-one 14 o H T / >~N > N 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-methyl-3,4-dihydroquinazolin -2(1H)-one 15 0 y—NH £ T / ^N  ) 0^n M 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-8-fluoro-3,4-dihydroquinazolin -2(1H)-one 16 I _____ iyo CD z 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-8-methoxy-3,4- dihydroquinazolin -2(1H)-one 17 O y—NH 0— 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-6-methoxy-3,4- dihydroquinazolin -2 (1H)-one 18 0 / —NH f X / >-\ ) M \__1         <\ / )-0 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-methoxy-3,4- dihydroquinazolin -2 (1H)-one 19 0 y—NH J T / >-N ) °J^N )=\ '--- / / 1 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-8- (dimethylamino)- 3,4- dihydroquinazolin -2(1H)-one 20 0 x^^S  y-NH N— 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-6- (dimethylamino)- 3,4- dihydroquinazolin -2(1H)-one 21 0 x^^- S    / —NH If T ) o^T N M / \ 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-(dimethylamino)-3,4- dihydroquinazolin -2 (1H)-one 22 0 y—NH y-'o —N \ 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-(dimethylamino)-3,4- dihydroquinazolin -2 (1H)-one 23 0 x^^-S   / —NH if T N ) F 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-methyl-3,4-dihydroquinazolin -2(1H)-one 24 O x^_-S  y—NH Cf 7-chloro-1-(7, 8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-3,4- dihydroquinazolin -2(1H)-one 25 0 y— NH f X / >-n ) °\2j N o Br 7-bromo-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-3,4-dihydroquinazolin -2(1H)-one 26 0 y—NH o2n 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-nitro-3,4-dihydroquinazolin -2(1H)-one 27 0 y—NH jf X ) \___1          4       Br 5-bromo-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-3,4-dihydroquinazolin -2(1H)-one 28 zx tn O    Y 11,0        1 'W 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7- (methylsulfonyl)-3,4- dihydroquinazolin -2 (1H)-one 29 zx co O I XIT ZE 7-acetyl-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-3,4-dihydroquinazolin -2(1H)-one 30 XXJ —'1 r zX o-^ 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(morpholinomethyl )-3,4- dihydroquinazolin -2(1H)-one 31 32 33 34 35 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5- [(dimethylamino)m ethyl]-7-fluoro-3,4- dihydroquinazolin -2 (1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5- {[ethyl(methyl)am ino]methyl}-7-fluoro-3,4- dihydroquinazolin -2 (1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(methoxymethyl)-3,4- dihydroquinazolin -2(1H)-one 2-(1- (7, 8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-2-oxo-1,2,3,4- tetrahydroquinazo lin-5- yl)acetonitrile 2-({ [1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-2-oxo-1,2,3,4- tetrahydroquinazo lin-5- yl]methyl}(methyl )amino)acetonitri le 36 0 s   y—NH If JT / >—n   ) °CjN He / \3- / 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-[(2- hydroxyethoxy)met hyl]-3,4- dihydroquinazolin -2(1H)-one 37 0 y—NH if X ) °vJ N ?) HO— / 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7- (hydroxymethyl)- 3,4- dihydroquinazolin -2(1H)-one 38 T o cn^z 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(hydroxymethyl)-3,4- dihydroquinazolin -2(1H)-one 39 0 y—NH If X ) o^N >=\ \__ /        4 #“Br F 5-bromo-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-3,4-dihydroquinazolin -2(1H)-one 40 0 y— NH [I X       > °C / N ?> 0= / 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-2-oxo- 1,2,3,4- tetrahydroquinazo line-7- carbaldehyde 41 0 s   y— NH Il JL / >“Nv > O^J N M 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7- (fluoromethyl)- 3,4- dihydroquinazolin -2(1H)-one 42 .O 0 v XXI 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7- (morpholinomethyl )-3,4- dihydroquinazolin -2(1H)-one 43 0 s y—NH Jj T / >-N ) °Cj ?> NC 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-2-oxo-1,2,3,4- tetrahydroquinazo line-7- carbonitrile 44 0 y—NH jj T      X- vJ N ?> F (RS)-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-4-methyl-3,4-dihydroquinazolin -2(1H)-one 45 0 y—NH jj jT N > vJ N ?> F—( F 7- (difluoromethyl)-1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-3,4-dihydroquinazolin -2(1H)-one 46 0 y—NH J T ) M / \__1          <\ / )—N \ F 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin -2(1H)-one 47 0 y—NH N / \ 7—\ 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-(piperidin-1-yl)-3,4-dihydroquinazolin -2(1H)-one 5-[(3- 48 49 50 51 chloropropyl)amin o]-1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-3,4- dihydroquinazolin -2 (1H)-one (RS)-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5- (dimethylamino)-7-fluoro-4-methyl-3,4-dihydroquinazolin -2(1H)-one 5-(azetidin-1-yl)-1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-3,4- dihydroquinazolin -2(1H)-one 5-{[2- (benzyloxy)ethyl] (methyl)amino}-1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-3,4- dihydroquinazolin -2(1H)-one 52 53 (Enantiomer A of 49) 1- ([1,3]dioxolo[4’, 5’:5,6]benzo[1,2-d]thiazol-7-yl)-7-fluoro-3,4-dihydroquinazolin -2(1H)-one 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5- (dimethylamino)-7-fluoro-4-methyl-3,4- dihydroquinazolin -2 (1H)-one 54 (Enantiomer B of 49) 0 y—NH if T N V— df1 >=( / \__ /          <\ / / —N V_y \ F 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5- (dimethylamino)-7-fluoro-4-methyl-3,4-dihydroquinazolin -2(1H)-one 55 O y— NH If X ) °C / N F 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-vinyl-3,4-dihydroquinazolin -2(1H)-one 56 O S   T—NH if T / >- N   S O^T N X_ N    F y \ 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-[(2-fluoroethyl)(meth yl)amino]-3,4-dihydroquinazolin -2(1H)-one 57 XXJ T (RS)-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(1-hydroxyethyl)-3,4-dihydroquinazolin -2 (1H)-one 58 O y—NH If T / >-« ) o^y'N W / \__1             / / ~N\ HO—' 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5- (dimethylamino)- 7- (hydroxymethyl)-3,4- dihydroquinazolin -2 (1H)-one 59 0 If X > o'Y'" W , \ F—' 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5- (dimethylamino)-7-(fluoromethyl)-3,4- dihydroquinazolin -2(1H)-one 60 0 ^x_,S y—NH f X / >-n ) o^T'^ M / \ 1           / —N\ 0= / 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-(dimethylamino)-2-oxo-1,2,3,4-tetrahydroquinazo line-7-carbaldehyde 61 XXJ X / j; 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(prop-1-en-2-yl)-3,4- dihydroquinazolin -2 (1H)-one 62 0 ^x^-S     NH j 2 / )-^ ) M / =\ \___1                            °\ F 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(4- methoxyphenyl)-3,4- dihydroquinazolin -2(1H)-one 63 0 (f T ) \__ <\ / )-(7 । —         / / \^N F 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-3,4- dihydroquinazolin -2(1H)-one 64 0 S / —NH if T / >-N ) °Cj n ryT} F 5-(cyclohex-1-en-1-yl)-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-3,4-dihydroquinazolin -2(1H)-one 65 0 if T / >-N ) M \ /      4 A—N— F 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 66 0 ^5^,3   / —NH If T / >-N ) cAr'-N W \ /       4 A—o F 5-(3,6-dihydro-2H-pyran-4-yl) -1(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-3,4-dihydroquinazolin -2(1H)-one 67 0 s   y—NH f X ) oV'" w , \ F—( F 7- (difluoromethyl)-1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5- (dimethylamino)- 3,4- dihydroquinazolin -2(1H)-one 68 69 70 71 72 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5- (dimethylamino)-7- (trifluoromethyl) -3,4- dihydroquinazolin -2 (1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-isopropyl-3,4-dihydroquinazolin -2(1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin -2 (1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(2,2,6,6- tetramethyl-3,6-dihydro-2H-pyran-4-yl)-3,4- dihydroquinazolin -2 (1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(1H-pyrazol-4-yl)-3,4- dihydroquinazolin -2(1H)-one 73 74 75 76 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-3,4- dihydroquinazolin -2 (1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(1H-pyrazol-3-yl)-3,4- dihydroquinazolin -2(1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-2-oxo-1,2,3,4- tetrahydroquinazo line-5- carbonitrile 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-(3- fluoroazetidin-1-yl)-3,4- dihydroquinazolin -2(1H)-one

[0076] Example 77 Production of 1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)- 7-fluoro-5-(1-methylpiperidin-4-yl)-3,4-dihydroquinazolin- 5    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) 5    was dissolved in a mixed solvent of methanol / THF (1:1, 200 mL), 10% palladium-activated carbon (500 mg, 0.47 mmol) was added thereto, and the resulting mixture was stirred under hydrogen atmosphere at room temperature overnight. The resulting insoluble matters were removed by Celite 10    filtration, and the resulting 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]+, Retention time: 1.9 min 15

[0077] [Table 1-2] Example Structural formula 78 79 80 81 Compound name (RS)-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(4- hydroxycyclohex-1-en-1-yl)-3,4-dihydroquinazolin -2 (1H)-one 5- (5,6-dihydro-2H-pyran-3-yl)-1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-3,4-dihydroquinazolin -2 (1H)-one 5-(3,4-dihydro-2H-pyran-5-yl)-1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-3,4-dihydroquinazolin -2(1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(1-methyl-1H-imidazol-5-yl)-3,4- dihydroquinazolin -2(1H)-one 82 83 84 85 86 (Enantiomer A of 57) 87 (Enantiomer B of 57) 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-(4,5-dihydrofuran-3-yl)-7-fluoro-3,4-dihydroquinazolin -2 (1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-(2,5-dihydrofuran-3-yl)-7-fluoro-3,4-dihydroquinazolin -2(1H)-one 1- ([1,3]dioxolo[4’, 5’:5,6]benzo[1,2-d]thiazol-7-yl)-5- (dimethylamino)-7-fluoro-3,4-dihydroquinazolin -2 (1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-ethyl-7-fluoro-3,4- dihydroquinazolin -2 (1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(1-hydroxyethyl)-3,4- dihydroquinazolin -2(1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(1-hydroxyethyl)-3,4- dihydroquinazolin -2 (1H)-one 88 0 If T / >-n $ °Cj n ?=w 'F F (RS)-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(1-fluoroethyl)-3,4-dihydroquinazolin -2(1H)-one 89 0 y— NH ff T / >-N ) °Cjn O F 5-acetyl-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-3,4-dihydroquinazolin -2(1H)-one 90 0 y—NH £ T / >-N  ) N )=\ ^~\ \__1                        / °\ F (RS)-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(4- methoxycyclohex-1-en-1-yl)-3,4-dihydroquinazolin -2 (1H)-one 91 0 y—NH n d ^~n> ) oQf N )=(^^ \—Z'3^ F ethyl (RS)-4-(1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinazo lin-5- yl)cyclohex-3-enecarboxylate 92 F 93 O F 94 O F 95 96 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(1-methyl-1H- pyrrol-3-yl)-3,4-dihydroquinazolin -2 (1H)-one (RS)-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(tetrahydrofuran-3-yl)-3,4- dihydroquinazolin -2(1H)-one (RS)-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(tetrahydro-2H-pyran-3-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-(hydroxymethyl)-3,4- dihydroquinazolin -2 (1H)-one 1-(7,8- dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(1-methyl-1H- pyrazol-5-yl)-3,4- dihydroquinazolin -2(1H)-one 97 98 99 100 101 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-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(4- (hydroxymethyl)cy clohex-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- (tetrahydro-2H-pyran-4-yl)-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 102 0 y—NH Jf T     ) / y N k^O        / / YJ F—' 1-(7,8-dihydro- [1,4]dioxino[2’ ,3 ’ :5,6]benzo[1,2-d] thiazol-2-yl) -5-(4,5- dihydrofuran-3-yl)-7- (fluoromethyl)- 3,4- dihydroquinazolin -2 (1H)-one 103 0 S    / —NH (T T / >-N ) N F 5-(cyclopent-1-en-1-yl)-1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-3,4-dihydroquinazolin -2(1H)-one 104 0 NH f T / >-n $ 0^7 N F 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 105 0 y—NH jj T / >-N   ) V o / / ^N )=\ / 7° \   /          G / )-(7 i '—          / / \^N F          / 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-7-fluoro-3,4- dihydroquinazolin -2 (1H)-one 106 0 y—NH H 2 / >“Nx  >      / P p2 / N F 1-(7,8-dihydrobenzofuro[ 4,5-d]thiazol-2-yl)-7-fluoro-5-(3-oxocyclohex-1-en-1-yl)-3,4-dihydroquinazolin -2(1H)-one

[0078] Example 107 Production 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 a mixed solvent of ethanol / ethyl acetate (1:1, 60 mL), 10% palladium-activated carbon (300 mg, 0.282 mmol) was added thereto, and the resulting mixture was stirred under hydrogen atmosphere at room temperature overnight. The resulting insoluble matters were removed by Celite filtration, and the resulting 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 min

[0079] [Table 1-3] Example Structural formula Compound name 108 0 if T >-N ) r / y^ H F 1- ([1,3]dioxolo[4’,5’:5 , 6] benzo [1,2- d]thiazol-7-yl)-5- (3,4-dihydro-2H-pyran-5-yl)-7-fluoro-3,4- dihydroquinazolin-2(1H) -one 109 0 S    / —NH l! X / )-n ) N 0      r~^ F 1- ([1,3]dioxolo[4’,5’:5 , 6] benzo [1,2- d] thiazol-7-yl)-5-(5,6-dihydro-2H-pyran-3-yl)-7-fluoro- 3,4- dihydroquinazolin-2(1H) -one 110 0 s    / —NH ff X ) VT N 0      r~^ ' F 1- ([1,3]dioxolo[4’,5’:5 , 6] benzo [1,2- d] thiazol-7-yl)-5-(3,4-dihydro-2H-pyran-6-yl)-7-fluoro- 3,4- dihydroquinazolin-2(1H) -one 111 0 y—NH if T >-N ) <JN ^W'0 F 1- ([1,3]dioxolo[4’,5’:5 , 6] benzo [1,2- d] thiazol-7-yl)-5- (4,5-dihydrofuran-3- yl)-7-fluoro-3,4- dihydroquinazolin- 2(1H) -one 112 113 114 115 116 1-(7,8- dihydrobenzofuro[4,5-d]thiazol-2-yl)-5-(3-hydroxyazetidin-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-(1H-pyrazol-4-yl)-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 (cis / trans)-1-(7,8-dihydrobenzofuro[4,5-d]thiazol-2-yl)-7-fluoro-5-(4- hydroxycyclohexyl)- 3,4- dihydroquinazolin-2(1H)-one 117 0 S   y—NH If T / >-N ) ozrN M \__(5          4       Br F—' 1- ([1,3]dioxolo[4’,5’:5 , 6] benzo [1,2- d]thiazol-7-yl)-5- bromo-7- (fluoromethyl)-3,4-dihydroquinazolin-2(1H) -one 118 0 y—NH f T / >-N ) ^"°          / / V-o F—' 1- ([1,3]dioxolo[4’,5’:5 , 6] benzo [1,2- d] thiazol-7-yl)-5-(2,5-dihydrofuran-3- yl)-7-(fluoromethyl)- 3,4- dihydroquinazolin- 2(1H) -one 119 O S   y— NH £ J7 N ) O^N )=\ kx O   y / vO F 1-(7,8-dihydro- [1,4]dioxino[2’,3’ :5, 6]benzo[1,2- d] thiazol-2-yl)-5-(2,5-dihydrofuran-3-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H) -one 120 O S   y—NH £ JT >- N ) o^n o  W~vO F (RS)-1-(7,8-dihydro-[1,4]dioxino[2’,3‘:5, 6]benzo[1,2- d]thiazol-2-yl)-7-fluoro-5- (tetrahydrofuran-3- yl)-3,4- dihydroquinazolin-2(1H) -one 121 O S   y—NH £ JC N ) O^[  N   / \^~OX O          , /  \   / F 5- (3,4-dihydro-2H-pyran-5-yl)-1-(7,8-dihydro- [1,4]dioxino[2’,3’ :5, 6]benzo[1,2- d]thiazol-2-yl)-7- fluoro-3,4- dihydroquinazolin-2(1H) -one 122 O S      NH 1 X N ) o^"n  )=\ / / —\ O                   OH F (RS)-1-(7,8-dihydro-[1,4]dioxino[2’,3’:5, 6]benzo[1,2- d] thiazol-2-yl)-7-fluoro-5-(4- hydroxycyclohex-1-en-1-yl)-3,4- dihydroquinazolin-2(1H) -one 123 O S      NH 1 X N ) Ot" N  ? ( / 'Nx o   yjvN F 1-(7,8-dihydro- [1,4]dioxino[2’,3’ :5, 6]benzo[1,2- d] thiazol-2-yl)-7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinazolin- 2(1H) -one 124 O S y—NH jT X / >— N ) O^N / >=V#'X o    Y # yJ F 1-(7,8-dihydro- [1,4]dioxino[2’,3’ :5, 6]benzo[1,2- d]thiazol-2-yl)-7- fluoro-5-(3- oxocyclopent-1-en-1- yl)-3,4- dihydroquinazolin- 2(1H) -one 125 0 ^x_,S   / —NH / X ) y=\ / / —\ L .0      Y    \ / u \—o F 5- (5,6-dihydro-2H-pyran-3-yl)-1-(7,8-dihydro- [1,4]dioxino[2’,3’:5, 6]benzo[1,2- d]thiazol-2-yl)-7- fluoro-3,4- dihydroquinazolin-2(1H) -one 126 0 s    / —NH J X ) 1^0    \     2 F (RS)-1-(7,8-dihydro-[1,4]dioxino[2’,3’:5, 6]benzo[1,2- d] thiazol-2-yl)-7-fluoro-5-(tetrahydro-2H-pyran-3-yl)-3,4-dihydroquinazolin-2(1H) -one

[0080] Example 127 Production 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), a 98% solution of sulfuric acid (37.5 mg, 0.375 mmol) in methanol (375 mg) was added dropwise thereto, and the resulting mixture was stirred 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). 1H-NMR (DMSO-d6) 6: 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 = 11.0, 2.4 Hz, 1H), 5.43 (br s, 2H), 4.35-4.27 (m, 4H), 4.24-4.21 (m, 2H), 2.67 (s, 6H). LCMS (m / z): 401.11 [M+H]+, Retention time: 1.27 min (Gradient mode 2)

[0081] Example 128 Production 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), a 4 M solution of hydrochloric acid in ethyl acetate (0.281 mL, 1.12 mmol) was added dropwise thereto, and the resulting mixture was stirred 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). 1H-NMR (DMSO-d6) 5: 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 min (Gradient mode 2)

[0082] [Table 2] Example No. 1H NMR 5 (ppm) LCMS m / z [M+H]+ 7 (DMSO-d6)  5 8.24 (br. s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.37 - 7.25 (m, 2H), 7.06 (dt, J = 1.3, 8.4 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 4.65 (t, J = 8.8 Hz, 2H), 4.43 (d, J = 1.5 Hz, 2H), 3.40 (t, J = 8.8 Hz, 2H). 342.13 8 (DMSO-d6)  5 8.37 (br. s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.26 - 7.16 (m, 3H),  6.80 (d, J = 8.3 Hz, 1H), 4.58 (t, J = 8.8 Hz, 2H),  4.29  (s, 2H), 3.26  (t, J = 8.7 Hz, 2H),  1.91  (s, 3H). 338.17 9 (DMSO-d6) 5 8.32 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 2.4, 11.5 Hz, 1H), 7.41 - 7.35 (m, 1H), 7.06 (dt, J = 2.4, 8.4 Hz, 1H),  6.89  (d, J = 8.3 Hz, 1H), 4.64  (t, J = 8.8 Hz, 2H), 4.36 (s, 2H), 3.40 (t, J = 8.8 Hz, 2H). 342.13 10 (DMSO-d6)  5 8.27 (br. s, 1H), 7.76 (dd, J = 4.9, 9.0 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H) , 7.27 (dd, J = 2.8, 8.7 Hz, 1H), 7.16 (dt, J = 2.9, 8.8 Hz, 1H) ,  6.87 (d, J = 8.3 Hz, 1H), 4.63 (t, J = 8.9 Hz, 2H), 4.36 (d, J = 1.5 Hz, 2H),  3.37  (t, J = 8.7 Hz, 2H). 342.17 11 (DMSO-de) 5 8.26 (s, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H),  6.87  (d, J = 8.3 Hz, 1H), 6.79 (dd, J = 2.4, 8.3 Hz, 1H), 4.64  (t, J = 8.8 Hz, 2H) , 4.30 (s, 2H), 3.72 (s, 3H), 3.39 (t, J = 8.8 Hz, 2H). 354.17 12 (DMSO-d6)  6 8.18 (br. s, 1H), 7.72 (d, J = 8.3 Hz, 1H) , 7.44 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.00  (d, J = 7.3 Hz, 1H) , 6.89 (d, J = 8.6 Hz, 1H) , 4.64 (t, J = 8.7 Hz, 2H), 4.32 (s, 2H), 3.39 (t, J = 8.7 Hz, 2H), 2.27  (s,  3H). 338.24 13 (500 MHz, DMSO-d6) 6 8.20 (br. s, 1H), 7.70  (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H) , 7.15 (s, 1H), 7.12  (d, J = 8.5 Hz, 1H),  6.86  (d, J = 8.5 Hz, 1H) , 4.63 (t, J = 8.7 Hz, 2H), 4.31 (d, J = 0.9 Hz, 2H), 3.36 (t, J = 8.7 Hz, 2H), 2.31  (s, 3H). 338.23 14 (DMSO-d6)  6 8.13 (br. s, 1H), 7.73  (d, J = 8.6 Hz, 1H) , 7.24 (d, J = 8.4 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H),  6.90  (d, J = 8.6 Hz, 1H) , 4.63  (t, J = 8.8 Hz, 2H) , 4.34 (d, J = 2.0 Hz, 2H), 3.37 (t, J = 8.8 Hz, 2H), 2.28  (s, 3H). 338.17 15 (500 MHz, DMSO-d6) 6 8.40 (br. s, 1H), 7.67  (d, J = 8.2 Hz, 1H), 7.34 - 7.22 (m, 3H), 6.83 (d, J = 8.2 Hz, 1H), 4.59 (t, J = 8.7 Hz, 2H), 4.40  (s, 2H), 3.29 - 3.23 (m,  2H). 342.15 16 (500 MHz, DMSO-d6) 6 8.23 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.24  (t, J = 8.0 Hz, 1H) , 7.10 (d, J = 7.3 Hz, 1H), 6.98 (d, J = 7.0 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 4.58  (t, J = 8.9 Hz, 2H) , 4.30 (d, J = 1.5 Hz, 2H) , 3.58 (s, 3H), 3.26 (t, J = 8.9 Hz, 2H). 354.25 17 (DMSO-d6) 6 8.20 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 2.7 Hz, 1H),  6.89 (dd, J = 2.9,  9.0 Hz, 1H),  6.84  (d, J = 8.4 Hz, 1H), 4.62  (t, J = 8.8 Hz, 2H) , 4.32 (d, J = 1.5 Hz, 2H), 3.78 (s, 3H),  3.36  (t, J = 8.9 Hz, 2H). 354.18 18 (DMSO-d6)  6 8.09 (br. s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.24 (t, J = 8.4 Hz, 1H),  6.98  (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H) ,  6.85  (d, J = 8.1 Hz, 1H) , 4.64  (t, J = 8.8 Hz, 2H), 4.31 (s, 2H), 3.85 (s, 3H), 3.39 (t, J = 8.8 Hz, 2H). 354.14 19 (DMSO-d6)  6 8.23 (br. s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.04  (d, J = 7.3 Hz, 1H), 6.94 (d, J = 7.1 Hz, 1H),  6.77  (d, J = 8.3 Hz, 1H), 4.57  (t, J = 8.8 Hz, 2H) , 4.27 (s, 2H), 3.23 (t, J = 8.8 Hz, 2H), 2.40  (s,  6H). 367.18 20 (DMSO-d6)  6 8.15 (br. s, 1H), 7.71 - 7.59 (m, 2H), 6.82 (d, J = 8.3 Hz, 1H), 6.72 - 6.65 (m, 2H), 4.62  (t, J = 8.8 Hz, 2H) , 4.27 (s, 2H), 3.35 (t, J = 8.8 Hz, 2H),  2.91  (s,  6H). 367.35 21 (DMSO-d6)  6 8.16 (br. s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.27 - 7.20 (m, 2H), 6.91 (dd, J = 2.0, 6.8 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.62  (t, J = 8.8 Hz, 2H), 4.29 (d, J = 2.0 Hz, 2H), 3.34 (t, J = 8.8 Hz, 2H), 2.67 (s, 6H). 367.35 22 (DMSO-de) 6 8.20 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H),  6.85  (d, J = 8.4 Hz, 1H) , 6.59 (dd, J = 2.0, 8.4 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H) , 4.23 (s, 2H), 3.36  (t, J = 8.8 Hz, 2H),  2.86  (s,  6H). 367.35 23 (DMSO-d6)  6 8.26  (t, J = 2.4 Hz, 1H), 7.77 - 7.67 (m, 1H) , 7.19 (dd, J = 11.2, 2.5 Hz, 1H) , 6.94 (dd, J = 9.6, 2.2 Hz, 1H) ,  6.91 (d, J = 8.5 Hz, 1H) , 4.64  (t, J = 8.8 Hz, 2H), 4.33 - 4.27 (m, 2H), 3.39 (t, J = 8.8 Hz, 2H) , 2.29 (s,  3H) . 356.07 24 (500 MHz, DMSO-d6) 5 8.32  (br. s, 1H), 7.77  (s, 1H), 7.73  (d, J = 8.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.29 - 7.23  (m, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.65 (t, J = 8.5 Hz, 2H) , 4.37  (s, 2H) , 3.39 (t, J = 8.7 Hz, 2H). 358.14 25 (500 MHz, DMSO-d6) 5 8.32  (s, 1H), 7.92  (d, J = 1.8 Hz, 1H), 7.73  (d, J = 8.2 Hz, 1H) , 7.40 (dd, J = 1.7, 8.1 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H),  6.90  (d, J = 8.2 Hz, 1H), 4.65 (t, J = 8.7 Hz, 2H), 4.35 (d, J = 1.5 Hz, 2H), 3.39 (t, J = 8.9 Hz, 2H) . 402.00 26 (DMSO-d6)  5 8.75  (d, J = 2.0 Hz, 1H), 8.45 (br. s, 1H), 8.07 (dd, J = 2.4, 8.4 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 4.66 (t, J = 8.8 Hz, 2H) , 4.52 (s, 2H), 3.40 - 3.36 (m, 2H). 369.06 27 (DMSO-d6)  5 8.27  (t, J = 2.2 Hz, 1H), 7.79 - 7.71  (m, 1H), 7.49 - 7.43  (m, 2H), 7.24  (t, J = 8.2 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 4.64  (t, J = 8.8 Hz, 2H), 4.42 (d, J = 2.3 Hz, 2H), 3.42 - 3.35  (m, 2H). 401.96 28 (DMSO-d6)  5 8.45 (br. s, 1H), 8.41 (br. s, 1H), 7.77 - 7.72  (m, 2H), 7.64  (d, J = 8.1 Hz, 1H) , 6.89 (d, J = 8.4 Hz, 1H) , 4.65 (t, J = 8.7 Hz, 2H), 4.48 (s, 2H), 3.39 - 3.33  (m, 2H), 3.20 (s,  3H) . 402.19 29 (DMSO-d6)  5 8.44  (d, J = 1.6 Hz, 1H), 8.34 (s, 1H), 7.79 (dd, J = 1.5, 7.8 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H),  6.89  (d, J = 8.6 Hz, 1H), 4.65 (t, J = 8.8 Hz, 2H) , 4.45 (d, J = 1.5 Hz, 2H), 3.37 (t, J = 8.8 Hz, 2H), 2.56  (s, 3H). 366.27 30 (DMSO-d6) 6 8.32 — 8.25 (m, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 11.2, 2.6 Hz, 1H), 7.03 (dd, J = 9.1, 2.6 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.47 - 4.36  (m, 2H), 3.60 - 3.53  (m, 4H), 3.52  (s, 2H),  3.38  (t, J = 8.8 Hz, 2H), 2.43 — 2.34  (m, 4H). 441.19 31 (DMSO-d6) 6 8.29 - 8.24 (m, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 11.2, 2.6 Hz, 1H), 7.00 (dd, J = 9.1, 2.6 Hz, 1H),  6.90 (d, J = 8.4 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.42 - 4.36 (m, 2H), 3.45 - 3.35  (m, 4H), 2.16 (s, 6H). 399.13 32 (CDCI3) 6 7.60 (d, J = 8.5 Hz, 1H), 7.06 (dd, J = 10.6, 2.5 Hz, 1H),  6.95 (d, J = 8.5 Hz, 1H) , 6.80 (dd, J = 8.8, 2.5 Hz, 1H), 5.40 - 5.33 (m, 1H), 4.72 (t, J = 8.8 Hz, 2H), 4.62 - 4.58 (m, 2H), 3.55 (t, J = 8.8 Hz, 2H) , 3.40 (s, 2H), 2.42 (q, J = 7.1 Hz, 2H), 2.16 (s, 3H), 1.08  (t, J = 7.1 Hz, 3H) . 413.19 33 (CDCI3) 6 7.60 (d, J = 8.5 Hz, 1H), 7.10 (dd, J = 10.6, 2.5 Hz, 1H),  6.96 (d, J = 8.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.5 Hz, 1H), 5.40 (s, 1H), 4.72 (t, J = 8.8 Hz, 2H), 4.55 - 4.48 (m, 2H), 4.42 (s, 2H), 3.55 (t, J = 8.8 Hz, 2H),  3.38  (s,  3H). 386.10 34 (CDCI3) 6 8.44 - 8.37 (m, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 11.1, 2.5 Hz, 1H), 7.12 (dd, J = 9.0, 2.5 Hz, 1H),  6.91 (d, J = 8.5 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.40 - 4.34 (m, 2H), 4.19 (s, 2H), 3.43 - 3.36 (m, 2H). 381.13 35 (CDCI3) 5 7.61 (d, J = 8.5 Hz, 1H), 7.12 (dd, J = 10.5, 2.5 Hz, 1H),  6.97  (d, J = 8.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.5 Hz, 1H), 5.41 — 5.32 (m, 1H), 4.72 (t, J = 8.8 Hz, 2H), 4.57 - 4.51 (m, 2H), 3.59 (s, 2H), 3.55 (t, J = 8.8 Hz, 2H), 3.45 (s, 2H), 2.44 (s, 3H). 424.14 36 (500 MHz, DMSO-d6) 5 8.23 (br. s, 1H), 7.71  (d, J = 8.2 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H),  6.88  (d, J = 8.2 Hz, 1H) , 4.64 (t, J = 8.9 Hz, 2H) , 4.58 (t, J = 5.5 Hz, 1H), 4.46 (s, 2H),  4.36  (s, 2H), 3.50  (q, J = 5.0 Hz, 2H), 3.44 (t, J = 5.0 Hz, 2H),  3.39  (t, J = 8.8 Hz, 2H). 398.10 37 (500 MHz, DMSO-d6) 5 8.18 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.11 (dd, J = 0.6, 7.6 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 5.19 (br. s, 1H), 4.65 (t, J = 8.9 Hz, 2H), 4.45 (s, 2H) , 4.35 (s, 2H), 3.39 (t, J = 8.9 Hz, 2H). 353.96 38 (DMSO-d6) 5 8.30 - 8.23 (m, 1H), 7.73  (d, J = 8.5 Hz, 1H) , 7.32 (dd, J = 11.1, 2.6 Hz, 1H) , 7.06 (dd, J = 9.3, 2.6 Hz, 1H) ,  6.90 (d, J = 8.4 Hz, 1H), 5.40 (t, J = 5.4 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.53 (d, J = 5.4 Hz, 2H), 4.37 - 4.28 (m, 2H), 3.39 (t, J = 8.8 Hz, 2H). 372.15 39 (DMSO-d6) 5 8.37 - 8.30 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 8.1, 2.4 Hz, 1H), 7.44 (dd, J = 11.1, 2.5 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 4.65 (t, J = 8.8 Hz, 2H), 4.43 - 4.36 (m, 2H), 3.40  (t, J = 8.8 Hz, 2H) . 420.01 40 (500 MHz, DMSO-d6) 5 9.97  (s, 1H),  8.34  (s,  1H),  8.24  (d, J = 1.5 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.59 (d, J = 7.9 Hz, 1H) , 6.91 (d, J = 8.5 Hz, 1H), 4.65 (t, J = 8.9 Hz, 2H) , 4.48  (s, 2H) , 3.38 (t, J = 8.9 Hz, 2H). 352.21 41 (500 MHz, DMSO-d6) 5 8.25 (s, 1H), 7.75 - 7.70 (m, 2H) , 7.39 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 5.44 (s, 1H), 5.34  (s, 1H), 4.64 (t, J = 8.9 Hz, 2H) , 4.39 (s, 2H), 3.38 (t, J = 8.7 Hz, 2H). 356.12 42 (500 MHz, DMSO-d6) 5 8.24 (br. s, 1H), 7.71  (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H),  6.88  (d, J = 8.5 Hz, 1H) , 4.65  (t, J = 8.7 Hz, 2H) , 4.34 (s, 2H), 3.54  (t, J = 4.1 Hz, 4H), 3.43 (s, 2H), 3.37 - 3.33 (m, 2H), 2.37 - 2.35  (m, 4H). 423.25 43 (DMSO-d6) 5 8.39 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.58 (d, J = 8.0 Hz, 1H) , 6.90 (d, J = 8.5 Hz, 1H), 4.65 (t, J = 8.8 Hz, 2H), 4.46 (d, J = 2.3 Hz, 2H), 3.44 - 3.37 (m, 2H). 349.11 44 (DMSO-d6)  5 8.41  (d, J = 2.9 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.52 (dd, J = 11.5, 2.5 Hz, 1H) , 7.40 (dd, J = 8.5,  6.2 Hz, 1H) , 7.07 (td, J = 8.4, 2.6 Hz, 1H) , 6.91 (d, J = 8.5 Hz, 1H), 4.69 - 4.53 (m, 3H), 3.41  (t, J = 8.8 Hz, 2H), 1.41  (d, J = 6.6 Hz, 3H). 356.16 45 (DMSO-d6) 5 8.32 (s, 1H), 7.97 (s, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.50  (d, J = 8.0 Hz, 1H), 7.40  (d, J = 7.3 Hz, 1H) , 7.18 - 6.87 (m, 2H), 4.65 (t, J = 8.9 Hz, 2H), 4.43 (s, 2H), 3.37 (t, J = 8.9 Hz, 2H). 374.23 46 (DMSO-d6) 6 8.28 — 8.19 (m, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.12 (dd, J = 10.8, 2.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 10.9, 2.4 Hz, 1H), 4.63 (t, J = 8.8 Hz, 2H) , 4.30 - 4.19  (m, 2H) , 3.36 (t, J = 8.8 Hz, 2H) , 2.68 (s,  6H) . 385.19 47 (DMSO-d6) 6 8.20 — 8.09 (m, 1H), 7.69 (dt, J = 8.4, 0.8 Hz, 1H), 7.35 - 7.17 (m, 2H), 6.91 (dd, J = 7.7, 1.3 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.62 (t, J = 8.8 Hz, 2H), 4.28 (d, J = 2.4 Hz, 2H), 3.40 - 3.32 (m, 2H), 2.88 — 2.76 (m,  4H),  1.74 - 1.61  (m,  4H), 1.61 - 1.47  (m, 2H). 407.24 48 (DMSO-d6)  6 8.10  (t, J = 2.1 Hz, 1H), 7.78 - 7.68 (m, 1H) , 7.04 (t, J = 8.2 Hz, 1H),  6.91  (d, J = 8.5 Hz, 1H), 6.53 (dd, J = 8.3, 0.8 Hz, 1H), 6.47 - 6.39 (m, 1H), 5.35 (t, J = 5.6 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.21 (d, J = 2.3 Hz, 2H), 3.76 (t, J = 6.5 Hz, 2H), 3.38  (t, J = 8.8 Hz, 2H) , 3.23 (q, J = 6.3 Hz, 2H), 2.13 - 1.94  (m, 2H). 415.10 49 (DMSO-d6)  6 8.44  (d, J = 4.5 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.18 (dd, J = 10.8, 2.4 Hz, 1H) , 6.98 (dd, J = 10.6, 2.5 Hz, 1H) , 6.91 (d, J = 8.5 Hz, 1H), 4.71 - 4.59 (m, 3H), 3.40 (t, J = 8.9 Hz, 2H),  2.66  (s,  6H),  1.35  (d, J = 6.5 Hz, 3H) . 399.21 50 (DMSO-d6) 6 8.13 - 8.01 (m, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 8.2 Hz, 1H), 6.91 (dd, J = 8.3, 0.9 Hz, 1H),  6.87  (d, J = 8.4 Hz, 1H), 6.38  (dd, J = 8.2, 1.0 Hz, 1H), 4.62 (t, J = 8.8 Hz, 2H), 4.18  (d, J = 2.3 Hz, 2H) , 3.84 (t, J = 7.2 Hz, 4H) , 3.35 (t, J = 8.9 Hz, 2H), 2.32 - 2.21 (m,  2H). 379.20 51 (DMSO-d6) 5 8.17  (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.41 — 7.16 (m, 7H), 7.01 - 6.94  (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.62 (t, J = 8.8 Hz, 2H), 4.49 (s, 2H), 4.33 (d, J = 2.3 Hz, 2H) , 3.67 - 3.56 (m, 2H), 3.40 - 3.34 (m, 2H), 3.11 (t, J = 5.5 Hz, 2H),  2.73  (s,  3H). 487.31 52 (DMSO-d6) 5 8.40 (s, 1H), 7.67 (dd, J = 11.4, 2.6 Hz, 1H) , 7.47 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.5, 6.3 Hz, 1H), 7.13 - 7.00 (m, 2H),  6.14  (s, 2H), 4.35  (d, J = 2.1 Hz, 2H). 344.07 53 (DMSO-de) 6 8.45 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 2.5, 10.8 Hz, 1H), 6.98 (dd, J = 2.5, 10.6 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 4.71 - 4.59 (m, 3H), 3.40 (t, J = 8.9 Hz, 2H), 2.66 (s,  6H),  1.35  (d, J = 6.5 Hz, 3H). 399.20 54 (DMSO-d6)  5 8.45  (d, J = 4.0 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 2.5, 10.8 Hz, 1H), 6.98 (dd, J = 2.5, 10.6 Hz, 1H), 6.91  (d, J = 8.4 Hz, 1H), 4.72 - 4.59 (m, 3H), 3.40 (t, J = 8.8 Hz, 2H), 2.66 (s, 6H), 1.35 (d, J = 6.5 Hz, 3H). 399.11 55 (DMSO-d6)  5 8.32  (t, J = 2.4 Hz, 1H), 7.73 (dt, J = 0.9, 8.5 Hz, 1H), 7.37 (dd, J = 2.5, 10.9 Hz, 1H), 7.29 (dd, J = 2.5,  9.8 Hz, 1H), 6.93 (ddd, J = 1.5, 11.0, 17.3 Hz, 1H),  6.90 (d, J = 8.5 Hz, 1H), 5.88 (dd, J = 1.1, 17.2 Hz, 1H), 5.51 (dd, J = 1.0, 11.0 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.44 - 4.38 (m, 2H), 3.39 (t, J = 8. Hz, 2H). 368.13 56 (DMSO-dg) 6 8.19 — 8.11 (m, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.33 — 7.22 (m, 2H), 7.01 (dd, J = 7.7, 1.3 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.70 — 4.50 (m, 4H), 4.32 (d, J = 2.4 Hz, 2H), 3.35 (t, J = 9.1 Hz, 2H), 3.19 (dt, J = 27.7, 4.9 Hz,  2H), 2.75  (s, 3H). 399.21 57 (DMSO-d6)  6 8.29  (t, J = 2.4 Hz, 1H), 7.72  (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 10.9, 2.6 Hz, 1H), 7.10 (dd, J = 9.8, 2.6 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H) , 5.44 (d, J = 4.3 Hz, 1H), 4.95 - 4.85 (m, 1H), 4.63  (t, J = 8.8 Hz, 2H), 4.43 - 4.35 (m, 2H) , 3.38 (t, J = 8.8 Hz, 2H), 1.32 (d, J = 6.4 Hz, 3H) . 386.17 58 (DMSO-d6) 6 8.13 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.22  (s, 1H), 6.90 - 6.84 (m, 2H), 5.17 (t, J = 5.9 Hz, 1H), 4.63 (t, J = 8.9 Hz, 2H), 4.43 (d, J = 5.8 Hz, 2H), 4.30 - 4.23 (m, 2H), 3.41 - 3.33  (m, 2H), 2.67  (s,  6H). 397.28 59 (DMSO-d6)  6 8.19 (br. s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H),  6.96  (s, 1H), 6.87  (d, J = 8.3 Hz, 1H), 5.42 - 5.31 (m, 2H), 4.63 (t, J = 8.9 Hz, 2H) , 4.30 (s, 2H), 3.38 - 3.33 (m, 2H),  2.69  (s,  6H). 399.35 60 (DMSO-d6) 6 9.94  (s, 1H), 8.29 - 8.27  (m, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.42  (d, J = 1.3 Hz, 1H) , 6.88  (d, J = 8.3 Hz, 1H) , 4.63 (t, J = 8.9 Hz, 2H), 4.38 (d, J = 2.3 Hz, 2H), 3.39 - 3.34 (m, 2H), 2.74  (s,  6H). 395.30 61 (DMSO-d6) 6 8.32 — 8.25 (m, 1H), 7.77 - 7.68 (m, 1H), 7.45 (dd, J = 2.5, 11.0 Hz, 1H), 7.04 (dd, J = 2.6, 9.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.39 (t, J = 1.7 Hz, 1H), 4.93 (t, J = 1.5 Hz, 1H) , 4.64 (t, J = 8.8 Hz, 2H), 4.29 (d, J = 2.2 Hz, 2H) , 3.38  (t, J = 8.8 Hz, 2H),  2.07  (s,  3H). 382.15 62 (DMSO-d6) 6 8.24 - 8.18 (m, 1H), 7.77 - 7.69 (m, 1H), 7.55 (dd, J = 2.5, 11.0 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.08 (dd, J = 2.3,  9.0 Hz, 3H),  6.89  (d, J = 8.5 Hz, 1H), 4.64  (t, J = 8.8 Hz, 2H) , 4.25 - 4.20  (m, 2H), 3.83 (s, 3H),  3.37  (t, J = 8.8 Hz, 2H). 448.20 63 (DMSO-d6) 6 8.27  (s, 1H), 8.02 (s, 1H), 7.77 - 7.68  (m, 2H), 7.41 (dd, J = 2.6, 10.9 Hz, 1H), 7.16 (dd, J = 2.6, 9.5 Hz, 1H), 6.90 (d, J = 8.44 Hz, 1H) , 4.64 (t, J = 8.8 Hz, 2H), 4.37 (s, 2H),  3.92  (s,  3H), 3.38  (t, J = 8.7 Hz, 2H). 422.21 64 (DMSO-d6) 6 8.25 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 2.5, 11.1 Hz, 1H), 6.94 (dd, J = 2.6, 9.4 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 5.71 - 5.60 (m, 1H), 4.63 (t, J = 8.8 Hz, 2H) , 4.25 (s, 2H), 3.38 (t, J = 8.9 Hz, 2H), 2.28 - 2.11  (m, 4H) , 1.78 - 1.57  (m,  4H). 422.21 65 (DMSO-d6)  6 8.27  (t, J = 2.5 Hz, 1H), 7.72 (dt, J = 0.9, 8.5 Hz, 1H), 7.4 (dd, J = 2.5, 11.0 Hz, 1H),  6.99 (dd, J = 2.6,  9.4 Hz, 1H),  6.88  (d, J = 8.4 Hz, 1H), 5.69 - 5.62 (m, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.29 - 4.23 (m, 2H), 3.37 (t, J = 8.8 Hz, 2H) , 3.04 - 2.97  (m, 2H), 2.58 (t, J = 5.6 Hz, 2H), 2.37  (s, 2H), 2.30 (s, 3H). 437.21 66 (DMSO-dg) 6 8.29 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.51 — 7.37 (m, 1H), 7.04 (dd, J = 2.6,  9.41 Hz, 1H),  6.89  (d, J = 8.5 Hz, 1H), 5.78  (tt, J = 1.4, 2.7 Hz, 1H), 4.63 (t, J = 8.8 Hz, 2H) , 4.30 (s, 2H), 4.22 (q, J = 2.8 Hz, 2H), 3.84  (t, J = 5.3 Hz, 2H), 3.38  (d, J = 17.8 Hz, 2H), 2.36 (dq, J = 3.0, 5.3 Hz, 2H). 424.14 67 (DMSO-d6)  6 8.25 (br. s, 1H), 7.71  (d, J = 8.3 Hz, 1H), 7.57 (s, 1H), 7.14 - 6.78  (m, 3H), 4.63 (t, J = 8.9 Hz, 2H), 4.33 (s, 2H), 3.37 - 3.36  (m, 2H), 2.71  (s,  6H). 417.23 68 (DMSO-d6)  6 8.30 (br. s, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.13 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.61  (t, J = 8.8 Hz, 2H), 4.33 (s, 2H), 3.27 - 3.24  (m, 2H), 2.72  (s,  6H). 435.14 69 (DMSO-d6)  6 8.31  (d, J = 8.9 Hz, 1H), 7.72  (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 2.5, 10.9 Hz, 1H), 7.00 (dd, J = 2.5, 10.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.37 (s, 2H),  3.38  (t, J = 8.8 Hz, 2H), 3.19 - 3.01 (m, 1H), 1.20 (d, J = 6.7 Hz, 6H) . 384.20 70 (DMSO-d6) 6 8.37 - 8.30 (m, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 2.5, 10.9 Hz, 1H), 7.02 (dd, J = 2.5, 10.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.43 - 4.37 (m, 2H), 3.99 - 3.90 (m, 2H), 3.51 (td, J = 2.2, 11.6 Hz, 2H), 3.38 (t, J = 8.8 Hz, 2H), 2.99 (td, J = 4.3, 10.1, 11.5 Hz, 1H), 1.79 - 1.58 (m,  4H). 426.19 71 (DMSO-d6)  6 8.21  (t, J = 2.4 Hz, 1H), 7.72  (dt, J = 0.8, 8.5 Hz, 1H), 7.43 (dd, J = 2.5, 11.0 Hz, 1H),  6.96 (dd, J = 2.6,  9.3 Hz, 1H),  6.89  (d, J = 8.4 Hz, 1H), 5.80 — 5.75 (m, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.36 - 4.30 (m, 2H), 3.38 (t, J = 8.8 Hz, 2H) , 2.23 (d, J = 1.5 Hz, 2H), 1.28 (s, 6H) ,  1.26  (s,  6H) . 480.24 72 (DMSO-d6) 6 13.22 (s, 1H), 8.24 (t, J = 2.5 Hz, 1H), 8.07 (s, 1H),  7.77  (s,  1H), 7.73  (dd, J = 0.9, 8.5 Hz, 1H), 7.40 (dd, J = 2.5, 10.9 Hz, 1H), 7.19 (dd, J = 2.6,  9.6 Hz, 1H),  6.90  (d, J = 8.5 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.38  (d, J = 2.4 Hz, 2H) , 3.38  (t, J = 8.8 Hz, 2H). 408.17 73 (DMSO-de) 6 8.27  (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 2.6, 10.9 Hz, 1H), 7.34 (dd, J = 2.6, 9.6 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H),  6.69 (d, J = 2.3 Hz, 1H), 4.68 - 4.59 (m, 4H), 3.94  (s, 3H),  3.39  (t, J = 8.8 Hz, 2H). 422.11 74 (DMSO-d6) 6 13.21 (s, 1H), 8.25 (t, J = 2.4 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 2.6, 10.9 Hz, 1H), 7.37 (dd, J = 2.6, 9.6 Hz, 1H),  6.9  (d, J = 8.5 Hz, 1H) , 6.76 — 6.70 (m, 1H), 4.69 - 4.59 (m, 4H), 3.39 (t, J = 8.8 Hz, 2H). 408.06 75 (DMSO-d6)  6 8.48  (t, J = 2.3 Hz, 1H), 7.93 (dd, J = 11.1, 2.5 Hz, 1H), 7.81 - 7.67 (m, 2H), 6.92 (d, J = 8.5 Hz, 1H) , 4.64  (t, J = 8.8 Hz, 2H), 4.55 - 4.39 (m, 2H), 3.39 (t, J = 8.8 Hz, 2H) . 367.06 76 (DMSO-d6)  6 8.12  (t, J = 2.3 Hz, 1H), 7.71  (dt, J = 8.5, 0.8 Hz, 1H), 7.16 (t, J = 8.2 Hz, 1H), 6.98 (dd, J = 8.4, 0.9 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.46 (dd, J = 8.1, 1.0 Hz, 1H), 5.47 (ddd, J = 58.1, 6.4, 3.7 Hz, 1H), 4.62 (t, J = 8.8 Hz, 2H) , 4.28 — 3.83 (m, 6H), 3.39 — 3.32 (m, 2H). 397.11 78 (DMSO-d6)  6 8.24  (t, J = 2.4 Hz, 1H), 7.72  (dt, J = 0.8, 8.5 Hz, 1H), 7.42 (dd, J = 2.6, 11.0 Hz, 1H),  6.95 (dd, J = 2.6,  9.3 Hz, 1H),  6.88  (d, J = 8.5 Hz, 1H), 5.53 (dt, J = 2.3, 4.1 Hz, 1H), 4.74  (d, J = 4.0 Hz, 1H) , 4.63 (t, J = 8.8 Hz, 2H), 4.25 (d, J = 2.3 Hz, 2H), 3.91 - 3.79 (m, 1H), 3.38 (t, J = 8.8 Hz, 2H), 2.45 - 2.36 (m, 1H), 2.36 - 2.27 (m, 2H), 2.06 (ddd, J = 3.1, 6.9, 17.6 Hz, 1H), 1.90 - 1.82 (m, 1H), 1.72 - 1.58  (m, 1H). 438.10 79 (DMSO-d6)  6 8.28  (t, J = 2.4 Hz, 1H), 7.72 (dt, J = 0.8, 8.4 Hz, 1H), 7.47 (dd, J = 2.5, 11.0 Hz, 1H), 7.02  (dd, J = 2.6,  9.3 Hz, 1H),  6.89  (d, J = 8.4 Hz, 1H), 5.87 - 5.80 (m, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.30 (d, J = 2.3 Hz, 2H),  4.23  (q, J = 2.2 Hz, 2H) , 3.79 (t, J = 5.4 Hz, 2H) , 3.37 (t, J = 8.8 Hz, 2H), 2.27 (td, J = 2.7, 5.6 Hz, 2H). 424.12 80 (DMSO-d6)  6 8.26  (t, J = 2.4 Hz, 1H), 7.71  (dt, J = 0.8, 8.5 Hz, 1H), 7.40 (dd, J = 2.5, 10.9 Hz, 1H),  6.99 (dd, J = 2.6,  9.6 Hz, 1H),  6.88  (d, J = 8.5 Hz, 1H), 6.55 - 6.48 (m, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.33 - 4.28 (m, 2H), 4.03 (dd, J = 4.3, 6.0 Hz, 2H), 3.37  (t, J = 8.9 Hz, 2H), 2.32 - 2.23 (m, 2H), 1.99 - 1.89 (m, 2H). 424.12 81 (DMSO-d6)  6 8.25  (t, J = 2.5 Hz, 1H),  7.81  (s,  1H), 7.74  (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 2.5, 11.1 Hz, 1H), 7.21 (dd, J = 2.6, 9.1 Hz, 1H), 7.01 (d, J = 1.2 Hz, 1H),  6.90  (d, J = 8.5 Hz, 1H), 4.65 (t, J = 8.8 Hz, 2H) , 4.18 (d, J = 2.0 Hz, 2H) , 3.58  (s, 3H),  3.40  (t, J = 8.8 Hz, 2H). 422.11 82 (DMSO-d6)  6 8.28  (t, J = 2.5 Hz, 1H), 7.72  (dd, J = 0.9, 8.4 Hz, 1H), 7.30 (dd, J = 2.5, 10.8 Hz, 1H), 6.96 (dd, J = 2.6, 10.0 Hz, 1H),  6.89  (d, J = 8.5 Hz, 1H) , 6.83 — 6.77 (m, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.46 (t, J = 9.6 Hz, 2H), 4.36 — 4.31 (m, 2H) , 3.37 (t, J = 8.8 Hz, 2H), 3.01 (td, J = 1.9, 9.6 Hz, 2H). 410.10 83 (DMSO-d6)  6 8.32  (t, J = 2.3 Hz, 1H), 7.73 (dt, J = 0.8, 8.5 Hz, 1H), 7.48 (dd, J = 2.5, 10.9 Hz, 1H), 7.07 (dd, J = 2.5, 9.5 Hz, 1H),  6.89  (d, J = 8.5 Hz, 1H), 6.13  (q, J = 1. 9 Hz, 1H) , 4.93 — 4.85 (m, 2H), 4.81 (tt, J = 2.4, 4.8 Hz, 2H), 4.63 (t, J = 8.8 Hz, 2H), 4.40  (d, J = 2.4 Hz, 2H) , 3.37  (t, J = 8.8 Hz, 2H) . 410.10 84 (DMSO-d6)  6 8.33  (s, br, 1H), 7.45 (d, J = 8.3 Hz, 1H) , 7.20 (dd, J = 10.7, 2.4 Hz, 1H) , 7.04 (d, J = 8.3 Hz, 1H), 6.78 (dd, J = 11.0, 2.4 Hz, 1H),  6.12  (s, 2H), 4.30 — 4.18  (m, 2H), 2.68 (s,  6H) . 387.10 85 (DMSO-d6)  6 8.28  (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 0.9, 8.5 Hz, 1H), 7.25 (dd, J = 2.6, 11.1 Hz, 1H),  6.95 (dd, J = 2.6,  9.6 Hz, 1H),  6.90  (d, J = 8.5 Hz, 1H) , 4.64 (t, J = 8.8 Hz, 2H) , 4.38 — 4.28 (m, 2H), 3.38 (t, J = 8.8 Hz, 2H), 2.64  (q, J = 7.7 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H). 370.09 86 (DMSO-d6)  6 8.29  (t, J = 2.5 Hz, 1H), 7.75 — 7.69 (m, 1H), 7.34 (dd, J = 10.9, 2.6 Hz, 1H) , 7.10 (dd, J = 9.8, 2.6 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 5.44 (d, J = 4.3 Hz, 1H), 4.95 - 4.86 (m, 1H), 4.63 (t, J = 8.8 Hz, 2H) , 4.40 - 4.36 (m, 2H), 3.38 (t, J = 8.8 Hz, 2H), 1.32  (d, J = 6.3 Hz, 3H). 386.08 87 (DMSO-d6)  6 8.30  (t, J = 2.5 Hz, 1H), 7.72  (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 10.9, 2.6 Hz, 1H), 7.10 (dd, J = 9.8, 2.6 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H) , 5.44 (d, J = 4.3 Hz, 1H), 4.96 - 4.84 (m,  1H),  4.63  (t, J = 8.8 Hz, 2H), 4.41 - 4.35 (m, 2H) , 3.38 (t, J = 8.8 Hz, 2H), 1.32 (d, J = 6.4 Hz, 3H) . 386.08 88 (DMSO-d6)  6 8.37  (t, J = 2.4 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 11.0, 2.5 Hz, 1H), 7.13 (dd, J = 9.4, 2.6 Hz, 1H), 6.90  (d, J = 8.5 Hz, 1H) , 6.00 (dq, J = 46.5, 6.4 Hz, 1H) , 4.64 (t, J = 8.8 Hz, 2H), 4.44 - 4.31 (m, 2H), 3.38  (t, J = 8.8 Hz, 2H), 1.59 (dd, J = 24.4, 6.3 Hz, 3H). 388.05 89 (DMSO-d6)  6 8.28  (t, J = 2.4 Hz, 1H), 7.82 - 7.67 (m, 3H) , 6.89 (d, J = 8.5 Hz, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.53 - 4.46 (m, 2H), 3.37 (t, J = 8.8 Hz, 2H), 2.64 (s,  3H) . 384.07 90 (DMSO-d6) 6 8.29 - 8.22 (m, 1H), 7.72  (d, J = 8.4 Hz, 1H) , 7.43 (dd, J = 11.0, 2.5 Hz, 1H) , 6.95 (dd, J = 9.3, 2.6 Hz, 1H) , 6.89 (d, J = 8.4 Hz, 1H), 5.58 - 5.49 (m, 1H), 4.64  (t, J = 8.8 Hz, 2H), 4.30 - 4.17 (m, 2H), 3.60 - 3.51 (m, 1H), 3.38 (t, J = 8.8 Hz, 2H), 3.31 (s, 3H), 2.53 - 2.45 (m, 1H), 2.36 - 2.27 (m, 2H), 2.19 - 2.08  (m, 1H) , 2.01 - 452.12 1.91 (m, 1H), 1.79 — 1.67 (m, 1H). 91 (DMSO-d6) 6 8.34 — 8.27 (m, 1H), 7.72 (d, J = 8.4 Hz, 1H) , 7.43 (dd, J = 11.0, 2.5 Hz, 1H) , 6.96 (dd, J = 9.3, 2.6 Hz, 1H) , 6.89 (d, J = 8.5 Hz, 1H), 5.65 (s, 1H), 4.63 (t, J = 8.8 Hz, 2H) , 4.29 - 4.19 (m, 2H), 4.17 — 4.07 (m, 2H), 3.41 - 3.34  (m, 2H), 2.75 - 2.64 (m, 1H), 2.43 - 2.19 (m, 4H), 2.12 - 2.01  (m, 1H), 1.87 - 1.71 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H) . 494.10 92 (DMSO-d6)  6 8.26  (t, J = 2.4 Hz, 1H), 7.72  (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 10.9, 2.6 Hz, 1H), 7.06 (dd, J = 9.8, 2.6 Hz, 1H), 7.02 - 6.97 (m, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.87 - 6.85 (m, 1H), 6.25 (dd, J = 2.7, 1.8 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.45 - 4.36 (m, 2H), 3.69 (s, 3H), 3.42 - 3.35  (m, 2H). 421.05 93 (DMSO-d6)  6 8.34  (t, J = 2.4 Hz, 1H), 7.73 (dt, J = 0.8, 8.5 Hz, 1H), 7.29 (dd, J = 2.5, 10.9 Hz, 1H), 7.01 (dd, J = 2.5, 10.1 Hz, 1H),  6.90  (d, J = 8.5 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H) , 4.40 (d, J = 2.4 Hz, 2H), 4.02 - 3.90 (m, 2H), 3.80  (dt, J = 7.4, 8.3 Hz, 1H), 3.66 (dd, J = 6.2, 8.4 Hz, 1H), 3.63 - 3.51  (m, 1H), 3.42 - 3.27 (m, 2H), 2.38 - 2.25 (m, 1H), 1.99 - 1.85  (m, 1H). 412.11 94 (DMSO-d6) 6 8.34 — 8.26 (m, 1H), 7.72 (dt, J = 0.8, 8.5 Hz, 1H), 7.30 (dd, J = 2.5, 10.9 Hz, 1H), 7.05 (dd, J = 2.5, 10.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.42 - 4.36 (m, 2H), 3.92 - 3.84  (m, 1H), 3.84 - 3.74 (m, 1H), 3.49 - 3.31 (m, 4H), 3.00 - 2.88  (m, 1H), 2.09 - 1.52  (m, 4H). 426.13 95 (DMSO-d6) 6 8.36 (s, 1H), 7.55 - 7.39 (m, 2H), 7.15 - 6.98 (m, 2H),  6.14  (s, 2H), 5.42  (t, J = 5.4 Hz, 1H), 4.53 (d, J = 5.4 Hz, 2H), 4.36 - 4.23  (m, 2H). 374.03 96 (DMSO-d6) 6 8.27 - 8.21 (m, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 11.1, 2.5 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.24 (dd, J = 8.9, 2.5 Hz, 1H),  6.91  (d, J = 8.5 Hz, 1H), 6.41 (d, J = 1.9 Hz, 1H), 4.65 (t, J = 8.8 Hz, 2H) , 4.14 - 4.08  (m, 2H), 3.74  (s, 3H), 3.41 (t, J = 8.8 Hz, 2H). 422.08 97 (DMSO-d6) 6 8.38 - 8.33 (m, 1H), 7.54 (dd, J = 10.8, 2.5 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.13 (s, 2H), 5.77 (s, 1H), 4.33 - 4.27  (m, 2H), 4.25 - 4.20 (m, 2H), 3.84 (t, J = 5.3 Hz, 2H), 2.40 - 2.32 (m, 2H). 426.09 98 (DMSO-d6)  6 8.23  (t, J = 2.2 Hz, 1H), 7.75 - 7.69 (m, 1H) , 7.41 (dd, J = 11.0, 2.5 Hz, 1H) , 6.95 (dd, J = 9.4, 2.6 Hz, 1H) ,  6.88 (d, J = 8.4 Hz, 1H), 5.64  (s, 1H), 4.63 (t, J = 8.8 Hz, 2H) , 4.53 (t, J = 5.3 Hz, 1H), 4.29 - 4.20 (m, 2H), 3.32 (s, 4H), 2.36 - 2.14 (m, 3H), 1.95 - 1.80 (m, 2H), 1.79 - 1.65  (m, 1H), 1.46 - 1.30  (m,  1H). 452.12 99 (DMSO-d6)  6 8.41  (t, J = 2.4 Hz, 1H), 7.47  (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 10.8, 2.5 Hz, 1H), 7.05 (dd, J = 8.0, 2.8 Hz, 2H), 6.13 (s, 2H), 4.44 - 4.35 (m, 2H), 3.98 - 3.89 (m, 2H), 3.57 - 3.45 (m, 2H), 3.06 - 2.94 (m, 1H), 1.79 - 1.65 (m, 2H), 1.65 - 1.56  (m,  2H). 428.06 100 (DMSO-d6)  6 8.31  (t, J = 2.3 Hz, 1H), 7.50 (dd, J = 10.9, 2.5 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.05  (d, J = 8.3 Hz, 1H) , 6.98 (dd, J = 9.4, 2.6 Hz, 1H) ,  6.13 (s, 2H), 5.56 - 5.48 (m, 1H), 4.73 (d, J = 4.0 Hz, 1H), 4.31 - 4.19 (m, 2H), 3.91 - 3.78  (m, 1H), 2.46 - 2.35 (m, 1H), 2.35 - 2.26 (m, 2H), 2.12 - 2.00 (m, 1H), 1.91 - 1.80  (m, 1H) , 1.71 - 1.58  (m,  1H). 440.07 101 (DMSO-de)  6 8.34  (t, J = 2.4 Hz, 1H), 8.03 (d, J = 0.8 Hz, 1H) , 7.72  (d, J = 0.8 Hz, 1H) , 7.51 (dd, J = 10.9, 2.5 Hz, 1H) , 7.47 (d, J = 8.3 Hz, 1H), 7.19 (dd, J = 9.6, 2.6 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.14 (s, 2H), 4.41 - 4.33  (m, 2H),  3.91  (s, 3H). 424.08 102 (DMSO-d6)  6 8.17  (t, J = 2.3 Hz, 1H), 7.42  (d, J = 8.6 Hz, 1H) , 7.29 (t, J = 1.6 Hz,  1H) , 7.14 (t, J = 1.6 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.77 (t, J = 1.8 Hz, 1H), 5.36 (d, J = 47.6 Hz, 2H), 4.46 (t, J = 9.5 Hz, 2H), 4.41 - 4.25  (m,  6H), 3.03 (td, J = 9.6, 1.9 Hz, 2H). 440.07 103 (DMSO-de)  6 8.26  (d, J = 2.5 Hz, 1H), 7.76 - 7.68 (m, 1H), 7.42 (dd, J = 2.5, 10.9 Hz, 1H) , 7.03 (dd, J = 2.6, 9.6 Hz, 1H) , 6.88 (d, J = 8.4 Hz, 1H), 5.82 (t, J = 2.1 Hz, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.37 - 4.31 (m, 2H), 3.37 (t, J = 8.8 Hz, 2H), 2.74 - 2.64 (m, 2H), 2.61 - 2.50  (m, 2H), 408.06 2.04 — 1.92  (m, 2H) . 104 (DMSO-d6) 6 8.30 — 8.24 (m, 1H), 7.75 - 7.68 (m, 1H), 7.52 (dd, J = 2.6, 11.0 Hz, 1H), 7.04 (dd, J = 2.6, 9.2 Hz, 1H),  6.88  (d, J = 8.5 Hz, 1H), 5.05 (t, J = 3.9 Hz, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.33 - 4.27 (m, 2H), 4.16 - 4.08 (m, 2H), 3.37  (t, J = 8.8 Hz, 2H), 2.18 (td, J = 3.7, 6.3 Hz, 2H),  1.92 - 1.81  (m, 2H). 424.05 105 (DMSO-d6) 6 8.35 - 8.27 (m, 1H), 7.74  (dd, J = 0.9, 8.5 Hz, 1H), 7.66 (dd, J = 2.5, 11.2 Hz, 1H), 7.13  (dd, J = 2.5, 8.9 Hz, 1H), 6.91  (d, J = 8.5 Hz, 1H) , 4.65 (t, J = 8.8 Hz, 2H), 4.14 - 3.95 (m, 2H), 3.41 (t, J = 8.8 Hz, 2H),  2.30  (s,  3H), 2.12  (s,  3H). 437.04 106 (DMSO-d6)  6 8.34  (d, J = 2.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 2.5, 11.0 Hz, 1H), 7.19 (dd, J = 2.5, 9.2 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 5.89 (d, J = 1.6 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.30 (d, J = 2.3 Hz, 2H),  3.39  (d, J = 8.7 Hz, 2H), 2.71 - 2.59 (m, 2H), 2.44 (t, J = 6.7 Hz, 2H), 2.17 - 2.02 (m, 2H). 436.06 108 (DMSO-d6) 6 8.38 - 8.29 (m, 1H), 7.52 - 7.42 (m, 2H), 7.10 - 6.97 (m, 2H),  6.55 - 6.46  (m,  1H), 6.13 (s, 2H), 4.33 - 4.28 (m, 2H), 4.07 - 3.99 (m, 2H), 2.31 - 2.24 (m, 2H), 1.98 - 1.90 (m, 2H). 426.05 109 (DMSO-d6)  6 8.36  (d, J = 2.5 Hz, 1H), 7.56 (dd, J = 10.9, 2.5 Hz, 1H), 7.47  (d, J = 8.3 Hz, 1H) , 7.10 — 7.02  (m, 2H),  6.13 (s, 2H), 5.86 — 5.80 (m, 1H), 4.33 - 4.27  (m, 2H), 4.26 - 4.21  (m, 2H),  3.79  (t, J = 5.4 Hz, 2H) , 2.31 - 2.23  (m, 2H). 426.09 110 (DMSO-d6)  6 8.36  (t, J = 2.5 Hz, 1H), 7.62 (dd, J = 10.9, 2.6 Hz, 1H), 7.47  (d, J = 8.3 Hz, 1H) , 7.12 - 7.02  (m, 2H),  6.13 (s, 2H), 5.06 (t, J = 3.9 Hz, 1H), 4.32 - 4.24 (m, 2H), 4.16 - 4.08 (m, 2H), 2.23 - 2.14  (m, 2H), 1.92 - 1.82  (m, 2H). 426.05 111 (DMSO-d6) 6 8.40 - 8.35 (m, 1H), 7.47 (d, J = 8.3 Hz, 1H) , 7.42 (dd, J = 10.7, 2.5 Hz, 1H) , 7.05 (d, J = 8.3 Hz, 1H), 7.00 (dd, J = 10.0, 2.5 Hz, 1H), 6.83 - 6.78 (m, 1H),  6.13  (s, 2H), 4.46 (t, J = 9.6 Hz, 2H), 4.36 - 4.31 (m, 2H),  3.07 - 2.97  (m, 2H). 412.07 112 (DMSO-de) 6 8.12 - 8.06 (m, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.13 (t, J = 8.2 Hz, 1H), 6.93 (dd, J = 8.4, 0.9 Hz, 1H),  6.87  (d, J = 8.5 Hz, 1H), 6.41 (dd, J = 8.1, 1.0 Hz, 1H) , 5.62  (s, 1H) , 4.62 (t, J = 8.8 Hz, 2H), 4.53 (s, 1H), 4.17  (d, J = 2.3 Hz, 2H) , 4.11 - 4.01 (m, 2H), 3.55 (dd, J = 7.6, 5.4 Hz, 2H), 3.40 - 3.34 (m,  2H). 395.10 113 (DMSO-d6) 6 13.24 (s, 1H), 8.34 (t, J = 2.4 Hz, 1H), 8.08 (s, 1H), 7.78 (s, 1H), 7.52  (dd, J = 10.9, 2.6 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.23  (dd, J = 9.6, 2.6 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.14 (s, 2H), 4.43 - 4.32 (m,  2H). 410.07 114 (DMSO-d6) 6 8.42 — 8.37 (m, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.43 (dd, J = 10.7, 2.5 Hz, 1H), 7.11 — 7.03  (m, 2H),  6.13  (s,  2H) , 4.42 — 4.35 (m, 2H), 3.92 - 3.83 (m,  1H),  3.82 - 3.75  (m,  1H), 3.50 - 3.36 (m, 2H), 3.02 - 2.89 (m, 1H), 1.94 - 1.58  (m, 4H). 428.10 115 (DMSO-d6)  6 8.34  (t, J = 2.3 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.64 (dd, J = 2.5, 10.8 Hz, 1H), 7.38 (dd, J = 2.6, 9.3 Hz, 1H), 6.90  (d, J = 8.4 Hz, 1H), 6.29 (t, J = 1.8 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.41 - 4.36  (m, 2H), 3.38 (t, J = 8.7 Hz, 2H), 3.08 - 3.00 (m, 2H), 2.53 - 2.67 (m, 2H). 422.11 116 (DMSO-d6) 6 8.34 - 8.26 (m, 1H), 7.72  (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 2.5, 10.8 Hz, 1H), 6.94 (dd, J = 2.6, 10.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.41 (d, J = 3.5 Hz, 1H), 4.39 - 4.34  (m, 2H) , 3.92 (d, J = 3.3 Hz, 1H), 3.38 (t, J = 8.8 Hz, 2H), 2.76 - 2.63 (m, 1H), 1.91 - 1.72 (m, 4H), 1.68 - 1.55 (m, 2H),  1.50 - 1.41  (m, 2H). 440.11 117 (DMSO-d6) 6 8.34  (s, 1H), 7.60 - 7.58 (m, 1H), 7.56 - 7.54 (m, 1H), 7.50  (d, J = 8.3 Hz, 1H), 7.10  (d, J = 8.3 Hz, 1H) , 6.15 (s, 2H), 5.39  (d, J = 47.2 Hz, 2H), 4.43 (t, J = 2.1 Hz, 2H). 435.94 118 (DMSO-d6) 6 8.32 (s, 1H), 7.66 (t, J = 1.5 Hz, 1H) , 7.48  (d, J = 8.3 Hz, 1H) , 7.22  (s, 1H) , 7.06 (d, J = 8.3 Hz, 1H), 6.13 (s, 2H),  6.12 - 6.05  (m, 1H) , 5.40 (d, J = 47.5 Hz, 2H), 4.96 - 4.86 (m, 2H), 4.86 - 4.75  (m, 2H), 4.44  (s, 2H). 426.05 119 (DMSO-d6) 6 8.36 - 8.23 (m, 1H), 7.43 (dd, J = 2.5, 10.8 Hz, 1H), 7.41  (d, J = 8.6 Hz, 1H), 7.07 (dd, J = 2.6,  9.6 Hz, 1H),  6.94 (d, J = 8.6 Hz, 1H) ,  6.18 - 6.06 (m, 1H), 4.94 - 4.84  (m, 2H), 4.85 - 4.76 (m, 2H), 4.44 - 4.37 (m, 2H), 4.38 - 4.33  (m, 2H), 4.33 - 4.28  (m, 2H). 426.05 120 (DMSO-d6) 6 8.34 - 8.26 (m, 1H), 7.41  (d, J = 8.6 Hz, 1H) , 7.23 (dd, J = 2.5, 10.7 Hz, 1H) , 7.01 (dd, J = 2.5, 10.2 Hz, 1H) , 6.95 (d, J = 8.6 Hz, 1H), 4.40 (d, J = 2.5 Hz, 2H), 4.38 - 4.27 (m, 4H), 4.02 - 3.90 (m, 2H), 3.85 - 3.75 (m, 1H), 3.66 (dd, J = 6.1, 8.4 Hz, 1H), 3.63 - 3.50  (m, 1H), 2.38 - 2.25 (m, 1H), 1.91 (dq, J = 7.3, 12.3 Hz, 1H). 428.06 121 (DMSO-d6) 6 8.27 - 8.21 (m, 1H), 7.40 (d, J = 8.6 Hz, 1H) , 7.35 (dd, J = 2.5, 10.8 Hz, 1H) , 7.00 (dd, J = 2.6,  9.7 Hz, 1H) ,  6.93 (d, J = 8.6 Hz, 1H), 6.54 - 6.48 (m, 1H), 4.38 - 4.27  (m,  6H), 4.07 - 4.00 (m, 2H), 2.32 - 2.24 (m, 2H), 2.00 - 1.89  (m, 2H). 440.07 122 (DMSO-d6) 6 8.26 - 8.19 (m, 1H), 7.44 - 7.33 (m, 2H), 6.99 - 6.90 (m, 2H), 5.55 - 5.48  (m, 1H), 4.74 (d, J = 4.0 Hz, 1H), 4.38 - 4.27  (m, 4H), 4.27 - 4.21  (m, 2H), 3.91 - 3.79 (m, 1H), 2.47 - 2.36 (m, 1H), 2.36 - 2.27 (m, 2H), 2.12 - 2.00 (m, 1H), 1.91 - 1.80 (m, 1H), 1.72 - 1.58 (m, 1H). 454.09 123 (DMSO-de) 6 8.28 - 8.22 (m, 1H), 8.03  (d, J = 0.8 Hz, 1H) , 7.72 (d, J = 0.8 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.37 (dd, J = 2.5, 10.9 Hz, 1H), 7.17 (dd, J = 2.6, 9.6 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 4.40 - 4.28  (m,  6H), 3.92 (s,  3H) . 438.06 124 (DMSO-d6)  6 8.32  (t, J = 2.4 Hz, 1H), 7.59 (dd, J = 2.5, 10.7 Hz, 1H), 7.42  (d, J = 8.6 Hz, 1H) , 7.38 (dd, J = 2.6, 9.4 Hz, 1H), 6.95  (d, J = 8.6 Hz,  1H) , 6.29 (t, J = 1.8 Hz, 1H), 4.41 — 4.36 (m, 2H), 4.37 - 4.27  (m, 4H), 3.12 - 2.97  (m, 2H). 438.06 125 (DMSO-d6) 6 8.29 - 8.22 (m, 1H), 7.46 - 7.37 (m, 2H), 7.02 (dd, J = 2.56, 9.36 Hz, 1H), 6.94 (d, J = 8.60 Hz, 1H), 5.87 - 5.80 (m, 1H), 4.38 - 4.27 (m, 6H), 4.27 - 4.20 (m, 2H), 3.79 (t, J = 5.46 Hz, 2H), 2.32 - 2.22  (m, 2H). 440.07 126 (DMSO-d6) 6 8.28 (t, J = 2.46 Hz, 1H), 7.41 (d, J = 8.62 Hz, 1H), 7.25 (dd, J = 2.48, 10.72 Hz, 1H), 7.06 (dd, J = 2.55, 10.19 Hz, 1H), 6.95 (d, J = 8.64 Hz, 1H), 4.42 - 4.37 (m, 2H), 4.37 - 4.28  (m, 4H), 3.92 - 3.84  (m, 1H), 3.83 - 3.74 (m, 1H), 3.49 - 3.35 (m, 2H), 2.99 - 2.87 (m, 1H), 1.96 - 1.84 (m, 1H), 1.85 - 1.61  (m,  3H). 442.08

[0083] Test Example 1 [Activity Inhibition Test 1 against DYRK Family (DYRK1A, DYRK1B, DYRK2, and DYRK3)] 5    (Method for Measuring Kinase Activity) The kinase activity was measured by mobility shift assay (MSA) method using QuickScout Screening Assist(TM) MSA (commercially available kit manufactured by Carna Biosciences, Inc.). The substrate of the kinase reaction 10    used was a FITC-labeled DYRKtide peptide included in the kit. An assay buffer [20 mM HEPES, 0.01% Triton X-100 (TM), 2 mM dithiothreitol, pH 7.5] was used to create a substrate mixture solution with a substrate (4 pM), MgCl2 (20 mM), and ATP (DYRK1A: 100 pM; DYRK1B: 200 pM; DYRK2: 40 pM; and DYRK3: 20 pM).  In addition, kinases (DYRK1A: manufactured by Carna Biosciences, Inc., Cat. No. 04-130; DYRK1B: manufactured by Carna Biosciences, Inc., Cat. No. 04-131; DYRK2: manufactured by Carna Biosciences, Inc., Cat. No. 04-132; and DYRK3: manufactured by Carna Biosciences, Inc., Cat. No. 04-133) were diluted with the assay buffer to prepare enzyme solutions (DYRK1A: 0.2 ng / pL; DYRK1B: 0.08 ng / pL; DYRK2: 0.04 ng / pL; and DYRK3: 0.25 ng / pL). The 10 mM solution of the test compound in DMSO was further diluted with DMSO to 10 levels of the concentration (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), each of which was subjected to 25-fold dilution with the assay buffer to obtain a drug solution (4% DMSO solution). 5 pL of the drug solution or a control solution (4% DMSO-assay buffer), 5 pL of the substrate mixture solution, and 10 pL of the enzyme solution were mixed in the wells of a polypropylene 384-well plate and allowed to react at room temperature for 1 hour, and then the reaction was quenched by adding 60 pL of the termination buffer included in the kit. Subsequently, the quantities of the substrate (S) and the phosphorylated substrate (P) in the reaction solution were measured using LabChip EZ Reader II system (manufactured by Caliper Life Sciences) according to the protocol of the assay kit.

[0084] (Method for Evaluating Inhibitory Activity) The heights of the peaks of the "substrate" and the "phosphorylated substrate" were expressed as S and P, respectively, and a blank containing the assay buffer instead of the enzyme solution was also measured. The inhibition rate (%) of the test compound was calculated according to the following equation: Inhibition rate (%) = (1 - (C - A) / (B - A)) x 100 wherein, 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-containing well, respectively. The IC50 value was calculated by a regression analysis of the inhibition rate and the test compound concentration (logarithm). (Evaluation Results) The inhibitory activities of representative compounds of the present invention against DYRK1A, DYRK1B, DYRK2, and DYRK3 are shown in [Table 3]. The kinase activity inhibitory action was indicated with the mark *** at an IC50 value of less than 0.01 p,M; the mark ** at 0.01 pM or more and less than 0.1 pM; the mark * at 0.1 pM or more and less than 1 pM; and the mark - at 1 pM or more (N.D. indicates not measured).

[0085] [Table 3] Test Compound Inhibitory Activity Example No. DYRK1A DYRK1B DYRK2 DYRK3 1 ** N.D. * * 7 ** N.D. * * 8 - N.D. - - 9 *** N.D. ** * 10 ** N.D. * * 11 * N.D. - - 12 ** N.D. - - 13 ** N.D. * * 14 ** N.D. * * 15 * N.D. * * 16 - N.D. - - 17 ** N.D. * * 18 ** N.D. * * 19 - N.D. - - 20 * N.D. * - 21 *** N.D. * ** 22 * N.D. - - 5         These results show that the compounds (I) of the present invention have potent DYRK-inhibitory activities.

[0086] Test Example 2 [Activity Inhibition Test 2 against DYRK Family (DYRK1A, 10    DYRK1B, DYRK2, and DYRK3)] The inhibitory activities of kinases were measured using ADP-Glo(TM) Kinase Assay (commercially available kit manufactured by Promega Corporation). The substrate of the kinase reaction used was a DYRKtide unless otherwise specified. The 10 mM solution of the test compound in DMSO was further diluted with DMSO to 10 levels of the concentration (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), each of which was subjected to 25-fold dilution with the assay buffer to obtain a drug solution. A 2 mM DYRKtide stock solution, 10 mM ATP, and 1 M MgCl2 were prepared with the assay buffer to a concentration 4 times the final concentration to obtain a substrate mixture solution. Kinases (DYRK1A: manufactured by Carna Biosciences, Inc., Cat. No. 04-130; DYRK1B: manufactured by Carna Biosciences, Inc., Cat. No. 04-131; DYRK2: manufactured by Carna Biosciences, Inc., Cat. No. 04-132; and DYRK3: manufactured by Carna Biosciences, Inc., Cat. No. 04-133) were diluted with the assay buffer to a concentration twice the final concentration to obtain enzyme solutions .  10 pL of the enzyme solution, 5 pL of the drug solution, and 5 pL of the substrate mixture solution were mixed in the wells of a polystyrene 384-well plate and reacted at room temperature for 1 hour (ATP final concentration: DYRK1A:25 pM; DYRK1B:25 pM; DYRK2: 10 pM; and DYRK3: 5 pM).  20 pL of ADP-Glo Reagent (10 mM Mg added) included in the kit was added to each well and reacted at 25°C for 40 minutes, then 40 pL of Kinase Detection Reagent was added thereto and reacted at 25°C for 40 minutes, and the luciferase activity in each well was measured by using a microplate reader (Envision, Perkinelmer).

[0087] (Method for Evaluating Inhibitory Activity) When the luminescence intensity of the compound-free and enzyme-added group was 100% and the luminescence intensity of the compound-free and enzyme-free group was 0%, the IC50 value was calculated by a regression analysis of the inhibition rate determined from the luminescence intensity at each compound concentration and the test compound concentration (logarithm). (Evaluation Results) The inhibitory activities of the compounds of the present invention against DYRK1A, DYRK1B, DYRK2, and DYRK3 are shown in [Table 4]. The kinase activity inhibitory action was indicated with the mark *** at an IC50 value of less than 0.01 pM; the mark ** at 0.01 pM or more and less than 0.1 pM; the mark * at 0.1 pM or more and less than 1 pM; and the mark - at 1 pM or more (N.D. indicates not measured).

[0088] [Table 4] Test compound Inhibitory Activity Example No. DYRK1A DYRK1B DYRK2 DYRK3 2 *** N.D. N.D. N.D. 3 *** N.D. - * 4 *** N.D. ** ** 5 *** N.D. ** ** 6 *** N.D. ** ** 23 *** N.D. N.D. N.D. 24 *** N.D. N.D. N.D. 25 ** N.D. N.D. N.D. 26 *** N.D. N.D. N.D. 27 ** N.D. N.D. N.D. 28 ** N.D. N.D. N.D. 29 * N.D. N.D. N.D. 30 ** N.D. N.D. N.D. 31 ** N.D. N.D. N.D. 32 ** N.D. N.D. N.D. 33 *** N.D. N.D. N.D. 34 *** N.D. N.D. N.D. 35 *** N.D. N.D. N.D. 36 ** N.D. N.D. N.D. 37 ** ** - - 38 *** *** * * 39 *** *** - * 40 ** N.D. - - 41 *** N.D. - - 42 * N.D. - - 43 ** N.D. - - 44 *** N.D. - * 45 *** N.D. * - 46 *** N.D. * ** 47 ** N.D. * * 48 ** N.D. * - 49 *** N.D. - - 50 *** N.D. * * 51 * N.D. - - 52 *** N.D. ** * 53 - N.D. - - 54 *** N.D. - * 55 *** N.D. * * 56 ** N.D. * * 57 *** N.D. * ** 58 ** N.D. — — 59 *** N.D. — * 60 *** N.D. — * 61 *** N.D. * * 62 ** N.D. — * 63 *** N.D. ** ** 64 ** N.D. — — 65 ** N.D. * * 66 *** N.D. * * 67 *** N.D. * * 68 *** N.D. — — 69 *** N.D. * * 70 *** N.D. * * 71 * N.D. — — 72 *** N.D. ** ** 73 ** N.D. — — 74 *** N.D. * * 75 *** N.D. * * 76 *** N.D. * ** 77 ** N.D. * * 78 *** N.D. ** ** 79 *** N.D. ** ** 80 *** N.D. ** ** 81 ** N.D. — * 82 *** N.D. ** ** 83 *** N.D. * ** 84 *** N.D. ** ** 85 *** N.D. * ** 86 *** N.D. * ** 87 *** N.D. * * 88 *** N.D. * * 89 *** N.D. — * 90 ** N.D. * * 91 ** N.D. — — 92 *** N.D. * * 93 *** N.D. * ** 94 *** N.D. * ** 95 *** N.D. ** * 96 ** N.D. * * 97 *** N.D. * * 98 *** N.D. * * 99 *** N.D. * * 100 *** N.D. ** ** 101 *** N.D. ** ** 102 *** N.D. * * 103 ** N.D. * * 104 ** N.D. * * 105 * N.D. — — 106 *** N.D. * ** 107 ** N.D. * * 108 *** N.D. ** * 109 *** N.D. ** * 110 *** N.D. * * 111 *** N.D. ** ** 112 *** N.D. * ** 113 *** N.D. ** ** 114 *** N.D. ** ** 115 *** N.D. ** *** 116 *** N.D. ** * 117 ** N.D. — — 118 *** N.D. — — 119 *** N.D. * * 120 *** N.D. * * 121 *** N.D. ** ** 122 *** N.D. ** ** 123 *** N.D. ** ** 124 *** N.D. ** ** 125 *** N.D. * * 126 *** N.D. * * 127 *** N.D. N.D. N.D. 128 *** N.D. N.D. N.D. Note that the compounds of Examples 2 and 23 to 36 were measured using a FITC-labeled DYRKtide instead of a 5    DYRKtide as a substrate. These results show that the compounds (I) of the present invention have potent DYRK-inhibitory activities. INDUSTRIAL APPLICABILITY

[0089] The compound provided by the present invention is useful as a prophylactic or therapeutic agent for a disease known to be associated with a DYRK1A-mediated abnormal cellular response, including a psychiatric and neurologic disease such as Alzheimer's disease, Parkinson's disease, Down syndrome, mental retardation, memory impairment, memory loss, and depression, and further cancers such as brain tumor. The compound is, as an inhibitor of DYRK1B, also useful as a pharmaceutical (pharmaceutical composition) for prevention or treatment of cancers such as pancreatic cancer. Further, the compound provided by the present invention is useful as a pharmaceutical (pharmaceutical composition) for prevention or treatment of bone resorption disease and osteoporosis because DYRK2 controls p53 in response to DNA damage and induces apoptosis. In addition, the compound provided by the present invention is, as an inhibitor of DYRK3, useful as a pharmaceutical (pharmaceutical composition) for prevention or treatment of sickle cell anemia, chronic renal disease, bone resorption disease, and osteoporosis. The compound that inhibits DYRK is also useful as a reagent for pathological imaging and as a reagent for a basic experiment and for research related to the above diseases.

Claims

1. A dihydroquinazolinone derivative represented by the following formula (I):(wherein:R1, R2 , R3, and R4 each independently represent ahydrogen 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 nonaromatic 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 substitutedheteroaryl group;R5 represents a hydrogen atom or a lower alkyl group;andQ represents the following structure (a),  (b), or (c))or a pharmaceutically acceptable salt thereof.

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

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

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

5. The dihydroquinazolinone derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R5 is a hydrogen atom in the formula (I).

6. The dihydroquinazolinone derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable saltthereof, wherein R1 , R2 , R3, and R4 are each independentlya hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted nonaromatic heterocyclic group, a halogen atom, an optionally substituted amino group, or an optionally substituted heteroaryl group in the formula (I).

7. The dihydroquinazolinone derivative according to any one of claims 1 to 6 or a pharmaceutically acceptable saltthereof, wherein R1 and R3 are each a hydrogen atom in theformula (I).

8. The dihydroquinazolinone derivative according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R2 is a fluorine atom, and R4 is an optionally substituted cycloalkenyl group, an optionally substituted nonaromatic heterocyclic group, an optionally substituted amino group, or an optionally substituted heteroaryl group in the formula (I).

9. The compound according to any one of claims 1 to 8selected from the following compound group or apharmaceutically acceptable salt thereof: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[1,2-d]thiazol-2-yl)-5-(dimethylamino)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one sulfate, and1-(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 medicament comprising the dihydroquinazolinone derivative according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient.

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

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

13. The therapeutic agent and / or the prophylactic agent according to claim 12, wherein the disease involving DYRK is frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease, Parkinson'sdisease, Down syndrome, depression, and their associatedmental retardation, memory impairment, memory loss, learning disability, intellectual disability, cognitive dysfunction, mild cognitive impairment, treatment of dementia symptom progression or prevention of dementia onset, or brain tumor, pancreatic cancer, ovarian cancer, osteosarcoma, colorectal cancer, lung cancer, bone resorption disease, osteoporosis, sickle cell anemia, chronic renal disease, or bone resorption disease.

14. A method for treating and / or preventing a diseaseinvolving DYRK, comprising administering a therapeuticallyeffective amount of the dihydroquinazolinone derivativeaccording to any one of claims 1 to 9 or a pharmaceuticallyacceptable salt thereof to a patient in need of treatment.

15. Use of the dihydroquinazolinone derivative accordingto any one of claims 1 to 9 or a pharmaceuticallyacceptable salt thereof, for producing a therapeutic agent and / or a prophylactic agent for a disease involving DYRK.

16. The dihydroquinazolinone derivative according to anyone of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of adisease involving DYRK.

17. A medicament comprising a combination of the medicament according to claim 10, and at least one or moreagents selected from agents classified into an anticancer agent, an antipsychotic drug, an antidementia drug, anantiepileptic drug, an antidepressant drug, a gastrointestinal drug, a thyroid hormone drug, or anantithyroid drug.

18. The medicament according to claim 10, for treating frontotemporal dementia, progressive supranuclear palsy,corticobasal degeneration, Lewy body dementia, vascular dementia, traumatic brain injury, chronic traumaticencephalopathy, stroke, Alzheimer's disease, Parkinson'sdisease, Down syndrome, depression, and their associatedcomplication, mental retardation, memory impairment, memoryloss, learning disability, intellectual disability, cognitive dysfunction, mild cognitive impairment, treatmentof dementia symptom progression or prevention of dementia onset, or brain tumor, pancreatic cancer, ovarian cancer,osteosarcoma, colorectal cancer, lung cancer, bone resorption disease, osteoporosis, sickle cell anemia, chronic renal disease, or bone resorption disease, in combination with at least one or more agents selected fromagents classified into an anticancer agent, an antipsychotic drug, an antidementia drug, an antiepileptic drug, an antidepressant drug, a gastrointestinal drug, a thyroid hormone drug, or an antithyroid drug.